AALL1331

Activated: 12/08/14 Version Date: 04/27/15

Closed: Amendment # 1B

CHILDREN’S ONCOLOGY GROUP

AALL1331

Risk-Stratified Randomized Phase III Testing of Blinatumomab (IND# 117467, NSC#765986) in First
Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

IND Sponsor for Blinatumomab: DCTD, NCI

A Groupwide Phase III Study

Participating Countries: Australia, Canada, New Zealand and United States

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION,
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION.

STUDY CHAIR

Patrick Brown, MD
1650 Orleans Street, CRB1 RM 2M49
Baltimore, MD. 21231
Phone: (410) 614-4915
Fax: (410) 955-8897
E-mail: [email protected]

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 AALL1331

ABBREVIATIONS

Abbreviation Term

aGVHD Acute graft versus host disease

B-ALL B-Lymphoblastic Leukemia
CR Complete remission
DFS Disease free survival
GVHD Graft vs. host disease
HR High risk
HSCT Hematopoietic stem cell
transplant
IEM Isolated extramedullary
IR Intermediate risk
IS Immune suppression
LR Low risk
MRD Minimal residual disease
PFS Progression free survival
+
Ph Philadelphia chromosome
positive
TF Treatment failure
TKI Tyrosine kinase inhibitor
URD Unrelated Donor

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TABLE OF CONTENTS
SECTION PAGE
STUDY COMMITTEE 7
ABSTRACT 10
EXPERIMENTAL DESIGN SCHEMA 11
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 12
1.1 Primary Aims 12
1.2 Secondary Aims 12
1.3 Exploratory Aims 12
2.0 BACKGROUND 13
2.1 Overview 13
2.2 Rationale for Selected Approach and Trial Design 13
3.0 STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 22
3.1 Study Enrollment 22
3.2 Patient Eligibility Criteria 27
3.3 Definitions 30
4.0 TREATMENT PLAN 34
4.1 Overview of Treatment Plan 34
4.2 Block 1 (All patients) - 4 Weeks Duration 37
4.3 Block 2 (HR/IR and LR Patients: Post-randomization) – 4 weeks duration 41
4.4 Block 3 (HR/IR Patients on Arm A; LR Patients on Arm C) - 4 weeks 45
4.5 Blinatumomab Block: Cycle 1 (HR/IR Patients in Arm B) - 5 weeks 48
4.6 Blinatumomab Block: Cycle 2 (HR/IR Patients in Arm B) - 5 weeks 51
4.7 Blinatumomab-S: Cycle 1 (Salvage Therapy) - 5 weeks 53
4.8 Blinatumomab-S: Cycle 2 (Salvage Therapy) - 5 weeks 56
4.9 Hematopoietic Stem Cell Transplant 59
4.10 Bridging Maintenance Therapy (All HR/IR Patients, as required) – up to 6 weeks 69
4.11 Continuation 1/Continuation 2 (All LR Patients) - 8 weeks 70
4.12 Maintenance Cycle 1 (All LR patients) – 12 weeks 74
4.13 Maintenance Chemoradiation - 3 weeks 77
4.14 Maintenance-Post Cycle 1 (All LR patients) 78
4.15 Blinatumomab Block: Cycle 1 (Patients in Arm D) - 5 weeks 80
4.16 Blinatumomab Block: Cycle 2/3 (LR Patients in Arm D) - 5 weeks 82
5.0 DOSE MODIFICATIONS FOR TOXICITIES 84
5.1 Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 84
5.2 Blinatumomab 86
5.3 Cyclophosphamide 89
5.4 Cytarabine (ARAC) 89
5.5 Anthracycline-Mitoxantrone 90
5.6 Etoposide 90
5.7 Intrathecal Methotrexate/Triple Intrathecal Therapy 91
5.8 Intermediate-Dose Methotrexate (ID MTX) and Leucovorin Rescue 92

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5.9 PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 95

5.10 Steroids (Dexamethasone) 98
5.11 PO 6-Thioguanine (TG) 99
5.12 Vincristine 99
5.13 Stem Cell Transplant Regimen Agents 101
6.0 DRUG INFORMATION 103
6.1 BLINATUMOMAB 103
6.2 ASPARAGINASE Erwinia chrysanthemi 113
6.3 CYCLOPHOSPHAMIDE INJECTION 115
6.4 CYCLOSPORINE A 117
6.5 CYTARABINE 120
6.6 DEXAMETHASONE 122
6.7 ETOPOSIDE 123
6.8 FILGRASTIM 126
6.9 FLUDARABINE 128
6.10 INTRATHECAL TRIPLES 131
6.11 LEUCOVORIN CALCIUM 132
6.12 MERCAPTOPURINE 134
6.13 METHOTREXATE-ALL ROUTES 136
6.14 MITOXANTRONE 140
6.15 MYCOPHENOLATE MOFETIL 142
6.16 PEGASPARGASE 146
6.17 TACROLIMUS 149
6.18 THIOGUANINE 152
6.19 THIOTEPA 153
6.20 VINCRISTINE SULFATE 155
7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 158
7.1 Required Clinical, Laboratory and Disease Evaluations 158
7.2 Research Studies 161
7.3 At Relapse 161
7.4 Follow-up 162
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY
CRITERIA 162
8.1 Criteria for Removal from Protocol Therapy 162
8.2 Off Study Criteria 162
9.0 STATISTICAL CONSIDERATIONS 162
9.1 Statistical Design 162
9.2 Patient Accrual and Expected Duration of Trial 163
9.3 Statistical Analysis Methods 165
9.4 Gender and Minority Accrual Estimates 174
10.0 EVALUATION CRITERIA 175
10.1 Common Terminology Criteria for Adverse Events (CTCAE) 175
10.2 Response Criteria 175

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11.0 ADVERSE EVENT REPORTING REQUIREMENTS 175

11.1 Purpose 175
11.2 Determination of reporting requirements 175
11.3 Expedited Reporting Requirements – Serious Adverse Events (SAEs) 176
11.4 Special Situations for Expedited Reporting 176
11.5 Reporting Requirements for Specialized AEs 179
11.6 Exceptions to Expedited Reporting 179
11.7 Reporting Requirements - Investigator Responsibility 180
11.8 General Instructions for Expedited Reporting via CTEP-AERS 180
11.9 Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 182
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 183
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated
pathway 183
11.12 Routine Adverse Event Reporting 183
12.0 RECORDS AND REPORTING 185
12.1 CDUS 185
12.2 CTA/CRADA 185
13.0 SPECIAL STUDIES AND SPECIMEN REQUIREMENTS 187
13.1 Banking for Future Research (optional) 187
13.2 Local Bone Marrow: Central review of cytogenetics/FISH 188
13.3 Bone Marrow for Central Flow-Immunophenotping and MRD (required) 189
13.4 Bone Marrow for CRLF2 expression (optional) 191
13.5 Blinatumomab Pharmacodynamics (optional) 191
13.6 Protein Cell Stress Pathways (optional) 192
13.7 Blinatumomab Immunogenicity Assessment (Required) 194
13.8 Blinatumomab PK (required) 195
14.0 RADIATION THERAPY GUIDELINES FOR ALL PATIENTS 196
14.1 General Guidelines 196
14.2 Indications for Radiation Therapy 197
14.3 Timing 198
14.4 Emergency Irradiation 198
14.5 Equipment and Methods of Delivery 198
14.6 Treatment Volumes 198
14.7 Target Dose 199
14.8 Treatment Technique 200
14.9 Organs at Risk 201
14.10 Dose Calculation and Reporting 201
14.11 Quality Assurance Documentation and Review 203
14.12 Definitions of Deviation in Protocol Performance 204
APPENDIX I: SUPPORTIVE CARE 206
APPENDIX II: THERAPY DELIVERY MAPS 209
APPENDIX III: MERCAPTOPURINE DOSING GUIDELINES 233

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APPENDIX IV: THIOGUANINE DOSING GUIDELINES 235

APPENDIX V: YOUTH INFORMATION SHEETS 236
APPENDIX VI: ADDITIONAL INFORMATION FOR BANKING FOR FUTURE RESEARCH
CORRELATIVE BIOLOGY STUDY 238
APPENDIX VII-A CLINICAL SITE MANAGEMENT OF OUT-PATIENT TREATMENT
USING CTEP-SUPPLIED BLINATUMOMAB 240
APPENDIX VII-B SHIPMENT OF BLINATUMOMAB IV BAG FROM SITE/PHARMACY
TO PATIENT’S HOME 244
APPENDIX VIII: ADDITIONAL INFORMATION FOR MRD CORRELATIVE BIOLOGY
STUDY 245
APPENDIX IX: ADDITIONAL INFORMATION FOR CRLF2 CORRELATIVE BIOLOGY
STUDY 246
APPENDIX X: ADDITIONAL INFORMATION FOR BLINATUMOMAB
PHARMACODYNAMICS CORRELATIVE BIOLOGY STUDY 249
APPENDIX XI: ADDITIONAL INFORMATION FOR PROTEIN CELL STRESS
PATHWAYS CORRELATIVE BIOLOGY STUDY 254
APPENDIX XII: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT
VERSUS HOST DISEASE (GVHD) 260
APPENDIX XIII: CTEP AND CTSU REGISTRATION PROCEDURES 267
APPENDIX XIV: POSSIBLE DRUG INTERACTIONS 269
REFERENCES: 277

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STUDY COMMITTEE

STUDY CHAIR STUDY COMMITTEE MEMBERS

Patrick Brown, MD Andrew Carroll, PhD.
Hematology/Oncology Cytogenetics
Johns Hopkins University Children’s Hospital of Alabama
1650 Orleans St. CRB2M49 1530 3rd Ave. South Kaul Bldg. Rm 314B
Baltimore, MD. 21231 Birmingham, AL 35294
Phone: (410) 614-4915 Phone: (205) 934-0665
Fax: (410) 955-8897 Fax: (205) 934-1078
E-mail: [email protected] E-mail: [email protected]

STUDY VICE CHAIR Alix Dabb, PharmD.

James A. Whitlock, MD Pharmacy
Hematology/Oncology Johns Hopkins University
Hospital for Sick Children 600 N. Wolfe Street
555 University Ave, Room 9409 Black Baltimore, MD. 21287
Toronto, ON M5G 1X8 Phone: (443) 287-0559
Phone: (416) 813-8885 Fax: (410) 955-0287
Fax: (416) 813-5327 E-mail: [email protected]
E-mail: [email protected]
Kala Kamdar, MD
STUDY STATISTICIAN Hematology/Oncology
Xiaomin Lu, PhD Baylor College of Medicine
Children’s Oncology Group Statistics and Data Center 6621 Fannin St. CC1410.00
University of Florida Houston, TX 77030
6011 NW 1st Place Phone: (832) 824-4163
Gainesville, FL 32607 Fax: (832) 825-1503
Phone: (352) 273-0568 E-mail: [email protected]
Fax: (352) 273-8162
E-mail: [email protected] Mignon Lee-Cheun Loh, MD
Hematology/Oncology
STUDY COMMITTEE MEMBERS Univ. of California San Francisco Medical Center-Parnassus
Michael Borowitz, MD Dept of Pediatrics, Room M647
Pathology 505 Parnassus Avenue
Johns Hopkins University San Francisco CA 94143-0106
401 N. Broadway Phone: (415) 514-0853
Baltimore, MD. 21231 Fax: (415) 502-5127
Phone: (410) 614-2889 E-mail: [email protected]
Fax: (410) 502-1493
E-mail: [email protected] Lia Gore MD
Hematology/Oncology
Stephen Hunger, MD Children’s Hospital Colorado
Hematology/Oncology Center for Cancer & Blood Disorders
Children’s Hospital Philadelphia Pediatrics, Mail Stop 8302
Colket Translational Research Building PO Box 6511
3501 Civic Center Blvd Aurora, CO 80045
Room 3060 Phone: (720) 777-4159
Philadelphia, PA Fax: (720) 777-7279
Phone: 267 425-0197 E-mail: [email protected]
E-mail: [email protected]

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STUDY COMMITTEE MEMBERS

Jennifer McNeer, MD Fady Mikhail, MD PhD
Hematology/Oncology Cytogenetics
University of Chicago Children’s Hospital of Alabama
5841 S. Maryland Ave 720 20th Street South, Kaul Bldg. Rm. 314A
MC 4060 Birmingham, AL 35294
Chicago, IL. 60637 Phone: (205) 934-9588
Phone: (773) 702-5782 Fax: (205) 934-1078
Fax: (773) 702-9881 E-mail: [email protected]
E-mail: [email protected]
Julie M. Gastier-Foster, PhD.
Maureen Megan O’Brien, MD Laboratory Science
Hematology/Oncology Nationwide Children’s Hospital
Cincinnati Children’s Hospital Medical Center 700 Children’s Drive, CO988A
3333 Burnet Avenue Columbus, OH. 43205
MLC 7015 Phone: (614) 722-2866
Cincinnati, OH. 45229 Fax: (614) 722-2887
Phone: (513) 803-1678 E-mail: [email protected]
Fax: (513) 636-3549
E-mail: [email protected] Terzah Horton, MD
Hematology/Oncology
Michael Pulsipher, MD Baylor College of Medicine
Stem Cell Transplantation 1102 Bates Avenue, Suite 750
Primary Children’s Hospital Houston, TX. 77030
100 North Mario Capecchi Dr. Phone: (832) 824-4269
Salt Lake City, UT. 84113 Fax: (832) 824-1206
Phone: (801) 662-4830 E-mail: [email protected]
Fax: (801) 662-4707
E-mail: [email protected] Stephanie Terezakis, MD.
Radiation Oncology
Sue Rheingold, MD Johns Hopkins University
Hematology/Oncology 401 N. Broadway, Ste 1440
Children’s Hospital of Philadelphia Baltimore, MD. 21231
34 & Civic Center Blvd. Phone: (443) 287-7889
Philadelphia, PA. 19104 Fax: (410) 502-1419
Phone: (215) 590-3079 E-mail: [email protected]
Fax: (215) 590-4183
E-mail: [email protected] Catherine Deveault, B.Sc.
Clinical Research Associate
Richard Tower, MD Hospital for Sick Children
Hematology/Oncology 555 University Ave.
Midwest Children’s Cancer Center Toronto, ON M5G1X8
8701 Watertown Plank Road. Phone: (416) 813-7654 (228554)
Milwaukee, WI. 53226 Fax: (416) 813-8897
Phone: (414) 955-5653 E-mail: [email protected]
Fax: (414) 955-6543
E-mail: [email protected] Debra Marie Schissel, RN CCRP CPON
Nursing
Laura Hogan, MD Children’s Hospital Colorado
Hematology/Oncology 13123 East 16th Avenue B115
Stony Brook University Medical Center Aurora, CO 80218
HSC T11-029, Stony Brook, NY 11794 Phone: (720) 777-2879
Phone: (631) 444-7720 Fax: (720) 777-7289
Fax: (631) 444-2785 Email: [email protected]
E-mail: [email protected]

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Meenakshi Devidas, PhD Sue Zupanec, NP

Children's Oncology Group - Data Center (Gaines) Nursing
University of Florida Hospital for Sick Children
6011 NW 1st Place 555 University Avenue
Gainesville FL 32607 Toronto, ON M5G1X8
Phone: 352 273-0551 Phone: (416) 813-3488
Fax: 352 392-8162 Fax: (416) 813-5574
Email: [email protected] E-mail: [email protected]

Sarah Tasian, MD
Children’s Hospital of Philadelphia
Hematology/Oncology
3501 Civic Center Blvd
CTRB, 3rd Floor Room 3100
Philadelphia, PA 19104
Phone: (215) 590-5476
Fax: (215) 590-3770
Email: [email protected]
AGENT NSC# IND#
Hui Zeng, MS Blinatumomab 765986 117467
Children's Oncology Group - Data Center (Gaines) (IND Sponsor: CTEP)
University of Florida Asparaginase E. chrysanthemi 106977 Exempt
6011 NW 1st Place Cytarabine 63878 Exempt
Gainesville FL 32607 Cyclophosphamide 26271 Exempt
Phone: 352 273-0570 Cyclosporine 290193 Exempt
Fax: 352 392-8162 Dexamethasone 34521 Exempt
Email: [email protected] Etoposide 141540 Exempt
Filgrastim 614629 Exempt
COG RESEARCH COORDINATOR Fludarabine 312887 Exempt
Susan Conway, BA, CCRP Hydrocortisone 10483 Exempt
Children's Oncology Group Statistics and Data Center Leucovorin 003590 Exempt
University of Florida Methotrexate 000740 Exempt
6011 NW 1st Place Mercaptopurine 000755 Exempt
Gainesville, FL 32607 Mitoxantrone 301739 Exempt
Phone: 352-273-0559 Mycophenolate Mofetil 724229 Exempt
Fax: 352-392-8162 Pegaspargase 624239 Exempt
E-mail: [email protected] Tacrolimus 717865 Exempt
Thioguanine 00752 Exempt
COG PROTOCOL COORDINATOR Thiotepa 6396 Exempt
Mary Beth Sullivan, BS Vincristine 67574 Exempt
Children’s Oncology Group Operations Center
Study Development Office
222 E. Huntington Dr., Suite 100
Monrovia, CA 91016
Phone: (626) 241-1539
Fax: (626) 445-4334
E-mail: [email protected]

SEE SECTION 13.0 FOR SPECIMEN SHIPPING ADDRESSES.

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government,
which will help us protect the privacy of our research subjects. The Certificate protects against the
involuntary release of information about your subjects collected during the course of our covered studies.
The researchers involved in the studies cannot be forced to disclose the identity or any information collected
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to
voluntarily disclose the protected information under certain circumstances. For example, if the subject or
his/her guardian requests the release of information in writing, the Certificate does not protect against that
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances,
such as a DHHS request for information for an audit or program evaluation or an FDA request under the
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases,
and/or possible threat of harm to self or others.

ABSTRACT

AALL1331 is a group wide risk-stratified, randomized Phase III study to test whether incorporation of
blinatumomab into the treatment of patients with childhood B-Lymphoblastic Leukemia (B-ALL) at first
relapse will improve disease free survival. Blinatumomab is being tested in this population based on its
demonstrated safety profile and single agent activity (induction of MRD-negative remissions in children
with multiple relapsed refractory B-ALL).

AALL1331 risk stratification is determined based on site of relapse [marrow versus isolated extramedullary
(IEM)], time to relapse and minimal residual disease (MRD) status following a uniform first block of
chemotherapy. High risk (HR) and intermediate risk (IR) patients will be eligible for randomization to
either a control arm with two additional blocks of chemotherapy, or an experimental arm with two blocks
of blinatumomab. Both arms will proceed to protocol-specified hematopoietic stem cell transplant (HSCT)
that includes a rapid taper of immune suppression for patients with residual disease and no graft vs. host
disease (GVHD). Low risk (LR) patients will be eligible for randomization to either a control arm with two
blocks of chemotherapy followed by continuation and maintenance chemotherapy, or an experimental arm
with one block of chemotherapy, 2 blocks of blinatumomab, each followed by continuation and a third
additional block of blinatumomab followed by maintenance.

AALL1331 includes correlative laboratory studies to refine risk stratification, identify new targets for
therapy, identify biomarkers to predict response to chemotherapy and blinatumomab, and to link host
polymorphisms with various disease characteristics and toxicities.

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EXPERIMENTAL DESIGN SCHEMA 1st Relapse B-ALL (On Study)

Pre-treatment Evaluation

Block 1

Evaluation 1 1

HR/IR LR
Treatment Failure@

HR/IR Randomization LR Randomization

Arm C Arm D

Arm A Arm B
Block 2^

Block 2^ Blinatumomab^ Evaluation 2

(1st cycle)
Relapse@

Blinatumomab
Evaluation 22 Block 3 (1st cycle)

Prior blinatumomab, or Continuation 1 Continuation 1

Block 3 Blinatumomab
CNS disease
(2nd cycle)
Blinatumomab
Yes Continuation 2 (2nd cycle)
Evaluation pre-HSCT
Off No
Continuation 2
Protocol Eligible Maintenance#
Therapy
Ineligible
Blinatumomab
Salvage Therapy^ HSCT* (3rd cycle)
(Blinatumomab-S)
Up to 2 Cycles % Off protocol therapy
Maintenance#
HR=High Risk R=Randomization HSCT=Hematopoietic Stem Cell Transplant
IR=Intermediate Risk CR=Complete response LR=Low Risk TF: Treatment Failure
@ See Section 3.3 for definitions of treatment failure and relapse.
1
End Block 1 Callback (completed via OPEN)
2
End Block 2 Callback (completed via OPEN) for eligible and consenting TF patients on Arm A
#
CNS3 patients receive chemoradiation post Maintenance Cycles 1 * Patient may receive bridge therapy prior to HSCT
^ Patients with persistent testicular involvement after Block 1 will receive testicular radiation (TRT) during designated blocks
%
Evaluation pre-HSCT at end of each cycle. See Section 4.7.6 and 4.8.5 for details

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1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Aims

1.1.1 To compare disease free survival (DFS) of HR and IR relapse B-ALL patients who
are randomized following Induction Block 1 chemotherapy to receive either two
intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR
Randomization).

1.1.2 To compare DFS of LR relapse B-ALL patients who are randomized following
Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus
blinatumomab (LR Randomization).

1.2 Secondary Aims

1.2.1 To compare overall survival (OS) of HR and IR relapse B-ALL patients who are
randomized following Induction Block 1 chemotherapy to receive either two
intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR
Randomization).

1.2.2 To compare OS of LR relapse B-ALL patients who are randomized following

Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus
blinatumomab (LR Randomization).

1.3 Exploratory Aims

1.3.1 To compare the rates of MRD ≥ 0.01% at the end of Block 2 and Block 3 for HR
and IR relapse B-ALL patients in HR/IR randomization.

1.3.2 To estimate, for treatment failure (TF) patients not previously receiving
blinatumomab, the hematologic complete remission rate (CR), rate of MRD
< 0.01%, and proportion able to proceed to hematopoietic stem cell transplant
(HSCT) in CR after treatment with blinatumomab.

1.3.3 To assess the feasibility and safety of rapid taper of immune suppression for the
subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-HSCT with no acute
graft versus host disease (aGVHD).

1.3.4 To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response

relationships for measures of safety and effectiveness.

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2.0 BACKGROUND

2.1 Overview
First relapse of childhood B-ALL is a vexing clinical problem with high rates of subsequent
relapse and death with current treatment approaches.1 This trial will determine if
blinatumomab can reduce rates of second relapse, and improve survival. If successful, these
interventions could become standard of care for this disease. Additionally, success in
relapsed B-ALL will identify interventions that can subsequently be studied in patients
with newly diagnosed B-ALL in order to reduce rates of first relapse.

This study also is a paradigm shift away from the non-randomized historical control
outcome comparisons pursued in recent COG trials for patients with early relapse of B-
ALL (ADVL04P2 and AALL07P1). Those trials were designed to screen promising new
agents for possible activity in order to identify which agents should be tested further in
more definitive trials. Because of the remarkable efficacy of blinatumomab in adult trials2-
5
and in the Phase I portion of COG AALL1121,6 this study will directly test the efficacy
of blinatumomab in two risk groups of relapsed B-ALL in a randomized fashion.

This trial also seeks to enhance accrual to relapse childhood ALL trials within COG. Prior
to this trial, COG has used a fragmented approach that has required institutions to open a
different protocol for each of the many subsets of first relapse ALL. This trial will address
this issue by studying first relapse B-ALL in a single, comprehensive protocol.

Importantly, this study will establish an infrastructure for systematic studies of the
classification and biology of relapsed childhood B-ALL. Due to the fragmented nature of
previous trials and poor accrual, these types of studies have not been possible in the COG
until now.

2.2 Rationale for Selected Approach and Trial Design

2.2.1 Rationale for Consolidated First Relapse B-ALL Trial
This study alters the approach to clinical investigation of relapsed B-ALL in COG.
Previous treatment protocols for the 3 major risk groups of first relapse ALL based
on duration of 1st complete remission (CR1) and site of relapse (see Table 1) have
been separate.
Table 1: Risk groups by duration of CR1, and site of relapse.
Risk group CR1 duration and site Studies
AALL02P2
Low ≥ 18 mo isolated extramedullary (Late IEM)
(closed)
≥ 36 mo marrow (Late marrow), AALL0433
Intermediate
< 18 mo isolated extramedullary (Early IEM) (closed)
ADVL04P2
< 36 mo marrow (Early marrow),
High (completed)
all T-ALL/T-LL relapses
AALL07P1
The approach for HR patients has been a series of single arm, limited
accrual/duration Phase II re-Induction studies of novel agents (epratuzumab for
ADVL04P2, bortezomib for AALL07P1) added to the 3-block backbone of
chemotherapy established by AALL01P2 (see Table 2) with the primary endpoint
being CR2 at end Block 1 as compared to historical control data using the

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backbone alone.7 Use of historical control data is problematic for a number of

reasons. COG trials for IR and LR patients have each utilized a unique multiagent
chemotherapy regimen with or without randomized interventions with a 3-year
event free survival (EFS) endpoint.

Table 2: Backbone Chemotherapy for relapse B-ALL

Block 1 Block 2 Block 3
2
PRED 40 mg/m /day, Days 1-29 ETOP Days 1-5 HD ARAC Days 1, 2, 8, 9
VCR 1.5 mg/m2, Days 1, 7, 15, 21 CPM Days 1-5 L-ASP Days 2, 9
PEG 2500 IU/m2, Days 2, 9, 16, 23 HDMTX Day 22 IT MTX or ITT Days 1, 22
DOXO 60 mg/m2, on Day 1 with leucovorin
IT ARAC Day 1 rescue
IT MTX Days 15, 29 (or ITT if CNS
positive)

This fragmented approach has been associated with problems in meeting accrual
goals and/or completion of studies in a timely and efficient manner. A major
obstacle to accrual is the reluctance of COG sites to open all of the relapse studies.
Since relapsed ALL is significantly less common than newly diagnosed ALL, the
annual accrual to each individual study is expected to be low enough at most COG
sites that it may not justify the regulatory burden involved in opening several
studies. This is exacerbated for the HR group by the limited accrual/duration of
each study, since individual COG sites may be unlikely to enroll any patients
during the conduct of such a study. For example, major frontline COG ALL trials
are typically open at 190-200 sites. In contrast the HR relapse trials have been open
in only about 100 sites, and the IR and LR trials at 125 to 150 sites.

We therefore are addressing these issues with a consolidated approach to the

classification and initial treatment of first relapse B-ALL, in which all patients are
eligible to enroll in a single trial. This approach has been successful in other
cooperative groups, including the International Berlin Frankfurt Munster (I-BFM)8
and United Kingdom Children’s Cancer and Leukemia Group
(UK CCLG)/Australia/New Zealand9 consortia.

2.2.2 Rationale for Studying Blinatumomab in First Relapse of B-ALL

Survival for first relapse of B-ALL is suboptimal. Blinatumomab is a promising
novel agent for the treatment of B-lineage lymphoid malignancies.1-5
Blinatumomab is a bispecific single-chain antibody that targets the CD19 antigen
and redirects CD3+ T cells for selective lysis of tumor cells. In a Phase II trial of
adult B-ALL, patients with MRD persistence or relapse after Induction and
Consolidation therapy received blinatumomab as a 4-week continuous intravenous
infusion at a dose of 15 µg/m2/24 hours.5 Of 21 treated patients, 16 patients became
MRD negative as assessed by quantitative polymerase chain reaction for either
rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic
aberrations. Among the 16 responders, 12 patients had been molecularly refractory
to previous chemotherapy. Probability for relapse-free survival was 78% at a
median follow-up of 405 days. Blinatumomab was similarly effective and well
tolerated in an anecdotal report of a small series of pediatric cases.2

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Blinatumomab is presently being evaluated in children with relapsed/refractory

ALL in an Amgen-sponsored Phase I/II study being conducted by COG (MT103-
205/AALL1121) and the I-BFM European childhood leukemia cooperative group
with extremely promising early results. As of September 2013, 34 patients have
been treated in the Phase I portion. Across all dose levels, 11 (32%) patients had
CR, 1 (3%) had hypocellular blast-free bone marrow, and 2 (6%) had partial
remission within the first two treatment cycles. All patients with CR also
experienced molecular remission (MRD level < 10-4) after one 4-week block of
blinatumomab.10 The recommended Phase 2 dose for patients with untreated
relapse has been determined to be a 4 week continuous IV infusion of 5 µg/m2/day
for the first week of Cycle 1 and 15 µg/m2/day thereafter (i.e. Weeks 2-4 of Cycle
1 and Weeks 1-4 of all subsequent cycles), with a 2 week break between each
cycle. The Phase 2 portion of the study is being conducted at 20 COG and 20
European institutions and began accrual in September 2013. A 2-week rest period
between 4-week cycles was selected arbitrarily in early studies of blinatumomab.
To preserve the symmetry of timing between arms as much as possible, in
AALL1331, a “block” of blinatumomab will be 5 weeks in duration, and will
consist of a 4 week continuous infusion followed by a 1 week break. AALL1331
will also use a flat dose of 15 µg/m2/day for all blinatumomab cycles except for
the first cycle for TF patients (who, like the Phase I/II study patients, will have
bulk disease at the time of initiating treatment), where the Phase 2 escalating
dosing strategy will be used.

The level of single agent activity seen with blinatumomab has not been seen in
recent Phase I ALL studies outside the use of tyrosine kinase inhibitors (TKI) in
patients with Philadelphia chromosome positive (Ph+) ALL, thus supporting a
Phase III randomized clinical trial with DFS endpoints. AALL1331 uses a risk-
stratified approach to test whether incorporating blinatumomab into treatment of
first relapse B-ALL will reduce rates of second relapse and improve DFS. If
successful, inclusion of blinatumomab could become standard of care for this
disease. Additionally, success in relapsed B-ALL will provide additional rationale
to test blinatumomab in newly diagnosed B-ALL patients in order to reduce rates
of first relapse.

As experience with blinatumomab remains relatively limited, this study will

include close early monitoring for uncommon but significant adverse events in
patients receiving blinatumomab. In addition, the potential for adverse effects from
long term depletion of CD19+ normal lymphocytes following blinatumomab
treatment is unknown and so monitoring for lymphocyte recovery and for potential
adverse effects related to delayed recovery are included.

Neurological adverse events have been described with blinatumomab and will be
closely monitored on this study. One potential concern regards the safety of
combining blinatumomab with IT chemotherapy. In the current Phase I/II pediatric
study cited above, IT methotrexate or IT triples are included prior to Cycle 1, at
Day 15 of Cycle 1 and at Day 29 of each cycle. No unusual or increased CNS side
effects have been seen in this setting.10

Cytokine release syndrome (CRS) has also been described. This is more prevalent
in patients with higher leukemia burden, however can occur in any patient treated

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with blinatumomab. Pre-medication with dexamethasone is mandated in the

protocol, and at the suggestion of the development of CRS, even after the
premedication doses, additional dexamethasone administration is suggested. There
is a published case report suggesting that for cases of life-threatening cytokine
release syndrome for which dexamethasone and supportive care measures are not
adequate, consideration may be given to the administration of tocilizumab, the
anti-IL-6 monoclonal antibody.11

2.2.3 Rationale for Risk Stratification

Long term survival rates for B-ALL early marrow (15% - 30%) and B-ALL early
IEM (30%-50%) relapses are very poor, and HSCT is generally considered to
provide the best chance for cure.1 This group of patients will be classified as HR
and will be eligible to participate in HR/IR randomization upon recovery from
Block 1 unless they meet TF criteria (see Table 6).

Late B-ALL marrow relapse patients have excellent end-reinduction CR2 rates
(> 95%),7 but long term EFS is suboptimal at about 50 – 60%. For these late B-
ALL marrow relapse patients, end-Block 1 MRD has been identified in multiple
studies to be a strong prognostic factor.7,12-14 In AALL01P2, for example, the 5-yr
EFS for late marrow/MRD-negative patients (< 0.01% by flow at end-Block 1,
occurring in about 50 % of patients) was 57% vs. 24% for those with MRD
≥ 0.01%.7 Thus, AALL1331 will use MRD response to stratify late pre-B marrow
relapse patients into those for whom HSCT is or is not indicated. We will use an
MRD threshold of 0.1% at end-Block 1 for this HSCT allocation (see Table 3
below). This is based on data from AALL01P2 and the ongoing AALL0433 trial,
in which MRD data (end Blocks 1, 2 and 3) have been collected for a large cohort
(~150) of late B-ALL marrow relapse patients. The AALL0433 cohort is
especially informative since the post-Block 3 therapy given in the context of
AALL0433 is uniform (this is not true for AALL01P2). Recent analyses of MRD
and outcome from patients enrolled on COG AALL0433 with BM or combined
relapse and available end Induction MRD data (n=175) showed 3-yr. EFS 80.2 ±
5.2% vs. 40.9 ± 8.4%, and 3-yr. OS of 87.1 ± 4.3% vs. 56.2 ± 9.0% for those below
(n=112) or above (n=63) an MRD cutoff of 0.1%.15 Thus far, about 62% of late
BM relapse patients enrolled in AALL0433 attain MRD < 0.1% by end Block 1.
Summarily, for late B-ALL marrow relapse patients, post-Block 1 treatment will
be risk-stratified, based on end-Block 1 MRD. MRD analysis will be performed
centrally in Dr. Borowitz’s laboratory at Johns Hopkins using flow cytometry and
a cutoff for MRD positivity of ≥ 0.1% will be used. Patients with end-Block 1
MRD levels of ≥ 0.1% will be classified as IR and will be eligible to participate in
HR/IR randomization. Those with end-Block 1 MRD levels of < 0.1% will be
classified as LR and will be eligible to participate in LR Randomization (see
Table 3 below).

For B-ALL IEM relapses, expected outcomes with chemotherapy and radiation for
those relapsing at least 18 months from diagnosis are similar to those for late
marrow LR patients.16,17 It is generally agreed that HSCT is not indicated for B-
ALL late IEM relapses. An exception to this will be patients found to have
detectable minimal marrow disease at study entry that does not clear to < 0.1% by
the end of Block 1, based on published literature that minimal marrow disease in
the setting of extramedullary relapse is associated with increased risk of

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subsequent marrow relapse.18,19 Thus, B-ALL late IEM relapses that have MRD
< 0.1% (or uninterpretable MRD results) at end Block 1 will be classified as LR
and will be eligible to participate in LR Randomization. B-ALL late IEM/end
Block 1 MRD ≥0.1% relapses will be classified as IR and will be eligible to
participate in HR/IR randomization.

Table 3: Risk Classification on AALL1331

Randomization HSCT Treatment
Risk Group Definition
Eligibility
• Late (≥ 36 months) marrow,
No HSCT
end-Block 1 MRD < 0.1%
LR (Treatment includes
Low • Late (≥ 18 months) Isolated
Randomization Continuation and
extramedullary (IEM),
Maintenance)
end-Block 1 MRD < 0.1%
• Late (≥ 36 months) marrow,
end-Block 1 MRD ≥ 0.1% HR/IR
Intermediate HSCT
• Late (≥ 18 months) IEM, Randomization
end-Block 1 MRD ≥ 0.1%
• Early (< 36 months)
HR/IR
High marrow HSCT
Randomization
• Early (< 18 months) IEM
Failure to achieve the
None (Possible
following at end Block 1:
treatment
Treatment • M2 or better
assignment to HSCT
Failure • CNS remission Salvage
(clearance of CSF
Therapy)
blasts, i.e. CNS1)

2.2.4 Rationale for Backbone Chemotherapy Treatment (Blocks 1, 2 and 3)

AALL1331 adopts the chemotherapy used in the recently published international
collaborative United Kingdom Medical Research Council ALLR3 study
(mitoxantrone arm).9 These results are the most promising for relapsed childhood
ALL published to date, and need to be confirmed using data from the standard
arms of this trial. In addition, adopting ALLR3 will pave the way for the
international collaboration that we know will be necessary as we begin to test
agents targeted to small molecularly-defined subsets of patients (i.e., JAK2
mutant). The first 3 blocks of therapy will serve as the control arm for all patients
on this study. These 3 blocks are quite similar to the AALL01P2 Blocks (Table 4).
Table 4: Comparison of AALL01P2 and AALLR3
COG AALL01P2 ALLR3 (mitoxantrone arm)
2
Block 1 PRED 40 mg/m /day, Day 1-29 DEX 20 mg/m2/day Days 1-5, 15-19
VCR 1.5 mg/m2, Days 1, 8, 15, 22 VCR1.5 mg/m2 Days 3, 10, 17, 24
PEG 2500 IU/m2 Days 2, 9, 16, 23 PEG 1000 IU/m2 Day 3 of weeks 1 & 3
DOXO 60 mg/m2 on Day 1 Mitoxantrone 10 mg/m2 Days 1, 2
IT ARAC Day 1 IT MTX Days 1, 8 (or weekly if CNS
IT MTX Days 15, 29 (or ITT if positive until 2 clear samples are
CNS positive) obtained)
Block 2 ETOP 100 mg/m2 Days 1-5 DEX 6 mg/m2/day Days 1-5
CPM 440 mg/m2 Days 1-5 VCR 1.5 mg/m2 Day 3
MTX 5 g/m2 Day 22 MTX 1 g/m2 Day 8

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IT MTX Days 1, 8 PEG 1000 IU/m2 Day 9

CPM 440 mg/m2 Days 15-19
ETOP 100 mg/m2 Days 15-19
IT MTX Day 8
Block 3 ARAC 3000 mg/m2 q12h DEX 6 mg/m2/day Days 1-5
Days 1, 2, 8, 9 VCR 1.5 mg/m2 Day 3
L-ASP 6000 IU/m2 Days 2, 9 ARAC 3000 mg/m2 q12 Days 1, 2, 8, 9
Erwinia asparaginase 20,000 IU/m2
Days 2, 4, 9, 11, 23
MTX 1 g/m2 Day 22
IT MTX Days 1, 22
CR2 end 96% for IR, 67% for HR (31% for 92% for IR, 58% for HR
Block 1 CR1 < 18 mo), 29% for T-ALL
MRD+ 51% for IR, 75% for HR 59% for IR, 100% for HR
end (small numbers)
Block 1
Survival 12 month EFS: 80% for IR, 35% 3-year PFS: 65% for mitoxantrone arm
for HR (includes HR and IR patients)
3-year EFS: 55% for IR, 15% for
HR

The ALLR3 trial randomized patients to mitoxantrone versus idarubicin in

Block 1, and found that the mitoxantrone arm with a 3-yr progression free survival
(PFS) of 65% was superior to the idarubicin arm in both 3-yr PFS (65% vs. 36%,
p=0.0004) and 3-yr overall survival (69% vs. 45%, p=0.004). The major
differences between Block 1 in ALLR3 and in the COG AALL01P2 backbone are
the replacement of doxorubicin with mitoxantrone and 28 days of prednisone with
two 5-day pulses of high-dose dexamethasone. Dexamethasone was used in
ALLR3 based on evidence in prior studies of superior CNS activity and survival
when compared with prednisone.20-22 For Block 2, the major differences are the
inclusion of a “prophase” week of dexamethasone and vincristine, a lower dose of
methotrexate (MTX; 1 g/m2 vs. 5 g/m2), and the inclusion of a dose of PEG
asparaginase in combination with MTX. For Block 3, the major differences are the
addition of dexamethasone and vincristine to the first week of high dose
cytarabine, the addition of intravenous (IV) MTX (1 g/m2) and 2 doses of
intrathecal (IT) MTX, the use of Erwinia asparaginase instead of E.coli
asparaginase and the inclusion of 3 additional doses of Erwinia asparaginase.
AALL1331 differs from ALLR3 in several ways:
• AALL1331 administers vincristine beginning on Day 1 of Block 1, rather
than beginning on Day 3.
• The pegaspargase preparation utilized in the ALLR3 trial, which is supplied
by Medac, differs from that utilized in North America, which is supplied by
Sigma Tau. Thus, it is possible that the pharmacokinetics (PK) and/or activity
profiles of the pegaspargase preparation utilized in Europe differ from that
used in North America. As the Medac pegaspargase product is not available
for use in North America, AALL1331 will use the COG standard dose
(2500 IU/m2) of intravenous Oncospar pegaspargase given on the same
schedule utilized in ALLR3. Recent and ongoing COG relapse ALL trials
utilize 4 doses of pegaspargase (2500 IU/m2) given weekly in Block 1, and
the most recent and current UKALL 2003/2011 trials and current frontline

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AIEOP-BFM 2009 ALL trial use 2 doses of pegaspargase during a 4-drug

Induction, so this change is expected to be safe.

2.2.5 Rationale for Backbone Chemotherapy Treatment (post-Block 3)

One attractive aspect of the post-Block 3 chemotherapy given in the ALLR3
protocol is that it is significantly less intensive than that given to similar patients
on the current COG study, AALL0433 (Table 5), affording us an opportunity to
decrease short and long term toxicity for relapsed patients with a relatively good
prognosis.

Table 5* Comparative Cumulative Dosing

Drug AALL0433 ALLR3
Intravenous methotrexate (IV MTX) 40 ---
Cytarabine (ARAC) 48 0.6
Etoposide (ETOP) 2.4 0.6
Cyclophosphamide (CPM) 10 1.2
Vincristine (VCR) 0.0525 0.030
Mercaptopurine (MP) 18 44
Dexamethasone (DEX) 0.39 0.24
Doxorubicin (DOXO) 0.075 ---
Pegaspargase (PEG) 6 doses (2500 IU/m2) ---
Intrathecal methotrexate (IT MTX) - CNS 15 doses 10 doses
negative
Oral Methotrexate (PO MTX) 1.2 1.7
*Units are cumulative grams/m2 of indicated drug unless otherwise indicated.

2.2.6 Therapy for CNS3 Patients

The majority of patients with isolated CNS relapse on the ALLR3 trial proceeded
to HSCT, so data regarding the efficacy of ALLR3 chemotherapy and radiation
alone are lacking. However, Pediatric Oncology Group (POG) studies
demonstrated excellent outcomes for late isolated CNS relapse with the
incorporation of drugs with both systemic and CNS efficacy (intermediate-dose
MTX 1 g/m2 and high-dose ARAC 3 g/m2) and delayed CNS-directed
radiation.16,17 On these trials, coordinated systemic and intrathecal therapy (IT)
were given early in therapy to target both the CNS relapse and the high risk for
subsequent marrow relapse. On POG 9061, radiation therapy (cranial 24 Gy, spinal
15 Gy) was given after 6 months of intensive chemotherapy and then followed by
maintenance chemotherapy, resulting in 84% EFS for late EM relapse patients.
The chemotherapy used on POG 9061 was similar to the proposed backbone for
this study but included additional CNS-directed therapy.17 The successor trial,
POG 9412, successfully reduced radiation to 18 Gy cranial and eliminated spinal
radiation for late CNS relapse patients but included maximal intensity
chemotherapy for 12 months prior to radiation.16

On AALL1331, the backbone described above will be modified to include

increased CNS-directed therapy. Throughout therapy, intrathecal triples (ITT) will
replace IT MTX. During Block 1, two additional ITT doses will be given. During
Block 2, one additional ITT dose will be given. Late B-ALL isolated CNS or late
B-ALL CNS3 combined relapse patients with MRD < 0.1% after Block 1 will be
LR and eligible for randomization to receive either standard Block 3, Continuation

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and Maintenance or Blinatumomab, Continuation/Blinatumomab and

Maintenance. We will further intensify CNS-directed therapy for these patients by
replacing lower dose oral MTX (25 mg/m2 every 6 hours x 4 doses) with
intermediate-dose IV MTX (1000 mg/m2 over 36 hours) during the each of the 2
continuation phases. All of these patients will then receive 1800 cGy cranial
radiation and concurrent chemotherapy (including high-dose dexamethasone)
between and the first and second 12 week blocks of Maintenance. Radiation will
be administered later on the current study (approximately Week 40 for the control
arm and Week 54 for the experimental arm) as compared to the ALLR3 trial (Week
14) to maximize delivery of early intensive chemotherapy; this is similar to the
timing of radiation in POG 9412 (Week 51).

All other CNS3 relapse patients that meet IR or HR criteria will proceed to total
body irradiation (TBI) based HSCT as described in Section 14.5. In addition to the
TBI, these patients will also receive a protocol-specified cranial radiation boost as
part of their HSCT preparative regimen.

2.2.7 Treatment of Testicular Relapse

Although historically testicular irradiation has been used for patients with
testicular leukemia at relapse, there are no studies that prove the necessity of this
approach. Studies conducted by St. Jude and the European Organization for
Research and Treatment of Cancer (EORTC) show that the prognostic significance
of overt testicular disease at first diagnosis of ALL has declined on modern
treatment protocols.23,24 The EORTC no longer irradiates any of these patients.24
The Dutch Childhood Oncology Group has shown that it is possible to effectively
treat patients with isolated testicular relapse without radiation.25,26 The COG has
been steadily decreasing the percentage of newly diagnosed and relapsed patients
with testicular leukemia that receive testicular irradiation due to the intensified
chemotherapeutic regimens and the associated long-term morbidity of testicular
irradiation. The findings described above, along with those that show testicular
relapses have decreased as chemotherapy regimens for newly diagnosed ALL have
intensified, patients with testicular relapse often have detectable disease in the
bone marrow, and patients with initial testicular disease usually relapse in the bone
marrow, suggest that cure of patients with testicular leukemia is a systemic control
problem, not a local control problem. Much of the decrease in testicular relapse
has been attributed to intermediate and high-dose MTX.27-29 Patients will receive
intermediate-dose MTX in Blocks 2 and 3 of AALL1331. Since the ALLR3
protocol has shown superior outcomes to previous relapsed leukemia therapies, we
believe the improved chemotherapy backbone on this protocol will allow the
elimination of testicular irradiation (beyond that which may be used in the HSCT
preparative regimen) for those patients that have a complete response of testicular
leukemia by end Block 1.
2.2.8 Treatment Failure (TF)
Recent COG early marrow relapse ALL studies have defined TF as not achieving
M1 marrow by Day 15 of Block 2. In both ALL R3 and in this study, the order of
Block 2 chemotherapy differs from that of prior COG studies and non-cross-
resistant therapy is not given until Day 15; thus in this study, TF is assessed at the
Blocks 1 and 2.

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Patients failing to achieve pre-defined response criteria at end-Block 1, end-Block

2/Blinatumomab Cycle 1 (Table 6) will be categorized as having TF (an event).
Such patients will be eligible to receive up to 2 blocks of blinatumomab if they had
not previously received it on study and do not have residual CNS disease, and will
be eligible to continue on study to HSCT if they achieve a CR. Otherwise they will
be removed from protocol therapy. Patients who achieve remission at end of Block
1 or Block 2 but are no longer in remission on a subsequent evaluation will be
removed from protocol therapy for relapse and will not be eligible to receive
blinatumomab. TF is assessed at the end of Blocks 1 and 2.

Table 6: Response criteria required to continue on study

Marrow CNS Testicular
None; patients with
persistent testicular
disease will receive
testicular radiation in
Remission Block 2 (LR and HR/IR
End-Block 1 M2 or
(clearance of CSF randomized to the
(All patients) better
blasts) control arm) or during
Blinatumomab Block:
Cycle 1 (HR/IR
randomized to the
experimental arm)
End-Block 2 or End
Remission (clearance of
Blinatumomab Block: M1 Continued remission
testicular disease)
Cycle 1(HR/IR only)

2.2.9 Additional non-randomized Pilot Intervention for Very High Risk Subset of HSCT
Recipients based on MRD and aGVHD
Relapse rates for patients with relapsed B-ALL who are MRD+ immediately prior
to HSCT or are MRD+ in the first 100 days post HSCT are exceedingly high,
particularly if there is no aGVHD.30-33 Table 7 below shows the relative risk of
relapse in the recently closed COG ASCT0431 trial according to MRD (using
0.01% as a threshold) and aGVHD status by Day +55.33

Table 7 Relapse risk on ASCT0431 per MRD and aGVHD status

Factor RR (95% CI)
Pre-MRD+ vs Pre-MRD- 1.9 (0.9-4.1)
aGVHD Yes vs No 0.29 (0.12-0.72)
Any post-MRD+ 2.8 (1.2-6.5)
Patients who were MRD+ pre-HSCT who did not develop acute GVHD and
patients with any MRD+ detected after HSCT had a relapse rate of 83%. Given
this unacceptably high relapse rate, including a post-HSCT immunological
intervention for such patients could potentially address this high relapse rate, and
should help standardize post-HSCT interventions and decrease dropout of MRD+
patients prior to HSCT. While the optimal immunological intervention is not
known, AALL1331 will include a relatively simple intervention (accelerated taper
of immune suppression as detailed in Section 4.9) that is designed to gather
additional data to set the stage for more definitive interventions in future trials (e.g.
post-HSCT blinatumomab, moxetumomab or other immunotherapy). Trials both

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in Europe and the US have shown that patients defined as high risk for relapse
based upon increasing recipient chimerism (i.e., increased percentage of recipient
DNA markers) can successfully undergo withdrawal of immune suppression (IS)
without excessive toxicity, and their survival is improved. Out of 46 patients with
increasing recipient chimerism (a group at very high risk for relapse), Bader et al
intervened in 31 patients with immune suppression (IS) withdrawal, donor
lymphocyte infusions (DLI), or both. Three-year EFS was 37% vs. 0% in the
intervention vs. non-intervention groups (p < 0.001).34 Of the 31 patients, 11
received IS withdrawal alone; 2 relapsed and 1 died of TRM with 8/11 surviving.
Three, 2, and 2 patients developed Grades 1, 2, and 3 aGHVD respectively, with
no Grade IV or chronic GVHD. A smaller portion of patients responded to DLI
(4/17) or a combination of both (1/3). Follow up publications by the Bader group
and American groups have shown that patients defined at high risk for relapse by
chimerism can safely undergo immune withdrawal with a survival benefit to the
patient.35,36 It is reasonable, therefore, to hypothesize that IS withdrawal may
provide benefit, and it is necessary to do this in a standardized manner in the
context of this trial. In addition, understanding the proportion of high risk patients
who can successfully discontinue IS is vital to future trial planning, as many
interventions to prevent relapse under consideration require patients to be on no or
minimal IS.

3.0 STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY

3.1 Study Enrollment
Note: This study is not on the CTSU Menu (i.e. it is not posted to the CTSU web site) but
is supported by the CTSU Regulatory Office, OPEN and Rave.

3.1.1 Patient Registration

Prior to enrollment on this study, patients must be assigned a COG patient ID
number. This number is obtained via the COG Registry system once authorization
for the release of protected health information (PHI) has been obtained. The COG
patient ID number is used to identify the patient in all future interactions with
COG. If you have problems with the registration, please refer to the online help.

In order for an institution to maintain COG membership requirements, every newly

diagnosed patient needs to be offered participation in ACCRN07, Protocol for the
Enrollment on the Official COG Registry, The Childhood Cancer Research Network
(CCRN).
A Biopathology Center (BPC) number will be assigned as part of the registration
process. Each patient will be assigned only one BPC number per COG Patient ID.
For additional information about the labeling of specimens please refer to the
Pathology and/or Biology Guidelines in this protocol.

Please see Appendix XIII for detailed CTEP Registration Procedures for Investigators
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures
including: how to download site registration documents; requirement s for site
registration, submission of regulatory documents and how to check your site’s
registration status.

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3.1.2 IRB Approval

Sites must obtain IRB/REB approval for this protocol and submit IRB/REB
approval and supporting documentation to the CTSU Regulatory Office before
they can be approved to enroll patients. Allow 3 business days for processing. The
submission must include a fax coversheet (or optional CTSU IRB Transmittal
Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may
be submitted in lieu of the signed IRB approval letter. All CTSU forms can be
located on the CTSU web page (https://www.ctsu.org). Any other regulatory
documents needed for access to the study enrollment screens will be listed for the
study on the CTSU Member’s Website under the RSS Tab.
IRB/REB approval documents may be faxed (1-215-569-0206),
E-mailed ([email protected]) or mailed to the CTSU Regulatory
office.
When a site has a pending patient enrollment within the next 24 hours, this is
considered a “Time of Need” registration. For Time of Need registrations, in
addition to marking your submissions as ‘URGENT’ and faxing the regulatory
documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general
(non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923.

Study centers can check the status of their registration packets by querying the
Regulatory Support System (RSS) site registration status page of the CTSU
members’ web site by entering credentials at https://www.ctsu.org. For sites under
the CIRB initiative, IRB data will automatically load to RSS.

Note: Sites participating on the NCI CIRB initiative and accepting CIRB
approval for the study are not required to submit separate IRB approval
documentation to the CTSU Regulatory Office for initial, continuing or
amendment review. This information will be provided to the CTSU Regulatory
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB
approval. The Signatory site may be contacted by the CTSU Regulatory Office or
asked to complete information verifying the participating institutions on the study.
Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the
CTSU Regulatory Office or compliance communicated per protocol instructions.

3.1.3 Study Enrollment

Patient enrollment will be facilitated using the Oncology Patient Enrollment
Network (OPEN). OPEN is a web-based registration system available on a 24/7
basis. To access OPEN, the site user must have an active CTEP-IAM account
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on
either the lead protocol organization (LPO) or participating organization roster.

All site staff will use OPEN to enroll patients to this study. It is integrated with the
CTSU Enterprise System for regulatory and roster data and, upon enrollment,
initializes the patient position in the Rave database. OPEN can be accessed at
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the
website at https://www.ctsu.org.

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Prior to accessing OPEN, site staff should verify the following:

• All eligibility criteria have been met within the protocol stated timeframes.
• All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).
Note: The OPEN system will provide the site with a printable confirmation of
registration and treatment information. Please print this confirmation for your
records.
Further instructional information is provided on the CTSU members' web site
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional
questions contact the CTSU Help Desk at 1-888-823-5923 or
[email protected].

See Section 3.1.6 below for details regarding randomization and treatment
assignment for patients.

3.1.4 Timing
Informed consent: Except for administration of intrathecal chemotherapy, informed
consent/parental permission MUST be signed before protocol therapy begins. See
Section 3.1.5 for summary of time points to obtain informed consent.
Study enrollment: Study enrollment must take place no later than five (5) calendar
days after beginning protocol therapy. If study enrollment takes place before
starting protocol therapy, the date that protocol therapy is projected to start must
be no later than five (5) calendar days after enrollment.
Eligibility studies: Patients must meet all eligibility criteria prior to the start of
protocol therapy or enrollment, whichever occurs first. All clinical and laboratory
studies to determine eligibility must be performed within 7 days prior to
enrollment.

3.1.5 Staged Consent

Informed consent will be obtained at critical stages of treatment for the different
groups of patients on this study (see summary table below). Informed consent that
describes Block 1 therapy (common to all patients on study) will be obtained before
starting treatment. At the end of Block 1 therapy, after risk groups have been assigned,
subsequent informed consent that describes further therapy will be obtained at the
various time points detailed in Table 8 below. Also see Experimental Design Schema

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Table 8: Summary of required consents for AALL1331

Consent Form Time point to Obtain Population for Post
Consent Consent Induction
exclusion
criteria
Consent for Before study entry All potential
additional marrow subjects
Block 1 consent Study Entry (Prior to start All subjects
of Block 1)
Consent for Evaluation 1 (prior to start HR/IR 3.2.5.14
HR/IR of post-Block 1 therapy)
randomization
and HSCT
Consent for LR Evaluation 1 (prior to start LR 3.2.5.14
randomization of Block 2)
Consent for Prior to start of Salvage Treatment
salvage therapy Therapy (Blinatumomab- Failures (TF)
and HSCT S):
• End Block 1 TF
• End Block 2 TF on Arm A

3.1.6 Risk Assignment, Randomization, and Treatment Assignment

• Evaluation 1 (detailed in Section 4.2.7).

Risk assignment according to the criteria outlined in Section 3.3 will occur prior
to submission of End-Block 1 callback. Consenting IR and HR patients will be
randomized according to HR/IR Randomization upon submission of callback.
Consenting LR patients will be randomized according to LR Randomization upon
submission of callback. Patients deemed Treatment Failure at Evaluation 1 who
are eligible for and consent to Salvage Therapy will be assigned to Salvage
Therapy upon submission of End-Block 1 callback.

• Evaluation 2 (detailed in Section 4.3.5).

Patients on Arm A who are deemed Treatment Failure at Evaluation 2 and are
eligible for and consent to Salvage Therapy will be assigned to Salvage
Therapy upon submission of End Block 2 callback

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3.1.7 Callbacks
Callback is performed using the Oncology Patient Enrollment Network (OPEN).
Population for
Callback Timing Purpose
Callback
End Block 1 Evaluation 1* Consenting LR Randomize LR
Callback patients not off patients to either of
(ALL protocol therapy 2 treatment arms:
patients after completion of Arm C (Control
continuing to Block 1 therapy. Arm) or
post-Block 1 Arm D
therapy) (Experimental Arm).

Consenting HR or Randomize HR/IR

IR patients not off patients to either of
protocol therapy 2 treatment arms:
after completion of Arm A (Control
Block 1 therapy Arm) or Arm B
(Experimental Arm).

Treatment Failure
patients who are Assign patients to
eligible for and Salvage Therapy
consent to Salvage (Blinatumomab-S)
Therapy

End-Block 2 Evaluation 2 Patients on Arm A Assign patients to

Callback who are deemed Salvage Therapy
(Arm A TF Treatment Failure at (Blinatumomab-S)
ONLY) end Block 2 and
who are eligible for
and consent to
Salvage Therapy
*See Section 3.1.10 for timing details
3.1.8 Drug Preparation and Administration
Sites must attest that their drug preparation and administration guidelines comply
with the USP. Each site's standard procedure for compounding blinatumomab must
be in compliance with USP <797> guidelines (ISO Class 5 or better). Documentation
of participating site training with regard to the preparation and administration of
blinatumomab must be submitted via RSS as protocol specific requirement at the time
of site activation for participation on the trial.

3.1.9 Inclusion of Women and Minorities

Both men and women of all races and ethnic groups are eligible for this study. To
allow non-English speaking patients to participate in the study, bilingual health care
services will be provided in the appropriate language.

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3.1.10 IMPORTANT NOTE:

In order to continue to receive protocol therapy, patients will need to begin
post-Block 1 therapy within a specified time frame (see Section 4.2). If a
patient has residual severe non-hematologic toxicities from Block 1 that are
likely to preclude beginning post-Block 1 therapy within this time frame,
please DO NOT complete end-Block 1 Callback for the patient. This is
important to minimize the number of patients who are randomized/assigned
but are unable to receive post-callback treatment.

Submission of end-Block 1 Callback must occur within 5 days of risk group/stratum

assignment (callback data will include local morphologic assessment, central flow
MRD result and confirmation of continued eligibility for blinatumomab treatment-
see Section 3.2).
3.2 Patient Eligibility Criteria
Important note: The eligibility criteria listed below are interpreted literally and cannot
be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for
determining eligibility of a patient enrolled on this trial must be available in the patient's
medical/research record which will serve as the source document for verification at the
time of audit.
All clinical and laboratory studies to determine eligibility must be performed within
7 days prior to enrollment unless otherwise indicated. Laboratory values used to
assess eligibility must be no older than seven (7) days at the start of therapy.
Laboratory tests need not be repeated if therapy starts within seven (7) days of
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits
of eligibility, or laboratory values are > 7 days old, then the following laboratory
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside
the limits of eligibility, the patient may not receive protocol therapy and will be
considered off protocol therapy. Imaging studies, if applicable, must be obtained
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if
necessary).

See Section 7.1 for required studies to be obtained prior to starting protocol therapy.

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INCLUSION CRITERIA
3.2.1 Age
Patients ≥1 year and < 31 years of age at the time of relapse will be eligible.

3.2.2 Diagnosis
First relapse of B-ALL with or without extramedullary disease.

Please refer to Section 3.3 for definitions of relapse and criteria for risk classification.

3.2.3 Prior Therapy

Please see Section 4.1.2 for the concomitant therapy restrictions for patients during
treatment.

3.2.3.1 No waiting period for patients who relapse while receiving standard
Maintenance therapy

3.2.3.2 Patients who relapse on frontline therapy in phases other than

Maintenance must have fully recovered from the acute toxic effects of
all prior chemotherapy, immunotherapy, or radiotherapy prior to
entering this study.

3.2.3.3 Cytotoxic therapy: At least 14 days since the completion of cytotoxic

therapy with the exception of hydroxyurea, which is permitted up to 24
hours prior to the start of protocol therapy, or Maintenance
chemotherapy (see Section 3.2.3.1).

3.2.3.4 Biologic (anti-neoplastic) agent: At least 7 days since the completion of

therapy with a biologic agent. For agents that have known adverse events
occurring beyond 7 days after administration, this period must be
extended beyond the time during which adverse events are known to
occur.

3.2.3.5 Stem cell transplant or rescue: Patient has not had a prior stem cell
transplant or rescue.

3.2.3.6 Patient has not had prior treatment with blinatumomab.

3.2.3.7 Patient has not received prior relapse-directed therapy (i.e., this
protocol is intended as the INITIAL treatment of first relapse).

3.2.4 Performance Status

Patients must have a performance status corresponding to ECOG scores of 0, 1,
or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16
years of age. Please refer to performance status scale at:
https://members.childrensoncologygroup.org/_files/protocol/Standard/Performan
ceStatusScalesScoring.pdf

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3.2.5 Organ Function Requirements

3.2.5.1 Adequate Renal Function Defined As:
- Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or
- A serum creatinine based on age/gender as follows:

Maximum Serum
Age
Creatinine (mg/dL)
Male Female
1 to < 2 years 0.6 0.6
2 to < 6 years 0.8 0.8
6 to < 10 years 1 1
10 to < 13 years 1.2 1.2
13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
The threshold creatinine values in this Table were derived from the Schwartz
formula for estimating GFR utilizing child length and stature data published
by the CDC.37

3.2.5.2 Adequate liver function defined as a direct bilirubin < 3.0 mg/dL.

3.2.5.3 Adequate Cardiac Function Defined As:

- Shortening fraction of ≥ 27% by echocardiogram, or
- Ejection fraction of ≥ 50% by radionuclide angiogram.

3.2.6 Exclusion Criteria

3.2.6.1 Patients with Philadelphia chromosome positive/BCR-ABL1+ ALL are

not eligible

3.2.6.2 Patients with Burkitt Leukemia/Lymphoma or mature B-cell leukemia

are not eligible

3.2.6.3 Patients with T-Lymphoblastic Leukemia (T-ALL)/Lymphoblastic

Lymphoma (T- LL) are not eligible

3.2.6.4 Patients with B-Lymphoblastic Lymphoma (B-LL) are not eligible

3.2.6.5 Patients with known optic nerve and/or retinal involvement are not
eligible. Patients who are presenting with visual disturbances should
have an ophthalmologic exam and, if indicated, an MRI to determine
optic nerve or retinal involvement.

3.2.6.6 Patients known to have one of the following concomitant genetic

syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia,
Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any
other known bone marrow failure syndrome.

3.2.6.7 Patients with known HIV infection.

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3.2.6.8 Patients with known allergy to mitoxantrone, cytarabine, or both

etoposide and etoposide phosphate (Etopophos).

3.2.6.9 Lactating females who plan to breastfeed.

3.2.6.10 Patients who are pregnant since fetal toxicities and teratogenic effects
have been noted for several of the study drugs. A pregnancy test is
required for female patients of childbearing potential.

3.2.6.11 Sexually active patients of reproductive potential who have not agreed
to use an effective contraceptive method for the duration of their study
participation.

3.2.6.12
a.) Patients with pre-existing significant central nervous system
pathology that would preclude treatment with blinatumomab,
including: history of severe brain injury, dementia, cerebellar
disease, organic brain syndrome, psychosis, coordination
/movement disorder, or autoimmune disease with CNS involvement
are not eligible. Patients with a history of cerebrovascular
ischemia/hemorrhage with residual deficits are not eligible.
(Patients with a history of cerebrovascular ischemia/hemorrhage
remain eligible provided all neurologic deficits have resolved)

b.) Patients with uncontrolled seizure disorder are not eligible.

(Patients with seizure disorders that do not require antiepileptic
drugs, or are well controlled with stable doses of antiepileptic drugs
remain eligible.)

3.2.7 Regulatory Requirements

3.2.7.1 All patients and/or their parent or legal guardian must sign a written
informed consent.

3.2.7.2 All institutional, FDA, and NCI requirements for human studies must be
met.

3.3 Definitions

Acute Lymphoblastic Leukemia (ALL)

Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow). Patients with > 25% L3
marrow lymphoblasts and/or evidence of c-myc translocation are considered to have
Burkitt or mature B-cell leukemia and are ineligible for this study.

Definitions of Relapse

RELAPSE:
Any recurrence of disease whether in marrow or extramedullary. Relapse should be
confirmed by pathology examination of appropriate tissue.

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ISOLATED BONE MARROW RELAPSE: Patients with an M3 marrow at any point after
achieving remission without involvement of the CNS and/or testicles. Every effort should
be made to confirm morphologic relapse using flow cytometry, FISH and/or cytogenetics.

CNS RELAPSE: Positive cytomorphology and WBC ≥ 5/µL OR clinical signs of CNS
leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome that
are, in the opinion of the investigator, more likely due to recurrent CNS leukemia than to
alternative causes (e.g., viral infection or chemotherapy toxicity). If any CSF evaluation shows
positive cytomorphology and WBC < 5/µL, a second CSF evaluation is recommended within
2-4 weeks. While identification of a leukemic clone in CSF by flow cytometry (TdT, CD19,
CD10, etc.) or FISH for diagnostic karyotypic abnormality may be useful, definitive evidence
of CNS involvement (i.e. WBC ≥ 5/µL OR clinical signs of CNS leukemia) is required for the
diagnosis of a CNS relapse. Note that AALL1331 excludes patients with known optic nerve
and/or retinal involvement (Section 3.2.5.4).

TESTICULAR RELAPSE: Must be documented by testicular biopsy, if not associated with

a marrow relapse.

ISOLATED EXTRAMEDULLARY (IEM) RELAPSE: CNS and/or testicular relapse with

an M1 marrow. The presence of MRD in the bone marrow does NOT exclude IEM.

COMBINED RELAPSE: M2 or M3 marrow at any point after achieving remission with

concomitant CNS and/or testicular relapse.

CNS Status:
NOTE: in this protocol “CNS-positive” means meeting the criteria for CNS Relapse
(whether isolated CNS or combined relapse) at the time of AALL1331 study entry as listed
in the Definitions of Relapse above. CNS 2 status first noted at the time of enrollment for
concurrent relapse at another site (i.e. bone marrow) will not be considered ‘CNS-positive’.

CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless
of the number of white blood cells (WBCs).

CNS 2: In CSF, presence < 5/µL WBCs and cytospin positive for blasts, or ≥ 5/µL WBCs
but negative by Steinherz/Bleyer algorithm:

CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;
CNS 2b: ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts; and
CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but negative
by Steinherz/Bleyer algorithm (see below).

CNS3: In CSF, presence of ≥ 5/µL WBCs and cytospin positive for blasts and/or clinical
signs of CNS leukemia:

CNS 3a: < 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts;
CNS 3b: ≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer algorithm
(see below);
CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye
involvement or hypothalamic syndrome).

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Method of Evaluating Initial Traumatic Lumbar Punctures:

If the patient has leukemic cells in the peripheral blood and the lumbar puncture is
traumatic and contains ≥ 5 WBC/µL and blasts, the following algorithm should be used to
distinguish between CNS 2 and CNS 3 disease:

CSF WBC > 2X Blood WBC

CSF RBC Blood RBC

A patient with CSF WBC ≥ 5/µL blasts, whose CSF WBC/RBC is 2X greater than the blood
WBC/RBC ratio, has CNS disease at diagnosis. Example: CSF WBC = 60/µL; CSF RBC =
1500/µL; blood WBC = 46000/µL; blood RBC = 3.0 X 106/µL:

60 = 0.04 > 2X 46000 = 0.015

1500 3.0 X 106

Bone Marrow Status:

M1 Marrow: < 5% blasts in a bone marrow aspirate with at least 200 cells counted.

M2 Marrow: 5% - 25% blasts in a bone marrow aspirate with at least 200 cells counted.

M3 Marrow: > 25% blasts in a bone marrow aspirate with at least 200 cells counted.

For initial remission an M1 marrow must be achieved.

Treatment Failure: Failure to achieve the following:

Marrow CNS Testicular
None; patients with persistent
testicular disease will receive
Remission testicular radiation in Block 2 (LR and
End-Block 1 M2 or
(clearance of CSF HR/IR randomized to the control arm)
(All patients) better
blasts, i.e. CNS1) or during Blinatumomab Block: Cycle
1 (HR/IR randomized to the
experimental arm)
End-Block 2, or
End Blinatumomab Continued Remission (clearance of testicular
M1
Block, Cycle 1 remission disease)
(HR/IR only)
NOTE: Patients who achieve remission at end-Block 1 or Block 2 but are no longer in
remission on a subsequent evaluation will be removed from protocol therapy for relapse.

Risk Assessment-End Block 1*:

Low Risk
• Late marrow (≥ 36 months); end-Block 1 MRD < 0.1%
• Late (≥ 18 months) Isolated Extramedullary (IEM),
end-Block 1 MRD < 0.1% (or indeterminate MRD)
Intermediate Risk
• Late (≥ 36 months) marrow, end-Block 1 MRD ≥ 0.1%

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• Late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1%

High Risk
• Early (< 36 months) marrow
• Early (< 18 months) IEM

* The timing of relapse is measured from the date of initial diagnosis to the date of
relapse

Complete Remission
Complete remission (CR) is defined as an M1 marrow (< 5% blasts) with no evidence of
circulating blasts or extramedullary disease and with peripheral count recovery, defined as
absolute neutrophil count higher than or equal to 500/µL and platelet count higher than or
equal to 50,000/µL.

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4.0 TREATMENT PLAN

Timing of protocol therapy administration, response assessment studies, and surgical

interventions are based on schedules derived from the experimental design or on established
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG
administrative Policy 5.14 (except where explicitly prohibited within the protocol).

4.1 Overview of Treatment Plan

All eligible patients with first relapse B-ALL who are enrolled on AALL1331 will receive
standard chemotherapy during Block 1. All patients will then be risk assessed at the end of
Block 1 as either HR, IR, LR or TF. Risk assessment is based on site of relapse, time to
relapse, end Block 1 bone marrow morphology and MRD levels. HR and IR patients will
be eligible to participate in HR/IR Randomization and LR patients will be eligible to
participate in LR Randomization. See summary table below. Treatment failures are those
patients whose disease status fails to meet pre-defined response criteria at end-Block 1 or
end-Block 2. These patients are eligible to receive up to 2 blocks of blinatumomab if they
have not previously received it on study and have no evidence of persistent CNS disease.
These patients will also be eligible to continue on to HSCT if they achieve a CR. Otherwise,
they will be removed from protocol therapy. See Section 3.3 for response definitions of TF
CR.
Risk Stratification at end Block 1
Randomization Treatment Arms
Risk Group Definition
Eligibility
• Early (< 36 months) marrow • Arm A (Control)
High HR/IR
• Early (< 18 months) IEM • Arm B (Experimental)
• Late (≥ 36 months) marrow,
end-Block 1 MRD ≥ 0.1% • Arm A (Control)
Intermediate HR/IR
• Late (≥ 18 months) IEM, • Arm B (Experimental)
end-Block 1 MRD ≥ 0.1%
• Late (≥ 36 months) marrow,
end-Block 1 MRD < 0.1% • Arm C (Control)
Low LR
• Late (≥ 18 months) IEM, • Arm D (Experimental)
End-Block 1 MRD < 0.1%
Failure to achieve the
following:
Treatment
• M2 or better None (treatment • Salvage therapy
Failure at
• CNS remission assignment) (Blinatumomab-S)
end Block 1
(clearance of CSF
blasts, i.e. CNS1)

Hospitalization:
Hospitalization is STRONGLY recommended during the first 3 days of the first
blinatumomab Cycle and the first 2 days of subsequent blinatumomab cycles in case of a
cytokine reaction.

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CNS Leukemia
All patients with CNS3 involvement at the time of relapse will receive intrathecal triples
(ITT) instead of IT MTX. During Block 1 these patients will receive two additional ITT
doses and during Block 2 they will receive one additional ITT dose. For LR patients with
CNS3 involvement, AALL1331 will further intensify CNS-directed therapy by replacing
lower dose oral MTX (25 mg/m2 every 6 hours x 4 doses) with intermediate dose IV MTX
(1 g/m2 over 24 hours) during the each of the 2 continuation phases. All of these patients
will then receive 1800 cGy cranial radiation and concurrent chemotherapy (including high
dose dexamethasone) between and the first and second 12 week blocks of Maintenance. IR
and HR patients will proceed to TBI-based HSCT and these patients will also receive a
protocol-specified cranial radiation boost as part of their HSCT preparative regimen.

Testicular Leukemia
Patients with suspected isolated testicular relapse or equivocal testicular enlargement with
concurrent bone marrow/CNS relapse must have a testicular biopsy performed at baseline.
Patients with persistent or equivocal testicular enlargement at the end of Block 1 must have
a testicular biopsy. Patients with persistent testicular leukemia at the end of Block 1 are
eligible to continue on study and will receive 2400 cGy of testicular radiation during either
Block 2 chemotherapy (for LR patients and HR/IR patients randomized to the control arm)
or during blinatumomab (for HR/IR patients randomized to the experimental arm and TF.)
Patients with extramedullary testicular leukemia that has resolved by end Block 1 will NOT
receive testicular irradiation, with the exception of that which may be used in the HSCT
preparative regimen for HR/IR patients.

HSCT
All patients enrolled on this protocol, their parents and full siblings should undergo
HLA tissue typing as soon as possible after diagnosis of relapse, and should have
transplantation consultation and initiation of a donor search. For HR/IR patients,
and for TF patients who achieve CR with Salvage Therapy (Blinatumomab-S), the
goal of this protocol is to move to transplant within 2 weeks of recovery from the last
block/cycle of therapy prior to transplant. Because unrelated donor acquisition can
take 8-12 weeks, centers must expedite the donor search process to meet this deadline.
Patient Pill Diary
It is recommended that patients use a Patient Pill Diary to keep track of oral medications.

4.1.1 TREATMENT ASSIGNMENTS

IMPORTANT NOTE:
In order to continue to receive protocol therapy, patients will need to
begin post-Block 1 therapy within a specified time frame (see Section
4.2). If a patient has residual severe non-hematologic toxicities from
Block 1 that are likely to preclude beginning post-Block 1 therapy
within this time frame, please DO NOT complete end-Block 1
Callback for the patient. This is important to minimize the number of
patients who are randomized/assigned but are unable to receive post-
callback treatment.

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4.1.1.1 HR/IR Randomization

Following submission of the end-Block 1 callback form HR and IR
patients will be randomized to receive treatment on either of 2 treatment
arms (see Experimental Design Schema):

• Arm A (Control Arm): Patients receive Block 2 and Block 3 of

standard therapy followed by HSCT.

• Arm B (Experimental Arm): Patients receive two 5 week blocks of

Blinatumomab, followed by HSCT.
4.1.1.2 LR Randomization
Following submission of the end-Block 1 callback form LR patients will
be randomized to receive treatment on either of 2 treatment arms (see
Experimental Design Schema):

• Arm C (Control): Patients receive Block 2 and Block 3 of

standard therapy followed by Continuation 1, Continuation 2, and
Maintenance.

• Arm D (Experimental): Patients receive Block 2 of standard

therapy followed by a 5-week Blinatumomab Block, Continuation
1, a 5-week Blinatumomab Block, Continuation 2, a 5-week
Blinatumomab Block, and Maintenance.

4.1.1.3 Salvage Therapy (Blinatumomab-S)

Following submission of the end-Block 1 or End-Block 2 callback form,
eligible Treatment Failure patients will be assigned to Salvage Therapy.

4.1.2 Concomitant Therapy Restrictions

4.1.2.1 Cytochrome P450 Interactions with Antileukemic Drugs.
Since concurrent use of enzyme inducing anticonvulsants (e.g., phenytoin,
phenobarbital, and carbamazepine) with anti-leukemic therapy has
recently been associated with inferior EFS, every effort should be made to
avoid these agents, as well as rifampin, which also induces many drug
metabolizing enzymes.38 Neither gabapentin nor levetiracetam induce
hepatic drug metabolizing enzymes and may be suitable alternative
anticonvulsants. Azole antifungals (listed in the table below) and the
macrolide group of antibiotics (listed in the table below) may have potent
inhibitory effects on drug-metabolizing enzymes. Patients receiving some
anti-leukemic drugs (e.g., vincristine, anthracyclines, etoposide) may
experience excess toxicity when these agents are given concomitantly;
alternate antifungal and antibacterial therapy should be used where
possible (see table below).
DRUGS POTENTIAL ACTION TO BE TAKEN
INTERACTION
Anticonvulsants Induction of drug AVOID phenytoin,
metabolizing enzymes phenobarbital, carbamazepine

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Lowered EFS Consider gabapentin or

levetiracetam as alternative
Rifampin Induction of drug DO NOT USE
metabolizing enzymes
Azole Antifungals Inhibition of drug CONSIDER ALTERNATIVE
(fluconazole, metabolizing enzymes MEDICATIONS
itraconazole*, May need dose reductions of
posaconazole vincristine*, anthracyclines,
voriconazole, etoposide, steroids
ketoconazole)
Macrolide Antibiotics Inhibition of drug CONSIDER ALTERNATIVE
(erythromycin, metabolizing enzymes MEDICATIONS
clarithromycin, May need dose reductions of
azithromycin, vincristine, anthracyclines,
roxithromycin, etoposide, steroids
telithromycin)
* Itraconazole should NOT be used in patients who are receiving vincristine due
to a serious drug-drug interaction leading to severe neurotoxicity.39,40

For a more complete list of CYP3A4/5 Inhibitors and Inducers, go to:

http://medicine.iupui.edu/flockhart/

4.1.2.2 Possible Drug Interactions with Intermediate Dose Methotrexate:

Avoid non-steroidal anti-inflammatory drugs (NSAIDs),
trimethoprim/sulfamethoxazole (TMP/SMX), penicillins, probenecid, IV
contrast media, proton pump inhibitors, phenytoin and fosphenytoin.
Urinary acidifiers can cause methotrexate to precipitate in the urinary tract.
For COG Supportive Care Guidelines see
https://members.childrensoncologygroup.org/prot/reference_materials.asp

4.2 Block 1 (All patients) - 4 Weeks Duration

Block 1 therapy is common to all patients on study. See Experimental Design
Schema. The therapy delivery map (TDM) for Block 1 is in APPENDIX II-A.

4.2.1 Disease Evaluation Pre-Treatment

See Section 7.0, Evaluations/Material and Data to be Accessioned

4.2.2 General Chemotherapy Guidelines

See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy
Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.

Dosing should be based on actual BSA.

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4.2.3 Block 1 Chemotherapy

Dexamethasone: PO (may be given IV)
Days: 1-5, 15-19
Dose: 10 mg/m²/dose (Total daily dose: 20 mg/m²/day, divided BID; dose capped
at 40 mg per day)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Days: 1, 8, 15, 22
Dose: 1.5 mg/m²/dose (maximum dose: 2 mg)

Pegaspargase: IV over 1-2 hours

Days: 3, 17
Dose: 2500 International Units/m²/dose
Administer through the tubing of a rapidly infusing solution of D5W or 0.9%
NaCl

MitoXANTRONE: IV over 15-30 minutes, administered through the tubing of a

rapidly infusing solution of D5W or 0.9% NaCl.
Days: 1, 2
Dose: 10 mg/m²

Methotrexate: Intrathecal (IT) - CNS 1/2 PATIENTS ONLY

Days: 1, 8
Note: For CNS2 patients continue weekly IT until 2 clear CSF samples
(CNS1) are obtained.
Age-based dosing:
Age (yrs) Dose (mg)
1-1.99 8
2-2.99 10
3-8.99 12
≥9 15
Intrathecal Triple Therapy (ITT) - ANY PATIENT WITH CNS3 AT THE
TIME OF RELAPSE
Days 1, 8, 15, and 22.
Age-based dosing:
Age (yrs) Dose (mg)
1 - 1.99 MTX: 8 HC: 8 ARAC: 16
2 - 2.99 MTX: 10 HC: 10 ARAC: 20
3 - 8.99 MTX: 12 HC: 12 ARAC: 24
≥9 MTX: 15 HC: 15 ARAC: 30

4.2.4 Disease Evaluation End Block 1

• The end-Induction evaluation should occur no earlier than Day 29 (± 1 day).

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• The evaluation may be delayed no later than Day 36 (± 1 day) if

ANC < 500/µL and platelets < 50,000/µL on Day 29.
• See Sections 7.1 and 13.0 for details on specimen acquisition, handling and
shipping.

4.2.5 Research Studies Block 1

See Section 7.2 for a full list of research studies.

4.2.6 HLA Tissue Typing for Hematopoietic Stem Cell Transplant

All patients enrolled on this protocol, their parents and full siblings should undergo
HLA tissue typing as soon as possible after diagnosis of relapse, and should have
transplantation consultation and initiation of a donor search. The goal of this
protocol is to initiate transplantation within 2 weeks of recovery from Block 3.
Since unrelated donor acquisition can take 8-12 weeks, centers must expedite the
search process to meet this timeframe.

4.2.7 Evaluation 1 (Risk Assessment following Block 1)

Following completion of Block 1, patients will be risk assessed based on end-
Block 1 criteria outlined in Section 3.3, as HR, IR, LR, or TF.

IMPORTANT NOTE:
In order to continue to receive protocol therapy, patients will need to begin
post-Block 1 therapy within a specified time frame (see below). If a patient
has residual severe non-hematologic toxicities from Block 1 that are likely to
preclude beginning post-Block 1 therapy within this time frame, please DO
NOT complete end-Block 1 Callback for the patient. This is important to
minimize the number of patients who are randomized/assigned but are
unable to receive post-callback treatment.

Post-Block 1 treatment should begin after receipt of risk assignment and

submission of end-Block 1 Callback as soon as clinically acceptable to the treating
institution. Patients should have time for full or partial recovery (judged by the
treating institution) from any toxicities experienced in the prior course(s) of
therapy before proceeding to the next course. However, treatment must begin
according to time frames below for patients to continue to receive protocol
therapy.HR B-ALL or IR B-ALL patients with M1 marrow- Eligible for the
HR/IR Randomization
• For HR/IR B-ALL patients randomized to Arm A, Block 2 (Section 4.3,
APPENDIX II-B) therapy should proceed with Day 1 vincristine and
dexamethasone without awaiting count recovery (no later than 5 days after
callback). It is recommended, but not required, that proceeding with Day 8 IV
methotrexate treatment await count recovery to ANC ≥ 500/µL and platelets
≥ 50,000/µL. Day 8 treatment must begin no later than 14 days after giving the
Day 1 vincristine and dexamethasone to continue to receive protocol therapy.
• For HR/IR B-ALL patients randomized to Arm B, Blinatumomab Block -
Cycle 1 (Section 4.5, APPENDIX II-D) starts when ANC ≥ 500/µL and
platelets ≥ 50,000/µL (awaiting count recovery is recommended, but not

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required). Treatment must begin no later than 14 days after risk assignment for
patient to continue to receive protocol therapy.

HR B-ALL or IR B-ALL patients with M2 marrow- Eligible for the HR/IR

Randomization:
• For HR/IR B-ALL patients randomized to Arm A, Block 2 (Section 4.3,
APPENDIX II-B) starts without awaiting count recovery (no later than 5 days
after callback).
• For HR/IR B-ALL patients randomized to Arm B, Blinatumomab Block -
Cycle 1 (Section 4.5, APPENDIX II-D) starts without awaiting count recovery
(no later than 5 days after callback).

LR B-ALL Eligible for the LR Randomization

• All LR B-ALL patients (Arm C and Arm D) will receive Block 2 therapy
(Section 4.3, APPENDIX II-B) and should proceed with Day 1 vincristine and
dexamethasone without awaiting count recovery (no later than 5 days after
callback). It is recommended, but not required, that proceeding with Day 8 IV
methotrexate treatment await count recovery to ANC ≥ 500/µL and platelets ≥
50,000/µL. Day 8 treatment must begin no later than 14 days after giving the
Day 1 vincristine and dexamethasone to continue to receive protocol therapy.

Treatment failures Post-Block 1 (see Section 3.3. for definition) have the option
to receive up to two 5 week cycles of Blinatumomab (Sections 4.7, 4.8 and
APPENDIX II-F, and II-G respectively) and continue on to HSCT after achieving
CR.
• TF patients with residual CNS disease (CNS2/3) regardless of marrow status
should be removed from protocol therapy.
• TF patients with M3 marrow disease and no residual CNS disease (CNS1)
should proceed to Blinatumomab-S Cycle 1 without awaiting count recovery
(no later than 5 days after callback).

NOTE: If residual non-hematologic toxicities prevent a patient from beginning

post Block-1 treatment within the time frames noted above, then the patient should
be removed from protocol therapy.

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4.3 Block 2 (HR/IR and LR Patients: Post-randomization) – 4 weeks duration

Block 2 therapy is for HR/IR patients, randomized to the control arm (Arm A) and all LR
patients post LR randomization (Arm C and Arm D). See Experimental Design Schema.

The Therapy Delivery Map (TDM) for Block 2 is in APPENDIX II-B.

END-BLOCK 1 CALLBACK OCCURS PRIOR TO STARTING BLOCK 2 THERAPY.

PLEASE SEE SUMMARY TABLE IN SECTION 3.1.5 FOR DETAILS ON STAGED
CONSENT, AND APPROPRIATE TIMING TO OBTAIN INFORMED CONSENT.

4.3.1 Criteria to Begin Block 2 Therapy

Block 2 should begin after receipt of risk assignment and submission of the
appropriate end-Block 1 Callback as soon as clinically acceptable to the treating
institution. Patients should have time for full or partial recovery (judged by the
treating institution) from any toxicities experienced in the prior course(s) of
therapy before proceeding to the next course. To continue to receive protocol
therapy, however, Block 2 must begin no later than 5 days after callback. Count
recovery is not required to proceed to Block 2.

4.3.2 Testicular Radiation Therapy (TRT)

Patients with persistent testicular leukemia at the end of Block 1 are eligible to
continue on study and will receive 2400 cGy of testicular radiation during either
Block 2 chemotherapy (HR/IR patients randomized to the control arm, and all LR
patients) or during the first cycle of Blinatumomab (for HR/IR patients randomized
to the experimental arm).
• Patients with extramedullary testicular leukemia that has resolved by end
Block 1 will NOT receive testicular irradiation with the exception of that
which may be used in the HSCT preparative regimen.
• See Section 14.2 for detailed testicular radiation guidelines

4.3.3 General Chemotherapy Guidelines

See Section 6.0, Drug Information, and the Parenteral and Oral Chemotherapy
Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.
Dosing should be based on actual BSA.

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4.3.4 Block 2 Chemotherapy

Dexamethasone: PO (may be given IV)
Days: 1-5
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Day: 1
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Intermediate Dose Methotrexate (ID MTX): IV over 36 hours

Day: 8
Dose: 1000 mg/m²/dose
Given as a 100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over
35.5 hours.
Be certain that the ID MTX infusion is completed in the 36 hour period. Even if
the infusion is not complete at this time point, it must be stopped.
Leucovorin rescue: See below.
Suggested hydration and alkalinization for IDMTX: Prehydrate with D5 ¼ NS
with 30 mEq NaHCO3/L at 125 mL/m2/hour to achieve a urine specific gravity ≤
1.010 and pH between 7 and 8. Ringers Lactate may be bused as the initial fluid
if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium
bicarbonate to maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A
bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH
relatively quickly; a normal saline bolus may also be helpful in facilitating
hydration. Continue hydration using D 5 ¼ NS with 30 mEq NaHCO3/L at
125 mL/m2/hour throughout IDMTX infusion after its completion until the last
dose of leucovorin has been given.

Timing of ID MTX:
• For patients beginning Block 2 with M1 marrow, it is recommended to await
count recovery to an ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to
beginning Day 8 IV methotrexate.
• Patients beginning Block 2 with M2 marrow should proceed without awaiting
count recovery.
• To continue to receive protocol therapy, all patients must begin Day 8 IV
methotrexate no later than 14 days after risk assignment.

Leucovorin: PO/IV
Day: 10, 11
Dose: 15 mg/m2/dose every 6 hours beginning 48 hrs after the START of ID
MTX infusion.
• If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two
doses of leucovorin (48 and 54 hours).

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• If MTX level at 48 hours is > 0.5 μM, then continue hydration and
leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours until MTX
levels are < 0.1 μM.
See Section 5.8 for ID MTX/LCV rescue and infusion guidelines.

Methotrexate: Intrathecal (IT) – CNS1/2 PATIENTS ONLY

Day: 8
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg
When IT therapy and ID MTX are scheduled for the same day, deliver the IT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Days: 8, 22
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
2 to < 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
3 to < 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
≥9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg
When ITT therapy and ID MTX are scheduled for the same day, deliver the ITT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).

Pegaspargase: IV over 1-2 hours

Administer 4 hours after completion of Day 8 IV MTX. (Day 9 or 10)
Dose: 2500 International Units/m2/dose

Cyclophosphamide: IV over 15-30 minutes (see note below)

Days: 15-19
Dose: 440 mg/m²/dose
Etoposide: IV over 1-2 hours (see note below)
Days: 15-19
Dose: 100 mg/m²/dose
NOTE: Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior
to beginning Day 15 IV cyclophosphamide and etoposide.

4.3.5 Evaluation 2 (Disease Evaluation End Block 2)

• Evaluation 2 should not be done earlier than Day 29 (± 1 day);
• The evaluation may be delayed no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.

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• See Sections 7.1 and 13.0 for details on specimen acquisition, handling and
shipping.

4.3.6 Following Completion of Block 2:

a. HR/IR B-ALL patients post-Block 2:
For HR/IR B-ALL patients randomized to Arm A, Block 3 (Section 4.4,
APPENDIX II-C) starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL.

b. HR/IR B-ALL Treatment Failures post-Block 2:

TF patients (see Section 3.3 for definition) have the option to receive up to two
5 week cycles of Blinatumomab (Sections 4.7, 4.8, and APPENDICES II-F
and II-G respectively) and continue on to HSCT after achieving CR on
Salvage Therapy (Blinatumomab-S) treatment arm. Eligible patients should
complete End-Block 2 callback before initiating Salvage Therapy treatment.
*HR/IR patients who are considered to be in relapse at end Block 2 are
removed from protocol therapy (see Section 3.3 for definition)

c. For LR B-ALL patients post-Block 2:

• Arm C, Block 3 (Section 4.4, APPENDIX II-C) starts when ANC ≥
500/µL and platelets ≥ 50,000/µL.
• Arm D, therapy with Blinatumomab Block Cycle 1 (Section 4.7,
APPENDIX II-M) starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL.

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4.4 Block 3 (HR/IR Patients on Arm A; LR Patients on Arm C) - 4 weeks

Block 3 therapy is for all HR/IR patients randomized to the control arm (Arm A), and LR
patients randomized to the control arm (Arm C). See Experimental Design Schema.

The Therapy Delivery Map (TDM) for Block 3 is in APPENDIX II-C.

4.4.1 Criteria to Begin Block 3 Therapy

Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL

4.4.2 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.
Dosing should be based on actual BSA.

4.4.3 Block 3 Chemotherapy

Dexamethasone: PO (may be given IV)
Days: 1-5
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Day: 1
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Cytarabine: IV over 3 hours

Days: 1, 2, 8, 9
Dose: 3000 mg/m2/dose Q12H
Administer steroid eye drops (0.1% dexamethasone or 1% prednisolone
ophthalmic solution), 2 drops to each eye every 6 hours, beginning
immediately before the first dose of cytarabine and continuing for 24 hours
after the last dose. If patient does not tolerate steroid eye drops, may
administer artificial tears on an every 2-4 hour schedule.

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Erwinia L-asparaginase: IM (may be given IV)

Day: 2, 4, 9, 11, 23
Dose: 25, 000 International Units/m2/dose
• Erwinia asparaginase should be given 4 hours after the last cytarabine
infusion on Days 2 and 9.
• Erwinia asparaginase should be given 4 hours after the MTX infusion is
complete on Day 23.
• If Erwinia asparaginase is not available, a single dose of Pegaspargase should
be substituted 4 hours after the last cytarabine dose is complete on Day 9, and
no asparaginase is given on Day 23.

Methotrexate: Intrathecal (IT)

Day: 1 FOR ALL PATIENTS
Day 22: CNS1/2 PATIENTS ONLY
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg
When IT therapy and ID MTX are scheduled for the same day, deliver the IT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).
NOTE: Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior
to beginning Day 22 IV Methotrexate and intrathecal chemotherapy.

Triple Intrathecal Therapy (ITT) -

CNS3 PATIENTS ONLY
Day: 22
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg HC: 8 mg ARAC: 16 mg
2 to < 2.99 MTX: 10 mg HC: 10 mg ARAC: 20 mg
3 to < 8.99 MTX: 12 mg HC: 12 mg ARAC: 24 mg
≥9 MTX: 15 mg HC: 15 mg ARAC: 30 mg
When IT therapy and ID MTX are scheduled for the same day, deliver the IT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).

Intermediate Dose Methotrexate: IV over 36 hours

Day: 22
Dose 1000 mg/m²/dose
See Sections 4.3.4 and 5.8 for ID MTX/LCV rescue and infusion guidelines

Leucovorin: PO/IV
Days: 24, 25
Dose: 15 mg/m2/dose beginning 48 hrs after the START of ID MTX infusion.

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• If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two doses of
leucovorin (48 and 54 hours).
• If MTX level at 48 hours is > 0.5 μM, then continue hydration and leucovorin
rescue at 15 mg/m2/dose po/IV every 6 hours until MTX levels are < 0.1 μM.
See Section 5.8 for ID MTX/LCV rescue and infusion guidelines.

4.4.4 Disease Evaluation End Block 3 (HR/IR Patients ONLY):

• The End Block 3 disease evaluation should not be done earlier than Day 29 (±
1 day);
• The evaluation may be delayed no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.
• See Sections 7.1 and 13.0 for details on specimen acquisition, handling and
shipping.
Notes regarding End Block 3 Disease Assessment:
• BM assessment should be coordinated so that patients begin their preparative
regimens no later than 2 weeks from BM documentation of M1.
• If delays > 14 days are required for donor timing or other reasons, patients may
receive up to 6 weeks of bridging maintenance therapy as described in Section
4.10.
• For patients who receive bridging therapy, a repeat BM assessment is required
to document remission and MRD status within 14 days of starting the HSCT
preparative regimen.
• Patients who are unable to begin the transplant preparative regimen within 8
weeks of initial BM assessment are off protocol therapy.

4.4.5 Following completion of Block 3:

a. HR/IR B-ALL patients:
Arm A, should proceed to HSCT as soon as possible after count recovery
(ANC ≥ 500/µL and platelets ≥ 50,000/µL). See Section 4.9. Patients may
receive up to 6 weeks of bridging maintenance therapy prior to HSCT as
described in Section 4.10.

b. For LR B-ALL patients:

Arm C, Continuation 1 (Section 4.11, APPENDIX II-I) starts when ANC
≥ 500/µL and platelets ≥ 50,000/µL.

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4.5 Blinatumomab Block: Cycle 1 (HR/IR Patients in Arm B) - 5 weeks

The therapy described in this section is for the 1st cycle of therapy with Blinatumomab in
the HR/IR randomization. See Experimental Design Schema.
The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 1 (Arm B) is in
APPENDIX II-D.
NOTE: Hospitalization is STRONGLY recommended during the first 3 days of this
cycle in case of a cytokine reaction.
END BLOCK 1 CALLBACK OCCURS PRIOR TO STARTING BLINATUMOMAB
BLOCK: CYCLE 1 THERAPY. PLEASE SEE SUMMARY TABLE IN SECTION 3.1.5
FOR DETAILS ON STAGED CONSENT, AND APPROPRIATE TIMING TO OBTAIN
INFORMED CONSENT.

4.5.1 Criteria to Begin Blinatumomab Block: Cycle 1

Blinatumomab Cycle 1 should begin after receipt of risk assignment and
submission of end- Block 1 Callback as soon as clinically acceptable to the treating
institution. Patients should have time for full or partial recovery (judged by the
treating institution) from any toxicities experienced in the prior course(s) of
therapy before proceeding to the next course.

For patients beginning Blinatumomab Cycle 1 with M1 marrow, it is

recommended to await count recovery to ANC ≥ 500/µL and
platelets ≥ 50,000/µL. To continue to receive protocol therapy, M1 patients must
begin Blinatumomab Cycle 1 no later than 14 days after risk assignment.

For patients beginning Blinatumomab Cycle 1 with M2 marrow, it is

recommended to proceed without awaiting count recovery. To continue to receive
protocol therapy, M2 patients must begin Blinatumomab Cycle 1 no later than 5
days after Callback.

4.5.2 Testicular Radiation Therapy (TRT)

• Patients with persistent testicular leukemia at the end of Block 1 are eligible
to continue on study and will receive 2400 cGy of testicular radiation during
the 1st cycle of Blinatumomab (for HR/IR patients randomized to the
experimental arm).
• Patients with extramedullary testicular leukemia that has resolved by end-
Block 1 will NOT receive testicular irradiation with the exception of that
which may be used in the HSCT preparative regimen.
• See Section 14.2 for detailed testicular radiation guidelines.

4.5.3 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

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See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

Dosing should be based on actual BSA. There is no maximum dosing

4.5.4 Blinatumomab Block: Cycle 1 Chemotherapy
Blinatumomab: IV; Continuous Infusion over 28 days*
Days: 1-28
Dose: 15 micrograms/m²/day
* IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Day: 1
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours prior
to initiation of the blinatumomab infusion.
• A single dose of 5 mg/m2/dose will be administered within 30 minutes
prior to the start of the blinatumomab infusion
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed
Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY
Day: 15, 29
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Days: 15, 29
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
2 to < 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
3 to < 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
≥9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg

4.5.5 Disease Evaluation End-Blinatumomab Block: Cycle 1

• The end block disease staging should be performed no earlier than Day 29 (±
1 day);
• The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.

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• Two (2 mL) of bone marrow will be collected and shipped to the flow
cytometry laboratory for MRD determination
• See Sections 7.1 and 13.0 for details on specimen handling and shipping.

4.5.6 Following completion of Blinatumomab Block: Cycle 1 (Arm B)

a. For HR/IR B-ALL patients randomized to Arm B:
Blinatumomab Block Cycle 2 (Section 4.6, APPENDIX II-E) starts when
ANC ≥ 500/µL and platelets ≥ 50,000/µL.
b. Treatment Failures post-Blinatumomab Block:
Patients with a TF post Blinatumomab Block: Cycle 1 (see Section 3.3. for
definition) will be taken off protocol therapy.

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4.6 Blinatumomab Block: Cycle 2 (HR/IR Patients in Arm B) - 5 weeks

The therapy described in this section is for the 2nd cycle of therapy with blinatumomab on
Arm B. See Experimental Design Schema.

The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 2 (Arm B) is in
APPENDIX II-E.

NOTE: Hospitalization is STRONGLY recommended during the first 2 days of this

cycle in case of a cytokine reaction.

4.6.1 Criteria to Begin Blinatumomab Block: Cycle 2

• Do not start Blinatumomab Cycle 2 before Day 36 after beginning of Cycle 1.
• Begin Blinatumomab Block: Cycle 2 therapy when ANC ≥ 500/µL and
platelets ≥ 50,000/µL.

4.6.2 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

Dosing should be based on actual BSA.

4.6.3 Blinatumomab Block: Cycle 2 Administration Guidelines

Blinatumomab: IV; Continuous Infusion over 28 days*
Days: 1-28
Dose: 15 micrograms/m²/day
* IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Day: 1
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours
prior to initiation of the blinatumomab infusion.
• A single dose of 5 mg/m2/dose will be administered within 30 minutes
prior to the start of the blinatumomab infusion

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If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY

Days: 8, 29
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Days: 8, 29
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg HC: 8 mg ARAC: 16 mg
2 to < 2.99 MTX: 10 mg HC: 10 mg ARAC: 20 mg
3 to < 8.99 MTX: 12 mg HC: 12 mg ARAC: 24 mg
≥9 MTX: 15 mg HC: 15 mg ARAC: 30 mg
4.6.4 Disease Evaluation End-Blinatumomab Block: Cycle 2
• The end block disease staging should be performed no earlier than Day 29 (±
1 day);
• The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.
• Two (2 mL) of bone marrow will be collected and shipped to the flow
cytometry laboratory for MRD determination
• See Sections 7.1 and 13.0 for details on specimen handling and shipping.

Notes regarding End Block 3 Disease Assessment:

• BM assessment should be coordinated so that patients begin their preparative
regimens no later than 2 weeks from BM documentation of M1.
• If delays > 14 days are required for donor timing or other reasons, patients may
receive up to 6 weeks of bridging maintenance therapy as described in Section
4.10.
• For patients who receive bridging therapy, a repeat BM assessment is required
to document remission and MRD status within 14 days of starting the HSCT
preparative regimen.
• Patients who are unable to begin the transplant preparative regimen within 8
weeks of initial BM assessment are off protocol therapy.

4.6.5 Following completion of Blinatumomab Block: Cycle 2 (Arm B):

• Patients will continue on to HSCT (See Section 4.9).Patients may receive up
to 6 weeks of bridging maintenance therapy prior to HSCT as described in
Section 4.10.
• Treatment Failures post-Blinatumomab Block: Cycle 2 (see Section 3.3. for
definition) will be taken off protocol therapy.

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4.7 Blinatumomab-S: Cycle 1 (Salvage Therapy) - 5 weeks

Patients classified as treatment failures after Block 1 or Block 2 treatment (see Section 3.3
for definitions) who have not previously received blinatumomab on study and who are
without evidence of CNS disease will have the option to be non-randomly assigned
treatment with up to 2 blocks of salvage blinatumomab (Blinatumomab-S), and continue
on study with HSCT therapy if a CR is achieved. Eligible patients should complete the
appropriate callback (Section 3.1.7) before initiating Salvage Therapy treatment. Note that
blinatumomab dosing in Blinatumomab-S cycles differs from dosing in
Blinatumomab Block cycles (See Section 4.7.4.) The schedule below describes treatment
for the 1st cycle only. See Experimental Design Schema.

The Therapy Delivery Map (TDM) for the Blinatumomab-S: Cycle 1 is in

APPENDIX II-F.

NOTE: Hospitalization is STRONGLY recommended during the first 3 days of this

cycle in case of a cytokine reaction.

OBTAIN INFORMED CONSENT PRIOR TO INITIATING THE FIRST CYCLE OF

SALVAGE THERAPY. PLEASE SEE THE SUMMARY TABLE IN SECTION 3.1.5
FOR DETAILS ON TIMING TO OBTAIN INFORMED CONSENT. CALLBACK
OCCURS PRIOR TO STARTING BLINATUMOMAB-S: CYCLE 1 THERAPY (See
Section 3.1.7 for appropriate callback).

4.7.1 Criteria to Begin Blinatumomab-S: Cycle 1

• None

4.7.2 Testicular Radiation Therapy (TRT)

• All Treatment Failures on the basis of M3 marrow at the end of Block 1 who
also have persistent testicular leukemia will receive 2400 cGy of testicular
radiation during the 1st cycle of Salvage Therapy (Blinatumomab-S: Cycle 1).
• Patients with extramedullary testicular leukemia that has resolved by end
Block 1 will NOT receive testicular irradiation with the exception of that
which may be used in the HSCT preparative regimen for HR/IR patients.
• See Section 14.2 for detailed radiation guidelines.

4.7.3 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

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Dosing should be based on actual BSA.

4.7.4 Blinatumomab-S: Cycle 1 Chemotherapy Guidelines

Blinatumomab: IV; Continuous Infusion over 28 days*
Days: 1-28
Dose: 5 micrograms/m²/day (Days 1-7) followed by 15 micrograms/m²/day
(Days 8-28)
* IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours
prior to initiation of the blinatumomab infusion.
• A single dose of 5 mg/m2/dose will be administered within 30 minutes
prior to the start of the blinatumomab infusion
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

Methotrexate: Intrathecal (IT)

Day: 15
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

4.7.5 Disease Evaluation End Blinatumomab-S Cycle 1:

• The end block disease staging should be performed no earlier than Day 29 (±
1 day);
• The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.
• Two (2 mL) of bone marrow will be collected and shipped to the flow
cytometry laboratory for MRD determination
• See Sections 7.1 and 13.0 for details on specimen handling and shipping.

4.7.6 Following completion of Blinatumomab-S: Cycle 1:

a. Patients with M1 marrow after Blinatumomab-S Cycle 1:
• If patient has recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL (i.e., have achieved a CR), then proceed to HSCT
on study as soon as possible. See Section 4.9.
• If patient has NOT recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL at the time of the marrow evaluation, but recovers
counts within 1 week of the marrow evaluation, then this will be

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considered a CR and the patient should proceed to HSCT as soon as

possible.
• If patient has NOT recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL at the time of the marrow evaluation, and does NOT
recover counts within 1 week of the marrow evaluation, a repeat marrow
every 1-2 weeks until either patient meets definition of CR (in which case
the patient may proceed to HSCT) or develops an M2/M3 marrow (in
which case proceed as detailed in Section 4.7.6.b).
• Patients should begin their preparative regimens no later than 2 weeks
from BM documentation of M1.
• If patient achieves a CR but delays > 14 days are required for donor timing
or other reasons, patients may receive Blinatumomab-S Cycle 2 as
described in Section 4.8 or up to 6 weeks of bridging maintenance therapy
as described in Section 4.10.
• For patients who receive bridging therapy, a repeat BM assessment will
be needed to document remission and MRD status within 14 days of
starting the HSCT preparative regimen.
• Patients who are unable to begin the transplant preparative regimen within
8 weeks of initial BM assessment are off protocol therapy.
b. Patients with M2/M3 marrow after Blinatumomab-S: Cycle 1
Such patients proceed to Blinatumomab-S: Cycle 2 (Section 4.8, APPENDIX
II-G) without awaiting count recovery.

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4.8 Blinatumomab-S: Cycle 2 (Salvage Therapy) - 5 weeks

Blinatumomab-S: Cycle 2 is for patients with M2/M3 marrow after completion of
Blinatumomab-S: Cycle 1. Patients who are M1 after completion of Blinatumomab-S:
Cycle 1 and have delays >14 days before initiating HSCT may also receive treatment on
Blinatumomab-S: Cycle 2 (See Section 4.7.6). Note that blinatumomab dosing in
Blinatumomab-S cycles differs from dosing in Blinatumomab Block cycles (See
Section 4.8.3.)

The schedule below describes treatment for the 2nd cycle only. See Experimental Design
Schema.

The Therapy Delivery Map (TDM) for the Blinatumomab-S: Cycle 2 is in APPENDIX II-
G.

NOTE: Hospitalization is STRONGLY recommended during the first 2 days of this

cycle in case of a cytokine reaction.

4.8.1 Criteria to Begin Blinatumomab-S: Cycle 2

Do not start Blinatumomab-S: Cycle 2 before Day 36 after beginning of Cycle 1.

4.8.2 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

Dosing should be based on actual BSA.

4.8.3 Blinatumomab-S: Cycle 2 Chemotherapy

Blinatumomab: IV; Continuous Infusion over 28 days*

Days: 1-28
Dose: 15 micrograms/m²/day (Days 1-28)
* IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours prior
to initiation of the blinatumomab infusion.

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• A single dose of 5 mg/m2/dose will be administered within 30 minutes

prior to the start of the blinatumomab infusion
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

Methotrexate: Intrathecal (IT)

Day: 8 & 29
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

4.8.4 Disease Evaluation End-Blinatumomab-S: Cycle 2

• The end block disease staging should be performed no earlier than Day 29 (±
1 day);
• The evaluation may be delayed to no later than Day 36 (± 1 day) if ANC
< 500/µL and platelets < 50,000/µL on Day 29.
• Two (2 mL) of bone marrow will be collected and shipped to the flow
cytometry laboratory for MRD determination
• See Sections 7.1 and 13.0 for details on specimen handling and shipping.

4.8.5 Following completion of Blinatumomab-S: Cycle 2:

a. Patients with M1 marrow after Blinatumomab-S Cycle 2:
• If patient has recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL (i.e., have achieved a CR), then proceed to HSCT
on study as soon as possible. See Section 4.9.
• If patient has NOT recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL at the time of the marrow evaluation, but recovers
counts within 1 week of the marrow evaluation, then this will be
considered a CR and the patient should proceed to HSCT as soon as
possible.
• If patient has NOT recovered counts to ANC ≥ 500/µL and
platelets ≥ 50,000/µL at the time of the marrow evaluation, and does NOT
recover counts within 1 week of the marrow evaluation, a repeat marrow
every 1-2 weeks until either patient meets definition of CR (in which case
the patient may proceed to HSCT) or develops an M2/M3 marrow (in
which case proceed as detailed in Section 4.8.6.b).
• Patients should begin their preparative regimens no later than 2 weeks from
BM documentation of M1.
• If patient achieves CR but delays > 14 days are required for donor timing
or other reasons, patients may receive up to 6 weeks of bridging
maintenance therapy as described in Section 4.10.

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• For patients who receive bridging therapy, a repeat BM assessment will be

needed to document remission and MRD status within 14 days of starting
the HSCT preparative regimen.
• Patients who are unable to begin the transplant preparative regimen within
8 weeks of initial BM assessment are off protocol therapy.

b. Patients with M2/M3 marrow after Blinatumomab-S Cycle 2

Remove from protocol therapy.

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4.9 Hematopoietic Stem Cell Transplant

All transplants performed on COG trials must occur at COG-accredited HSCT programs with
the exception of adolescents/adults being treated on COG trials who are referred to an adult
transplant facility. See the COG Administrative Policy 3.3 regarding the agreement
requirements for these cases.
4.9.1 Overview
Stem cell transplantation in this study will be utilized in patients with HR/IR
relapse ALL (see Section 3.3 for risk definitions).

All patients enrolled on this protocol and their full siblings should undergo
HLA tissue typing as soon as possible after diagnosis of relapse. All high-risk
patients should have transplantation consultation and initiation of a donor
search early while undergoing their initial Block 1 therapy. It is recommended
that all intermediate-risk patients also undergo transplantation consultation
as soon as possible after Block 1 therapy, so that a donor search can be
initiated immediately if they are noted to be MRD+ after initial induction. The
goal of this protocol is to move to transplantation within 2 weeks of recovery
from the final consolidation cycle or completion of Salvage Therapy
(Blinatumomab-S). As unrelated donor acquisition can take 8-12 weeks, to
meet this deadline centers must expedite the search process. Please see Section
7.1c for details of required evaluations.
Patients going on to HSCT will undergo an extensive pre-transplant
evaluation to assess remission status, assure adequate organ system function,
and document freedom from active viral, bacterial, and fungal infection.
Patients should begin their preparative regimen no later than 2 weeks after
obtaining the BM aspiration scheduled after recovery from their final
consolidation cycle or completion of Salvage Therapy (Blinatumomab-S). If
transplantation is delayed by 14 days for donor timing or other reasons,
patients may receive up to 6 weeks of bridging maintenance therapy as
described in Section 4.10, Appendix II-H. For patients who receive bridging
therapy, a repeat BM assessment will be needed to document remission and
MRD status within 14 days of starting the HSCT preparative regimen.
Patients who are unable to begin the transplant preparative regimen within 8
weeks of initial BM assessment are off protocol therapy.
Patients will receive 1 of 3 designated preparative regimens
(cyclophosphamide/total body irradiation (TBI) [cy/TBI] alone or with thiotepa or
etoposide). Fludarabine will be added to cy/TBI for cord blood recipients. GVHD
prophylaxis varies slightly according to stem cell source.
Patients who are high risk for relapse (MRD+ pre-HSCT with no evidence of
GVHD by Day +55, or with + MRD post BMT) are eligible for early taper of
immune suppression. The intent of the protocol will be for patients to undergo TBI-
based myeloablative conditioning. If patients are not eligible for a myeloablative
regimen and either do not undergo HSCT or undergo a reduced intensity
procedure, limited data will be collected regarding post transplant survival and
relapse.

In the recent COG ASCT0431 trial some variability was allowed in lung shielding
with total body irradition. Review of ASCT0431 data showed that lung irradiation

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doses above 800 cGy were significantly associated with an increased risk of
treatment-related mortality and relapse, largely due to toxicity (Pulsipher and Lu,
unpublished data November 2014). Accordingly, AALL1331 mandates lung
shielding with total body irradiation to limit the lung dose to less than 800 cGy
(See Section 14.0 for Radiation Therapy Guidelines).

4.9.1.1 Eligibility Criteria for Hematopoietic Stem Cell Transplant (HSCT)

Patients who have an appropriately matched stem cell source (see Section
4.9.1.5) and who meet one of the following criteria:

1. Patients with HR relapse:

• Early (< 36 months) marrow
• Early (< 18 months) IEM
2. Patients with IR relapse with persistent MRD:
• Late (≥ 36 months) marrow, end-Block 1 MRD ≥ 0.1%
• Late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1%
3. Patients with treatment failure (TF) who achieve a CR after receiving
blinatumomab.

NOTE: Patients must maintain an M1 marrow (< 5% blasts) through

the BM assessment prior to transplant. (Patients who achieve a
remission and relapse prior to HSCT can go to HSCT later, but as they
have met a study endpoint (relapse), this procedure will be as per
center preference and the patient will only be followed for survival.)

4.9.1.2 Exclusion Criteria for Hematopoietic Stem Cell Transplant (HSCT)

Interval development of significant pathology that would preclude HSCT
including the following infectious and organ system pathologies:

1. Infections
Patients with uncontrolled fungal, bacterial or viral infections are
excluded.
Patients acquiring fungal disease during induction therapy may
proceed if they have a significant response to antifungal therapy with
no or minimal evidence of active disease remaining by CT evaluation.

2. Organ Function Requirements for HSCT

Must meet the criteria for renal, biliary and cardiac function as
outlined in Section 3.2.4. In addition, must have adequate pulmonary
function defined as anFEV1, FVC, and DLCO (corrected for Hgb) ≥
60% by pulmonary function tests (PFTs).

For children who are unable to cooperate for PFTs, the criteria are: no
evidence of dyspnea at rest, no exercise intolerance, and not requiring
supplemental oxygen therapy.

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3. Performance Status
Patients must have a performance status corresponding to ECOG
scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients ≤ 16 years of age. Please refer to performance
status scale at:
https://members.childrensoncologygroup.org/_files/protocol/Standar
d/PerformanceStatusScalesScoring.pdf

4.9.1.3 Eligibility for Accelerated Taper of Immune Suppression

a. Patients who are MRD+ (≥ 0.01%) within 2 weeks of beginning HSCT
preparative regimen who do not have any evidence of aGVHD by Day
+55 post HSCT (pre-MRD+ group)

b. Patients who are MRD- (< 0.01%) within 2 weeks of beginning HSCT
preparative regimen but are found to be MRD+ (≥ 0.01%) on peri-
engraftment (Day +28-55) or Day +100 marrow who do not have any
evidence of aGVHD by Day +55 (peri-engraftment group) or Day
+100 (Day +100 group)

4.9.1.3.1 Adjustment of TBI/chemotherapy During the Preparative Regimen.

The full dose of preparative regimen TBI and chemotherapy agents will
be administered unless patients have a life threatening reaction thought
likely to occur again with continued administration and an appropriate
substitution cannot be made (i.e. etopophos for etoposide).

4.9.1.4 Dose Adjustment of Chemotherapy for Patients Whose Weight Exceeds

> 125% Ideal Body Weight (IBW)
Chemotherapy given during the preparative regimen (thiotepa,
cyclophosphamide, and etoposide) will be dosed based on actual weight
for patients ≤ 125% IBW. Those > 125% IBW will be dosed based upon
adjusted ideal body weight as follows:
Adjusted ideal body weight = IBW + 0.25 (Actual weight – IBW).
The following formulas for pediatric and adult IBW calculations are
recommended, but IBW may be calculated according to institutional
standard operating procedures (SOPs).

Recommended Ideal Body Weight Calculation for Children Age 1- 17

years

IBW = Height (cm)2 x 1.65

1000
Recommended Ideal Body Weight Calculation for Adults (Height >5
feet/60 inches)
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg
IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg

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4.9.1.5 Stem Cell Source Requirements

Molecular typing at high resolution of HLA A, B, C, and DRB1 is
required, and DQB1 suggested, for all bone marrow or peripheral blood
stem cell (PBSC) donors who are either unrelated or related but not
matched siblings (i.e. matched parent, partially mismatched sibling, etc.).
For matched sibling donors and cord blood units, intermediate level
matching of class I antigens is acceptable, but allele level typing is
required for DRB1 and encouraged for class I antigens and DQB1.
Hierarchy of stem cell choices is as follows:
1) Preferred: Genotypically HLA matched siblings
2) If genotypically matched sibling is not available, the following are
equally acceptable:
a) Unrelated or “other” related (non-genotypically matched)
donors must be matched at 8/8 or 7/8 alleles (HLA-A, B, C and
DRB1 at high resolution).
b)Unrelated Cord blood units must be matched at 4/6, 5/6, or 6/6
antigens (HLA A, B [intermediate), and DRB1 [high resolution]).
Published data show lower non-relapse mortality when patients
receive units matched at 8/8, 7/8, or 6/8 alleles (HLA-A, B, C and
DRB1 at high resolution), therefore allele-level typing is strongly
encouraged. Use of cords matched at 5/8 or 4/8 alleles leads to more
TRM, but are acceptable if better matches are not available. It is
recommended that units matching at the 3/8 allele level be avoided
if possible. Minimum pre-thaw cell dose of 3x107 nucleated cells/kg
recipient weight is required. Two cords may be used if this cell dose
is not achieved with a single unit. The two units must each match
the recipient at a minimum of 4/6 antigens and must match each
other at a minimum of 3/6 antigens.
NOTE: Centers using unlicensed cord blood must consent the
patient on the NMDP cord blood IND protocol or other cord blood
IND protocols as appropriate in order to use such units on this study
3) Use of Peripheral Blood Stem Cells (PBSC)
Bone marrow should be requested from allogeneic donors. PBSC is
allowed only if the donor is unable or unwilling to give marrow.
4.9.1.5.1 Recommended minimum cell doses:
HPC-M cell dose should be at least 1 x 108 TNC/kg
HPC-A cell dose should be at least 2 x 106 CD34/kg
4.9.1.6 Preparative Regimens
Preparative regimens allowed on this protocol are standard regimens used
in ASCT0431 for related and unrelated BM/PBSC recipients and BMT
CTN 0501 for cord blood recipients. ASCT0431 designated TBI
1200cGy/thiotepa/cyclophosphamide, but also allowed a variation
substituting VP-16 for thiotepa and a second variation substituting a
slightly higher TBI dose (1320cGy) for thiotepa. BMT CTN 0501 used
TBI 1320/cyclophosphamide/fludarabine for all patients.

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4.9.2 Preparative Regimen Administration

4.9.2.1 TBI Administration

Fractionated TBI will be administered according to protocol guidelines
(see Section 14.5 for radiotherapy guidelines). TBI may be delivered from
either linear accelerator or Cobalt sources.

4.9.2.2 Thiotepa Administration (for centers choosing the thiotepa-containing

regimen).
• Thiotepa will be administered intravenously. To minimize skin
toxicity, frequent bathing (minimum 2-3x daily) is required on the
days of thiotepa administration as per center standard.
• See above for dose modification if weight exceeds 125% of IBW

4.9.2.3 Cyclophosphamide Administration

• Cyclophosphamide will be administered intravenously.
• Hyperhydration and maintenance of significant urine output after
administration is required. Mesna administration is encouraged, but
not required.
• Recommended mesna dosing: 360 mg/m2 during cyclophosphamide
followed by 120 mg/m2/hour for 24 hours after each dose. Institutional
standards or protocols for mesna administration may also be used.
• See above for dose modification if weight exceeds 125% of IBW

4.9.2.4 Etoposide Administration (for centers choosing etoposide regimen)

• Patients should be given 1.5X maintenance fluids during etoposide
administration to minimize the risk of hypotension.
• Etopophos substitution is allowed.
• See above for dose modification if weight exceeds 125% of IBW

4.9.2.5 Fludarabine Administration

• Fludarabine will be administered over 30-60 minutes each day.
• Fludarabine will not be adjusted for body weight.

4.9.3 Preparative Regimen Administration Tables

4.9.3.1 TBI 1200/thiotepa/cyclophosphamide Regimen (related and unrelated

BM/PBSC)
Treatment Route Dose Days Notes
TBI 200 cGy BID Day -8, -7, & -6 May deliver
1200 cGy
fractionated TBI
over 4 days per
center preference
Thiotepa IV 5 mg/kg/day Day -5 & -4
Cyclophosphamide IV 60 mg/kg/day Day -3 & -2
Rest Day -1
Infusion of Day 0
allogeneic HSCT

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4.9.3.2 TBI 1200/etoposide/cyclophosphamide Regimen (related and unrelated

BM/PBSC)
Drug/Treatment Route Dose Days Notes
TBI 200 cGy BID Day -7, -6, & -5 May deliver
1200 cGy
fractionated TBI
over 4 days per
center preference
Etoposide IV 1500 mg/m2 Day -4
Cyclophosphamide IV 60 mg/kg/day Day -3 & -2
Rest Day -1
Infusion of Day 0
allogeneic HSCT

4.9.3.3 TBI 1320/cyclophosphamide Regimen (related and unrelated BM/PBSC)

Treatment Route Dose Days Notes
TBI 165 cGy BID Day -7, -6, -5, & -4 Total dose
must be
1320 cCy
Cyclophosphamide IV 60 mg/kg/day Day -3 & -2
Rest Day -1
Infusion of Day 0
allogeneic HSCT

4.9.3.4 TBI 1320/fludarabine/cyclophosphamide Regimen (related and unrelated

cord blood)
Treatment Route Dose Days Notes
Fludarabine IV 25 mg/m2/day Day -10, -9, -8
TBI 165 cGy BID Day -7, -6, -5, & -4 Total dose
must be
1320 cCy
Cyclophosphamide IV 60 mg/kg/day Day -3 & -2
Rest Day -1
Infusion of Day 0
allogeneic HSCT

4.9.4 Sanctuary Site Therapy (see Section 14.0)

Prior to transplant, designated patients with extramedullary relapse must receive
cranial or testicular radiotherapy boosting in addition to the doses of TBI
associated with the preparative regimen. The cranial boost and/or testicular boosts
should be given over 3 days prior to the beginning of TBI.
4.9.4.1 Radiotherapy boost for patients with CNS leukemia (CNS3) at
relapse:
Patients with CNS3 involvement at the time relapse with or without a history of
prior CNS leukemia and/or radiotherapy will receive a cranial radiotherapy boost
just prior to TBI (3 doses, maximum 200 cGy daily: total dose to cranial axis =

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1800 cGy (unless alternative TBI dose given in which case the dose will be 1920
cGy). If the patient is ≤ 3 years at the time of transplant, centers may elect not to
give a boost because of developmental concerns. If the patient has CNS1 or CNS2
status at relapse, no boost will be given.

4.9.4.2 Testicular boost for patients with testicular leukemia at relapse:

The only patients that will receive a testicular boost prior to TBI (3 daily doses,
200 cGy fractions, total 600 cGy) are IR/HR/TF patients with extramedullary
testicular leukemia at the time of relapse that DID resolve by end Block 1, since
those without resolution have already received 2400 cGy of testicular radiation.

4.9.4.3 Prophylactic testicular boosting:

Prophylactic testicular boosting of 400 cGy for patients without testicular relapse
is allowed, but not part of the designated therapy.

4.9.5 Growth Factor Administration

Filgrastim (G-CSF) at a dose of 5 micrograms/kg/day given IV or subcutaneously
is required for recipients of cord blood starting at day +1 and continuing until
patients are fully engrafted. G-CSF is generally not necessary for BM/PBSC
recipients and is not recommended, unless engraftment is delayed.

4.9.6 GVHD Prophylaxis

GVHD prophylaxis will consist of tacrolimus/methotrexate (TAC/MTX) for
recipients of related and unrelated donor BM/PBSC and cyclosporine and
mycophenylate mofetil (CYA/MMF) for cord blood recipients. Substitution of
CYA for TAC or TAC for CYA according to center preference is allowed.

Drug Route* Dose Days Important

Notes

BM Recipient
Tacrolimus IV 0.02 mg/kg/day Begin Day -3 Target
(TAC) cont infusion concentration
8-12 ng/mL
Methotrexate IV 5 mg/m2 sib +1, +3, &+6
(MTX) donor 10mg/m2 sibs
URD^ +1, +3, +6, +11
URD

Cord Recipient
Cyclosporine A IV Varies by age, Begin Day -3 Target
(CYA) adjusted to concentration
target 200-400 ng/mL
Mycophenylate IV ≥50 kg: 1000 Begin Day -3
mofetil (MMF) mg q8h
< 50kg:
15mg/kg q8h
*
All drugs may be switched to PO after engraftment when patients are able to tolerate and
absorb PO medications.
^ URD, unrelated donor

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4.9.6.1 Tacrolimus Administration, Monitoring and Dose Adjustments

(related or unrelated BM/PBSC)
Tacrolimus should be administered by continuous IV infusion until patients are
able to take PO. Serum tacrolimus troughs and serum magnesium, potassium, and
creatinine should be drawn at least twice per week while hospitalized, then as per
good clinical practice thereafter unless a change in medication (e.g. use of
concomitant CYP3A4 inhibitors) or renal function might result in an acute change
in level.
At that point, concentrations will be measured as clinically indicated.
Concentrations sent when dosing by continuous infusion are not true trough
concentrations, however, the same target range of drug concentration will be used
for both continuous IV and bolus PO routes of administration.
When converting patients at a therapeutic tacrolimus level from IV to PO
formulation, multiply total daily IV dose times 4 and administer in 2 divided oral
doses per day, every 12 hours (e.g., 1 mg of IV tacrolimus per day equates to 4 mg
of PO tacrolimus per day). The oral dose should be administered 8-12 hours after
the end of the tacrolimus continuous infusion.41

The target serum trough concentration for tacrolimus is 8-12 ng/mL. Dose
adjustments are based on clinical judgment of the treating physician after
considering clinical toxicity, serum levels, GVHD, concomitant drug use and the
rate of rise or decline of the serum level.

4.9.6.2 Methotrexate Administration, Monitoring and Dose Adjustments

(related or unrelated BM/PBSC)
For patients receiving sibling donors, methotrexate should be given at a dose of 5
mg/m2 on Days +1, 3, and 6 after transplant. For patients receiving unrelated BM
or PBSC, methotrexate should be given at a dose of 10 mg/m2 on Days +1, 3, and
6, and 11. All doses of methotrexate should be administered as scheduled if
possible, but centers may modify or hold methotrexate for significant toxicity (see
Section 5.8 for methotrexate dose modification guidelines).

4.9.6.3 Leucovorin Administration

Leucovorin may be given at the physician’s discretion for patients at risk for
methotrexate toxicity. Patients at risk for methotrexate toxicity include those with
extravascular fluid collections (ascites, pleural effusions) or with decreased renal
function (see Section 5.8).

4.9.6.4 Cyclosporine Administration, Monitoring and Dose Adjustments

(related and unrelated cord blood)
Cyclosporine should be administered by IV infusion until patients are able to take
PO. Cyclosporine levels as well as serum magnesium, potassium, and creatinine
levels should be drawn at least twice per week while hospitalized, then weekly or
monthly thereafter unless a change in medication (e.g. use of concomitant
CYP3A4 inhibitors) or renal function might result in an acute change in level. At
that point, levels will be measured as clinically indicated. When converting
patients at a therapeutic tacrolimus level from IV to PO formulation, multiply the
IV dose times 2.5 if using the modified formulation (i.e., Neoral or Gengraf) or
times 3 if using the non-modified formulation (i.e., SandIMMUNE).

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The target serum trough concentration for cyclosporine is 200-350 ng/mL.

Dose adjustments are based on clinical judgment of the treating physician after
considering clinical toxicity, serum levels, GVHD, concomitant drug use and the
rate of rise or decline of the serum level.

4.9.6.5 Mycophenylate Mofetil (MMF) Administration and Dose

Adjustments (related and unrelated cord blood)
MMF should be given at a dose of 1 gram IV q8 hours for patients ≥ 50kg or
15 mg/kg IV q8 hours for patients < 50 kg beginning the morning of Day -3. MMF
should be given IV until patient can tolerate oral medications. MMF should be
dosed upon actual body weight.

The FDA has determined that a REMS (Risk Evaluation and Mitigation Strategy)
program is necessary to ensure the benefits of mycophenolate outweigh the risks
of first trimester pregnancy loss and congenital malformations associated with
mycophenolate use during pregnancy. Mycophenolate REMS is a program to tell
doctors, nurses, pharmacists and patients about the risks of taking mycophenolate
during pregnancy. Providers and patients (females of child-bearing potential) are
required to enroll in the program. The program also contains important information
about patient education and reporting details for pregnancy. Providers and patients
are required to sign acknowledgement forms prior to initiating therapy. Please refer
to the website for additional information (https://www.mycophenolaterems.com/).
If ≤ Grade 1 acute GVHD, MMF will be discontinued by Day +30. For patients
with > Grade 1 acute GVHD, the MMF taper will be per institutional protocols.
Patients may transition to PO formulations at a 1:1 IV to PO conversion when
clinically appropriate. Refer to Section 5.13 for dose adjustments based on serum
drug levels.

4.9.7 Standard Taper of Immune Suppression

This applies to all patients who are MRD negative pre- and at all times post-
transplant who have not developed aGVHD requiring systemic therapy. (Patients
who develop significant aGVHD will be tapered at the discretion of the transplant
center.)

Drug Stem Cell Source Taper Schedule

Tacrolimus Matched Sibling Start Day +42 over 8 weeks, off by
BM/PBSC Day +98
Tacrolimus Unrelated Donor Start Day +100 off by Day +180
BM/PBSC
Cyclosporine Unrelated Cord Start Day +100 off by Day +180
Mycophenylate Unrelated Cord Continue until Day +45 or 7 days after
Mofetil engraftment, whichever day is later.
Stop without a taper.

4.9.8 Accelerated Taper of Immune Suppression

See Section 4.9.1 for eligibility requirements.

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4.9.8.1 Taper for patients who are MRD positive pre-HSCT with no aGVHD by
Day +55 and for patients who are MRD positive > 0.01% by flow cytometry at
their peri-engraftment BM test (approx. Day +30)
Drug Stem Cell Source Taper Schedule
Tacrolimus Matched Sibling Taper already started by Day +42. At Day +55
BM/PBSC increase rate of taper to complete taper by Day
+70
Tacrolimus Unrelated Donor Start Day+55 off by Day +100
BM/PBSC
Cyclosporine Unrelated Cord Start Day+55 off by Day +100
Mycophenylate Unrelated Cord Continue until Day +45 or 7 days after
Mofetil engraftment, whichever day is later. Stop
without a taper.

4.9.8.2 Taper for patients who are MRD negative pre- HSCT with no aGVHD by
Day +55 who are MRD positive > 0.01% by flow cytometry at their Day +100 test.
Drug Stem Cell Source Taper Schedule
Tacrolimus Matched Sibling Taper already started by Day +42 and pt
BM/PBSC should be off immune suppression. Stop
tacrolimus without taper if still on medication.
Tacrolimus Unrelated Donor Taper over 2-3 weeks as soon as MRD report
BM/PBSC is received.
Cyclosporine Unrelated Cord Taper over 2-3 weeks as soon as MRD report
is received.
Mycophenylate Unrelated Cord
Mofetil Should be off this medication.

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4.10 Bridging Maintenance Therapy (All HR/IR Patients, as required) – up to 6 weeks

This therapy is for all HR/IR patients who have completed either Blocks 2 and 3 of
chemotherapy or both cycles of blinatumomab and due to stem cell source or facility
scheduling issues have a lag time > 2 weeks after count recovery prior to starting HSCT
therapy. Patients should start bridging therapy when clinically able after meeting count
requirements and continue until approximately one week prior to beginning the transplant
preparative regimen.
The Therapy Delivery Map (TDM) for Bridging therapy is in Appendix II-H.
4.10.1 Criteria to Begin Bridging Maintenance Therapy
Start when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50,000/µL.
4.10.2 General Chemotherapy Guidelines
See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I for
Supportive Care Guidelines.
Dosing should be based on actual BSA.
4.10.3 Bridging Maintenance Chemotherapy Guidelines
VinCRIStine: IV push over 1 minute or infusion via minibag as per
institutional policy
Days: 1, 22
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Mercaptopurine: PO
Days: 1-42
Dose: 75 mg/m²/dose*
Other Considerations:
• *See Section 5.9 for suggested starting dose based on TPMT status (if status
is known)
• Administer in the evening on an empty stomach (at least 1 hour before or
two (2) hours after food or drink except water).
• The liquid or tablet formulation may be used. If using tablets, adjust daily
dose using the dosing nomogram in Appendix III to attain a weekly
cumulative dose as close to 525 mg/m2/week as possible

Methotrexate: PO
Days: 1, 8, 15, 22, 29, 36
Dose: 20 mg/m2/dose
Administer on an empty stomach (at least 1 hour before or 2 hours after food or
drink except water).

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4.11 Continuation 1/Continuation 2 (All LR Patients) - 8 weeks

The therapy described in this section is for all LR patients in either Arm C or Arm D and
represents therapy given during Continuation 1 and Continuation 2. See Experimental
Design Schema.

The therapy delivery map for Continuation 1 and Continuation 2 is in APPENDIX II-I.

4.11.1 Criteria to Begin and During Continuation Therapy

a. Begin Continuation when ANC ≥ 500/µL and platelets ≥ 50,000/µL.
b. All Patients should have ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to
starting therapy on Days 22 and 43.
• If at Day 22 the ANC is < 500/µL and platelets < 50,000/µL, it is
permissible to delay the divided dose oral methotrexate (ddMTX)
(25 mg/m2/dose for CNS1/2) or ID MTX (for CNS3) by 14 days. Omit
the Day 29 standard dose oral methotrexate (20 mg/m2/dose) in this case.
• If counts are not recovered after one (1) week, omit the ddMTX and ID
MTX for this cycle and resume with the Day 29 standard dose MTX.

4.11.2 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.

Dosing should be based on actual BSA.

4.11.3 Continuation 1/Continuation 2 Chemotherapy Guidelines

Dexamethasone: PO (may be given IV)

Days: 1-5
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Day: 1
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

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Methotrexate: Intrathecal (IT) –CNS1/2 PATIENTS ONLY

Days: 1, 43
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg
When IT therapy and ID MTX are scheduled for the same day, deliver the IT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Days 1, 43
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
2 to < 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
3 to < 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
≥9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg
When ITT therapy and ID MTX are scheduled for the same day, deliver the ITT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,
with 0 being the start of the MTX bolus).

Mercaptopurine: PO
Days: 1-42
Dose: 75 mg/m²/dose*
Other Considerations:
• *See Section 5.9 for suggested starting dose based on TPMT status, if
known
• Administer in the evening on an empty stomach (at least 1 hour before
or two (2) hours after food or drink except water).
• The liquid or tablet formulation may be used. If using tablets, adjust
daily dose using the dosing nomogram in Appendix III to attain a
weekly cumulative dose as close to 525 mg/m2/week as possible

Methotrexate: PO
Days: 8, 15, 29, 36
Dose: 20 mg/m2/dose
Administer on an empty stomach (at least 1 hour before or 2 hours after food
or drink except water).

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Divided Dose Methotrexate (dd MTX): PO - CNS1/2 PATIENTS ONLY

Day: 22
Dose: 25 mg/m2/dose Q6H x4 doses
Other Considerations:
• ANC must be ≥ 500/µL and platelets must be ≥ 50 000/µL prior to Day
22 therapy.
• Administer on an empty stomach (at least 1 hour before or 2 hours after
food or drink except water).

Leucovorin: PO
Day: 24
Dose: 10 mg/m2/dose for 2 doses 6 hours apart beginning 48 hrs after the
START of Day 22 Methotrexate

Intermediate Dose Methotrexate (ID MTX): IV over 36 hours - CNS3

PATIENTS ONLY
Day: 22
Dose: 1000 mg/m²/dose
Given as a 100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over
35.5 hours.
Be certain that the ID MTX infusion is completed in the 36 hour period. Even if
the infusion is not complete at this time point, it must be stopped.
Leucovorin rescue: See below.
Suggested hydration and alkalinization for IDMTX: Prehydrate with D5 ¼ NS
with 30 mEq NaHCO3/L at 125 mL/m2/hour to achieve a urine specific gravity ≤
1.010 and pH between 7 and 8. Ringers Lactate may be bused as the initial fluid
if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium
bicarbonate to maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A
bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH
relatively quickly; a normal saline bolus may also be helpful in facilitating
hydration. Continue hydration using D 5 ¼ NS with 30 mEq NaHCO3/L at
125 mL/m2/hour throughout IDMTX infusion, and for a minimum of 48 hours after
its completion. In patients with delayed MTX clearance, continue hydration until
the plasma MTX concentration is < 0.25 μM.
Timing of ID MTX
ANC must be ≥ 500/µL and platelets must be ≥ 50 000/µL prior to ID MTX.

Leucovorin: PO/IV
Days: 24, 25
Dose: 15 mg/m2/dose every 6 hours beginning 48 hrs after the START of ID
MTX infusion.
• If 48 hr methotrexate level is ≤ 0.5 μM, do not give more than two doses of
leucovorin (48 and 54 hours).
• If MTX level at 48 hours is > 0.5 μM, then continue hydration and
leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours until MTX levels
are < 0.1 μM.
•

See Section 5.8 for ID MTX/LCV rescue and infusion guidelines.

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Cyclophosphamide: IV over 15-30 minutes

Days: 43, 50
Dose: 300 mg/m²/dose (see note below)

Etoposide: IV over 1-2 hours

Days: 43, 50
Dose: 150 mg/m²/dose
Note: ANC must be ≥ 500/µL and platelets must be ≥ 50,000/µL prior to Day 43
therapy. Once the Day 43 cyclophosphamide/etoposide is given, the Day 50
cyclophosphamide/etoposide doses should be given regardless of blood counts
(hold only for presumed or proven significant infection).

Thioguanine: PO
Days 43-49.
Dose: 40 mg/m2/dose/once daily
Other Considerations:
• Administer in the evening on an empty stomach (at least 1 hour before or two
(2) hours after food or drink except water).
• Adjust daily dose using the dosing nomogram in Appendix IV to attain a
weekly cumulative dose as close to 280 mg/m2/week as possible.
• An oral suspension can also be compounded for patients who cannot swallow
pills. The compounded oral suspension is recommended for patients with a
BSA between 0.27 and 0.48 m2. (see Section 6.18)

Cytarabine: IV/SQ
Days: 44-47, 51-54
Dose: 50 mg/m2/dose

4.11.4 Following Continuation 1:

a. LR B-ALL patients randomized to the control arm (Arm C) will receive
Continuation 2 (Section 4.11, APPENDIX II-I) when ANC ≥ 500/µL and
platelets ≥50,000/µL.
b. LR B-ALL patients randomized to the experimental arm (Arm D) will receive
Blinatumomab Block: Cycle 2 (Arm D) - (Section 4.16, APPENDIX II-N)
when ANC ≥ 500/µL and platelets ≥50,000/µL.

4.11.5 Following Continuation 2:

a. LR B-ALL patients randomized to the control arm (Arm C) will receive
Maintenance Cycle 1 therapy (Section 4.12, Appendix II-J) when ANC
≥ 500/µL and platelets ≥50,000/µL.
b. LR B-ALL patients randomized to the experimental arm (Arm D) will receive
Blinatumomab Block: Cycle 3 (Arm D) - (Section 4.16, APPENDIX II-N)
when ANC ≥ 500/µL and platelets ≥50,000/µL.

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4.12 Maintenance Cycle 1 (All LR patients) – 12 weeks

Maintenance Cycle 1 therapy is for common for all LR B-ALL patients randomized to
either Arm C or Arm D. See Experimental Design Schema.
The Therapy Delivery Map (TDM) for Maintenance Cycle 1 is in Appendix II-J.
CNS3 patients ONLY are to be given Chemoradiation (Section 4.13, Appendix II-K)
BETWEEN Maintenance Cycle 1 and subsequent Maintenance cycles (Maintenance-
Post Cycle 1, Section 4.14, Appendix II-L).

All other patients receive Maintenance-Post Cycle 1 treatment (Section 4.14, Appendix
II-L) immediately following Maintenance Cycle 1.

4.12.1 Criteria to Begin Maintenance Therapy

• Maintenance begins when peripheral counts recover to ANC ≥ 500/μL and
platelets ≥ 50 000/μL, whichever occurs later. This count recovery applies to
Maintenance Cycle 1 only.
• For subsequent Maintenance cycles, please follow the dose modifications for
low ANC or low platelets (Section 5.9).
• Only oral mercaptopurine and methotrexate will be interrupted for
myelosuppression as outlined in Section 5.9. Triple Intrathecal therapy (ITT),
vincristine and prednisone will be delivered as scheduled, despite
myelosuppression.
4.12.2 Duration of Cycles in Maintenance Therapy
• Maintenance consists of 12-week cycles repeated until total duration of
therapy is 2 years from start of Block 1 therapy for both male and female
patients.
• Therapy may be stopped on anniversary date if the 5-day dexamethasone is
completed for the cycle (i.e. complete all 5 days of dexamethasone before
ending therapy). Otherwise continue current cycle through dexamethasone
administration.

4.12.3 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.
Dosing should be based on actual BSA.

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4.12.4 Maintenance Chemotherapy Cycle 1

Dexamethasone: PO (may be given IV)
Days: 1-5, 29-33, & 57-61
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Days: 1, 29, 57
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Mercaptopurine: PO
Days: 1-84
Dose: 75 mg/m²/dose*
Other Considerations:
• *See Section 5.9 for suggested starting dose based on TPMT status, if
known
• Administer in the evening on an empty stomach (at least 1 hour before
or two (2) hours after food or drink except water).
• The liquid or tablet formulation may be used. If using tablets, adjust
daily dose using the dosing nomogram in Appendix III to attain a
weekly cumulative dose as close to 525 mg/m2/week as possible

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Day: 1
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
2 to < 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
3 to < 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
≥9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg

Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY

Day: 1
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

Methotrexate: PO
Days: 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
Dose: 20 mg/m2/dose

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4.12.5 Following Maintenance Cycle 1:

• ONLY CNS3 will receive Chemoradiation (see Section 4.13, APPENDIX
II-K) prior to moving on to subsequent Maintenance cycles (Maintenance-
Post Cycle 1, Section 4.14, APPENDIX II-L).
• All other patients in both Arm C and Arm D will continue on to
Maintenance-Post Cycle 1 (Section 4.14, APPENDIX II-L).

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4.13 Maintenance Chemoradiation - 3 weeks

The CNS-directed therapy described in this section is for LR B-ALL CNS3 Patients
ONLY (Patients with late B-ALL isolated CNS3 or CNS3 combined relapse).
The Therapy Delivery Map for this additional CNS-directed therapy during Maintenance
is in APPENDIX II-K.
4.13.1 Criteria to Begin Maintenance Chemoradiation
Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL.
4.13.2 Cranial Radiation Therapy
Cranial radiation will be administered during this phase of therapy, which is
between the 1st and 2nd cycles of Maintenance therapy. Patients with CNS3 and
isolated CNS relapse will receive 1800 cGy cranial radiation to the brain in 10
daily fractions along with concurrent chemotherapy. See Section 14.1 for details
on cranial irradiation.
4.13.3 General Chemotherapy Guidelines
See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.
See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.
Dosing should be based on actual BSA.
4.13.4 Chemotherapy Guidelines for Maintenance Chemoradiation
Dexamethasone: PO (may be given IV)
Days: 1-7, 15-21
Dose: 5 mg/m²/dose (Total daily dose: 10 mg/m²/day, divided BID; dose capped
at 40 mg per day)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Days: 1, 8, and 15
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Pegaspargase: IV over 1-2 hours

Day: 1
Dose: 2500 International Units/m2/dose

4.13.5 Following Maintenance Chemoradiation:

• All patients will continue on to Maintenance-Post Cycle 1 (see Section 4.14,
APPENDIX II-L).

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4.14 Maintenance-Post Cycle 1 (All LR patients)

Maintenance-Post Cycle 1 therapy is common for all LR B-ALL patients randomized to
either Arm C or Arm D. See Experimental Design Schema.

NOTE: CNS3 and Isolated CNS Relapse ONLY are to be given Chemoradiation (see
Section 4.13, APPENDIX II-K) between Maintenance Cycle 1 and subsequent
Maintenance cycles (Maintenance-Post Cycle 1). All other patients receive
Maintenance-Post Cycle 1 immediately following Maintenance Cycle 1.

4.14.1 Criteria to Continue Maintenance Therapy

Maintenance continues based on the dose modifications for low ANC or low
platelets (see Section 5.9). Only oral mercaptopurine and methotrexate will be
interrupted for myelosuppression as outlined in Section 5.9. Triple Intrathecal
therapy, vincristine and prednisone will be delivered as scheduled, despite
myelosuppression.

4.14.2 Duration of Cycles in Maintenance Chemotherapy

• Maintenance consists of 12-week cycles repeated until total duration of
therapy is 2 years from start of Block 1 therapy for both male and female
patients.
• Therapy may be stopped on anniversary date if the 5-day dexamethasone is
completed for the cycle (i.e. complete all 5 days of dexamethasone before
ending therapy). Otherwise continue current cycle through dexamethasone
administration.

4.14.3 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.

Dosing should be based on actual BSA.

4.14.4 Chemotherapy Guidelines for Maintenance-Post Cycle 1

Dexamethasone: PO (may be given IV)
Days: 1-5, 29-33, &57-61
Dose: 3 mg/m²/dose (Total daily dose: 6 mg/m²/day, divided BID)
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed.

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VinCRIStine: IV push over 1 minute or infusion via minibag as per

institutional policy
Days: 1, 29, 57
Dose: 1.5 mg/m2/dose (maximum dose: 2 mg)

Mercaptopurine: PO
Days: 1-84
Dose: 75 mg/m²/dose*
Other Considerations:
• *See Section 5.9 for suggested starting dose based on TPMT status
(if status is known)
• Administer in the evening on an empty stomach (at least 1 hour
before or two (2) hours after food or drink except water).
• The liquid or tablet formulation may be used. If using tablets, adjust
daily dose using the dosing nomogram in Appendix III to attain a
weekly cumulative dose as close to 525 mg/m2/week as possible

Methotrexate: PO - CNS3 PATIENTS ONLY

Day: 1
Dose: 20 mg/m²/dose

Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY

Day: 1
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

Methotrexate: PO
Days: 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
Dose: 20 mg/m2/dose

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4.15 Blinatumomab Block: Cycle 1 (Patients in Arm D) - 5 weeks

The therapy described in this section is for the 1st cycle of therapy with Blinatumomab on
Arm D. See Experimental Design Schema.

The Therapy Delivery Map (TDM) for the Blinatumomab Block: Cycle 1 (Arm D) is in
APPENDIX II-M.

NOTE: Hospitalization is STRONGLY recommended during the first 3 days of this

cycle in case of a cytokine reaction.

END- BLOCK 1 CALLBACK OCCURS PRIOR TO STARTING BLINATUMOMAB

BLOCK: CYCLE 1 THERAPY. PLEASE SEE SUMMARY TABLE IN SECTION 3.1.5
FOR DETAILS ON STAGED CONSENT, AND APPROPRIATE TIMING TO OBTAIN
CONSENT.

4.15.1 Criteria to Begin Blinatumomab

Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL

4.15.2 General Chemotherapy Guidelines

See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.

Dosing should be based on actual BSA. There is no maximum dosing.

4.15.3 Blinatumomab Block: Cycle 1 (Patients in Arm D) Chemotherapy

Blinatumomab: IV; Continuous Infusion over 28 days*

Days: 1-28
Dose: 15 micrograms/m²/day
*. IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Day: 1
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours prior
to initiation of the blinatumomab infusion.

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• A single dose of 5 mg/m2/dose will be administered within 30 minutes

prior to the start of the blinatumomab infusion
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed

Methotrexate: Intrathecal (IT) - CNS1/2 PATIENTS ONLY

Day: 8, 29
Age-based dosing:
Age (yrs) Dose
1 – 1.99 8 mg
2 – 2.99 10 mg
3 – 8.99 12 mg
≥9 15 mg

Triple Intrathecal Therapy (ITT) - CNS3 PATIENTS ONLY

Days: 8, 29
Age-based dosing:
Age (yrs) Dose
1 to < 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
2 to < 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
3 to < 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
≥9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg

4.15.4 Following Blinatumomab Block: Cycle 1 (Arm D)

The next phase of therapy is Continuation 1 (Section 4.11, APPENDIX II-I).

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4.16 Blinatumomab Block: Cycle 2/3 (LR Patients in Arm D) - 5 weeks

The therapy described in this section is therapy given during Blinatumomab Block Cycle
2 and Blinatumomab Block Cycle 3. Do not start Blinatumomab Cycle 2 before Day 56
after beginning of Continuation 1. Do not start Blinatumomab Cycle 3 before Day 56 after
beginning of Continuation 2. See Experimental Design Schema.

NOTE: Hospitalization is STRONGLY recommended during the first 2 days of these

cycles in case of a cytokine reaction.

4.16.1 Criteria to Begin Blinatumomab Block: Cycle 2/3

Start when ANC ≥ 500/µL and platelets ≥ 50,000/µL
4.16.2 General Chemotherapy Guidelines
See Section 6.0, DRUG INFORMATION, and the Parenteral and Oral
Chemotherapy Administration Guidelines (CAGs) on the COG website at:
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdmin
Guidelines.pdf for special precautions associated with chemotherapy
administration. As applicable, also see the CAGs for suggestions on hydration, or
hydrate according to institutional guidelines.

See Appendix VII-A for the management options of blinatumomab in the

outpatient setting.

See Section 5.0 for Dose Modifications based on Toxicities and Appendix I
for Supportive Care Guidelines.

Dosing should be based on actual BSA. There is no maximum dosing.

4.16.3 Blinatumomab Block: Cycle 2/3: Chemotherapy Guidelines

Blinatumomab: IV; Continuous Infusion over 28 days*

Days: 1-28
Dose: 15 micrograms/m²/day
*. IV bag will be changed every 24-48 hours

Dexamethasone: PO/IV
Day: 1
Dose: Prior to day 1 therapy -
• A single dose of 10 mg/m2/dose will be administered 6 to 12 hours prior
to initiation of the blinatumomab infusion.
• A single dose of 5 mg/m2/dose will be administered within 30 minutes
prior to the start of the blinatumomab infusion
If using tablets, adjust dose upward to the nearest 0.25 mg. Oral solutions
are acceptable and intravenous preparations may be used on a temporary
basis, if needed
4.16.4 Following Blinatumomab Block Cycle 2:
LR B-ALL patients randomized to the experimental arm (Arm D) will receive
Continuation 2- (Section 4.11, APPENDIX II-I)

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4.16.5 Following Blinatumomab Block Cycle 3:

LR B-ALL patients randomized to the experimental arm (Arm D) will receive
Maintenance Cycle 1 therapy- (Section 4.12, Appendix II-J.)

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5.0 DOSE MODIFICATIONS FOR TOXICITIES

Notify the Study Chair at the time of removing a patient from protocol therapy for toxicity. The
drugs are listed in alphabetical order.

5.1 Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia]

Allergy
Local Allergic Reactions (inflammation at injection site, swelling): Note these
recommendations only apply when the asparaginase product is administered
intramuscularly. Continue asparaginase administration in the presence of Grade 1 allergy
as defined by CTCAE v4.0 (transient flushing or rash; drug fever < 38ºC).

Systemic Allergic Reactions: In the event of Grade 1 reactions, characterized by transient

flushing or rash and drug fever < 38ºC, without the need for treatment with antihistamines
or steroids, the dose of asparaginase being administered intravenously may be continued
with close observation.

Discontinuation is recommended for Grade 2 or higher allergic reactions as defined by

CTCAE v4.0, which require medical intervention

Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms is
strongly discouraged since anti-histamine use may mask the appearance of systemic
allergy. Systemic allergy is frequently associated with the presence of asparaginase
neutralizing antibodies, which render asparaginase therapy ineffective. In the event of
severe systemic or recurrent local allergic reaction, Erwinia chrysanthemi asparaginase
(Erwinaze®), which is FDA-approved for this indication, should be substituted.

Therapeutic Drug Monitoring (TDM): TDM of asparaginase activity is available as a CLIA

approved assay from AIBioTech®. Centers may elect to discontinue pegaspargase and
switch to Erwinia asparaginase based upon laboratory evidence of silent inactivation of
asparaginase activity in the absence of clinical symptoms of hypersensitivity at their
discretion.

NOTE: Patients with allergy/anaphylaxis to pegaspargase may be eligible to receive IV

pegcrisantaspase, a pegylated form of Erwinia asparaginase, on COG AALL1421 at doses
prescribed on that protocol. Patients who have previously received Erwinia asparaginase
or are receiving other investigational agents are not eligible for AALL1421. PATIENTS
ENROLLED IN AALL1331 ARE NOT ELIGIBLE TO ENROLL IN AALL1421.

Anaphylaxis
Discontinue pegaspargase if the patient develops Grade 3 anaphylaxis as defined by
CTCAE v4.0 (symptomatic bronchospasm, with or without urticaria, parenteral
intervention indicated; allergy-related edema/angioedema; hypotension). If this occurs,
Erwinia asparaginase should be substituted.

Erwinia asparaginase has a shorter half-life and is associated with a shorter duration of
asparagine depletion than native E. coli asparaginase, with “head-to-head” comparisons of
Erwinia and E. coli asparaginase, using the same dose and schedule for both preparations,
demonstrating a superior outcome, favoring E. coli asparaginase.67,68 Pegaspargase has a
longer half-life and is associated with more prolonged asparagine depletion than native E.

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coli asparaginase, but the largest randomized trial comparing weekly native to bi-weekly
pegaspargase wasn’t powered to detect a difference in outcome.69 Current COG trials have
adopted pegaspargase as the preparation of choice, based on the results of CCG 1962.70
COG AALL07P2 showed that Erwinia asparaginase was well tolerated and achieved nadir
serum asparaginase activity at both 48 and 72 hours after dosing that was similar to that
achieved with pegaspargase. Based on these and other data, the FDA initially approved
Erwinia asparaginase for use following allergy to pegaspargase, with a dose of Erwinia
25,000 IU/m2 x 6 doses IM on a Monday/Wednesday/Friday schedule substituted for a
single dose of pegaspargase. In December 2014, the FDA expanded its approval to include
intravenous as well as intramuscular administration.

The dose modification guidelines for ALL trials recommend the substitution for
replacement of Erwinia asparaginase for either native or pegaspargase utilizing the
following schedule:

Phase(s) of Treatment Drug(s) Replacement Schedule for Erwinia

asparaginase#
Block 1/Block 2 One or more doses of 25,000 IU/m2/dose IM or IV
pegaspargase M/W/F x 6 doses for each dose of
(2,500 IU/m2) pegaspargase.
Chemoradiation Pegaspargase 25,000 IU/m2/dose IM or IV
(2,500 IU/m2) M/W/F x 6 doses for each dose of
pegaspargase.
#
If a patient develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future asparaginase therapy.
Consider discontinuation for severe Grade 2 or higher allergic reactions
* qod: every other day

To replace a dose of intravenous pegaspargase that was discontinued during the infusion
due to an allergic reaction, the following recommendations may be used to guide patient
care.
In the event that a pegaspargase infusion is discontinued for an allergic reaction, regardless
of amount received, substitution with Erwinia asparaginase should begin approximately 48
hours after pegaspargase has been discontinued and preferably to coincide with the
recommended Monday/Wednesday/Friday administration schedule detailed above in
patients who are clinically stable. Up to 6 doses of Erwinia asparaginase may be
administered, as tolerated, to replace the incomplete intravenous pegaspargase dose. Of
note, Erwinia asparaginase is recommended only for pegaspargase hypersensitivity
reactions, and not for pancreatitis, hepatitis, coagulation abnormalities, or other non-
hypersensitivity toxicities associated with pegaspargase. To best suit the needs of each
individual patient, additional modifications to these recommendations may be made at the
discretion of the treating physician.
Coagulopathy: If symptomatic, hold asparaginase until symptoms resolve, then resume with
the next scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do
not withhold dose for abnormal laboratory findings without clinical symptoms.

Hyperbilirubinemia: asparaginase may need to be withheld in patients with an elevated

direct bilirubin, since asparaginase has been associated with hepatic toxicity. No specific
guidelines are available.
Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically indicated.

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Hyperlipidemia: Do not modify dose

Ketoacidosis: Hold asparaginase until blood glucose can be regulated with insulin.
Pancreatitis: Discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the
case of asymptomatic Grade 2 pancreatitis (enzyme elevation or radiologic findings only),
asparaginase should be held until symptoms and signs subside, and amylase/lipase levels
return to normal and then resumed. Grade 3-4 pancreatitis is a contraindication to
additional asparaginase administration.
Thrombosis: Withhold asparaginase until resolved, and treat with appropriate antithrombotic
therapy, as indicated. Upon resolution of symptoms consider resuming asparaginase, while
continuing LMWH or antithrombotic therapy. Do not withhold dose for abnormal laboratory
findings without clinical correlate. For significant thrombosis, which is not catheter-related,
consider evaluation for inherited predisposition to thrombosis.
CNS Events (bleed, thrombosis or infarction): Hold asparaginase. Treat with FFP, factors or
anticoagulation as appropriate. Consider resuming at full dose when all symptoms have
resolved (and evidence of recanalization in case of thrombosis by CT/MRI). Consider
evaluation for inherited predisposition to thrombosis.

Centers may elect to discontinue pegaspargase and switch to erwinia asparaginase based
upon laboratory evidence of silent inactivation of asparaginase activity in the absence of
clinical symptoms of hypersensitivity at their discretion.

5.2 Blinatumomab
The most frequent serious adverse events noted in patients treated with
blinatumomab to date are disorders of the nervous system, both peripheral and
central, and systemic cytokine release syndrome (CRS). Both categories of events are
more likely to occur within the first week of treatment with blinatumomab, and both
categories of events are usually reversible and able to be managed with attentive
supportive care.
AEs related to blinatumomab that require treatment interruption (according to table below)
and do not resolve to CTCAE ≤ Grade 1 within 14 days will require permanent
discontinuation of blinatumomab treatment. If the patient is eligible to continue protocol
therapy (chemotherapy and/or HSCT), then the patient may, at the discretion of the
investigator and family, continue to receive protocol therapy. Otherwise, the patient will
be off protocol therapy.
In the case that the AE(s) DO resolve within 14 days, blinatumomab treatment may
resume at a reduced dose of 5 µg/m2/day to complete the 28 day course (not counting the
duration of treatment interruption). NOTE: For Grade 4 Nervous System/Psychiatric and
thromboembolic AEs, blinatumomab must be permanently discontinued.

For patients who had experienced a ≥ Grade 2 Neurologic Systems and Psychiatric AE
related to blinatumomab, no dose escalation beyond 5 µg/m2/day will be permitted for
subsequent cycles. For patients who experienced other AEs related to blinatumomab,
subsequent cycles will begin at the reduced dose of 5 µg/m2/day, but may escalate to 15
µg/m2/day after 7 days if there are no significant blinatumomab-related AEs.

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A second AE that requires interruption will require permanent discontinuation of

treatment and the patient will be off protocol therapy.
The resumption of the infusion at the reduced dose should be accompanied by
dexamethasone premedication as indicated in the relevant subsection of Section 4.0,
should be performed in the hospital under supervision of the investigator and patients
should be observed for at least 72 hours after the start of the next infusion before
considering discharge to the outpatient setting.

Table: Dose modifications for Adverse Events (AE) Possibly, Probably or Definitely Related to
Blinatumomab:
Supportive Escalation to
Restart allowed
Care (in 15 mcg/m2/day
Category: AE AE Stop (with premeds) if Restarting dose
addition to after 7 days in
(CTCAE v4.03) Grade Infusion? Gr 1 within 14 (mcg/m2/day)
institutional subsequent
days?
guidelines)* cycle allowed?
Nervous system/ 1 N - - -
Psychiatric1: 2, 3 Y DEX, CNS Y 5 N
All (other than seizure) 4 Y DEX, CNS N - -
1,2,3 Y SZ, DEX, CNS Y 5 N
Nervous system: Seizure
4 Y SZ, DEX, CNS N
2
Immune system : Cytokine
release syndrome, allergic 1 N - - -
reaction, anaphylaxis and
General: Infusion related 2,3 Y DEX Y 5 Y
reaction 4 Y DEX N - -
Blood and lymphatic
system3: Disseminated 1,2 N - - -
intravascular coagulation,
hemolysis, hemolytic
uremic syndrome, 3,4 Y Y 5 Y
thrombotic
thrombocytopenic purpura
Blood and lymphatic
system4: All others
(lymphopenia, neutropenia, 1,2,3,4 N - - -
anemia, thrombocytopenia,
etc.)
1 N - - -
Vascular: Thromboembolic
2, 3 Y Y 5 Y
event
4 Y N - -
Investigations5,6,
Metabolism and Nutrition:
All
(if not considered 1,2,3,4 N - - -
clinically relevant or
responding to routine
medical management)

1,2 N - - -

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Investigations5,6,
Metabolism and Nutrition:
All
3,4 Y Y 5 Y
(if clinically relevant and
not responding to routine
medical management)
1,2 N - - -
All other AE
3,4 Y Y 5 Y
Table Footnotes:
1
Most AEs in the psychiatric disorders category are unlikely to be caused by blinatumomab and
generally require supportive care rather than dose modification or discontinuation of
blinatumomab (e.g., Insomnia, Depression, Anxiety). Psychiatric AEs that may reflect underlying
central nervous system toxicity (e.g., Confusion, Delirium, Hallucinations, Psychosis) are of greater
interest, particularly if accompanied by other AEs in the nervous system disorders category.
2
Close monitoring of fluid status by intake and output should be undertaken for the first week of
blinatumomab infusion. Efforts to keep patients balanced between intake and output should be
maintained, even if diuretic therapy (furosemide or similar) is needed to do this. Careful attention to
fluid status may prevent deterioration from capillary leak, however even with meticulous attention
some patients will experience pulmonary edema and require more aggressive respiratory support.
Treating physicians should use their clinical judgment and institutional standards for whatever
supportive care measures are needed during this period of time.
3
In the first days of treatment, transient DIC-like pictures may develop. Because patients are at risk
for capillary leak syndrome and cytokine release syndrome, appropriate supportive care with
dexamethasone (described above), blood products and factors (packed red cells, platelets,
cryoprecipitate, fresh frozen plasma), vitamin K, and/or albumin should be considered according to
institutional standards of care. Particularly in the first week of infusion, when the risk of capillary
leak and cytokine release is more prominent, appropriate use of blood products and factors is
preferred if laboratory indications suggest the need for replacement, as large volumes of crystalloid
fluids tend to exacerbate the capillary leak.
4
In the first days of treatment, a rapid transient drop in platelets, neutrophils and/or hemoglobin
may be observed. These effects are not necessarily cytokine-mediated. Counts typically recover to
baseline during treatment, and usually within two weeks of starting blinatumomab. Transfusion of
blood and platelets should be performed according to appropriate institutional standards.
5
In the first days of treatment, transient increases in transaminases up to over 1000 U/L may develop.
These have generally returned to baseline in the 1st week of treatment.
6
Decrease in serum immunoglobulins have been observed in patients treated with blinatumomab.
Intravenous immunoglobulin should be administered according to institutional standards, but is
recommended for any patient with a total IgG level below 400. Immunoglobulin must not be
administered through the line through which blinatumomab is actively being infused.

* Definitions of supportive care abbreviations:

DEX: Dexamethasone should be administered at a total daily dose of at least 0.2-0.4 mg/kg/day (maximum
24 mg per day) administered preferably intravenous divided 3-4 times daily for 4 days. The dose should
then be tapered over up to 3-4 days or as clinically indicated.
SZ: Appropriate imaging should be performed to evaluate for possible hemorrhage or thrombosis, and other
diagnostic procedures should be performed as clinically appropriate. Prophylactic anticonvulsant treatment
with a therapeutic dose of institutional standard agents (e.g., lorazepam, phenytoin, levetiracetam) should

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be administered if seizures develop, and continued throughout the blinatumomab infusion. Anti-convulsant
therapy should be considered starting at least 24-48 hours prior to any subsequent blinatumomab infusions,
and continuing for the remainder of those treatment cycles. Diagnostic measures to exclude potential
infectious causes should be conducted once the patient has stabilized (i.e., a lumbar puncture to evaluate
for bacterial, viral or fungal sources should be performed). Any identified pathology should be treated as
clinically appropriate.
CNS: A daily finger-nose-finger or writing sample test is recommended according to age-appropriate
activities for patients. In adults treated with blinatumomab, it has been found that a daily handwriting
sample can often predict future nervous system toxicity before the clinical toxicity develops. In case of a
change in finger-nose-finger or handwriting test it is recommended to start dexamethasone on the schedule
above to prevent

5.3 Cyclophosphamide
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of previous
significant hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010
and hydrate at 125 mL/m2/hr for 24 hours after dose. Monitor for adequate urine output as
per institution guidelines. Give IV mesna at a total dose that is 60% of the
cyclophosphamide dose divided to 3 doses (e.g., if the cyclophosphamide dose is 1000
mg/m2, the total mesna dose is 600 mg/m2 or 200 mg/m2/dose). Give the first mesna dose
15 minutes before or at the same time as the cyclophosphamide dose and repeat 4 and
8 hours after the start of cyclophosphamide. This total daily dose of mesna can also be
administered as IV continuous infusion. The continuous infusion should be started 15-30
minutes before or at the same time as cyclophosphamide and finished no sooner than
8 hours after the end of cyclophosphamide infusion.
Renal Dysfunction: If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2,
reduce dose of cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the
creatinine clearance should be repeated with good hydration.

5.4 Cytarabine (ARAC)

ARAC Syndrome: Do not withhold ARAC for fever if it is likely to have been caused by
the ARAC. Obtain blood cultures if a central line is present. For rash or conjunctivitis,
withhold for Grade 3-4 toxicity until resolved. Make up missed doses and consider
concurrent treatment with hydrocortisone or dexamethasone, and/or with dexamethasone
ophthalmic drops for conjunctivitis. Note that steroid eye drops should be administered
routinely with high dose (3000 mg/m2/dose) ARAC.

Myelosuppression: Do not interrupt high dose (3000 mg/m2/dose) ARAC, once started, for
uncomplicated myelosuppression; do hold for proven or presumed serious infection and do
not make up missed doses during Block 3.
Once Continuation 1 and 2 have started, do not interrupt for uncomplicated
myelosuppression; do hold for proven or presumed serious infection.

Renal Dysfunction: Adequate renal function (defined as creatinine within normal range) is
required for the administration of high dose (3000 mg/m2/dose) ARAC. Creatinine
clearance (CrCl) should be measured for patients with elevated creatinine or suspected
renal insufficiency. For CrCl < 60 mL/min/1.73 m2, hold pending recovery and omit if
recovery requires > 3 weeks.

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5.5 Anthracycline-Mitoxantrone
Cardiac Toxicity: Discontinue for clinical or echocardiographic evidence of
cardiomyopathy (SF < 27% or EF < 50%) or Grade 3-4 left ventricular systolic dysfunction
(LVSD) per CTCAE version 4.0.
Note: use the following updated term to report decreases in the EF or SF: cardiac
disorders-others

Hyperbilirubinemia:42
Direct Bili % Dose Reduction
< 1.2 mg/dL Full dose
1.2 – 3.0 mg/dL 50%
3.1 – 5.0 mg/dL 75%
> 5.0 mg/dL Withhold dose and administer next scheduled dose if toxicity has
resolved. Do not make up missed doses.

Extravasation:
In the event of an extravasation, discontinue the IV administration of the drug and
institute appropriate measures to prevent further extravasation and damage according to
institutional guidelines. Also see
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.
pdf for COG guidelines.

5.6 Etoposide
Allergic Reaction: Premedicate with diphenhydramine (1-2 mg/kg slow IV push,
maximum dose is 50 mg). If symptoms persist, add hydrocortisone 100-300 mg/m2.
Continue to use premedication before etoposide in future. Also consider substituting an
equimolar amount of etoposide phosphate, in the face of significant allergy and/or
hypotension. Etoposide phosphate is a water soluble prodrug that does not contain
polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that may induce
allergic reactions and hypotension. Etoposide phosphate is rapidly converted to etoposide
in vivo and provides total drug exposure, as represented by AUC (0-infinity), that is
statistically indistinguishable from that measured for etoposide at equimolar doses.

Hypotension: If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion,

reduce infusion rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to
recover or falls further. Stop infusion if BP does not recover, continue NS. If the patient
has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours
prior to any subsequent infusion.

Renal Insufficiency: If renal function decreases, adjust etoposide as follows: CrCl 10-50
mL/min/1.73 m2, decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by
50%.

Hyperbilirubinemia: If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct

bilirubin is > 5 mg/dL, hold etoposide.

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5.7 Intrathecal Methotrexate/Triple Intrathecal Therapy

Systemic toxicity: The dosage for IT methotrexate will not be reduced for systemic toxicity
(myelosuppression, mucositis, etc.). Instead, leucovorin may be used at a dose of 5
mg/m2/dose every 12 hours x 2 doses, beginning 48 hours after the IT therapy may be
administered in an attempt to reduce the risk of worsening already existent
myelosuppression (ANC < 500/µL) or mucositis. Do not administer leucovorin solely to
prevent myelosuppression.

Dose modifications following an episode of acute neurotoxicity:

Neurotoxicity has extremely protean manifestations, ranging from transient events,
seizures or episodes of acute hemiparesis, to severe necrotizing encephalopathies.43-45
These toxicities are poorly understood and currently it is impossible to predict who will
suffer these complications. In addition, there are no data clearly linking the occurrence of
an acute neurotoxic event with an increased risk of long-term neurocognitive dysfunction,
nor do changes present on MRI at the time of an acute event clearly correlate with or predict
outcome.45-50 It is clear however, that CNS prophylaxis is a mandatory component of
curative therapy for children with ALL. Effective prophylaxis generally takes 2 forms;
cranial, or less commonly, craniospinal radiation, with a limited number of doses of IT
therapy or prolonged IT therapy with either IT MTX or triple IT therapy (MTX, ARAC
and hydrocortisone). Certain protocols, for example BFM 2000,51include fewer doses of
IT MTX, with an acceptably low frequency of CNS relapse, but the backbone of the BFM
therapies is not the same as those currently used by the Children’s Oncology Group. The
exclusive use of IT ARAC has not been studied or described in the context of ALL therapy
nor can one demonstrate the safety of omitting multiple doses of IT therapy without
concomitant use of cranial irradiation or high dose methotrexate.

The following guidelines are offered for consideration following an acute event, but it must
be recognized that there are little data to support these approaches or any others. Thus the
treating physician must evaluate the patient and, with the family, make the best possible
decision with respect to the relative risk and benefit of continued therapy.

Following an acute neurotoxic event, a history and physical exam should guide the
differential diagnosis. A neurology consult may be of value and should be considered.
Seizures and other transient events may be linked to fever, infection, encephalitis,
meningitis, hypertension, electrolyte disturbance, hypoglycemia, trauma, intracranial
hemorrhage or thrombosis, narcotic withdrawal, illicit drug use, or other causes in addition
to the direct side effects of chemotherapy. Appropriate laboratory studies may include, but
are not limited to, blood cultures, a CBC, electrolytes, including glucose, calcium,
magnesium and phosphorus, renal and liver function studies and/or an examination of the
CSF. Imaging studies may include a CT scan and/or an MRI. The CT is commonly normal,
in the absence of stroke, but if calcifications are present, this finding may be indicative of
a more severe mineralizing leukoencephalopathy.52 MRI abnormalities may be
pronounced, but transient. Posterior reversible encephalopathy may be present on MR with
extensive diffusion abnormalities, but these do not appear to correlate with subsequent
demyelination or gliosis.53-55 Additional studies, including MR angiography and/or
venogram should be considered, if clinically indicated (e.g., focal deficits).
Many acute events, seizures or episodes of transient hemiparesis, are temporally related to
the administration of intrathecal therapy, commonly 9 to 11 days after the IT
administration.56 For patients who return to their “pre-event” status, without residual

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deficits of physical or neurologic exam, there are few data to support or guide therapeutic
interventions. It is reasonable to hold the next dose of IT therapy, or, substitute IT Ara-C
for 1 dose of IT MTX, or triple IT therapy. It is also reasonable to include leucovorin rescue
at a dose of 5 mg/m2 q 12 hrs x 2 doses beginning 48 hours after the LP. This pattern of
rescue was associated with a clear diminution in the incidence of acute neurotoxicity in
one case series.56 There have been questions about potential interference of leucovorin with
the efficacy of the IT MTX, but there are little data to support or refute this position.
Moreover, the administration 48 hours later would minimize any potential interference. If
the event does not recur, resumption of standard therapy should be considered, following
1 modified or omitted IT dose. In the face of multiply recurrent events, or evidence of
progressive encephalopathy, another evaluation is warranted and the treating physician
may consider a more prolonged or definitive change in therapy. These decisions are
extremely difficult and may hinge on an individual’s view of the importance of quality of
life versus an increase in the risk of relapse. Since the greatest impact of CNS prophylaxis
occurs early in therapy, the timing of these events may also influence clinical decisions.
Cranial radiation has been suggested as an alternative to continued IT therapy though much
of the literature on long-term neurocognitive dysfunction supports a more deleterious effect
from CRT than IT therapy.57-60 Dramatic deviations from protocol recommended therapy
might result in the child being taken off protocol therapy.
The use of dextromethorphan (DM) has been suggested as a neuroprotectant, capable of
preventing NMDA mediated neurotoxicity without prohibitive toxicity. Low dose therapy
has been recommended, in part, based on data suggesting that DM is concentrated in brain
relative to serum. However, the literature on the use of DM supports a tight dose response
relationship, with the likelihood of sparing an initially unaffected area, following ischemic
damage, linked to dose, in both clinical trials and animal models of CNS ischemia.61-64 At
doses thought to be therapeutic, side effects have included nystagmus, nausea and
vomiting, distorted vision, ataxia, and dizziness. In addition, Hollander et al 65 have raised
concerns about the potential deleterious effects of long-term NMDA receptor blockade on
memory because hippocampal long-term potentiation is dependent on the activation of the
NMDA receptor. Thus in the absence of a clinical trial there are few data to support the
addition of DM.

Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal

chemotherapy via lumbar puncture:
Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal
therapy delivered by LP. Intraventricular chemotherapy should be given according to the
same schedule, but at 50% of the corresponding age-based doses that would be given
by LP. NOTE: Obstruction to CSF flow may be a contraindication to intrathecal and/or
intraventricular therapy.

Viral, bacterial, or fungal meningitis: Omit until resolved.

5.8 Intermediate-Dose Methotrexate (ID MTX) and Leucovorin Rescue

[Please note that IDMTX refers to IV MTX 1000 mg/m2 given over 36 hrs]

5.8.1 ID MTX Infusion Guidelines

When IT therapy and ID MTX are scheduled for the same day, deliver the IT
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6,

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with 0 being the start of the MTX bolus).

Hold trimethoprim/sulfamethoxazole (TMP-SMX), any nonsteroidal anti-

inflammatory medications, penicillins, proton pump inhibitors or aspirin-
containing medications on the day of ID MTX infusion and for at least 72 hours
after the start of the ID MTX infusion and until the MTX level is less than 0.5 µM
for ID MTX. In the presence of delayed clearance continue to hold these medications
until MTX level is less than 0.1 µM.

Recommended Prehydration: to start at least 6 hours prior to commencement of

intravenous methotrexate. Fluid: D5 ¼ NS with 30 mEq NaHCO3/L at
125 mL/m2/hour. Ringers Lactate may be used as the initial fluid if a bicarbonate
containing solution is unavailable. Adjust fluid volume and sodium bicarbonate to
maintain urine specific gravity ≤ 1.010 and pH between 7 and 8. A bicarbonate
bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH relatively
quickly; a normal saline bolus may also be helpful in facilitating hydration.

Hour 0: MTX 100 mg/m2 IV mixed in a final volume of 65 mL/m2 D5 ¼ NS with

30 mEq NaHCO3/L and infused over 30 minutes. This is followed, immediately,
by MTX 900 mg/m2 mixed in a final volume of 4437.5 mL/m2 D5 ¼ NS with 30
mEq NaHCO3/L given by continuous IV infusion over 35.5 hours at 125 mL/m2/hr.
Be certain that the ID MTX infusion is completed in the 36 hour period. Note,
even if the infusion is not complete at this time point, it must be stopped.

Recommended Posthydration: Continue hydration using D 5 ¼ NS with 30 mEq

NaHCO3/L at 125 mL/m2/hour (3 L/m2/day) throughout IDMTX infusion until the
last dose of leucovorin has been given. In patients with delayed MTX clearance,
continue hydration until the plasma MTX concentration is below 0.1 μM.

Leucovorin rescue: 15 mg/m2 PO/IV at 48 and 54 hrs after the start of the MTX
infusion. If 48 hr methotrexate level is ≤ 0.5 μM, then only two doses of leucovorin
are administered (at 48 and 54 hours). If MTX level at 48 hours is > 0.5 μM, then
continue hydration and leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours
until MTX levels are < 0.1 μM.

Hour 48: Check plasma methotrexate level at 48 hours after start of the
methotrexate infusion. If the level is ≤ 0.5 μM, then do not give more than two
doses of leucovorin (48 and 54 hours). If MTX level at 48 hours is > 0.5 μM, then
continue hydration and leucovorin rescue at 15 mg/m2/dose po/IV every 6 hours
until MTX levels are < 0.1 μM.

For MTX levels that exceed these expected values modify the rescue regimen
as noted below and increase hydration to 200 mL/m2/hr. Monitor urine pH to
assure a value ≥ 7.0 and monitor urine output to determine if volume is ≥ 80% of
the fluid intake, measured every 4 hours. If serum creatinine rises significantly, at
any time point (> 100% in 24 hours), assure appropriate urine pH and urine volume
as above and consider glucarpidase If urine output fails to continue at 80% of the
fluid intake, consider furosemide or acetazolamide. Regardless of urine output,
also consider glucarpidase (carboxypeptidase G2) (see below).

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48 hr MTX Leucovorin Rescue

level
≤ 0.5 µM Continue 15 mg/m2 IV/PO q 6hrs for 2 doses.
0.5 – 1 µM Increase to 15 mg/m2 q 6 hrs until MTX level < 0.1 µM (draw q 6-
24 hrs).
1 – 5 µM Increase to 15 mg/m2 q 3 hrs until MTX level < 0.1 µM (draw q 6-
24 hrs).
5 – 10 µM Increase to 100 mg/m2 q 6hrs until MTX level < 0.1 µM (draw q 6-
24 hrs).
> 10 µM Increase to 1000 mg/m2 q 6hrs until MTX level < 0.1 µM (draw q 6-
24 hrs).
Consider glucarpidase.
Nephrotoxicity: Postpone course if pre-treatment (MTX) serum creatinine is > 1.5
x baseline or GFR creatinine clearance < 65 mL/minute/1.73m2. If there is a rising
creatinine (> 100% in 24 hours) or the 48 hour methotrexate level is > 10 μ/l
consider using glucarpidase. If renal function does not recover, omit MTX. Do not
give ID MTX to a patient with this degree or renal impairment, assuming that
prolonged excretion can be managed with glucarpidase.

NOTE: For patients who have markedly delayed MTX clearance secondary to
renal dysfunction, consider using glucarpidase (carboxypeptidase G2,
Voraxaze).66,67 To obtain supplies of glucarpidase in the US contact the Voraxaze
24-hour Customer Service line at 855-786-7292. Additional information can be
found at http://www.btgplc.com/products/specialty-pharmaceuticals/voraxaze
regarding product availability through ASD Healthcare, Cardinal, and McKesson.
Canadian sites should contact McKesson at (877) 384-7425 for further
information. Sites in Australia and New Zealand should contact Hospira at 1300-
046-774 (local) or [email protected]. Patients requiring
glucarpidase rescue will remain on study.

Stop leucovorin 2 hours before administering glucarpidase as it is a competitive

substrate and may compete with MTX for glucarpidase binding sites.

Dose of glucarpidase: 50 units/kg administered by intravenous bolus over

5 minutes. Reconstitute each vial with 1 mL sodium chloride 0.9% (do not further
dilute). Each vial contains 1000 units/mL (after reconstitution) and round dose up
to vial size. No further dose is required.

Maintaining alkalinization of urine with sodium bicarbonate is essential to

maintain urinary pH > 7.

It is essential that patients are NOT co-prescribed the following medicines which
reduce MTX excretion: NSAIDS, aspirin, ciprofloxacin, co-trimoxazole,
penicillin, probenecid, omeprazole.

Two hours after administration of glucarpidase, leucovorin should be administered

at a dose of 250 mg/m2 every 6 hours by IV bolus (maximum rate: 160 mg/min)
for up to 48 hours and then decreased based on plasma MTX concentrations to
15mg/m2 intravenously or orally every 6 hours until the plasma MTX
concentration is < 0.2 μM.

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Liver Dysfunction: Samples for the determination of ALT value must be drawn
within 72 hours, PRIOR to a course of intravenous MTX. Blood samples for ALT
should not be drawn following the start of MTX infusions as MTX causes
significant short term elevation in ALT levels.

ALT IV MTX
< 10 X ULN Continue with therapy as scheduled
10 – 20 X ULN Continue with therapy as scheduled for 1 cycle
10 – 20 X ULN for 2 Discontinue TMP/SMX*
consecutive cycles Hold therapy until ALT < 10 X ULN, then
resume at full doses at point of interruption.
Do not skip doses.
> 20 X ULN Hold therapy until ALT < 10 X ULN, then
resume at full doses at point of interruption.
Do not skip doses.
> 20 X ULN for > 2 weeks Evaluate with AST, Bili, Alkaline phosphatase,
PT, albumin, total protein, and hepatitis A, B,
C, CMV, and EBV serologies.
Consider liver biopsy before additional therapy
given. Notify Study Chair.
* Please see COG Supportive care Guidelines at:
https://members.childrensoncologygroup.org/prot/reference_materials.asp for TMP/SMX
substitutions.

Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL.

Mucositis: For Grade 3-4 mucositis, withhold IV MTX until resolved. Increase
leucovorin rescue following the next course from 2 to 4 doses on a q6 hr schedule. If
subsequent course is not associated with Grade 3-4 mucositis, attempt to decrease the
number of leucovorin doses to 2. If mucositis recurs despite the extended leucovorin,
decrease the dose of MTX by 25%, increase hydration to 200 mL/m2/hr and continue
increased leucovorin as above. Should subsequent courses be well tolerated, use a
stepwise approach to resuming a standard approach to drug delivery. Consider
culturing lesions for herpes simplex if mucositis persists or recurs.

Myelosuppression: All chemotherapy should be held for ANC < 750/µL and
platelets < 75 000/µL.

See Section 5.13 for dose modifications when MTX is used post HSCT.

5.9 PO Methotrexate (MTX) and 6-Mercaptopurine (MP)

During Continuation:
a) ANC ≥ 750/µL and < 1000/µL and/or platelets ≥ 75 000/µL and < 100 000/µL:
Do not modify dose but recheck CBC in 1 week. If during subsequent 4 weeks
CBCs, ANC remains ≥ 750/µL and platelets remain ≥ 75 000/µL, continue at
100% doses and monitor CBC weekly.

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b) ANC ≥ 500/µL and < 750/µL and and/or platelets ≥ 50 000/µL and < 75 000/µL:
Reduce dose to 50% of original dose until ANC recovers to ≥ 750/µL and platelets
recover to ≥ 75 000/µL. Increase dose approximately every 2 weeks, first to 75%
of the original dose and then to full dose, provided ANC remains ≥ 750/µL and
platelets remain ≥ 75 000/µL.
c) ANC < 500/µL and/or platelets < 50 000/µL:
Discontinue dose until ANC is ≥ 750/µL and platelets are ≥ 75 000/µL. Restart
mercaptopurine and/or MTX at 50% of the original dose on the same day the
counts recover. Increase to 75% and then 100% of the original dose at 2-week
intervals provided ANC remains ≥ 750/µL and platelets remain ≥ 75 000/µL.
Consider a marrow evaluation in the face of persistent or prolonged neutropenia.

Prolonged cytopenia is defined as ANC < 750/µL and/or platelets < 75 000/µL after
withholding therapy for > 2 weeks. Perform a bone marrow examination after 2 weeks of
withholding chemotherapy, if no recovery is apparent. If monocyte count is increasing or
viral myelosuppression is clinically suspected, the bone marrow examination may be
postponed for 1-2 weeks and omitted if ANC and platelets fully recover by the 4th week
after therapy is withheld.

If patient develops severe or unexpected myelosuppression, i.e., doesn’t tolerate at least

half dose MP, see section below on thiopurine pharmacology testing.

During Maintenance:
If neutrophil count falls below 500/µL or if platelet count falls below 50 000/µL during
Maintenance, MP and MTX will be held until recovery above these levels. For the first drop
in ANC or platelets, resume chemotherapy (both MP and MTX) at the same dose the patient
was taking prior to the episode of myelosuppression. If neutrophil count falls below 500/µL
or if platelet count falls below 50 000/µL for a second (or greater) time, discontinue doses of
MP and MTX until ANC is ≥ 750/µL and platelets are ≥ 75 000/µL. Restart both MP and
MTX at 50% of the dose prescribed at the time the medication was stopped. Then continue to
increase to 75% and then 100% of the dose prescribed prior to stopping the medication at 2-4
week intervals provided ANC remains ≥ 750/µL and platelets remain ≥ 75 000/µL. May
increase both 6-MP and MTX simultaneously.

Consider discontinuing TMP/SMX as per COG Supportive care Guidelines at:

https://members.childrensoncologygroup.org/prot/reference_materials.asp.

If neutrophil count falls below 500/µL or if platelet count falls below 50 000/µL on > 2
occasions during Maintenance, perform thiopurine pharmacology testing as described below.
Should therapy be withheld for myelosuppression or elevated transaminase, do not “make up”
that week. Resume therapy at the correct point, chronologically.

Dose escalation during Maintenance:

No dose escalations are recommended during the first cycle of Maintenance.
• For ANC ≥ 1500/µL on 3 CBC(s) done over 6 weeks or 2 successive monthly CBC(s)
alternately increase doses of MTX or MP by 25%. As a general rule, do not increase doses
more often than every 4 weeks.
• If both MTX and MP are increased once without a fall in ANC, consider noncompliance
as a possibility. Noncompliance can be assessed by obtaining a sample for RBC

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thioguanine nucleotides (TGNs). Consider observing the administration of an oral dose

of MTX and checking plasma MTX concentration 2-4 hours later. This will document
whether or not poor absorption contributes to lack of response and may facilitate
discussions about noncompliance.

Mucositis Grade 3-4:

MTX should be reduced to 50% if Grade 3 toxicity develops; withhold in the presence of
Grade 4 toxicity until there is a resolution, then resume at 50% of original dose with gradual
dose escalation. If mucositis persists or recurs, consider culturing for herpes simplex.

Liver Dysfunction:
For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN
consistent with Grade 3 toxicity, obtain total bilirubin. Monitor SGPT/ALT or SGOT/AST
and total bilirubin weekly during Continuation and every 4 weeks during Maintenance as long
as transaminases remain over 5x ULN.

Continue full dose therapy unless either of the following occurs:

1) Direct bilirubin > 2.0 mg/dL
2) SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) on 2
determinations at least 1 week apart.

If either of these occurs, hold MTX and monitor labs as above, weekly. Restart at full dose
therapy when the transaminase is less than 5x ULN, if bilirubin is normal. If liver dysfunction
persists, consider a trial period with MTX but without MP, especially if red cell MP
methylated derivatives are elevated. Also consider liver biopsy.

Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT or
SGOT/AST above 5x ULN.

For dose modifications when MTX is given for GVHD prophylaxis see Section 5.13.3.

Thiopurine Pharmacology Testing and Dosage Adjustments:

MP and 6-TG are methylated directly by thiopurine methyltransferase (TPMT) to an
inactive metabolite. TPMT activity varies tremendously among patients, because of a
common inherited genetic defect in TPMT. One in 300 patients is completely deficient
(homozygous defective) and 10% of the population are moderately deficient in TPMT
activity because they have inherited one variant (non-functional) TPMT allele (i.e.,
heterozygotes). 68-71 Patients with low TPMT form higher concentrations of the 6-thioguanine
nucleotides (6-TGN) and are more susceptible to acute thiopurine toxicity (primarily
myelosuppression, involving neutropenia, thrombocytopenia, and anemia). Patients with
the complete deficiency of TPMT tolerate less than 10% of protocol doses of 6-MP (10 to
30 mg/m2/day 3 days per week). About 35% of heterozygotes require a lower dose of 6-
MP to avoid dose-limiting myelosuppression. 72

There are now CLIA certified tests for TPMT genotype and phenotype, and for thiopurine
metabolites (6-methyl mercaptopurine [6-MMP] and 6-TGN) measurements. Only 3 SNPs
constitute well over 90% of the inactivating mutations in the gene, based on studies in
numerous racial and ethnic groups worldwide. 68,73-76 Thus, the genotyping test has a low
false negative rate, and may be preferable to TPMT phenotype testing in cases where a
history of red cell transfusions would potentially confound assessments of RBC TPMT

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activity. When the genotyping result is coupled with a phenotyping test for TPMT or with
thiopurine metabolite concentrations in erythrocytes, the reliability of the tests will be even
greater. Moreover, metabolite levels can provide an index of patient compliance with
thiopurine therapy.

Recommendations for Thiopurine Monitoring and Dosage Adjustments:

When myelosuppression has led to significant delays in therapy (> 2 weeks) or is
disproportionate to the therapy, thiopurine testing should be performed:
- For patients who have received full dose thiopurine therapy during the 2 weeks
immediately preceding the test, RBC thiopurine metabolites will likely predict TPMT
status and actual thiopurine exposure.
- In the absence of RBC transfusions for 3 months prior, TPMT activity will accurately
reflect TPMT status
- TPMT genotyping will be informative in all patients, if at least 1 mutant allele is
identified. If not, and myelosuppression continues, send samples for TPMT activity
and/or metabolites since TPMT genotyping will miss 5%-10% of mutants. NOTE:
Genotyping can be done despite recent transfusions.

Suggested Dose Adjustments in Patients With Unacceptable Myelosuppression:

- If the patient is homozygous deficient for TPMT, the thiopurine dose should be
reduced to 10-20 mg/m2/day 3 days per week. If the patient is heterozygous for TPMT
and has experienced significant myelosuppression, the thiopurine dose should be
reduced by 30%-50%. Do not increase the dose in response to a high ANC for 4 weeks
to allow for achievement of steady state. All other myelosuppressive medications
should be delivered at full dose, and the thiopurine dose should be titrated based on
blood counts. Further thiopurine pharmacologic measures are not often necessary.

- If the patient is homozygous wild-type (high activity) for TPMT, then discontinue
TMP/SMX and use pentamidine or dapsone. For modifications of the oral MP and
MTX see the beginning of this section.
5.10 Steroids (Dexamethasone)
Hypertension: Dose should not be reduced. Sodium restriction and anti-hypertensives
should be employed in an effort to control hypertension. Avoid calcium channel blockers
due to their potential prohemorrhagic effect.

Hyperglycemia: Dose should not be reduced for hyperglycemia. Rather, insulin therapy
should be employed to control the blood glucose level.

Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase.
Discontinue steroids, except for stress doses, in the presence of hemorrhagic pancreatitis or
severe pancreatitis.

Osteonecrosis (ON): Do not modify corticosteroid therapy for osteonecrosis (also referred to
as avascular necrosis) prior to Maintenance therapy. Consider omitting Maintenance steroid
for osteonecrosis Grade 1 (clinically asymptomatic, radiographic finding only). Omit
Maintenance steroid for osteonecrosis Grade 2 or greater, and notify study chair. Consider
resuming Maintenance steroid after 6 months if joint symptoms have resolved and if MRI
findings have significantly improved or normalized.

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Varicella: Steroids should be held during active infection except during Induction. Do not hold
during incubation period following exposure.

Inability to use oral doses:

For dexamethasone, substitute the IV preparation mg for mg.

Severe infection: Do not hold or discontinue steroids during Induction without serious
consideration, as this is a critical period in the treatment of ALL. Later in therapy, one may
consider holding steroid until patient achieves cardiovascular stability, except for “stress
doses.”

Severe psychosis: Dexamethasone dose may be reduced by 50% for severe psychosis. If
symptoms persist, consider switching to an equivalent dose of prednisone.
5.11 PO 6-Thioguanine (TG)
Continuation:
Oral TG will be held for suspected or proven serious infection.

For severe and/or unexpected myelosuppression, evaluate for TPMT activity as described
in Section 5.9.

5.12 Vincristine
PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See text box
below)

Severe neuropathic pain (Grade 3 or greater):

Hold dose(s). When symptoms subside, resume at 50% previous calculated dose
(maximum dose: 1 mg), then escalate to full dose as tolerated. NOTE: neuropathic pain
can be not only severe but difficult to treat. However, because vincristine is an important
component of curative therapy and the majority of neuropathies are ultimately reversible,
vincristine therapy may be given at full dose at investigator discretion. Severe peripheral
neuropathies, with or without a positive family history might suggest the need for a
molecular diagnostic evaluation to rule out Charcot Marie Tooth Disease (CMT), Type 1A
or Hereditary neuropathy with liability to pressure palsies. Drugs such as gabapentin may
be of value.

Vocal Cord paralysis:

Hold dose(s). When symptoms subside, resume at 50% previous calculated dose
(maximum dose: 1 mg), then escalate to full dose as tolerated. See above for comment on
CMT.

Foot Drop, paresis:

Should be Grade 3 to consider holding or decreasing dose. These toxicities are largely
reversible but over months to years. Accordingly, holding doses of vincristine and/or
lowering the dose may not result in rapid resolution of symptoms and may compromise
cure. See above for comment on CMT. Physical therapy may be beneficial to maintain
range of motion and provide AFO’s and other forms of support. Drugs such as gabapentin
may be of value.
Jaw pain: Treat with analgesics; do not modify vincristine dose.

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Hyperbilirubinemia77,78:
Direct Bili Dose reduction
< 3.1 mg/dL Full dose (maximum dose: 2 mg),
3.1- 5.0 mg/dL 50% of calculated dose (maximum dose: 1 mg),
5.1-6.0 mg/dL 75% of calculated dose (maximum dose: 0.5 mg),
> 6.0 mg/dL Withhold dose and administer next scheduled dose if toxicity has
resolved.
Do not make up missed doses.

Constipation or ileus (≥ Grade 3) or typhlitis: Hold dose(s); institute aggressive regimen to

treat constipation if present. When symptoms abate resume at 50% of calculated dose
(maximum dose: 1 mg) and escalate to full dose as tolerated.

Extravasation:
In the event of an extravasation, discontinue the IV administration of the drug and
institute appropriate measures to prevent further extravasation and damage according to
institutional guidelines. Also see
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.
pdf for COG guidelines.

Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies

Peripheral Motor Neuropathy:

• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other
than abnormal deep tendon reflexes.

• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or
drawing, using eating utensils) or gait without abrogating ability to perform these
tasks.

• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or
drawing, using eating utensils) or unable to ambulate without assistance.

• Grade 4: Paralysis.

Peripheral Sensory Neuropathy:

• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with
extremity function.

• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic

medications (without causing loss of function), or alteration of fine motor skills
(buttoning shirt, writing or drawing, using eating utensils) or gait, without abrogating
ability to perform these tasks.

• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with

extremity function (gait, fine motor skills as outlined above), or quality of life (loss of
sleep, ability to perform normal activities severely impaired).

• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics.

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5.13 Stem Cell Transplant Regimen Agents

5.13.1 Tacrolimus
Tacrolimus commonly causes mild/moderate hypertension and alopecia and less
commonly kidney or liver dysfunction, transplant associated microangiopathy
(TAM), and neurological changes associated with significant hypertension. When
trough levels are kept in the therapeutic range and patients receive adequate
hydration and magnesium replacement, most of these side effects can be
minimized. Hypertension should be managed with single or combination
antihypertensive therapy. Tacrolimus should be held for severe toxicities thought
to be related to its administration (significant neurological changes/malignant
hypertension, TAM, kidney failure, etc.). Other immune suppressive medications
may be substituted if tacrolimus is not tolerated (MMF, cyclosporine, etc.).

5.13.2 Cyclosporine
Cyclosporine commonly causes mild/moderate hypertension and less commonly
kidney or liver dysfunction, TAM, and neurological changes associated with
significant hypertension. When trough levels are kept in the therapeutic range and
patients receive adequate hydration and magnesium replacement, most of these
side effects can be minimized. Hypertension should be managed with single or
combination antihypertensive therapy. Cyclosporine should be held for severe
toxicities thought to be related to its administration (significant neurological
changes/malignant hypertension, TAM, kidney failure, etc.). Other immune
suppressive medications may be substituted if cyclosporine is not tolerated

5.13.3 Methotrexate
The most common acute side-effects of methotrexate include delay of count
recovery, worsened mucositis, and kidney and liver damage (can contribute to
VOD). Toxicity is directly related to the length of exposure to the drug. While
methotrexate is generally excreted rapidly, delayed excretion of methotrexate
occurs with decreased renal function and in circumstances where patients have
third-space fluid collections (pulmonary effusions, ascites, joint effusions, etc.).
The attending transplant physician should assess each patient prior to delivery of
each dose and decide whether full dose methotrexate should be administered.
Guidelines for modification of methotrexate dosing are listed in the tables below.

Table 5.13.3.1: Methotrexate Dose Modification for Renal Impairment

Mild Moderate Severe Life-Threatening
Serum creatinine > 1.5-2 x baseline > 2-2.5 x > 2.5-3 x > 3 x baseline or
baseline baseline dialysis
% Methotrexate 0-50% 50-100% 100% 100%
Dose reduction (no drug) (no drug)
(Day +1, 3, 6, 11)

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Table 5.13.3.2: Methotrexate Dose Modification for Significant Mucositis

Stomatitis, Painless ulcers, Painful Cannot eat Complete
mucositis erythema, mild erythema, solids or obstruction or
soreness or mild edema, requires perforation
dysphagia ulcers or narcotics to
moderate eat, requires
dysphagia, parenteral
but can eat or enteral
without support.
narcotics
% Methotrexate 0% 0% 0-50% 50-100%
Dose reduction
(Day +1, 3, 6,
11)

For significant third spacing (ascites, effusions, significant edema or weight gain
> 5-10% above baseline) consider dose reductions of 50% and leucovorin rescue.

5.13.4 Guidelines for Leucovorin Rescue

Dose: Patients at risk for methotrexate toxicity should receive leucovorin at a dose
of 5-10 mg/m2 IV Q6H x 4 doses beginning 24 hours after administration of
methotrexate. While most patients will need only 4 doses of leucovorin, if
methotrexate levels are elevated due to renal dysfunction or other problems,
leucovorin doses should be continued until serum methotrexate concentration is <
1x10-7M. If serum methotrexate concentration is > 5x10-6M, increase dose to 100
mg/m2/dose IV Q3H until the serum methotrexate level is < 1x10-8M.

5.13.5 Mycophenylate Mofetil (MMF)

MMF can cause decreased counts, nausea, vomiting, diarrhea, hypertension,
dizziness, insomnia, hyperglycemia, electrolyte imbalances, rash, leg cramps, and
bone pain. For significant diarrhea or low counts (neutropenia, etc.), a decrease of
MMF by approximately 20% is usually sufficient to decrease the toxicity. Further
dose medications for significant toxicity likely caused by MMF are allowed.

5.13.6 Adjustment of TBI/chemotherapy During the Preparative Regimen.

The full dose of preparative regimen TBI and chemotherapy agents will be
administered unless patients have a life threatening reaction thought likely to occur
again with continued administration and an appropriate substitution cannot be
made (i.e. etopophos for etoposide).

5.13.7 Dose Adjustment of Chemotherapy for Patients Whose Weight Exceeds > 125%
Ideal Body Weight (IBW)
Chemotherapy given during the preparative regimen (thiotepa, cyclophosphamide,
and etoposide) will be dosed based on actual weight for patients ≤ 125% IBW.
Those > 125% IBW will be dosed based upon adjusted ideal body weight as
follows:
Adjusted ideal body weight = IBW + 0.25 (Actual weight – IBW).

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The following formulas for pediatric and adult IBW calculations are
recommended, but IBW may be calculated according to institutional standard
operating procedures (SOPs).

Recommended Ideal Body Weight Calculation for Children Age 1- 17 years

IBW = Height (cm)2 x 1.65

1000
Recommended Ideal Body Weight Calculation for Adults (Height > 5 feet/60
inches)
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg
IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg

6.0 DRUG INFORMATION

6.1 BLINATUMOMAB (AMG103, MT103, recombinant bispecific antibody derivative,

NSC#-707389), IND# 117467 (9/22/14)
Source and Pharmacology
Blinatumomab is a fusion protein composed of two single-chain antibodies (scFv), murine
anti-CD19 scFv and murine anti-CD3 scFv. Through CD3 binding, blinatumomab recruits
and engages T cells for redirected lysis of CD19-positive B cells, including those expressed
with B-cell malignancies. T cells are bound by its anti-CD3 moiety, whereas B cells are
bound by the anti-CD19 moiety. The subsequent serial lysis of multiple malignant cells by
a single blinatumomab-activated T cell closely resembles a natural cytotoxic T cell
reaction. Treatment with blinatumomab is associated with a rapid depletion of peripheral
B cells, accompanied by T cell activation and a transient increase in cytokines.
Blinatumomab consists of a single chain of 504 amino acids with a molecular weight of
approximately 54 kDa. The pharmacokinetics of blinatumomab was assessed over a dose
range from 5 to 90 mcg/m2/day (approximately equivalent to 9-162 mcg/day). Following
continuous intravenous infusion, the steady state serum concentration (Css) was achieved
within a day and remained stable over time. The estimated mean (SD) volume of
distribution based on terminal phase (Vz) was 4.52 (2.89) L. The estimated mean (SD)
systemic clearance was 2.92 (2.83) L/hour and the estimated mean (SD) half-life was
2.11(1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the
tested clinical doses. Like other protein therapeutics, blinatumomab is expected to be
degraded into small peptides and amino acids via catabolic pathways. At the clinical doses
of 9 mcg/day and 28 mcg/day for the treatment of adult relapsed/refractory ALL, the mean
(SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.
At this time there are no known drug interactions with blinatumomab.

Comprehensive Adverse Events and Potential Risks list (CAEPR)

for
Blinatumomab (AMG 103, NSC 765986)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single

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list of reported and/or potential adverse events (AE) associated with an agent using a
uniform presentation of events by body system. In addition to the comprehensive list, a
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a
separate column and is identified with bold and italicized text. This subset of AEs (SPEER)
is a list of events that are protocol specific exceptions to expedited reporting to NCI (except
as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting
Requirements'
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 486 patients. Below is the
CAEPR for Blinatumomab (AMG 103).

NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using
multiple investigational agents and has an AE listed on different SPEERs, use the lower of
the grades to determine if expedited reporting is required.

Version 2.2, February 11, 20151

Adverse Events with Possible

Relationship to Blinatumomab (AMG 103) Specific Protocol Exceptions to
(CTCAE 4.0 Term) Expedited Reporting (SPEER)
[n= 486]

Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%)

BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia Anemia (Gr 2)
Blood and lymphatic system Blood and lymphatic system disorders - Other
disorders - Other (coagulopathy)2
(coagulopathy)2 (Gr 2)
Blood and lymphatic system
disorders - Other
(lymphadenitis)
Blood and lymphatic system
disorders - Other
(pancytopenia)
Disseminated intravascular Disseminated intravascular coagulation2,3
coagulation2,3 (Gr 2)
Febrile neutropenia Febrile neutropenia (Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal pain Abdominal pain (Gr 2)
Constipation Constipation (Gr 2)
Diarrhea Diarrhea (Gr 2)
Gastric hemorrhage
Gastrointestinal disorders -
Other (pneumoperitoneum)
Nausea Nausea (Gr 2)
Oral hemorrhage
Pancreatitis
Vomiting Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Chills3 Chills3 (Gr 2)

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Adverse Events with Possible

Relationship to Blinatumomab (AMG 103) Specific Protocol Exceptions to
(CTCAE 4.0 Term) Expedited Reporting (SPEER)
[n= 486]

Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%)

Edema limbs Edema limbs (Gr 2)
Fatigue3 Fatigue3 (Gr 2)
Fever3 Fever3 (Gr 2)
Infusion related reaction
Non cardiac chest pain
HEPATOBILIARY DISORDERS
Hepatobiliary disorders - Other Hepatobiliary disorders - Other (hepatic
(hepatic function abnormal)4 function abnormal)4 (Gr 2)
IMMUNE SYSTEM DISORDERS
Allergic reaction3
Cytokine release syndrome3
Immune system disorders - Immune system disorders - Other
Other (immunodeficiency (immunodeficiency [immunoglobulin
[immunoglobulin decreased]) decreased]) (Gr 2)
INFECTIONS AND INFESTATIONS
Infection5 Infection5 (Gr 2)
INVESTIGATIONS
Activated partial thromboplastin
time prolonged2
Alanine aminotransferase Alanine aminotransferase increased4 (Gr 2)
increased4
Alkaline phosphatase increased4 Alkaline phosphatase increased4 (Gr 2)
Aspartate aminotransferase Aspartate aminotransferase increased4 (Gr 2)
increased4
Blood bilirubin increased4 Blood bilirubin increased4 (Gr 2)
Creatinine increased6
GGT increased4 GGT increased4 (Gr 2)
Investigations - Other (blood
fibrinogen increased)2
Investigations - Other (C- Investigations - Other (C-reactive protein
reactive protein increased) increased) (Gr 2)
Investigations - Other (fibrin D
dimer increased)2
Lymphocyte count decreased Lymphocyte count decreased (Gr 2)
Neutrophil count decreased Neutrophil count decreased (Gr 2)
Platelet count decreased2 Platelet count decreased2 (Gr 2)
Weight gain Weight gain (Gr 2)
White blood cell decreased White blood cell decreased (Gr 2)
METABOLISM AND NUTRITION DISORDERS
Hyperglycemia Hyperglycemia (Gr 2)
Hypokalemia Hypokalemia (Gr 2)
Hypomagnesemia
Hypophosphatemia
Tumor lysis syndrome7
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Back pain Back pain (Gr 2)

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Adverse Events with Possible

Relationship to Blinatumomab (AMG 103) Specific Protocol Exceptions to
(CTCAE 4.0 Term) Expedited Reporting (SPEER)
[n= 486]

Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%)

Bone pain
Pain in extremity Pain in extremity (Gr 2)
NERVOUS SYSTEM DISORDERS
Ataxia8
Cognitive disturbance8
Dizziness8 Dizziness8 (Gr 2)
Dysarthria8
Dysphasia8
Encephalopathy8

Facial nerve disorder8

Headache8 Headache8 (Gr 2)
Intracranial hemorrhage
Leukoencephalopathy
Memory impairment8
Nervous system disorders -
Other (apraxia)
Nervous system disorders -
Other (cerebellar syndrome)
Nervous system disorders -
Other8
Reversible posterior
leukoencephalopathy syndrome
Seizure8
Transient ischemic attacks8
Tremor8 Tremor8 (Gr 2)
PSYCHIATRIC DISORDERS
Agitation8
Anxiety8
Confusion8
Hallucinations8
Insomnia Insomnia (Gr 2)
Personality change8
Psychosis8
RENAL AND URINARY DISORDERS
Acute kidney injury8
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough Cough (Gr 2)
Dyspnea
Hypoxia
Pleural effusion
Pneumonitis
Respiratory failure
Voice alteration8
SKIN AND SUBCUTANEOUS TISSUE DISORDERS

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Adverse Events with Possible

Relationship to Blinatumomab (AMG 103) Specific Protocol Exceptions to
(CTCAE 4.0 Term) Expedited Reporting (SPEER)
[n= 486]

Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%)

Skin and subcutaneous tissue Skin and subcutaneous tissue disorders -
disorders - Other (rash)9 Other (rash)9 (Gr 2)
VASCULAR DISORDERS
Capillary leak syndrome3
Flushing3
Hypertension3 Hypertension3 (Gr 2)
Hypotension3 Hypotension3 (Gr 2)
Thromboembolic event Thromboembolic event (Gr 2)

1
This table will be updated as the toxicity profile of the agent is revised. Updates will be
distributed to all Principal Investigators at the time of revision. The current version can
be obtained by contacting [email protected]. Your name, the name of the
investigator, the protocol and the agent should be included in the e-mail.
2
Blinatumomab (AMG 103) is known to cause a variety of adverse events associated with
coagulopathy which may include: Activated partial thromboplastin time prolonged,
Disseminated intravascular coagulation, Fibrinogen decreased, INR increased,
Investigations - Other (blood fibrinogen increased), Investigations - Other (fibrin D dimer
increased), Investigations - Other (activated partial thromboplastin time shortened),
Investigations - Other (antithrombin III decreased), Investigations - Other (coagulation
factor XII level decreased), Investigations - Other (coagulation factor XIII level
increased), Investigations - Other (haptoglobin decreased), Investigations - Other (protein
S decreased), Platelet count decreased, and Thromboembolic events.
3
Symptoms of cytokine release syndrome (CRS) and/or allergic reaction may include
chills, fever, fatigue, flushing, bronchospasm, and hypotension. In some cases,
disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and
hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)
have been reported in the setting of CRS.
4
Symptoms of hepatic dysfunction may include Alanine aminotransferase increased,
Alkaline phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin
increased, and GGT increased under the INVESTGATIONS SOC.
5
Infection includes all 75 sites of infection under the INFECTIONS AND
INFESTATIONS SOC.
6
Acute kidney injury (acute renal failure) is associated with increased creatinine levels.
7
Tumor lysis syndrome is defined as a massive overload of potassium, phosphate, uric
acid, plus hypocalcemia, potentially causing lethal cardiac arrhythmias and/or renal
failure.

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8
Blinatumomab (AMG103) is known to cause a variety of nervous system disorders which
may include: Ataxia, Dizziness, Cognitive disturbance, Concentration impairment,
Depressed level of consciousness, Dysphagia, Dysarthria, Dysesthesia, Encephalopathy,
Facial nerve disorder, Headache, Memory impairment, Paresthesia, Peripheral sensory
neuropathy, Seizure, Somnolence, Syncope, Transient ischemic attacks, Tremor, Voice
alteration, Nervous system disorders - Other (allodynia), Nervous Systems disorders -
Other (cerebellar syndrome), Nervous system disorders - Other (dysgraphia), Nervous
system disorders - Other (epilepsy), Nervous system disorders - Other (facial palsy),
Nervous system disorders - Other (hemiparesis), Nervous system disorders - Other
(hypertonia), Nervous system disorders - Other (pleocytosis), and Nervous system
disorders - Other (polyneuropathy). Additionally, symptoms of some nervous system
disorders are adverse events under the PSYCHIATRIC DISORDERS SOC and may
include: Confusion, Agitation, Anxiety, Hallucinations, Personality change, and
Psychosis.
9
Rash includes rash, rash maculo-papular, erythema, erythematous rash, generalized rash,
exanthema, allergic dermatitis, and palmar-plantar erythrodysesthesia syndrome.

Adverse events also reported on blinatumomab (AMG 103) trials but with the
relationship to blinatumomab (AMG 103) still undetermined:

BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis

CARDIAC DISORDERS - Atrial fibrillation; Heart failure; Cardiac arrest; Myocardial
infarction; Pericardial effusion; Sinus bradycardia; Sinus tachycardia; Supraventricular
tachycardia
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial
and genetic disorders - Other (aplasia)
EAR AND LABYRINTH DISORDERS - Vertigo
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema
face; Gait disturbance; General disorders and administration site conditions - Other
(thrombosis in device); Hypothermia
INVESTIGATIONS - Investigations - Other (blood lactate dehydrogenase increased);
Investigations - Other (hypoproteinemia); Investigations - Other (lipase decreased);
Lipase increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Acidosis; Anorexia; Dehydration;
Hyperuricemia; Hypoalbuminemia; Metabolism and nutrition disorders - Other (fluid
overload)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia;
Generalized muscle weakness
NERVOUS SYSTEM DISORDERS - Somnolence; Syncope
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary incontinence
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS -
Bronchospasm3; Epistaxis; Respiratory, thoracic and mediastinal disorders - Other
(chronic obstructive pulmonary disease)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Periorbital
edema; Pruritus; Skin and subcutaneous tissue disorders - Other (skin irritation)

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Note: Blinatumomab (AMG 103) in combination with other agents could cause an
exacerbation of any adverse event currently known to be caused by the other agent, or the
combination may result in events never previously associated with either agent

Pregnancy and lactation

Pregnancy Category Unknown: The effect of blinatumomab on fertility has not been
evaluated. Blinatumomab is not recommended in pregnant women and in women of
childbearing potential not using contraception. It is not known whether blinatumomab or its
metabolites are excreted in human milk. Women are not allowed to breastfeed while receiving
blinatumomab.

Formulation and Stability

Blinatumomab is available as a 30.3 mcg preservative-free, white to off-white lyophilized
powder for injection in 4 mL single-use vial. The agent is formulated with 2.89 mg citric
acid monohydrate, 82.5 mg trehalose dihydrate, 20.1 mg lysine hydrochloride, and 0.55 mg
polysorbate 80, pH 7. The stopper of the vial is butyl rubber (IIR), latex free.

IV solution stabilizer for blinatumomab (NSC 773150) is not for reconstitution of

blinatumomab; it is a component of the final intravenous product. The stabilizer is available
as a 10 mL single-use vial of a preservative-free, clear, colorless-to-slightly yellow liquid
solution. Each solution consists of 25 mM citric acid monohydrate, 1.25 M L-lysine
hydrochloride, and 0.1% (w/v) polysorbate 80, pH 7. The stopper of the vial is latex free butyl
rubber (IIR).

Store intact vials of blinatumomab and the IV solution stabilizer of blinatumomab refrigerated
at 2° – 8°C (36° – 46°F). Protect from light. Shelf life stability studies of the intact vials of
blinatumomab and stabilizer solution are on-going. The stability of the final prepared IV
solution is 8 days when stored refrigerated at 2° – 8°C. For storage prior to administration,
the prepared infusion solution must be kept at 2° C to 8° C ( 36°F to 46°F). The total storage
and administration time must not exceed 8 days. Once at room temperature, discard the IV
bag after 48 hours.

Preparation
Only trained staff may prepare the blinatumomab IV solution. Each site’s standard
procedure for compounding blinatumomab must be in compliance with the USP < 797 >
guidelines (ISO Class 5 or better). Use aseptic technique and prepare blinatumomab IV
solution under a qualified biological safety cabinet.

The label on the IV bag must include the following:

• Patient name and number
• Name of the drug
• Dose (mcg/day and volume/day)
• Infusion rate
• Expiration date and time
• CAUTION: NEW DRUG – Limited by United States law to investigational
use.
• Bag number
• Additional information as required by state, local, and country pharmacy
regulations.

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Blinatumumab must be dispensed in an acceptable IV bag. Acceptable bags

include those made of polyolefin/polyethylene, ethylene vinyl acetate (EVA), or
PVC non-DEHP.

The final IV solution must be prepared in the following sequential order (do not
deviate from this order; refer to the table below for volume details):
1. Reconstitute blinatumomab lyophilized powder (30.3 mcg/vial)
a. Add 3 mL of Sterile Water for Injection (SWFI) to the vial to yield
3.07 mL of blinatumomab at a final concentration of 9.87
mcg/mL.
b. Rotate the vial to dissolve all powder. Do not shake.
c. The stability of the reconstituted vial is 4 hours at room
temperature (22°C – 27°C) or 24 hours refrigerated at 2° – 8°C.
2. Add the appropriate amount of 0.9% NaCl into the IV bag
3. Add the IV solution stabilizer for blinatumomab to the IV bag
4. Add the calculated dose (mL) of blinatumomab into the solution in the IV
bag
a. Rotate the IV bag to mix the solution thoroughly. Do not shake.
Avoid foaming the IV bag.
b. Visually inspect for floating particles or discoloration of the IV
solution. If floaters or discoloration is present, do not use the
prepared solution.
c. The total volume of blinatumomab IV solution will account for the
volume of the IV infusion set for the inpatient or outpatient setting.

VOLUME CALCULATION TABLE

Volume to be
Volume to be prepared
infused
INPATIENT
1. Add ____ mL NaCl (calculated volume
24-hour IV bag of 0.9% NaCl)1 into approved IV bag*
(includes 30 mL 2. Add 3 mL IV solution stabilizer for
overfill) blinatumomab2 120 mL
3. Add ____ mL blinatumomab (calculated
dose volume per 150 mL bag)3
150 mL total volume4
1
0.9% NaCl (mL) = total volume to be prepared (150 mL) – stabilizer solution volume (3 mL)
– blinatumomab calculated dose volume (mL) per 150 mL bag
2
stabilizer solution (3 mL) = 0.02 x total volume to be prepared (150 mL)
3
blinatumomab calculated dose volume per 150 mL bag (mL) = 24 hour dose (mcg) / 24 hour
infusion volume (120 mL) x total volume to be prepared (150 mL) / blinatumomab
concentration (9.87 mcg/mL)
4
total volume (150 mL) = Volume to be infused (120 mL) + 30 mL overfill per 24 hour dose
(IV infusion set)
Volume to be
Volume to be prepared
infused
OUTPATIENT

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1. Add ____ mL NaCl (calculated volume

48-hour IV bag of 0.9% NaCl)1 into approved IV bag*
(includes 10 mL 2. Add 5 mL IV solution stabilizer for
overfill) blinatumomab2 240 mL
3. Add ____ mL blinatumomab (calculated
dose volume per 250 mL bag)3
250 mL total volume4
1
0.9% NaCl (mL) = total volume to be prepared (250 mL) – stabilizer solution volume (5 mL)
– blinatumomab calculated dose volume (mL) per 250 mL bag
2
stabilizer solution (5 mL) = 0.02 x total volume to be prepared (250 mL)
3
blinatumomab calculated dose volume per 250 mL bag (mL) = 48 hour dose (mcg) / 48 hour
infusion volume (240 mL) x total volume to be prepared (250 mL) / blinatumomab
concentration (9.87 mcg/mL)
4
total volume (250 mL) = Volume to be infused (240 mL) + Outpatient IV infusion set volume
(10 mL)

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

IV infusion and infusion set details:

Blinatumumab must be administered through a central line at rate of 5 mL/hr IV over 24
hours through an acceptable IV line. Only PVC non-DEHP lines with a 0.2 µm inline
filter are acceptable. Do not flush the IV line as it will create an IV bolus to be
administered into the patient. For outpatient administration, use FDA approved pumps. Only
the exact volume should be administered; any remaining overfill should be discarded
appropriately.

Infusion pump requirements:

Use a programmable pump that is approved by the appropriate regulatory authority for the
country in which the subject is undergoing treatment. The pump alarm must be visual and
auditory. The pump must be lockable. Elastomeric pumps are NOT allowed. Cassettes
for CADD Infusion pumps are NOT allowed.

Should blinatumomab need to be administered through a pharmacy satellite or home health

care service center, refer to the outpatient administration guidelines in Appendix VII .

Record all infusion interruptions. Technical or logistical interruption must be as minimal

as possible and re-start the infusion as soon as possible. If an interruption is longer than four
hours, the re-start of the infusion must take place in the hospital under supervision of the
investigator. Monitor patients for potential adverse events as described in the protocol and
the Investigator Brochure.

Monitor patients for cytokine release syndrome, tumor lysis syndrome, and infusion
reaction. Refer to protocol for specific recommendation. Monitor patients for psychiatric
events such as confusion, disorientation, and cognitive attention disturbances. Patients
should not drive or operate dangerous machinery while receiving blinatumomab.

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Supplier
Blinatumomab and the solution stabilizer for blinatumomab is supplied by Amgen, Inc
and distributed by the Division of Cancer Treatment and Diagnosis (DCTD), NCI.

Obtaining the Agent

Agent Ordering:
NCI supplied agent may be requested by the Principal Investigator (or their authorized
designee) at each participating institution. Pharmaceutical Management Branch (PMB)
policy requires that agent be shipped directly to the institution where the patient is to be
treated. PMB does not permit the transfer of agents between institutions (unless prior
approval from PMB is obtained). The CTEP assigned protocol number must be used for
ordering all CTEP supplied investigational agents. The responsible investigator at each
participating institution must be registered with CTEP, DCTD through an annual
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae,
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there
are several participating investigators at one institution, CTEP supplied investigational
agents for the study should be ordered under the name of one lead investigator at that
institution.

Active CTEP-registered investigators and investigator-designated shipping designees and

ordering designees must submit agent requests through the PMB Online Agent Order
Processing (OAOP) application https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx.
Access to OAOP requires the establishment of a CTEP Identity and Access Management
(IAM) account https://eapps-ctep.nci.nih.gov/iam/ and the maintenance of an “active”
account status and a “current” password. For questions about drug orders, transfers, returns,
or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30
pm (ET) or email [email protected] anytime.

Agent Accountability
Agent Inventory Records:
The investigator, or a responsible party designated by the investigator, must maintain a
careful record of the inventory and disposition of all agents received from DCTD using the
NCI Drug Accountability Record Form (DARF). See the CTEP home page at
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain
a copy of the DARF and Clinical Drug Request form.

Agent Returns:
Investigators/Designees must return unused DCTD supplied investigational agent to the
NCI clinical repository as soon as possible when: the agent is no longer required because
the study is completed or discontinued and the agent cannot be transferred to another
DCTD sponsored protocol; the agent is outdated or the agent is damaged or unfit for use.
Regulations require that all agents received from the DCTD, NCI be returned to the DCTD,
NCI for accountability and disposition. Return only unused vials/bottles. Do NOT return
opened or partially used vials/bottles unless specifically requested otherwise in the
protocol. See the CTEP web site for Policy and Guidelines for Investigational agent
Returns at: http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs.
The appropriate forms may be obtained at:
http://ctep.cancer.gov/forms/docs/return_form.pdf

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6.2 ASPARAGINASE Erwinia chrysanthemi

(Erwinia chrysanthemi, Erwinase®, Erwinaze®, Crisantaspase) NSC #106977 (01/21/15)

Source and Pharmacology:

L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic
acid by a reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells
associated with acute lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic
lymphosarcoma are asparagine-dependent but lack asparagine synthetase activity. The
administration of L-asparaginase produces an anti-neoplastic effect by catalyzing
asparagine into aspartic acid and ammonia. As a result, these cells lack the ability to
produce the asparagine necessary for protein metabolism and survival. Deamination of
glutamine may also play a role in the antineoplastic activity of asparaginase.

Asparaginase Erwinia chrysanthemi (Erwinaze®) is asparaginase derived from cultures of

Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical
subunits has a molecular weight of approximately 35 kDa. Asparaginase Erwinia
chrysanthemi is immunologically distinct from E. coli L-asparaginase and may allow
continued asparaginase therapy when a hypersensitivity reaction occurs to Escherichia
coli-derived asparaginase. The package labeling states that there is insufficient information
to characterize the incidence of antibodies to asparaginase Erwinia chrysanthemi. Several
factors are involved in immunogenicity assay results and the assessment of antibodies,
including assay methodology, assay sensitivity and specificity, sample handling, timing of
sample collection, concomitant medications, and the underlying disease state. The
following data have been reported on each of the three preparations of asparaginase:

Clinical Pharmacology % Anti-Asparaginase

of Asparaginase Elimination half-life (IM) Antibody positive
Formulation patients
Native Escherichia Coli 26-30 hours 45-75
Pegylated-asparaginase 5.5-7 days 5-18
Erwinia Asparaginase 16 hours (7-13 hrs package insert) 30-50
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase
Formulations: The Past, the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 (4):
367-393.

Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per
mL. Clinical trials with asparaginase Erwinia chrysanthemi demonstrated that 100% of
patients achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13,
respectively) following the third total dose when given on a Monday, Wednesday, Friday
schedule using the IM route of administration. In a multicenter study characterizing the
pharmacokinetic profile of 25,000 International Units/m2 Erwinaze® given intravenously
over one hour on the same dosing schedule of Monday, Wednesday, Friday for 2
consecutive weeks, 83% (20/24) and 43% (9/21) of evaluable patients achieved an
asparaginase activity level of ≥ 0.1 International Units/mL at 48 post-dose 5 and 72 hours
post-dose 6, respectively.79 No formal drug interaction studies have been performed with
asparaginase Erwinia chrysanthemi.

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Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Allergic reactions, Local injection site
Within 1-2 days of anaphylaxis, urticaria reactions, fever
receiving drug
Prompt: Pancreatitis, glucose
Within 2-3 weeks, intolerance,
prior to the next thrombosis, hemorrhage,
course transient ischemic attack,
disseminated intravascular
coagulation,
hyperbilirubinemia,
alanine aminotransferase
increased, aspartate
aminotransferase
increased, hyperglycemia,
hyperammonemia,
vomiting, nausea,
abdominal pain,
headache, diarrhea, seizure
Unknown Fetal toxicities and teratogenic effects of L-asparaginase have been noted in
Frequency and animals. It is unknown whether the drug is excreted in breast milk. Adequate,
Timing: well-controlled studies of asparaginase Erwinia chrysanthemi have NOT
been conducted. It is not known whether asparaginase Erwinia chrysanthemi
will cause fetal harm or affect the ability to reproduce. It is not known if
asparaginase Erwinia chrysanthemi is excreted into breast milk. The use of
asparaginase Erwinia chrysanthemi should be avoided in pregnant or
lactating patients.
(L) Toxicity may also occur later.

Formulation and Stability:

Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000
International Units of asparaginase Erwinia chrysanthemi and the following inactive
ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg). Store intact vials
between 2°C and 8°C (36° to 46ºF). Protect from light.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Erwinia asparaginase can be administered by intramuscular injection or by intravenous

infusion. Use appropriate precautions for preparation of a hazardous agent. Visually inspect
the powder in vial for foreign particles or discoloration prior to reconstitution.

For intramuscular administration, the contents of each vial should be reconstituted by slowly
adding 1 mL or 2 mL of sterile, preservative-free NS to the inner vial wall. The final
concentration is 10,000 International Units per mL when using 1 mL for reconstitution or
5,000 International Units per mL when using 2 mL for reconstitution. Gently mix or swirl the
contents to dissolve the contents of the vial. Do not shake or invert the vial. The resulting
solution should be clear and colorless. Discard if any particulate matter or protein aggregates

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are visible. Withdraw the appropriate dosing volume into a polypropylene syringe
within 15 minutes of reconstitution. Polycarbonate luer-lok syringes from B-D (1 mL) are
also acceptable (personal communication, EUSA Pharma). Discard any unused drug; do not
save or use any unused drug remaining in the vial.

For intravenous use, infuse Erwinia asparaginase in 100 mL of normal saline over 1-2 hours.
Do not infuse other intravenous drugs through the same intravenous line while infusing
Erwinia asparaginase.

Drug Ordering:
In the United States, asparaginase Erwinia chrysanthemi (ErwinazeTM) is distributed by
Accredo Health Group, Inc. An institutional contract with Accredo is required in order to
purchase the product. Accredo’s contact information is as follows:

Accredo Health Group, Inc.

1640 Center Parkway, Suite 8
Memphis, TN 38134
Phone: 1-877-900-9223
Fax: 1-866-628-8942
Email: [email protected]

CANADIAN SITES
Asparaginase Erwinia chrysanthemi is commercially available in Canada. Canadian sites
may purchase the Canadian commercial supply from EUSA via CGF Pharmatech,
Montreal, Quebec, a subsidiary of EUSA (order desk phone: 1-514-343-0344 or 1-866-
343-0344, fax: 1-514-343-0340). CGF requests that a site fax a Purchase Order number.
There is no special fax order form. Shipments are sent Monday to Wednesday only and
usually arrive at the site within 48-72 hours.

Special precautions:
1. Pegaspargase is contraindicated with a history of severe pancreatitis with any prior
asparaginase therapy. Caution should be used if serious thrombosis or hemorrhagic
events have occurred with any prior asparaginase therapy (see Section 5.1)
2. Pegaspargase may affect coagulation factors and predispose to bleeding and/or
thrombosis. Caution should be used when administering any concurrent anticoagulant
therapy.
3. Suggested monitoring during and after administration: Because pegaspargase is long
acting, hypersensitivity reactions may not appear for hours after drug administration.
Monitor vital signs, for signs of fever, chills, or acute allergic reactions including
anaphylaxis. Have medications to treat hypersensitivity reactions readily available at
each administration (e.g., epinephrine, IV corticosteroids, antihistamines). Consider
prescribing an EpiPen® for home use.

6.3 CYCLOPHOSPHAMIDE INJECTION (Cytoxan) NSC #26271

Source and Pharmacology:

Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in
the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC),

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which is in equilibrium with aldophosphamide, which spontaneously releases acrolein to

produce phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional
alkylating species, is 10 times more potent in vitro than is 4-HC and has been shown to
produce interstrand DNA cross-link analogous to those produced by mechlorethamine.
Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive
carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges from 4.1 to
16 hours after IV administration.

Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Anorexia, nausea & Abdominal discomfort, Transient blurred vision,
Within 1-2 vomiting diarrhea nasal stuffiness with
days of (acute and delayed) rapid administration,
receiving drug arrhythmias (rapid
infusion), skin rash,
anaphylaxis, SIADH
Prompt: Leukopenia, alopecia, Thrombocytopenia, Cardiac toxicity with
Within 2-3 immune suppression anemia, hemorrhagic high dose (acute – CHF
weeks, prior to cystitis (L) hemorrhagic myocarditis,
the next course myocardial necrosis) (L),
hyperpigmentation, nail
changes, impaired wound
healing, infection
secondary to immune
suppression
1
Delayed: Gonadal dysfunction: Amenorrhea Gonadal dysfunction:
Any time later azoospermia or ovarian failure1 (L),
during therapy oligospermia (prolonged interstitial pneumonitis,
or permanent)1 (L) pulmonary fibrosis2 (L)
Late: Secondary malignancy
Any time after (ALL, ANLL, AML),
completion of bladder carcinoma (long
treatment term use > 2 years),
bladder fibrosis
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of cyclophosphamide
(alone or in combination with other antineoplastic agents) have been noted in humans. Toxicities
include: chromosomal abnormalities, multiple anomalies, pancytopenia, and low birth weight.
Cyclophosphamide is excreted into breast milk. Cyclophosphamide is contraindicated during
breastfeeding because of reported cases of neutropenia in breast fed infants and the potential for
serious adverse effects.
1
Dependent on dose, age, gender, and degree of pubertal development at time of treatment.
2
Risk increased with pulmonary chest irradiation and higher doses.
(L) Toxicity may also occur later.

Formulation and Stability:

Cyclophosphamide for injection is available as powder for injection or lyophilized powder
for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains
75 mg mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is
recommended. The product will withstand brief exposures to temperatures up to 30ºC
(86ºF).

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Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Cyclophosphamide for Injection:

If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then
reconstitute to 20 mg/mL with NS ONLY to avoid a hypotonic solution. If the drug will be
further diluted prior to administration, then first reconstitute with NS, SWFI, or Bacteriostatic
Water for Injection (paraben preserved only) to a concentration of 20 mg/mL. Following
reconstitution further dilute in dextrose or saline containing solutions for IV use.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.4 CYCLOSPORINE A (Cyclosporine, CYA, Sandimmune®, Neoral®, Gengraf®)

Source and Pharmacology:

Cyclosporine (CSA) is a lipophilic fungal peptide consisting of 11 amino acids. CSA is a
potent immunosuppressive agent that prolongs survival of allogeneic transplants involving
skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Current evidence
suggests that cyclosporine selectively inhibits the transcription of IL-2, the action of which
stimulates the proliferation of activated T-lymphocytes. CSA has been shown in vitro to be
a potent inhibitor of P-glycoprotein, which has been postulated to be a factor in multi-drug
resistance to various antineoplastic agents. The terminal half-life of CSA is approximately
19 hours (range 10 to 27 hours). Ninety-nine percent of CSA is metabolized. Elimination is
primarily biliary with approximately 6% excreted in the urine. In the circulation, CSA is
mainly bound to high, low, or very low density lipoproteins and to chylomicrons. Only a
small fraction circulates unbound. The volume of distribution varies from 3.5 L/kg to 13 L/kg
with higher concentrations of drug found in the liver, lymphocytes, kidney, heart, lung,
pancreas, fat, neural, and muscle cells. CSA clearance rates have been shown to be higher in
pediatric patients and for patients < 25 years old. The absorption of cyclosporine from the
gastrointestinal tract is incomplete and variable exhibiting large intra- and inter-patient
variability. Drugs that stimulate or inhibit hepatic P450 enzymes will alter clearance of CSA
and close attention to potential drug interactions is crucial.

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Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 Happens to < 5 children
children out of every 100 children out of every 100 out of every 100
Immediate: Hypertension (L), Headache (L), nausea Anaphylaxis,
Within 1-2 days immunosuppression (L) and vomiting, diarrhea angioedema, seizure (L),
of receiving drug arrhythmia, chest pain,
fever, facial flushing
Prompt: Tremor (L), renal Hypomagnesemia (L), Confusion (L),
Within 2-3 dysfunction (acute with hyperlipidemia (L) somnolence (L),
weeks, prior to decrease in GFR, insomnia, depression (L),
the next course impaired urinary anxiety, dizziness, rash,
concentrating ability, and urticaria, acne,
sodium retention) hyperkalemia,
encephalopathy,
hemolytic-uremic
syndrome, cardiac failure,
MI, leukopenia (L),
anemia,
thrombocytopenia,
increased creatinine,
infections,
hyperbilirubinemia (L),
hepatic insufficiency
Delayed: Hirsutism (L) Gingival hyperplasia (L) Tinnitus, vestibular
Any time later disorder, cholelithiasis,
during therapy, cataracts (L),
excluding the gynecomastia, chronic
above conditions renal dysfunction
Late: Lymphoproliferative
Any time after disorders, skin
completion of malignancies
treatment
Unknown Fetal toxic effects of cyclosporine have been noted in animals. Of the reported
Frequency and outcomes of 116 pregnancies in women receiving cyclosporine during
Timing: pregnancy, 90% of whom were transplant patients, and most of whom received
cyclosporine throughout the entire gestational period, the only consistent
patterns of abnormality were premature birth (gestational period of 28 to 36
weeks) and low birth weight for gestational age. Cyclosporine is excreted in
human milk; nursing should be avoided.
(L) Toxicity may also occur later.

Formulation and Stability:

IV formulation:
Cyclosporine (non-modifiedSandIMMUNE®) is available as a (50 mg/mL) 5 mL ampule
use containing 650 mg polyoxyethylated castor oil (cremophor) and 32.9% alcohol. Store at
temperatures below 30°C (86°F) and protected from light.
Oral formulations:
Non-modified:
Cyclosporine (SandIMMUNE®) 25 mg and 100 mg capsule, 100 mg/mL oral solution.
Inactive ingredients include: Sandimmune® Capsule = dehydrated alcohol, sorbitol,

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glycerol, corn oil, gelatin, polyoxyethylated glycolysed glycerides. Sandimmune®

Solution = olive oil, dehydrated alcohol, polyoxyethylated glycolysed glycerides.
Modified:
Cyclosporine (modified, Neoral®, Gengraf®) is available as a 25 mg capsule, 100 mg
capsule, and 100 mg/mL oral solution. Inactive ingredients include: Neoral® capsule and
solution = dehydrated alcohol, corn oil, polyoxyl 40 hydrogenated castor oil, α tocopherol,
gelatin, and propylene glycol. Gengraf® Capsule and solution = dehydrated alcohol,
gelatin, polyethylene glycol, polyoxyl 35 castor oil, polysorbate 80, propylene glycol, and
sorbitan monooleate.
Store capsules in the original unit-dose container at controlled room temperature, 15°-30°C
(59°-86°F). Store oral solutions in the original container at controlled room temperature,
68°-77°F (20°-25°C). Do not store in the refrigerator. Once opened, the contents must be
used within two months. At temperatures below 68°F (20°C) the solution may gel; light
flocculation or the formation of a light sediment may also occur. There is no impact on
product performance or dosing using the syringe provided. Allow to warm to room
temperature, 77°F (25°C), to reverse these changes.
NOTE: Sandimmune®, Neoral®, and Gengraf® ARE NOT BIOEQUIVALENT. Liquid
formulations of each trade name are equivalent to capsules of that same trade name.
Conversion from one trade name product to another is generally done at a 1:1 ratio, but
requires close monitoring. Conversions from IV to PO are usually done at a 1:3 ratio, but
should be monitored closely. Adjusting emulsion products to the same trough concentration
as other oral products results in greater total exposure to the drug.
Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.
Injection:
Dilute 1 mL (50 mg) of cyclosporine injection IV concentrate (non-modified,
SandIMMUNE®) in 20 mL-100 mL NS or D5W (0.5-2.5 mg/mL). Diluted infusion
solutions are stable for 24 hours at room temperature under fluorescent light.
The Cremophor® EL (polyoxyethylated castor oil) contained in the concentrate for
intravenous infusion can cause phthalate stripping from PVC. It is strongly recommended
that glass bottles and non-PVC tubing be used to minimize patient exposure to DEHP.
Monitor closely for an acute allergic reaction for the first 30 minutes and at frequent
intervals thereafter. Note: cyclosporine absorbs into plastics and can give falsely high
serum or blood concentrations if blood samples are collected from the same line through
which cyclosporine was administered.
Oral:
Administer at a consistent time of day and at consistent intervals with regard to meals. Do
not use plastic or styrofoam cups. If diluted with juice or milk, use a glass container and rinse
with additional diluent, and then consume to ensure that complete dose has been taken. Do
not use water or cleaning agents on the dosing syringe. To improve palatability, mix
Sandimmune® with milk, chocolate milk or orange juice; mix Neoral® or Gengraf® with
orange juice or apple juice but NOT milk. After mixed, have patient consume immediately.
DO NOT MIX GRAPEFRUIT JUICE with any cyclosporine-containing product.
Grapefruit juice consumption should be avoided during therapy with cyclosporine.

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Supplier: Commercially available. See package insert for further information.

6.5 CYTARABINE - ALL ROUTES

(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878
Source and Pharmacology:
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but
significant, incorporation of cytarabine into both DNA and RNA has also been reported. It
exhibits cell Phase specificity, primarily killing cells undergoing DNA synthesis (S-Phase)
and under certain conditions blocking the progression of cells from the G1 Phase to the S-
Phase. Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to
the nucleotide triphosphate (Ara-CTP), an effective inhibitor of DNA polymerase. Ara-
CTP is inactivated by a pyrimidine nucleoside deaminase, which converts it to the nontoxic
uracil derivative (Ara-U). It appears that the balance of kinase and deaminase levels may
be an important factor in determining sensitivity or resistance of the cell to cytarabine. It
has an initial distributive Phase t½ of about 10 minutes, with a secondary elimination Phase
t½ of about 1 to 3 hours. Peak levels after intramuscular or subcutaneous administration of
cytarabine occur about 20 to 60 minutes after injection and are lower than IV
administration. Intrathecally administered doses are metabolized and eliminated more
slowly with a t½ of about 2 hours.

Toxicity: (Intravenous, SubQ, IM)

Common Occasional Rare
Happens to 21-100 children Happens to 5-20 children Happens to < 5 children
out of every 100 out of every 100 out of every 100
Immediate: Nausea, vomiting, anorexia Flu-like symptoms with Ara-C syndrome (fever,
Within 1-2 days of fever, rash myalgia, bone pain,
With High Dose:
receiving drug occasionally chest pain,
conjunctivitis
maculopapular rash,
malaise, conjunctivitis),
anaphylaxis
With High Dose:
cardiomyopathies
(vasculitis, and
pericarditis), cerebral and
cerebellar dysfunction
including:
encephalopathy, aseptic
meningitis, ataxia,
dysphasia, nystagmus, a
decreased level of
consciousness,
personality changes,
somnolence, seizures
Prompt: Myelosuppression (anemia, Diarrhea, hypokalemia, Hepatotoxicity, sinusoidal
Within 2-3 weeks, thrombocytopenia, hypocalcemia, obstruction syndrome
prior to the next course leukopenia, megaloblastosis, hyperuricemia (SOS, formerly VOD),
reticulocytopenia), urinary retention, renal
With High Dose: capillary
stomatitis, alopecia dysfunction, pain and
pulmonary leak syndrome
erythema of the palms
(RDS, pulmonary edema)
and soles
Delayed: Asymptomatic
Any time later during nonoliguric
therapy, excluding the rhabdomyolysis
above conditions

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Unknown Frequency Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It
and Timing: is unknown whether the drug is excreted in breast milk.

Toxicity: (Intrathecal)
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Nausea, vomiting, fever, Arachnoiditis Rash, somnolence,
Within 1-2 days of headache meningismus,
receiving drug convulsions, paresis
Prompt: Myelosuppression,
Within 2-3 weeks, ataxia
prior to the next
course
Delayed: Necrotizing
Any time later leukoencephalopathy,
during therapy, paraplegia, blindness (in
excluding the above combination with XRT
condition & systemic therapy)

Formulation:
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a
sterile powder for reconstitution. It is also available at a 20 mg/mL concentration with
benzyl alcohol (25 mL per vial) or as a preservative free solution (5 mL, 50 mL per vial),
and at a 100 mg/mL concentration with benzyl alcohol (20 mL vial) or as preservative free
solution (20 mL vial). Hydrochloric acid and/or sodium hydroxide may be added to adjust
the pH. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Cytarabine
solutions should be protected from light.
Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.
IV Infusion:
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection.
Solution containing bacteriostatic agent should not be used for the preparation of doses
> 200 mg/m2. May be further diluted with dextrose or sodium chloride containing solutions.
May give by IV push injection, by IV infusion, or by continuous infusion.
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a
concentration of 20-100 mg/mL.
High Dose (≥ 1000 mg/m²/dose): Administer steroid eye drops (dexamethasone or
prednisolone), 2 drops each eye q6h beginning immediately before the first dose and
continuing 24 hours after the last dose. If patient does not tolerate steroid eye drops,
administer artificial tears on a q2-4 hour schedule.
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for
48 hours at room temperature. Solutions reconstituted without a preservative should be used
immediately. Discard if solution appears hazy. Diluted solutions in D5W or NS are stable
for 8 days at room temperature; however, the diluted cytarabine should be used within 24
hours for sterility concerns.

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Subcutaneous or IM: Dilute with Bacteriostatic Water for Injection or NS to a concentration

not to exceed 100 mg/mL. Rotate injection sites for subcutaneous/IM administration.
Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.6 DEXAMETHASONE (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521

Source and Pharmacology:
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid
effects. Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to
approximately 5 mg of prednisone. Glucocorticoids produce widespread and diverse
physiologic effects on carbohydrate, protein, and lipid metabolism, electrolyte and water
balance, functions of the cardiovascular system, kidney, skeletal muscle, and the nervous
systems. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes
(T-lymphocytes), monocytes, and eosinophils. Glucocorticoids selectively bind to the
cortisol receptors on human lymphoid cells that are found in larger numbers on leukemic
lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors and
inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte
blastogenesis and reducing expansion of the primary immune response. The specific cellular
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose
transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis.
Elimination half-lives for the following age groups have been reported to be: infants and
children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults
(age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is primarily
metabolized in the liver and excreted by the kidneys.
Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Insomnia, hyperphagia Gastritis Hyperuricemia
Within 1-2 days
of receiving
drug
Prompt: Immunosuppression, Hyperglycemia, facial Pancreatitis (L),
Within 2-3 personality changes (mood erythema, poor wound increased intraocular
weeks, prior to swings, euphoria, anxiety, healing, infections pressure (L),
the next course depression), pituitary- (bacterial, fungal, parasitic, hypertension, psychosis,
adrenal axis suppression, viral), edema vertigo, headache
acne (L)
Delayed: Cushing’s syndrome Striae and thinning of the Spontaneous fractures
Any time later (moon facies, truncal skin, easy bruising, muscle (L), growth suppression,
during therapy obesity) weakness, osteopenia peptic ulcer and GI
bleeding, pseudotumor
cerebri (increased
intracranial pressure
with papilledema,
headache), aseptic
necrosis of the femoral
and humeral heads (L),
urolithiasis1 (L)
Late: Cataracts (which may be
reversible on

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Any time after discontinuation of

completion of dexamethasone in
treatment children)
Unknown Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54%
Frequency and metabolized by enzymes in the placenta. In animal studies, large doses of
Timing: cortisol administered early in pregnancy produced cleft palate, stillborn fetuses,
and decreased fetal size. Chronic maternal ingestion during the first trimester
has shown a 1% incidence of cleft palate in humans. There are no reports of
dexamethasone excretion into breast milk in humans; however, it is expected
due to its low molecular weight that it would partition into breast milk.
1
Mainly reported in pediatric patients with ALL. Howard SC et al. Urolithiasis in pediatric patients
with acute lymphoblastic leukemia. Leukemia 2003; 17: 541-6.
(L) Toxicity may also occur later.

Formulation and Stability:

Oral:
Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid formulations
are available in 0.5 mg/5 mL and 1 mg/1 mL concentrations. Inactive ingredients vary
depending on manufacturer but tablet formulations may include: calcium or magnesium
stearate, corn starch, lactose, and various dyes. Liquid formulations may include: 5%-30%
alcohol, benzoic acid, sorbitol, sodium saccharin, glycerin, purified water, and various
dyes.

Injection:
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL,
5 mL, and 30 mL vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Vials are available in
multi-dose vials as well as unit of use vials and syringes. Inactive ingredients vary depending
on manufacturer but include creatinine, sodium citrate, sodium hydroxide to adjust pH,
Water for Injection, sodium sulfite, bisulfite and metabisulfite, methyl and propyl paraben,
benzyl alcohol, and EDTA.

Guidelines for Administration: See Treatment and Dose Modifications section of the
protocol.

Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV
use, it may be further diluted in dextrose or saline containing solutions. Avoid using benzyl
alcohol-containing dexamethasone solutions in neonates. Diluted solutions that contain no
preservatives should be used within 24 hours, but maintain stability for at least 14 days in
PVC bags at room temperature protected from light.

Supplier:
Commercially available from various manufacturers. See package insert for further
information.

6.7 ETOPOSIDE – INJECTION (VePesid®, Etopophos®,VP-16) NSC #141540

Source and Pharmacology:
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase
II and DNA which results in single and double strand DNA breaks. Its main effect appears
to be in the S and G2 Phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal
half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately

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55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance
of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose
range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non renal
processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma
etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide.
Metabolism accounts for most of the non renal clearance of etoposide.

The maximum plasma concentration and area under the concentration time curve (AUC)
exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins
(~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide
systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure
for unbound etoposide correlates better than total (bound and unbound) etoposide. There
is poor diffusion into the CSF < 5%.

Etoposide phosphate is a water soluble ester of etoposide that is rapidly and completely
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate
that etoposide phosphate is bioequivalent to etoposide when it is administered in molar
equivalent doses.

Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Nausea, vomiting Anorexia Transient hypotension
Within 1-2 days during infusion;
of receiving anaphylaxis (chills, fever,
drug tachycardia, dyspnea,
bronchospasm,
hypotension)
Prompt: Myelosuppression Thrombocytopenia, Peripheral neuropathy,
Within 2-3 (anemia, diarrhea, abdominal pain, mucositis, hepatotoxicity,
weeks, prior to leukopenia), alopecia asthenia, malaise, rashes chest pain,
next course and urticaria thrombophlebitis,
congestive heart failure,
Stevens-Johnson
Syndrome, exfoliative
dermatitis
Delayed: Dystonia, ovarian failure,
Any time later amenorrhea, anovulatory
during therapy cycles, hypomenorrhea,
onycholysis of nails
Late: Secondary malignancy
Any time after (preleukemic or leukemic
completion of syndromes)
treatment
Unknown Fetal toxicities and teratogenic effects of etoposide have been noted in animals
Frequency and at 1/20th of the human dose. It is unknown whether the drug is excreted in breast
Timing: milk.

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Formulation and Stability:

Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5
mL, 25 mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to
4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v)
alcohol. Vial headspace contains nitrogen. Unopened vials of etoposide are stable until
expiration date on package at controlled room temperature (20˚-25˚C or 68˚-77˚F).

Etoposide phosphate for injection is available for intravenous infusion as a sterile

lyophilized powder in single-dose vials containing etoposide phosphate equivalent to
100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide
phosphate must be stored under refrigeration (2°-8°C or 36°-46°F). Unopened vials of
etoposide phosphate are stable until the expiration date on the package.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Etoposide:
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions
are stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL;
stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to
precipitation is highly unpredictable at concentrations > 0.4 mg/mL. Use in-line filter
during infusion secondary to the risk of precipitate formation. However, the use of an in-
line filter is not mandatory since etoposide precipitation is unlikely at concentrations of
0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow rate
of administration if hypotension occurs.

Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred
with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close
as possible, preferably within 4 hours, to the time of administration or alternatively as per
institutional policy; glass or polyethylene-lined (non-PVC) containers and polyethylene-
lined tubing may be used to minimize exposure to DEHP.

Etoposide Phosphate:
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS,
Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride
for Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or
10 mg/mL etoposide equivalent (22.7 mg/mL or 11.4 mg/mL etoposide phosphate),
respectively. Use diluents without benzyl alcohol for neonates and infants < 2 years of
age or patients with hypersensitivity to benzyl alcohol.

When reconstituted as directed, etoposide phosphate solutions can be stored in glass or

plastic containers under refrigeration for 7 days. When reconstituted with a diluent
containing a bacteriostat, store at controlled room temperature for up to 48 hours.
Following reconstitution with SWFI, D5W, or NS store at controlled room temperature for
up to 24 hours.

Following reconstitution, etoposide phosphate may be further diluted to a concentration as

low as 0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under
refrigeration or at controlled room temperature for 24 hours.

Supplier:

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Commercially available from various manufacturers. See package insert for more detailed
information.

CANADIAN SITES
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may
purchase and import the USA commercial supply from Bristol Laboratories via an
International Distributor (Pharma Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-
8022, email: [email protected]) under the authority of the protocol’s No Objection Letter
(NOL). Drug Accountability Log (DAL) must record Lot #’s and expiry dates of shipments
received and doses dispensed. Sites may use their own DAL as long as it complies with
all elements of ICH GCP and Division 5 of the Food and Drugs Act. Each site is responsible
for the procurement (import +/- purchase) of Etoposide Phosphate (Etopophos). Sites may
import and manage a single clinical trial supply for multiple protocols as long as each
protocol has an NOL and the protocol the patient is registered on is recorded on the DAL.

6.8 FILGRASTIM (Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF,

Neupogen®) NSC #614629
Source and Pharmacology:
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli
bacteria into which has been inserted the human granulocyte colony stimulating factor
gene. It differs from the natural protein in that the N- amino acid is methionine and the protein
is not glycosylated. G-CSF is a lineage specific colony-stimulating factor that regulates the
production of neutrophils within the bone marrow and affects neutrophil progenitor
proliferation, differentiation, and selected end-cell functional activation (including
enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory
burst, antibody dependent killing, and the increased expression of some functions
associated with cell surface antigens). The elimination half-life is similar for subcutaneous
and intravenous administration, approximately 3.5 hours. The time to peak concentration
when administered subcutaneously is 2-8 hours

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Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children out Happens to < 5 children
children out of every 100 of every 100 out of every 100
Immediate: Local irritation at the Allergic reactions (more
Within 1-2 days of injection site, headache common with IV
receiving drug administration than
subq):skin (rash,
urticaria, facial edema),
respiratory (wheezing,
dyspnea) and
cardiovascular
(hypotension,
tachycardia), low grade
fever
Prompt: Mild to moderate Increased: alkaline Splenomegaly, splenic
Within 2-3 weeks, medullary bone pain phosphatase, lactate rupture, rash or
prior to the next dehydrogenase and uric acid, exacerbation of pre-
course thrombocytopenia existing skin rashes,
sickle cell crises in
patients with SCD,
excessive leukocytosis,
Sweet’s syndrome
(acute febrile
neutrophilic
dermatosis)
Delayed: Cutaneous vasculitis,
Anytime later ARDS
during therapy
Late: MDS or AML (confined
Anytime after to patients with severe
completion of chronic neutropenia and
treatment long term
administration)
Unknown Fetal toxicities and teratogenic effects of filgrastim in humans are unknown.
Frequency and Conflicting data exist in animal studies and filgrastim is known to pass the
Timing: placental barrier. It is unknown whether the drug is excreted in breast milk.

Formulation and Stability:

Supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. It is also available as
prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL. Vials are preservative
free single use vials. Discard unused portions of open vials. Store refrigerated at 2º-8ºC
(36º-46ºF). Prior to injection, filgrastim may be allowed to reach room temperature for a
maximum of 24 hours. Avoid freezing and temperatures > 30ºC.
For IV use, dilute in D5W only to concentrations > 15 mcg/mL. At concentrations between
5 and 15 mcg/mL, human serum albumin should be added to make a final albumin
concentration of 0.2% (2 mg/mL) in order to minimize the adsorption of filgrastim to
plastic infusion containers and equipment. Dilutions of 5 mcg/mL or less are not
recommended. Diluted filgrastim should be stored at 2º-8ºC (36º-46ºF) and used within 24
hours. Do not shake.

Do not dilute with saline-containing solutions at any time; precipitation will occur.

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Guidelines for Administration:

See Treatment, Dose Modifications and Supportive Care sections of the protocol.
Filgrastim should not be administered within 24 hours of (before AND after)
chemotherapy.

Supplier: Commercially available from various manufacturers. See package insert for
further information

6.9 FLUDARABINE(Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) NSC# 312887

Source and Pharmacology:

Fludarabine phosphate is a synthetic purine nucleoside. It differs from the physiologic
nucleosides, adenosine, in that the sugar moiety is arabinose instead of ribose, and by the
addition of a fluorine atom to the purine base adenine. Fludarabine is also a fluorinated
nucleotide analog the antiviral agent vidarabine, (ara-A). The addition of fluorine results
in increased aqueous solubility and resistance to enzymatic degradation by adenosine
deaminase. Fludarabine (2-fluoro-ara-A) is commercially available as the monophosphate
salt (2-fluoro-ara-AMP). The monophosphorylation increases the drug's aqueous solubility
while maintaining pharmacologic activity. The chemical name for fludarabine phosphate
is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono β-D-arabino-furanosyl) (2-fluoro-ara-
AMP) and the molecular weight is 365.2.

Fludarabine is a purine antagonist antimetabolite. In vivo, fludarabine phosphate is rapidly

dephosphorylated to 2-fluoro-ara-A and then it is phosphorylated intracellularly by
deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears
to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase,
thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not
completely characterized and may be multi-faceted.

Phase I studies in humans have demonstrated that within several minutes after intravenous
infusion, fludarabine phosphate is converted to the active metabolite, 2-fluoro-ara-A and
becomes undetectable. Therefore, pharmacokinetics studies have focused on 2-fluoro-ara-
A. Fludarabine phosphate 25 mg/m2 infused intravenously over 30 minutes to adult cancer
patients, showed a moderate accumulation of 2-fluoro-ara-A. During a 5-day treatment
schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2.
Fludarabine is widely distributed. The volume of distribution at steady state (Vss) reported
after daily administration of 25mg/m2 for 5 days to adults averaged at 96-98 L/m2. Tissue
distribution studies in animals indicate that the highest concentrations of the drug are in
liver, kidney, and spleen. Although the extent to which fludarabine and/or its metabolites
distribute into the CNS in humans has not been determined to date, severe neurologic
toxicity (e.g., blindness, coma) has been reported in patients receiving the drug, particularly
in high dosages. There is evidence from animal studies that fludarabine distributes into the
CNS and that a toxic metabolite (2-fluoroadenine, possibly formed by bacteria in the GI
tract), can be absorbed systematically via enterohepatic circulation and distributed into
CSF. According to in vitro data, about 19-29% of fludarabine is bound to plasma proteins.

Following IV administration, fludarabine phosphate is dephosphorylated rapidly to

fludarabine. Plasma concentrations of fludarabine decline in a linear, dose-independent
manner. The elimination profile of fludarabine also has been reported to be either biphasic

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or triphasic; however, reported terminal elimination half-lives have been similar. In adult
cancer patients receiving fludarabine 25 mg/m2 as a 30-minute IV infusion daily for 5 days,
a terminal half-life of about 20 hours was reported. In a limited number of pediatric
patients, the plasma concentration profile of fludarabine exhibited both monoexponential
and biexponential decay, with a mean t1/2 of 10.5 hours in patients with monoexponential
elimination and a t1/2 of 1.2-1.4 and 12.4-19 hours, respectively, in patients with
biexponential elimination.

Renal clearance accounts for about 40% of the total body clearance of fludarabine. Renal
elimination appears to become more important at high dosages of the drug. The dose of
fludarabine needs to be adjusted in patients with moderate renal impairment.

The use of fludarabine in combination with pentostatin is not recommended due to the risk
of severe pulmonary toxicity.

Toxicity:
Common Occasional Rare
Happens to 21- Happens to 5-20 Happens to < 5 subjects out of every
100 subjects out subjects out of every 100
of every 100 100
Immediate: Fever, fatigue, Edema including Anaphylaxis, tumor lysis syndrome,
Within 1-2 weakness, pain, peripheral edema, dehydration*
days of nausea, vomiting, chills, rash, diarrhea,
receiving drug anorexia, cough, rhinitis, diaphoresis,
dyspnea malaise, abdominal
pain, headache, back
pain, myalgia,
stomatitis, flu-like
syndrome
Prompt: Myelosuppressio Weight loss, Sinusitis, dysuria, opportunistic
Within 2-3 n (anemia, gastrointestinal infections and reactivation of latent
weeks, prior to neutropenia, bleeding, viral infections like Epstein-Barr virus
next course thrombocytopeni hemoptysis, (EBV), herpes zoster and John
a), infection paresthesia, allergic Cunningham (JC) virus (progressive
(urinary tract pneumonitis, multifocal leukoencephalopathy
infection, herpes bronchitis, [PML])L, EBV associated
simplex infection, pharyngitis, visual lymphoproliferative disorder,
pneumonia, upper disturbance, hearing panycytopenia (can be prolonged),
respiratory) loss, hyperglycemia pulmonary hypersensitivitya (dyspnea,
cough, hypoxia, interstitial pulmonary
infiltrate), pulmonary toxicity (acute
respiratory distress syndrome
[ARDS], pulmonary fibrosis,
pulmonary hemorrhage, respiratory
distress, respiratory failure),
pericardial effusion, skin toxicity
(erythema multiforme, Stevens-
Johnson syndrome, toxic epidermal
necrolysis, pemphigus), liver failure,
renal failure, hemorrhage, transfusion-
associated graft-versus-host disease
has occurred following transfusion of
nonirradiated blood products,
phlebitis*, sleep disorder*, cerebellar

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syndrome*, depression*, mentation

impaired*, alopecia*, pruritus*,
seborrhea*, esophagitis*,
constipation*, mucositis*, dysphagia*,
hesitancy*, cholelithiasis*, abnormal
liver function tests *, osteoporosis*,
arthralgia*, abnormal renal function
test*, proteinuria*, epistaxis*,
hemorrhagic cystitis*, eosinophilia*
Delayed: Neurotoxicity (increased with high
Any time later doses): seizures, agitation, confusion,
during therapy, weakness, visual disturbances, optic
excluding the neuritis, optic neuropathy,
above photophobia, blindness, paralysis,
conditions coma, death, peripheral neuropathya);
autoimmune phenomena:
thrombocytopenia/thrombocytopenic
purpura (ITP), Evans syndrome,
hemolytic anemia, acquired
hemophilia
Late: Myelodysplastic syndrome/acute
Any time after myeloid leukemia (mainly associated
completion of with prior or concomitant or
treatment subsequent treatment with other
anticancer treatments), skin cancer
(new onset or exacerbation)
Unknown Pregnancy Category D
Frequency
Based on its mechanism of action, fludarabine phosphate can cause fetal harm
and Timing:
when administered to a pregnant woman. Fludarabine phosphate was
embryolethal and teratogenic in both rats and rabbits.
(L) Toxicity may also occur later.
* Reported in ≤ 3% of subjects. Since these are not considered life threatening they are not included
in the consent.
a
These effects were not reported in children.

Formulation and Stability:

Fludarabine phosphate injection is available as sterile lyophilized powder and in solution.
Each single-dose vial of powder contains 50 mg of the active ingredient fludarabine
phosphate, 50 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. After
reconstitution, the pH range for the final product is 7.2-8.2. The single-dose solution vial
contains 25 mg/mL, 2 mL of fludarabine phosphate. It may contain mannitol and is
preservative-free.
Fludarabine phosphate vials should be stored refrigerated at 2-8ºC (36-46ºF).

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Prior to administration fludarabine phosphate powder should be reconstituted with Sterile

Water for Injection and further diluted in D5W or NS to a concentration of 10 – 25 mg/mL.
Fludarabine 25 mg/mL solution should be further diluted in the same manner.
Fludarabine phosphate powder should be reconstituted with 2 mL of Sterile Water for
Injection. The solid cake should fully dissolve in 15 seconds or less. The resulting

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concentration is 25 mg/mL. When reconstituted to a final concentration of 25 mg/mL, the

drug is stable for at least 16 days at room temperature and normal light conditions. The
manufacturer recommends that the solution be used within 8 hours after reconstitution.
Prior to administration, fludarabine 25 mg/mL solution or the reconstituted 25 mg/mL
solution should be further diluted in 100 mL or 125 mL of D5W or NS. When diluted to a
final concentration of 1 mg/mL, fludarabine is stable for at least 16 days at room
temperature and normal light conditions. The manufacturer recommends that the diluted
solution be used within 8 hours after preparation. Parenteral drug products should be
inspected visually for particulate matter and discoloration prior to administration.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.10 INTRATHECAL TRIPLES (Methotrexate/Hydrocortisone/Cytarabine, IT-3)

Source and Pharmacology:
The intrathecal route of administration of a drug produces more consistent CSF drug
concentrations at relatively smaller doses because of the volume difference between the CSF
and blood compartments (140 mL vs. 3500 mL in an adult). (The CSF volume of children
after the first 3 years is equivalent to that of an adult). Drug half-lives are longer as well
because clearance is related to flow rather than metabolism or protein binding. Intrathecal
methotrexate has a biphasic elimination curve from the CSF with a t½ of 4.5 and 14 hours
respectively. Following IT injection of cytarabine the elimination of the drug from the CSF
is biphasic with a t½ of 1 and 3.4 hours respectively, which is 8-fold longer than the clearance
from plasma. The elimination of hydrocortisone is similarly prolonged.

Intrathecal Triple Therapy (Methotrexate/ Hydrocortisone/Cytarabine) Toxicity:

Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Nausea, vomiting, fever, Arachnoditis: (headache, Rash, anaphylaxis (L),
Within 1-2 headache fever, vomiting, paresis, bleeding into
days of meningismus and subarachnoid or subdural
receiving drug pleocytosis) space (risk > with
platelet counts < 20,000),
confusion, fatigue,
disorientation, seizures
Prompt: Myelosuppression,
Within 2-3 somnolence, ataxia,
weeks, prior to cranial nerve palsy,
the next course transient and rarely
permanent paraplegia
(L), speech disorders
Delayed: Cognitive Demyelinating
Any time later disturbances (L), learning leukoencephalopathy1
during therapy, disabilities (L) (L), blindness1
excluding the
above condition
Late: Progressive CNS
Any time after deterioration1
the completion
of treatment

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1
May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial
irradiation.
(L) Toxicity may also occur later.

Formulation and Stability:

Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg preservative
free sterile powder for injection vial. Cytarabine 100 mg preservative free sterile powder for
injection. Hydrocortisone sodium succinate 100 mg vial sterile powder for injection.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

For intrathecal administration, dilute each agent with 5-10 mL preservative free NS, lactated
ringers or Elliot’s B solution or as per institutional standard of practice. The volume of CSF
removed should be equal to at least half the volume delivered.
Doses
Patient Age (MTX/Hydrocortisone/ Recommended 10% CSF
CSF Volume *
(years) Ara-C) volume volume

0 – 0.99 7.5 mg / 7.5 mg / 15 mg 5-10 mL 5 mL 50 + 10 mL

(babies)
1 – 1.99 8 mg / 8 mg / 16 mg 5-10 mL 5 mL 50 + 10 mL
(babies)
2 – 2.99 10 mg / 10 mg / 20 mg 5-10 mL 8 mL 80 + 20 mL
(younger children)
3 – 8.99 12 mg / 12 mg / 24 mg 5-10 mL 10 mL 100 + 20 mL
(older children)
9 or greater 15 mg / 15 mg / 30 mg 5-10 mL 13 mL 130 + 30 mL
(adults)
*Rieselbach, *R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med
1962 Dec 20; 267:1273-8

Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric
delivery, with the patient remaining prone after the procedure may facilitate drug distribution.
These procedures have not been validated in clinical trials. They are allowed but not mandated
for patients on COG studies.

Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative and should
be administered as soon as possible after preparation.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.11 LEUCOVORIN CALCIUM (LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC
#003590

Source and Pharmacology:

Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of
tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)- l-
isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require
reduction by the enzyme dihydrofolate reductase in order to participate in reactions

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utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can

counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate,
which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the
therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-
fluorouracil. Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid
(an active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition
of this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life
of total reduced folates was approximately 6.2 hours. Following oral administration,
leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At a dose of
25 mg, almost 100% of the l-isomer (the biologically active form) but only 20% of the d-
isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The
apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for
100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels.
Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children out
children out of every 100 out of every 100 of every 100
Immediate: Anaphylaxis, urticaria,
Within 1-2 days of seizure
receiving drug
Unknown Fetal toxicities and teratogenic effects of leucovorin in humans are unknown.
Frequency and It is unknown whether the drug is excreted in breast milk.
timing:

Formulation and Stability:

Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile
powder for injection. The 10 mg/mL preservative free liquid is available in 50 mL vials
containing sodium chloride 400 mg/vial. Store preservative free liquid in the refrigerator at
2°-8°C (36°-46°F) protected from light. The powder for injection is available in 50 mg,
100 mg, 200 mg, and 350 mg vials. Store at room temperature 15°-25°C (59°-77°F)
protected from light. Reconstitute the sterile powder with sterile water for injection or
bacteriostatic water for injection to a concentration of 10 mg/mL leucovorin calcium. Do not
use diluents containing benzyl alcohol for doses > 10 mg/m² or in infants < 2 years of
age or patients with allergy to benzyl alcohol. When Bacteriostatic Water is used, the
reconstituted solution is good for 7 days. If reconstituted with SWFI, use solution
immediately as it contains no preservative. One milligram of leucovorin calcium contains
0.004 mEq of leucovorin and 0.004 mEq of calcium.

The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive
ingredients vary depending on manufacturer but tablet formulations may include: corn
starch, dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose,
microcrystalline cellulose, and sodium starch glycolate.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

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Injection:
Because of the calcium content of the leucovorin solution, no more than 160 mg of
leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL solution per
minute). IV leucovorin and sodium bicarbonate are incompatible.

Oral:
Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and
may be taken without regard to meals. Doses > 25 mg should be given IV due to the
saturation of absorption.

Leucovorin should not be administered < 24 hours after intrathecal injections that contain
methotrexate unless there are special circumstances.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.12 MERCAPTOPURINE (08/25/14)

(6-MP, Purinethol®, PurixanTM, 6-mercaptopurine) NSC #000755

Source and Pharmacology:
Mercaptopurine is an analogue of the purine bases adenine and hypoxanthine. The main
intracellular pathway for MP activation is catalyzed by the enzyme hypoxanthine-guanine
phosphoribosyl transferase (HGPRT) which catalyzes the conversion of MP to several
active nucleotide metabolites including thioinosinic acid, a ribonucleotide which can
interfere with various metabolic reactions necessary for nucleic acid (RNA and DNA)
biosynthesis. It can also cause pseudofeedback inhibition of the first step in de novo purine
biosynthesis or convert to another ribonucleotide which can cause feedback inhibition.
Mercaptopurine can be incorporated into DNA in the form of TG nucleotides as well and
thus produce toxicity. The absorption of an oral dose of MP is incomplete and variable,
with only about 16%-50% of an administered dose reaching the systemic circulation
secondary to a first pass metabolism in the liver. Food intake and co-administration with
cotrimoxazole (TMP/SMX) significantly reduces absorption of MP. After IV
administration, MP has a plasma half-life of 21 minutes in children and 47 minutes in adults.
Approximately 19% is bound to protein. Mercaptopurine is well distributed into most body
compartments except the CSF. (With high dose IV MP the CSF to plasma ratio is 0.15.) MP
is metabolized by xanthine oxidase in the liver to 6-Thiouric acid an inactive metabolite. In
patients receiving both MP and allopurinol (a xanthine oxidase inhibitor) the dose of MP
must be reduced by 50-75%. Since TPMT, 6-thiopurine methyltransferase, is also one of
the enzymes involved in the metabolism of MP, those individuals who have an inherited
deficiency of the enzyme may be unusually sensitive to the myelosuppressive effects of
MP and prone to develop rapid bone marrow suppression following the initiation of
treatment. Mercaptopurine is excreted in urine as metabolites and some unchanged drug;
about half an oral dose has been recovered in 24 hours. A small proportion is excreted over
several weeks.

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Toxicity:
Incidence Toxicities
Common
(>20% of Anemia, neutrophil count decreased, white blood cell decreased, platelet count decreased
patients)

Occasional
(4 - 20% of Anorexia, diarrhea, nausea, vomiting, erythematous rash, malaise, oligospermia
patients)

Rare Urticaria, skin hyperpigmentation, alopecia, hyperuricemia, hepatic failure, hepatic

(≤3% of necrosis, blood bilirubin increased, alanine aminotransferase increased, aspartate
patients) aminotransferase increased, pulmonary fibrosis, secondary malignant neoplasm
Pregnancy Category D
Mercaptopurine can cause fetal harm, including an increased incidence of abortion and
Pregnancy and stillbirth. Advise women to avoid becoming pregnant while receiving mercaptopurine.
Lactation Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse,
rabbit, and hamster). It is not known whether mercaptopurine is excreted in human milk;
breastfeeding should be avoided.

Formulation and Stability:

Mercaptopurine is available as a 50 mg tablet containing mercaptopurine and the inactive
ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. Store at
15°-25°C (59°-77°F) in a dry place. In the United States, mercaptopurine is also available
as an oral suspension in a concentration of 20 mg/mL (2000 mg/100 mL per bottle). The
oral suspension is a pink to brown viscous liquid supplied in amber glass multiple-dose
bottles with a child resistant closure. It should be stored at 15°-25°C (59°-77°F) in a dry
place.

NOTE: the concentration of the commercially available suspension (20 mg/mL) and the
compounded suspension (50 mg/mL) are NOT the same; doses should be prescribed in the
milligrams required, not mL.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Do not give oral mercaptopurine with food or milk. Concurrent milk products can decrease
absorption and mercaptopurine effect is enhanced if given at bedtime on an empty stomach.
If allopurinol is also given, the oral dose of mercaptopurine should be reduced by 67-75%.
Patients with severe myelosuppression should have their thiopurine S-methyltransferase
(TPMT) status and/or their thiopurine metabolite concentrations evaluated, so that the dose
of mercaptopurine can be reduced in patients with a TPMT defect. Patients with the rare
homozygous deficient TPMT phenotype may tolerate only 1/10th to 1/20th the average
mercaptopurine dose. TPMT testing and thiopurine metabolite measurements are
commercially available.

Suspension:
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be
compounded. The suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a
mortar and adding 8.5 mL sterile water for irrigation. The mixture is triturated to form a
smooth paste. Next, 16.5 mL simple syrup (pH=7) are added with continuous mixing and
finally cherry syrup (pH=7.1) is added to a total volume of 50 mL. The suspension is stable
in amber glass bottles at room temperature (19ºC -23ºC) for up to 5 weeks. The suspension

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should be shaken well before each use. Procedures for proper handling and disposal of
cytotoxic drugs should be used when preparing the suspension. (Aliabadi HM, Romanick
M, Desai S et al. Effect of buffer and antioxidant on stability of mercaptopurine suspension.
Am J Heath-Syst Pharm. 65:441-7, 2008.)

Supplier: The tablets are commercially available from various manufacturers. In the
United States, the commercially available oral suspension is available through AnovoRx
Distribution, LLC (1-888-470-0904). See package insert for further information. PLEASE
NOTE there is a difference in the concentration of the commercially available (20
mg/mL) and extemporaneously compounded (50 mg/mL) oral suspensions.

6.13 METHOTREXATE-ALL ROUTES (MTX, amethopterin, Trexall®) NSC #000740

Source and Pharmacology:
A folate analogue that reversibly inhibits dihydrofolate reductase, the enzyme that reduces
folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the
availability of one carbon fragments necessary for the synthesis of purines and the conversion
of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The
polyglutamated metabolites of MTX also contribute to the cytotoxic effect of MTX on DNA
repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute drug
concentration and the duration of drug exposure. MTX is actively transported across cell
membranes. At serum methotrexate concentrations exceeding 0.1 µmol/mL, passive
diffusion becomes a major means of intracellular transport of MTX. The drug is widely
distributed throughout the body with the highest concentration in the kidney, liver, spleen,
gallbladder and skin. Plasma concentrations following high dose IV MTX decline in a
biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of
8-15 hours. About 50% is bound to protein. After oral administration, approximately 60% of
a 30 mg/m2 dose is rapidly absorbed from the GI tract, with peak blood levels at 1 hour. At
doses > 30 mg/m² absorption decreases significantly. Even at low doses absorption may be
very erratic, varying between 23% and 95%. The elimination of MTX from the CSF after an
intrathecal dose is characterized by a biphasic curve with half-lives of 4.5 and 14 hours. After
intrathecal administration of 12 mg/m², the lumbar concentration of MTX is ~100 times
higher than in plasma. (Ventricular concentration is ~ 10% of lumbar concentration). MTX
is excreted primarily by the kidneys via glomerular filtration and active secretion into the
proximal tubules. Renal clearance usually equals or exceeds creatinine clearance. Small
amounts are excreted in the feces. There is significant entero-hepatic circulation of MTX.
The distribution of MTX into third-space fluid collections, such as pleural effusions and
ascitic fluid, can substantially alter MTX pharmacokinetics. The slow release of accumulated
MTX from these third spaces over time prolongs the terminal half-life of the drug, leading to
potentially increased clinical toxicity.

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Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children Happens to < 5 children out
children out of every 100 out of every 100 of every 100
Immediate: Transaminase elevations Nausea, vomiting, Anaphylaxis, chills, fever,
Within 1-2 days of anorexia dizziness, malaise,
receiving drug drowsiness, blurred vision,
acral erythema, urticaria,
pruritus, toxic epidermal
necrolysis, Stevens-Johnson
Syndrome, tumor lysis
syndrome, seizures1,
photosensitivity
Prompt: Myelosuppression, Alopecia, folliculitis, acne,
Within 2-3 weeks, stomatitis, gingivitis, renal toxicity (ATN,
prior to the next photosensitivity, fatigue increased creatinine/BUN,
course hematuria), enteritis, GI
ulceration and bleeding,
acute neurotoxicity1
(headache, drowsiness,
aphasia, paresis, blurred
vision, transient blindness,
dysarthria, hemiparesis,
decreased reflexes)
diarrhea, conjunctivitis
Delayed: Learning disability1 (L) Pneumonitis, pulmonary
Any time later fibrosis (L), hepatic fibrosis
during therapy, (L), osteonecrosis (L),
excluding the leukoencephalopathy1 (L),
above conditions pericarditis, pericardial
effusions,
hyperpigmentation of the
nails
Late: Progressive CNS
Any time after the deterioration1
completion of
therapy
Unknown Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of
Frequency and methotrexate have been noted in humans. The toxicities include: congenital defects,
Timing: chromosomal abnormalities, severe newborn myelosuppression, low birth weight,
abortion, and fetal death. Methotrexate is excreted into breast milk in low
concentrations.
1
May be enhanced by HDMTX and/or cranial irradiation.
(L) Toxicity may also occur later.

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Intrathecal Therapy (Methotrexate Single Agent)

Toxicity:

Common Occasional Rare

Happens to 21-100 Happens to 5-20 children Happens to < 5 children
children out of every 100 out of every 100 out of every 100
Immediate: Nausea, headache Arachnoditis: (headache, Anaphylaxis, vomiting,
Within 1-2 fever, vomiting, seizures(L), malaise,
days of meningismus, nuchal confusion, back pain,
receiving drug rigidity, and pleocytosis) rash, bleeding into
subarachnoid or subdural
space (risk > with platelet
counts < 20,000),
Prompt: Myelosuppression, ataxia,
Within 2-3 somnolence, cranial nerve
weeks, prior to palsy, subacute
the next course myelopathy
(paraparesis/paraplegia),
speech disorders, pain in
the legs, bladder
dysfunction
Delayed: Cognitive disturbances Leukoencephalopathy1 (L)
Any time later (L)1,
during therapy, learning disability (L)1
excluding the
above condition
Late: Progressive CNS
Any time after deterioration1
the completion
of treatment
1
May be enhanced by HDMTX and/or cranial irradiation.
(L) Toxicity may also occur later.

Formulation & Stability:

Methotrexate for oral use is available as 2.5 mg, 5 mg, 7.5 mg, 10 mg and 15 mg tablets.
Inactive ingredients vary depending on manufacturer but tablet formulations may include:
anhydrous lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch,
sodium carbonate monohydrate, talc and titanium dioxide and various dyes. Store at
controlled room temperature 15°-30°C (59°-86°F) and protect from light.

Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg

vials. The powder for injection contains approximately 7 mEq sodium in the 1000 mg vial.
Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL
preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL
solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial,
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative.

Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions

permitted to 15º-30ºC (59º- 86 Fº). Protect from light

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Guidelines for Administration: See Treatment and Dose Modifications sections of

protocol. Leucovorin rescue may be necessary with certain doses of methotrexate.

Oral administration: Food or milk delays absorption and reduces peak concentration.
Methotrexate for oral use should preferentially be given on an empty stomach, 1 hour
before or 2 hours after food or milk and at the same time each day. Methotrexate injection
diluted in water can be used for oral administration (Marshall PS, Gertner E. Oral
administration of an easily prepared solution of injectable methotrexate diluted in water: a
comparison of serum concentrations vs methotrexate tablets and clinical utility. J
Rheumatol 23:455-8, 1996).

For IM/IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative
free SWFI, D5W or NS to a 50 mg/mL concentration. The powder for injection may be
further diluted in NS or dextrose containing solutions to a concentration of ≤ 25mg/mL for
IV use.

The 25 mg/mL solution may be given directly for IM administration or further diluted in
Saline or Dextrose containing solutions for IV use. Do not use the preserved solution for
high dose methotrexate administration due to risk of benzyl alcohol toxicity.
Methotrexate dilutions are chemically stable for at least 7 days at room temperature but
contain no preservative and should be used within 24 hours. Diluted solutions especially
those containing bicarbonate exposed to direct sunlight for periods exceeding 4 hours
should be protected from light.

High dose methotrexate requires alkalinization of the urine, adequate hydration and
leucovorin rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump
inhibitors, and NSAIDS as renal excretion of MTX is inhibited by these agents.

For Intrathecal use: Use preservative free 25 mg/mL solution.

For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s,
or Elliot’s B solution as per institutional standard of practice. The volume of CSF removed
should be equal to at least half the volume delivered.
Note: When IT therapy and ID MTX are scheduled for the same day, deliver the IT therapy
within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the
start of the MTX bolus).

For IT administration, use the preservative free formulation. The volume to be given IT
should be in the range of 5-10 mL. The volume of CSF removed should be equal to at least
half the volume delivered (see drug monograph).

Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery,
with the patient remaining lying down after the procedure may facilitate drug distribution.
These procedures have not been validated in clinical trials. They are allowed but not mandated
for patients on COG studies.

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Methotrexate Recommended 10% CSF

Patient Age (years) CSF Volume *
dose volume volume
50 + 10 mL
1–1.99 8 mg 5–10 mL 5 mL
(babies)
80 + 20 mL
2–2.99 10 mg 5-10 mL 8 mL
(younger children)
100 + 20 mL
3–8.99 12 mg 5-10 mL 10 mL
(older children)
130 + 30 mL
9 or greater 15 mg 5-10 mL 13 mL
(adults)
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med.
1962 Dec 20; 267:1273-8

Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric
delivery, with the patient remaining prone after the procedure may facilitate drug distribution.
These procedures have not been validated in clinical trials. They are allowed but not mandated
for patients on COG studies.

Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains
no preservative and should be administered as soon as possible after preparation.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

6.14 MITOXANTRONE (Novantrone®, CL 232315, DAD, DHAD, Mitozantrone) NSC

#301739

Source and Pharmacology:

Mitoxantrone is a substituted alkylaminoanthraquinone and is a potent inhibitor of DNA and
RNA synthesis in vitro and binds strongly to DNA. Mitoxantrone most likely acts through
intercalation between base pairs of the DNA double helix causing crosslinks and strand
breaks. In addition, it is a topoisomerase II inhibitor, an enzyme responsible for uncoiling
and repairing damaged DNA. It has a cytocidal effect on both proliferating and non-
proliferating cultured human cells, suggesting lack of cell cycle Phase specificity. The drug
disappears rapidly from plasma (drug found only in the 3-minute sample) and < 1% appears
in the urine in 24 hours. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the
mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-
life is 23 to 215 hours (median approximately 75 hours). Primary excretion is biliary with
25% appearing in the feces; renal excretion accounting for only 11% of the total dose.
Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic
dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that
of patients with normal hepatic function receiving the same dose. Mitoxantrone is
approximately 95% protein bound.

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Toxicity:
Common Occasional Rare
Happens to 21- Happens to 5- Happens to
100 children out of 20 children out of < 5 children out of
every 100 every 100 every 100
Immediate: Nausea, vomiting, Abdominal pain, back Anaphylaxis,
Within 1-2 days of diarrhea, fever, pain, headache, angioedema, cardiac
receiving drug anorexia, green blue phlebitis, constipation arrhythmias1
discoloration of the (bradycardia), seizures,
urine and/or sclera extravasation reactions
rare but if occur can
lead to: (erythema,
swelling, pain, burning
and/or blue
discoloration of the
skin and rarely tissue
necrosis), tumor lysis
Prompt: Myelosuppression (L),Transient elevation of Rash, conjunctivitis,
Within 2-3 weeks, mucositis /stomatitis,
LFTs, pruritus with (GI) hemorrhage,
prior to the next course immunosuppression, desquamation of the interstitial pneumonitis
alopecia, fatigue skin due to progressive
dryness
Delayed: Amenorrhea, menstrual Cardiotoxicity CHF, hepatotoxicity
Any time later during disorders, temporary (decreased LVEF)2 (L)
therapy reduction in sperm
count
Late: Secondary malignancy
Any time after
completion of
treatment
Unknown Frequency Fetal toxicities and teratogenic effects of mitoxantrone have been noted
and Timing: in animals. Toxicities include: low birth weight and prematurity.
Mitoxantrone is excreted in human milk and significant concentrations
(18 ng/mL) have been reported for 28 days after the last administration.
1Rarely clinically significant.
2Risk increases with chest radiation and prior anthracycline dosage
(L) Toxicity may also occur later.

Formulation and Stability:

The concentrate is a sterile, non-pyrogenic, non-preserved, dark blue aqueous solution
containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base,
with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046%
w/v) as inactive ingredients with 0.14 mEq of sodium per mL. Mitoxantrone is provided
as 20 mg (10 mL), 25 mg (12.5 mL) and 30 mg (15 mL) vials. Store intact vials at 15°-25°C
(59°-77°F). Undiluted mitoxantrone injection should be stored not longer than 7 days
between 15°-25°C (59°-77°F) or 14 days under refrigeration. Refrigeration of the
concentrate may result in a precipitate, which redissolves on warming to room temperature.
DO NOT FREEZE.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

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Mitoxantrone must be diluted prior to injection. DO NOT GIVE IV PUSH. The dose of
mitoxantrone should be diluted in at least 50 mL or to a concentration ≤ 0.5 mg/mL with
either NS or D5W. The dilution is stable at room temperature for 48 hours with no loss of
potency. Admixture with heparin may result in precipitation. Mitoxantrone is an irritant:
Care should be taken to avoid extravasation; the use of a central line is suggested. If it is
known or suspected that subcutaneous extravasation has occurred, it is recommended that
intermittent ice packs be placed over the area of extravasation and that the affected
extremity be elevated. Because of the progressive nature of extravasation reactions, the
area of injection should be frequently examined and surgery consultation obtained early if
there is any sign of a local reaction.

Supplier: Commercially available. See package insert for more detailed information.

Special precautions: Incompatible with heparin; precipitation may form.

6.15 MYCOPHENOLATE MOFETIL (CellCept®, MMF, RS-61443) NSC# 724229

Source and Pharmacology:
Mycophenolate (MMF) is the morpholinoethyl ester of mycophenolic acid (MPA), an
antibiotic with immunosuppressant properties isolated from Penicillium spp. The chemical
name for oral mycophenolate mofetil is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-
6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical
formula of C23H31NO7 and a molecular weight of 433.50. Mycophenolate mofetil is a white
to off-white crystalline powder that is slightly soluble in water (43 μg/mL at pH 7.4); the
solubility increases in acidic medium (4.27 mg/mL at pH 31 3.6). The intravenous product
is the hydrochloride salt of mycophenolate mofetil. The chemical name for the
hydrochloride salt of mycophenolate mofetil is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-
hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate
hydrochloride. It has an empirical formula of C23H31NO7 HCl and a molecular weight of
469.96.

MMF has been used in a variety of solid organ and hematopoietic stem cell transplant
settings for the prevention of acute rejection. MMF is a prodrug that after oral
administration is rapidly hydrolyzed, primarily by the liver, to the biologically active
metabolite mycophenolic acid. MPA is metabolized principally by glucuronyl transferase
to form the pharmacologically inactive phenolic glucuronide of MPA (MPAG). In vivo,
MPAG is converted to MPA via enterohepatic recirculation. Mycophenolic acid inhibits
nucleic acid synthesis and produces a potent, noncompetitive, and reversible inhibition of
inosine monophosphate dehydrogenase (IMPDH), blocking the de novo synthesis of
guanosine nucleotides without being incorporated into DNA. Both T and B lymphocytes
rely on this de novo pathway for purine synthesis. As a result, the proliferative responses
of T and B lymphocytes to both mitogenic and allospecific stimulation are inhibited. Other
rapidly dividing cell lines are capable of recycling purine nucleotides via the "salvage"
pathway, which is not blocked by mycophenolic acid.

In vitro and in vivo studies have demonstrated the ability of mycophenolic acid to block
proliferative responses of T and B lymphocytes, inhibit antibody formation and the
generation of cytotoxic T-cells, and suppress antibody formation by B lymphocytes.
Mycophenolic acid prevents the glycosylation of lymphocyte and monocyte glycoproteins
that are involved in intercellular adhesion of these cells to endothelial cells, and may inhibit

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recruitment of leukocytes into sites of inflammation and graft rejection. Antirejection

effects have been attributed to decreased recruitment of activated lymphocytes to the graft
site.

The mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous

mycophenolate mofetil (based on MPA AUC) was 94% in a small sample of healthy, adult
volunteers. In this group the mean (±SD) apparent volume of distribution of MPA was
approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral
administration, respectively. At clinically relevant concentrations, MPA is 97% bound to
plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges
that are normally seen in stable renal transplant patients; however, at higher MPAG
concentrations (e.g., patients with renal impairment), the binding of MPA may be reduced
as a result of competition between MPAG and MPA for protein binding. A negligible
amount of the agent (< 1% of dose) is excreted as MPA in the urine. Most of the
administered dose (~87%) is excreted in the urine as MPAG. Bile acid sequestrants (e.g.,
cholestyramine) reduce the AUC of MPA by interfering with the enterohepatic circulation
of the drug.

Mycophenolate mofetil can cause fetal harm when administered to a pregnant woman. Use
of MMF during pregnancy is associated with an increased risk of first trimester pregnancy
loss and an increased risk of congenital malformations, especially external ear and other
facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart,
esophagus, and kidney. According to the package labeling, the National Transplantation
Pregnancy Registry (NTPR) presents data on 33 MMF-exposed pregnancies in 24
transplant patients. Of these, there were 15 spontaneous abortions and 18 live-born infants.
Four of the 18 infants had structural malformations (22%). In postmarketing data (collected
1995-2007) of 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous
abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear
abnormalities. Because these postmarketing data are reported voluntarily, it is not always
possible to reliably estimate the frequency of particular adverse outcomes. These
malformations seen in offspring were similar to findings in animal reproductive toxicology
studies. In animal reproductive toxicology studies, there were increased rates of fetal
resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits
received MMF doses equivalent to 0.02 to 0.9 times the recommended human dose for
renal and cardiac transplant patients, based on body surface area conversions. In rat
offspring, malformations included anophthalmia, agnathia, and hydrocephaly. In rabbit
offspring, malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia,
and umbilical hernia. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to
the fetus.

Women of childbearing potential should have a negative serum or urine pregnancy test
with a sensitivity of at least 25 mIU/mL within 1 week prior to beginning therapy
(manufacturer’s recommendation). MMF should not be initiated until a negative pregnancy
test report is obtained. Women of childbearing potential taking MMF must receive
contraceptive counseling and use effective contraception. It is recommended by the
manufacturer that the patient begin using two chosen methods of contraception 4 weeks
prior to starting MMF, unless abstinence is the chosen method. She should continue
contraceptive use during therapy and for 6 weeks after stopping MMF. Patients should be

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aware that MMF reduces blood levels of the hormones in the oral contraceptive pill and
could theoretically reduce its effectiveness.

An approved medication guide

(www.fda.gov/downloads/Drugs/DrugSafety/UCM170919.pdf) must be dispensed with
each refill of mycophenolate mofetil.

The table below lists the toxicity profile of mycophenolate mofetil:

Incidence Toxicities
Hypertension, edema (face, limbs, trunk), rash
maculopapular, cholesterol high, hyperglycemia,
hyperkalemia, hypocalcemia, hypokalemia,
hypomagnesemia, abdominal pain, constipation, diarrhea,
nausea, vomiting, anemia, white blood cell decreased,
Common
platelet count decreased, back pain, anxiety, generalized
(> 20% of patients)
muscle weakness, dizziness, headache, insomnia, tremor,
creatinine increased, dyspnea, cough, fever, pleural
effusion, alanine aminotransferase increased, alkaline
phosphatase increased, aspartate aminotransferase
increased, blood bilirubin increased, GGT increased, pain
Occasional Sepsis, infection1, paresthesia, urinary tract pain, urinary
(5-20% of patients) frequency
Phlebitis, Neoplasms benign, malignant and unspecified
(incl cysts and polyps) - Other, [Malignant epithelial
neoplasm of skin, non-melanoma; lymphoma], gastric
Rare
ulcer, gastrointestinal hemorrhage, gastric perforation,
(< 5% of patients)
mucositis oral, thromboembolic event, infective
endocarditis, renal calculi, pulmonary fibrosis, pneumonitis
neutrophil count decreased, leukoencephalopathy
Pregnancy Category D
Mycophenolate is associated with an increased risk of
congenital malformations and spontaneous abortions
when used during pregnancy. Adverse events have been
reported in animal studies at doses less than the equivalent
recommended human dose. Data from the National
Transplantation Pregnancy Registry (NTPR) have observed
Pregnancy & an increase in structural malformations (including ear
Lactation malformations) in infants born to mothers taking
mycophenolate during pregnancy. Spontaneous abortions
have also been noted. Females of childbearing potential
should have a negative pregnancy test within 1 week prior to
beginning therapy. Two reliable forms of contraception
should be used beginning 4 weeks prior to, during, and for
6 weeks after therapy. The effectiveness of hormonal
contraceptive agents may be affected by mycophenolate.

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It is unknown if mycophenolate is excreted in human milk.

Due to potentially serious adverse reactions, the decision to
discontinue the drug or discontinue breast-feeding should
be considered. Breast-feeding is not recommended during
therapy or for 6 weeks after treatment is complete.
1
Infection includes all 75 sites of infection under the INFECTIONS AND
INFESTATIONS SOC.

Formulation and Stability:

Mycophenolate mofetil is available in the following preparations:
• Capsule: 250 mg
• Tablet: 500 mg
• Powder for suspension, oral: 200 mg/mL (following reconstitution)
• Powder for reconstitution, injection: 500 mg per vial

A delayed release tablet (mycophenolic acid, Myfortic) is also commercially available.

This preparation is not interchangeable with mycophenolate mofetil (Cellcept®, MMF)
due to differences in absorption. This tablet is not discussed in this monograph and should
not be used by patients treated on this protocol.

Inactive ingredients in the 250 mg capsules include the following: croscarmellose sodium,
magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells contain
black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium lauryl
sulfate, titanium dioxide, and yellow iron oxide.

Inactive ingredients in the 500 mg tablets include black iron oxide, croscarmellose sodium,
FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90),
red iron oxide, talc, and titanium dioxide; may also contain ammonium hydroxide, ethyl
alcohol, methyl alcohol, n-butyl alcohol, propylene glycol, and shellac.

Inactive ingredients in the powder for oral suspension include aspartame, citric acid
anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate
dihydrate, sorbitol, soybean lecithin, and xanthan gum.

The injectable product is available as a sterile, white to off-white, lyophilized powder in

vials containing mycophenolate mofetil hydrochloride for administration by intravenous
infusion only. Each vial contains the equivalent of 500 mg mycophenolate mofetil as the
hydrochloride salt. Inactive ingredients include polysorbate 80 (25 mg), citric acid (5 mg),
and sodium hydroxide to adjust the pH. Reconstitution and dilution with D5W yields a
final solution of mycophenolate mofetil that is slightly yellow in color.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Preparation:
To prepare the oral suspension, add 47 mL of water to the bottle and shake well for
approximately 1 minute. Add another 47 mL of water to the bottle and shake well for an
additional minute. The final concentration is 200 mg/mL of mycophenolate mofetil. Avoid
inhalation or direct contact with skin or mucous membranes of the dry powder or the

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constituted suspension. If such contact occurs, wash thoroughly with soap and water; rinse
eyes with water.

To prepare the intravenous injection, reconstitute the contents of each vial with 14 mL of
D5W. Dilute the contents of a vial with D5W to a final concentration of 6 mg/mL. Each
vial is vacuum-sealed; if a lack of vacuum is noted during preparation, the vial should not
be used.

Stability:
Oral formulations should be stored at 25°C (77°F); excursions are permitted to 15°C to
30°C (59°F to 86°F). Protect from moisture and light. Once reconstituted, the oral solution
may be stored at room temperature or under refrigeration. Do not freeze. The mixed
suspension is stable for 60 days.

Store intact vials and diluted solutions at 25°C (77°F); excursions permitted to 15°C to
30°C (59°F to 86°F). Do not freeze. Begin infusion within 4 hours of reconstitution.

Administration:
Oral formulations of MMF should be administered on an empty stomach to avoid
variability in MPA absorption. The oral solution may be administered via a nasogastric
tube (minimum 8 French, 1.7 mm interior diameter). Do not mix the oral suspension with
other medications. Some products may contain phenylalanine; refer to the package labeling
for additional details.

The intravenous solution should be given over at least 2 hours. Do not administer by rapid
or bolus injection.

Supplier:
Commercially available from various manufacturers. See package insert for further
information.

6.16 PEGASPARGASE (PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene

glycol-L-asparaginase, Oncaspar®) NSC #624239
Source and Pharmacology:
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase is
modified by covalently conjugating units of monomethoxypolyethylene glycol (PEG),
molecular weight of 5000, to the enzyme, forming the active ingredient PEG-L-
asparaginase. The L-asparaginase (L-asparagine amidohydrolase, type EC-2, EC 3.5.1.1)
used in the manufacture of Pegaspargase is derived from Escherichia coli that is purchased
in bulk from Merck, Sharp and Dohme. L-asparagine is a nonessential amino acid
synthesized by the transamination of L-aspartic acid by a reaction catalyzed by the enzyme
L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in
malignancies of lymphoid origin. Asparaginase depletes L-asparagine from leukemic cells
(especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic acid and
ammonia. In predominately L-asparaginase naive adult patients with leukemia and
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of
pegaspargase were determined. Apparent volume of distribution was equal to estimated
plasma volume. L-asparaginase was measurable for at least 15 days following the initial
treatment with Pegaspargase. The approximate t½ in adult patients is 5.73 days. The

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enzyme could not be detected in the urine. The half-life is independent of the dose
administered, disease status, renal or hepatic function, age, or gender. In a study of newly
diagnosed pediatric patients with ALL who received either a single intramuscular injection
of pegaspargase (2500 IU/m2), E. coli L-asparaginase (25000 IU/m2), or Erwinia
(25000 IU/m2), the plasma half-lives for the three forms of L-asparaginase were:
5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The plasma half-life
of pegaspargase is shortened in patients who are previously hypersensitive to native
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is cleared by
the reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal
fluid levels are < 1% of plasma levels.
Toxicity:
Common Occasional Rare
Happens to 21-100 children Happens to 5-20 children Happens to < 5 children out
out of every 100 out of every 100 of every 100
Immediate: Allergic reactions (total Allergic reactions Anaphylaxis,
Within 1- likelihood of local, and or (total likelihood of hyper/hypotension,
2 days of systemic reaction local, and or systemic tachycardia, periorbital
receiving especially if previous reaction if no previous edema, chills, fever,
drug hypersensitivity reaction to hypersensitivity dizziness, dyspnea,
native asparaginase), pain reaction to native bronchospasm, lip edema,
at injection site, weakness, asparaginase), rash arthralgia, myalgia,
fatigue, diarrhea urticaria, mild
nausea/vomiting,
abdominal pain, flatulence,
somnolence, lethargy,
headache, seizures (L),
hyperuricemia
Prompt: Hyperammonemia (L), Hyperglycemia, Hemorrhage (L), DIC,
Within 2- coagulation abnormalities abnormal liver thrombosis, anorexia,
3 weeks, with prolonged PTT, PT function tests, weight loss, CNS ischemic
prior to the and bleeding times pancreatitis (L), attacks, edema, azotemia
next course (secondary to decreased increased serum and decreased renal
synthesis of fibrinogen, lipase/amylase function, mild leukopenia,
AT-III & other clotting granulocytopenia,
factors) (L) thrombocytopenia,
pancytopenia, hemolytic
anemia, infections (sepsis
with/without septic shock,
subacute bacterial
endocarditis [SBE], URI),
CNS changes including
irritability, depression,
confusion, EEG changes,
hallucinations, coma and
stupor, paresthesias,
hypertriglyceridemia,
hyperlipidemia, Parkinson-
like syndrome with tremor
and increase in muscular
tone, hyperbilirubinemia,
chest pain
Delayed: Renal failure, urinary
Any time frequency, hemorrhagic
later during cystitis, elevated creatinine
therapy and BUN, fatty liver

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deposits, hepatomegaly,
liver failure
Unknown Animal reproduction studies have not been conducted with pegaspargase. It is not
Frequency known whether pegaspargase can cause fetal harm when administered to a pregnant
and woman or can affect reproduction capacity. However, fetal toxicities and teratogenic
Timing: effects of asparaginase have been noted in animals. It is unknown whether the drug
is excreted in breast milk.
(L)Toxicity may also occur later.

Formulation and Stability:

Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic
sodium phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%,
sodium chloride, USP 8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific
activity of pegaspargase is at least 85 IU per milligram protein. Available in 5 mL vials as
Sterile Solution for Injection in ready to use single-use vials, preservative free. Keep
refrigerated at 2°-8°C (36°-46°F). Do not use if stored at room temperature for more than
48 hours. DO NOT FREEZE. Do not use product if it is known to have been frozen.
Freezing destroys activity, which cannot be detected visually.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

For IM administration: the volume at a single injection site should be limited to 2 mL. If
the volume to be administered is greater than 2 mL, multiple injection sites should be used.

For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to

2 hours through a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of
NS or D5W is stable for 48 hours at room temperature. Pegaspargase diluted in 100 mL of
NS is stable for up to 72 hours refrigerated (4ºC [39°F]) (refrigerated stability data on file
with Sigma-Tau). Avoid excessive agitation. DO NOT SHAKE. Do not use if cloudy of
if precipitate is present.

Have available during and after the infusion: antihistamine, epinephrine, oxygen, and IV
corticosteroids. Observe patient for ONE hour after administration for signs of
hypersensitivity reactions.

Supplier: Pegaspargase (Oncaspar®) is commercially available from Sigma-Tau

Pharmaceuticals. US sites can purchase the drug through their usual ordering channels
(wholesalers). If needed, the Sigma Tau Customer Service phone number for the US is 1-
888-276-2217.

CANADIAN SITES
Pegaspargase is not commercially available in Canada. Sites may purchase and import the
USA commercial supply directly from Sigma Tau Pharmaceuticals under the authority of
the protocol’s No Objection Letter (NOL). The Canadian Senior Medical Officer (SMO)’s
office is responsible for coordinating the “Fax Back” for all lot numbers and expiry dates
to Health Canada’s Biologics and Genetic Therapies Directorate for approval for use in
Canada on behalf of all Canadian sites. A list of approved lot numbers is distributed to all
Canadian sites by the SMO’s office. If an unapproved lot is received from Sigma Tau
Pharmaceuticals, quarantine the lot and contact the COG Canada Regulatory Affairs Office
at 1-780-492-7064. Note: Pegaspargase may have orders placed and Drug Accountability

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Logs maintained on a multiple protocol basis (Multiple Protocol—Imported Biologic) as

long as each protocol has a NOL. Drug Accountability Logs (DAL) must record Lot #’s
and expiry dates of shipments received and doses dispensed. Sites may use their own DAL
as long as it complies with all elements of ICH GCP and Division 5 of the Food and Drugs
Act. Sites may import and manage a single clinical trial supply for multiple protocols as
long as each protocol has an NOL and the protocol the patient is registered on is recorded
on the DAL.

6.17 TACROLIMUS (FK-506, Prograf®) NSC #717865

Source and Pharmacology:
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.
Tacrolimus is a potent immunosuppressive agent that prolongs the survival of the host and
transplanted grafts in animal transplant models of liver, kidney, heart, bone marrow, small
bowel and pancreas, lung and trachea, skin, cornea, and limb. Tacrolimus inhibits T-
lymphocyte activation, although the exact mechanism of action is not known. Experimental
evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex
of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the
phosphatase activity of calcineurin inhibited. This effect may prevent the
dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a
nuclear component thought to initiate gene transcription for the formation of lymphokines
(such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte
activation (immunosuppression). Additionally, tacrolimus may inhibit cellular activities
such as nitric oxide synthetase activation and apoptosis, and may potentiate the action of
corticosteroids in these processes. Tacrolimus activity is primarily due to the parent drug.
The plasma protein binding of tacrolimus is approximately 99% and is independent of
concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and
alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The t½ in
adult patients ranges from 11-19 hours. The pharmacokinetics of tacrolimus have been
studied in pediatric liver transplant patients (0.7 to 13.2 years of age). Following the IV
administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life,
volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and
0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 pediatric patients,
the absolute bioavailability was 31 ± 21%. Whole blood trough concentrations from
31 patients less than 12 years old showed that pediatric patients needed higher doses than
adults to achieve similar tacrolimus trough concentrations. Tacrolimus is extensively
metabolized by the mixed-function oxidase system, primarily the cytochrome P-450
system (CYP3A) in the liver and to a lesser extent in the intestinal mucosa. The major
metabolite identified in incubations with human liver microsomes is 13-demethyl
tacrolimus. The main route of elimination is via the biliary tract and excretion in feces. The
mean clearance in renal dysfunction and mild hepatic dysfunction is the same as normal
volunteers. Severe hepatic dysfunction (Pugh score > 10) led to a substantially decreased
clearance. A retrospective comparison of Black and Caucasian kidney transplant patients
indicated that Black patients required higher tacrolimus doses to attain similar trough
concentrations; there were no gender-based differences. The absorption of tacrolimus from
the gastrointestinal tract is incomplete and variable exhibiting large intra- and inter-patient
variability. Administration with food significantly decreases the rate and extent of
absorption Drugs that stimulate or inhibit hepatic p-450 enzymes will alter clearance of
tacrolimus and close attention to potential drug interactions is crucial.

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Toxicity:
Common Occasional Rare
Happens to 21- Happens to 5- Happens to < 5 children out
100 children out of 20 children out of of every 100
every 100 every 100
Immediate: Headache (L), Chest pain Anaphylaxis with the
Within 1-2 days hypertension (L), nausea, injection, allergic reaction,
of receiving drug vomiting, anorexia, hypotension, asthma,
immunosuppression (L), dyspnea, increased cough,
diarrhea, constipation, flu like syndrome, pleural
fever effusion, seizure (L),
tachycardia, angina
Prompt: Tremor (L), ), renal Alopecia, dizziness, Dyspepsia, dysphagia,
Within 2- dysfunction (acute with elevated LFTs, UTI, gastritis, esophagitis,
3 weeks, prior to decrease in GFR, peripheral edema, flatulence, CNS
the next course impaired urinary rash, pruritus, abnormalities (confusion
concentrating ability, and hyperlipidemia, (L), somnolence (L),
sodium retention), hypercholesteremia depression (L), anxiety,
elevated creatinine/BUN, anxiousness, abnormal
anemia, insomnia, dreams, emotional labiality,
asthenia, pain hallucinations, psychosis,
(abdominal, back, pain), hypertonia, incoordination,
hyperglycemia, neuropathy, nervousness
hypomagnesemia (L), encephalopathy),
hyper/hypokalemia (L), coagulation disorder,
hypophosphatemia, leukopenia (L),
paresthesia thrombocytopenia,
polycythemia, anemia,
leukocytosis, infections
(bacterial, fungal, viral –
sepsis, cellulites, fungal
dermatitis, herpes simplex,
sinusitis, pharyngitis,
abscess, pneumonia,
bronchitis, peritonitis),
hyperbilirubinemia (L),
thrombosis, phlebitis,
arthralgia, myalgia,
electrolyte abnormalities
Delayed: Acne, exfoliative dermatitis,
Any time later skin discoloration,
during therapy, photosensitivity reaction,
excluding the skin ulcer, delayed wound
above conditions healing, hirsutism
(hypertrichosis) (L), gingival
hyperplasia, abnormal
vision, amblyopia, ear pain,
otitis, tinnitus, GI
hemorrhage, GI perforation,
cholelithiasis, cholestatic
jaundice, chronic renal
dysfunction, renal failure,
post-transplant diabetes
mellitus (L), myocardial
hypertrophy, elevated liver

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function tests, liver damage,

ascites
Late: Lymphoproliferative
Any time after disorders, skin malignancies
completion of
treatment
Unknown Fetal toxic effects of tacrolimus have been noted in animals. Tacrolimus is
Frequency and transported across the placenta and its use during pregnancy has been associated
Timing: with neonatal hyperkalemia and renal dysfunction. Tacrolimus is excreted in
human milk, nursing should be avoided.
(L) Toxicity may also occur later.

Formulation and Stability:

Injection:
Tacrolimus is available as a sterile solution (tacrolimus injection) containing the equivalent
of 5 mg anhydrous tacrolimus per 1 mL. Each mL also contains polyoxyl 60 hydrogenated
castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80% v/v. Store between 5°C
and 25°C (41°F and 77°F).
Oral:
Tacrolimus is available for oral administration as capsules containing the equivalent of
0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include lactose,
hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The
0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule
shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin,
titanium dioxide and ferric oxide. Store at 25°C (77°F); excursions permitted to 15°-30°C
(59°-86°F).
Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Injection:
Tacrolimus Injection must be diluted with NS or D5W before use to a concentration
between 0.004 mg/mL and 0.02 mg/mL. Diluted infusion solution should be stored in glass
or polyethylene containers and should be discarded after 24 hours. The polyoxyethylated
castor oil contained in the concentrate for intravenous infusion can cause phthalate
stripping from PVC. It is strongly recommended that glass bottles and non-PVC tubing
be used to minimize patient exposure to DEHP. Due to the chemical instability of
tacrolimus in alkaline media, tacrolimus injection should not be mixed or co-infused with
solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

Monitor closely for an acute allergic reaction for the first 30 minutes and at frequent
intervals thereafter.

Oral:
Administer at a consistent time of day and at consistent intervals with regard to meals.
Tacrolimus may be given with food as long as it is given the same way each time; however;
administration with food significantly decreases the rate and extent of absorption.
Grapefruit juice should be avoided during the entire course of tacrolimus administration.

Supplier: Commercially available from various manufacturers. See package insert for
further information.

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6.18 THIOGUANINE (10/28/11)

(6-thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141, Tabloid®, Lanvis®)
NSC #752
Source and Pharmacology:
Thioguanine is a purine analogue of the nucleic acid guanine with the substitution of a thiol
group in place of the hydroxyl group on guanine. The main intracellular pathway for 6-TG
activation is catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl transferase
(HGPRT) which catalyzes the conversion of 6-TG to the active nucleotide, 6-thioguanylic
acid. The monophosphate nucleotide form of 6-TG inhibits de novo purine synthesis and
purine interconversion reactions, whereas the nucleotide triphosphate metabolite is
incorporated directly into nucleic acids. Incorporation of fraudulent nucleotides into DNA
interferes with DNA replication and results in the formation of DNA strand breaks. The
net consequence of its action is a sequential blockade of the synthesis and utilization of the
purine nucleotides. The relative contribution of each of these actions to the mechanism of
cytotoxicity of 6-TG is unclear. The absorption of an oral dose of 6-TG is incomplete and
variable, averaging approximately 30% of the administered dose (range: 14% to 46%).

6-TG undergoes deamination by the enzyme guanine deaminase resulting in 6-

thioxanthene, which is then oxidized by xanthine oxidase to 6-thiouric acid. In contrast to
mercaptopurine, 6-TG is not a direct substrate for xanthine oxidase. Because the inhibition
of xanthine oxidase results in the accumulation of 6-thioxanthene, an inactive metabolite,
adjustments in 6-TG dosage are not required for patients receiving allopurinol. Since
TPMT, 6-thiopurine methyltransferase, is one of the enzymes involved in the deactivation
of 6-TG, those individuals who have an inherited deficiency of the enzyme may be
unusually sensitive to the myelosuppressive effects of 6-TG and prone to developing rapid
bone marrow suppression following the initiation of treatment.

Peak levels occur 2 to 4 hours after oral administration with a median half-life is about
90 minutes (range: 25-240 minutes). Very little unchanged drug is excreted renally.

Toxicity:
Common Occasional Rare
Happens to 21- Happens to 5- Happens to < 5 children out of
100 children out of 20 children out of every 100
every 100 every 100
Immediate: Anorexia, nausea, Urticaria, rash, hyperuricemia
Within 1-2 days of vomiting, diarrhea,
receiving drug malaise
Prompt: Myelosuppression Toxic hepatitis (L), increased
Within 2-3 weeks, SGOT (AST)/SGPT (ALT),
prior to next course ataxia, mucositis
Delayed: Hepatic fibrosis(L), sinusoidal
Anytime later during obstruction syndrome (SOS,
therapy formerly VOD) (L),
hyperbilirubinemia
Unknown Frequency Fetal toxicities and teratogenic effects of thioguanine have been noted in animals.
and Timing: It is unknown whether the drug is excreted in breast milk.
(L) Toxicity may also occur later.

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Formulation and Stability:

Each greenish-yellow, scored tablet contains 40 mg thioguanine. Store at 15°-25°C (59°-
77°F) in a dry place.

For patients unable to swallow tablets, a 20 mg/mL oral suspension may be compounded.
Crush fifteen (n=15) 40 mg tablets in a mortar and reduce to a fine powder. Add 10 mL
methylcellulose 1% in incremental proportions and mix to a uniform paste. Transfer to a
graduated cylinder, rinse mortar with simple syrup, and add quantity of simple syrup
sufficient to make 30 mL. Dispense in an amber glass bottle and label "shake well" and
"refrigerate". If methylcellulose is not available, substitute 15 mL of Ora-Plus in place of
the methylcellulose and qs with Ora-Sweet (in place of simple syrup) to a final volume of
30 mL. Both preparations are stable for 63 days at 19°C – 23°C. (Aliabadi HM, Romanick
M, Somayah V, et al. Stability of compounded thioguanine oral suspensions. Am J Health
Syst Pharm 2011;68:1278. Dressman JB, Poust RI. Stability of Allopurinol and Five
Antineoplastics in Suspension. Am J Hosp Pharm 1983;40(4):616-8.)

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.

Administer on an empty stomach, preferably at bedtime.

Substantial dosage reductions may be required in patients with an inherited deficiency of

the enzyme thiopurine methyltransferase (TPMT) due to accumulation of active
thioguanine metabolites resulting in a higher incidence of myelosuppression.

Supplier: Commercially available. See package insert for more detailed information.

6.19 THIOTEPA (Tepadina, Tespa, Thiophosphamide, Triethylenethiophosphoramide

Tspa, WR-45312) NSC #6396

Source and Pharmacology:

Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and
pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to
occur through the release of ethylenimine radicals that, like irradiation, disrupt the bonds
of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the
N-7 position, which severs the linkage between the purine base and the sugar and liberates
alkylated guanines. Thiotepa is desulfurated by cytochrome P-450 enzymes such as 2B1
and 2C11, which catalyze the conversion of thiotepa to tepa. Tepa is less toxic than thiotepa
and has been demonstrated to produce alkali-labile sites in DNA, rather than cross-links.
These findings indicate that tepa reacts differently from thiotepa and produces
monofunctional alkylation of DNA. A second metabolite of thiotepa, a mercapturic acid
conjugate, is formed via glutathione conjugation. Monochloro tepa is the third metabolite
found in the urine.
Following short intravenous infusion (less than 5 minutes), peak concentrations of thiotepa
were measured within 5 minutes. At steady state, the volume of distribution was
independent of dose and ranged from 0.3 to 1.6 liters per kilogram (L/kg).
Approximately 4.2% of the original dose is eliminated in the urine within 24 hours as tepa.
The elimination half-life of thiotepa ranges from 2.3 to 2.4 hours. The half-life of tepa
ranged from 3 to 21.1 hours in one study.

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Toxicity:
Common Occasional Rare
Happens to 21-100 children Happens to 5-20 children Happens to < 5 children
out of every 100 out of every 100 out of every 100
Immediate: Nausea, vomiting, anorexia, Pain at the injection site, Anaphylaxis, laryngeal
Within 1-2 days fatigue, weakness dizziness, headache, edema, wheezing, hives
of receiving blurred vision, abdominal
drug pain, contact dermatitis,
rash
Prompt: Myelosuppression; at At higher doses in Febrile reaction,
Within 2- higher doses in conditioning regimens conjunctivitis, dysuria,
3 weeks, prior to conditioning regimens for for BMT: urinary retention
next course BMT: mucositis, encephalopathy
esophagitis (inappropriate behavior,
confusion, somnolence),
increased liver
transaminases, increased
bilirubin,
hyperpigmentation of the
skin (bronzing effect)
Delayed: Gonadal Alopecia, secondary
Anytime later dysfunction/infertility, malignancy
during therapy, azoospermia, amenorrhea
excluding the
above
conditions
Unknown Fetal and teratogenic toxicities: Carcinogenic and teratogenic effects of thiotepa
Frequency and have been noted in animal models at doses ≤ to those used in humans. It is not
Timing: known if thiotepa is excreted into human breast milk.
(L) Toxicity may also occur later.

Formulation and Stability:

Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of
nonpyrogenic, sterile lyophilized powder. Store in a refrigerator at 2°-8°C (36°-46°F).
PROTECT FROM LIGHT AT ALL TIMES.

Guidelines for Administration: See Treatment and Dose Modifications sections of the
protocol.
Reconstitute Thiotepa for Injection with 1.5 mL of Sterile Water for Injection resulting in
a drug concentration of approximately 10 mg/mL. (As per manufacturer’s information:
Actual content per vial 15.6 mg; withdrawable amount 14.7 mg/1.4 mL; approximate
reconstituted concentration: 10.4 mg/mL). When reconstituted with Sterile Water for
Injection, solutions of thiotepa should be stored at refrigerated temperatures 2°-8°C (36°-
46°F) protected from light and used within 8 hours. The reconstituted solution is hypotonic
and should be further diluted with Sodium Chloride Injection (0.9% NaCl) prior to use.
Thiotepa at a concentration of 1-5mg/mL in 0.9% NaCl is stable for 24 hours at room
temperature. At concentration of 0.5mg/mL it is stable for only one hour and stability
decreases significantly at concentrations of less than 0.5mg/mL. Therefore, solutions
diluted to 0.5mg/mL should be used immediately

In order to eliminate haze, filter solutions through a 0.22 micron filter [Polysulfone
membrane (Gelman’s Sterile Aerodisc®, Single Use) or triton-free mixed ester of
cellulose/PVC (Millipore’s MILLEX®-GSFilter Unit)] prior to administration. Filtering

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does not alter solution potency. Reconstituted solutions should be clear. Solutions that
remain opaque or precipitate after filtration should not be used.

When thiotepa is given in bone marrow transplant doses, bath the patient and change linen
frequently (≥ 2 baths/day) to avoid the contact dermatitis and discoloration of the skin that
is seen with high dose.

Supplier: Commercially available. See package insert for further information.

CANADIAN SITES
Thiotepa is not commercially available in Canada. Sites may purchase and import thiotepa
through the following two routes:

Commercial supply may be purchased from the USA through Bedford Laboratories via an
International Distributor (Pharma Exports LLC; Contact: Pete Bigley, phone: 1-412-885-
3700, fax: 1-412-885-8022, email: [email protected] or [email protected])
under the authority of the protocol’s No Objection Letter (NOL).

Commercial supply may also be purchased through Adienne Pharma & Biotec, Bergama,
Italy (tel: +39.035.402.872, fax: +39.035.264.207, email: [email protected])
under the authority of the protocols’ No Objection Letter (NOL). They have available a
commercial 15mg and 100mg vial. Consult the product monograph for appropriate
reconstitution and infusion preparation instructions.

NOTE: A “Fax Notification” of the lot number and expiry date of each lot is no longer
required by Health Canada (effective: January 2011). Canadian sites must keep a drug
accountability log recording manufacturer, lot number and expiry date of all vials of
thiotepa. Separate accountability logs must be kept for different manufacturers and
strengths. Thiotepa may have orders placed and Drug Accountability Logs maintained on
a multiple protocol basis (Multiple Protocol—Imported Therapeutic) as long as each
protocol has a NOL and the DAL clearly indicates on which protocol the subject is
registered.

6.20 VINCRISTINE SULFATE (Oncovin®, VCR, LCR) NSC #67574

Source and Pharmacology:
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin,
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic.
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours
respectively; however, the range of the terminal half-life in humans is from 19 to 155 hours.
The liver is the major excretory organ in humans and animals; about 80% of an injected
dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the urine.
The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to
30 minutes after injection, over 90% of the drug is distributed from the blood into tissue,
where it remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There
is poor CSF penetration.

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Toxicity:
Common Occasional Rare
Happens to 21-100 children Happens to 5-20 children Happens to < 5 children
out of every 100 out of every 100 out of every 100
Immediate: Jaw pain, headache Extravasation (rare) but if
Within 1-2 days occurs = local ulceration,
of receiving drug shortness of breath, and
bronchospasm
Prompt: Alopecia, constipation Weakness, abdominal Paralytic ileus, ptosis,
Within 2- pain, mild brief diplopia, night blindness,
3 weeks, prior to myelosuppression hoarseness, vocal cord
the next course (leukopenia, paralysis, SIADH, seizure,
thrombocytopenia, defective sweating
anemia)
Delayed: Loss of deep tendon Peripheral paresthesias Difficulty walking or
Any time later reflexes including numbness, inability to walk;
during therapy tingling and pain; sinusoidal obstruction
clumsiness; wrist drop, syndrome (SOS, formerly
foot drop, abnormal gait VOD) (in combination);
blindness, optic atrophy;
urinary tract disorders
(including bladder atony,
dysuria, polyuria, nocturia,
and urinary retention);
autonomic neuropathy
with postural hypotension;
8th cranial nerve damage
with dizziness, nystagmus,
vertigo and hearing loss
Unknown Fetal toxicities and teratogenic effects of vincristine (either alone or in
Frequency and combination with other antineoplastic agents) have been noted in humans. The
Timing: toxicities include: chromosome abnormalities, malformation, pancytopenia,
and low birth weight. It is unknown whether the drug is excreted in breast milk.

Formulation and Stability:

Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine
sulfate 1 mg (1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are
added for pH control. The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5.
This product is a sterile, preservative free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F.
Protect from light and retain in carton until time of use.
Do not mix with any IV solutions other than those containing dextrose or saline.

Guidelines for Administration: See Treatment and Dose Modifications sections of

protocol.

The World Health Organization, the Institute of Safe Medicine Practices (United States)
and the Safety and Quality Council (Australia) all support the use of minibag rather than
syringe for the infusion of vincristine. The delivery of vincristine via either IV slow push
or minibag is acceptable for COG protocols. Vincristine should NOT be delivered to the
patient at the same time with any medications intended for central nervous system
administration. Vincristine is fatal if given intrathecally.

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Injection of vincristine sulfate should be accomplished as per institutional policy.

Vincristine sulfate must be administered via an intact, free-flowing intravenous needle or
catheter. Care should be taken to ensure that the needle or catheter is securely within the
vein to avoid extravasation during administration. The solution may be injected either
directly into a vein or into the tubing of a running intravenous infusion.

Special precautions: FOR INTRAVENOUS USE ONLY.

The container or the syringe containing vinCRIStine must be enclosed in an overwrap
bearing the statement: “Do not remove covering until moment of injection. For intravenous
use only - Fatal if given by other routes.”

Supplier: Commercially available from various manufacturers. See package insert for
more detailed information.

Note: Medication errors have occurred due to confusion between vinCRIStine and
vinBLAStine. VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate
liposomal injection, VSLI, Marqibo®). The conventional and liposomal formulations are
NOT interchangeable; use of the liposomal formulation is not permitted in this trial.

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7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED

Timing of protocol therapy administration, response assessment studies, and surgical
interventions are based on schedules derived from the experimental design or on established
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG
administrative Policy 5.14 (except where explicitly prohibited within the protocol).
7.1 Required Clinical, Laboratory and Disease Evaluations
All baseline studies must be performed prior to starting protocol therapy unless otherwise
indicated. Obtain other studies prior to start of phase unless otherwise indicated.
7.1a HR/IR Patients
STUDIES TO BE Baseline Block 1 Block 2 Block 3 Blinatumomab Blocks
OBTAINED
Hx/PE with VS/Wt (BSA) X start of start of start of phase*
phase phase
CBC/diff/plts X weekly weekly weekly weekly
Bilirubin, ALT, creatinine, X weekly weekly weekly weekly
BUN
Local Bone Marrow (BM) X1 end of end of end of end of phase
Evaluation phase phase phase
Bone Marrow (BM) for end of end of end of end of Cycle 1++,
central flow MRD2 phase+ phase++ phase+++ end of Cycle 2+++
Bone Marrow (BM) for X2,7
Immunophenotyping
CSF cell count and cytospin X with with each with each with each IT
each IT IT IT
Peripheral Blood for Cycle 1: Day 2 and Day
Pharmacokinetics (PK) 6
14
Peripheral Blood for • Prior to (Hour 0) start of
Immunogenicity first blinatumomab
infusion (Cycle 1)
• End of Cycle 2$
Echocardiogram X
Pregnancy test3 X
Testicular exam X end of end of end of end of phase
phase phase phase
Testicular biopsy X4 X5
1 BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse patients should include
morphology, immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis must be performed at a COG approved
cytogenetics lab and cases will be reviewed retrospectively by the COG Cytogenetics Committee. See Section 13.2 for details.
2 See Section 13.3 for details on shipping and handling
3 Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients
must use an acceptable method of birth control.
4 Patients with suspected testicular involvement at relapse (either isolated or with concurrent BM/CNS relapse) must have
biopsy performed at baseline.
5 Patients with definite or equivocal residual testiculomegaly at end of Block 1 must have a biopsy to determine whether
TRT is to be given during designated blocks of therapy (see Experimental Design Schema).
6
See lab manual on protocol webpage for sample collection and shipping details
7
Includes optional sample for CRLF2 expression for consenting patients (see Section 7.2 and Section 13.4).
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
$
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1.
+ Evaluation 1 ++ Evaluation 2 +++pre-HSCT evaluation
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain
other studies as indicated for good clinical care.

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7.1b LR Patients
STUDIES TO BE Baseline Block 1 Block 2 Block 3, Blinatumomab Maintenance and
OBTAINED blocks, Continuation post-therapy
Hx/PE with VS/Wt X start of start of phase* every 28 days
(BSA) phase
CBC/diff/plts X weekly weekly weekly every 28 days
Bilirubin, ALT, X weekly weekly weekly every 28 days
creatinine, BUN
Local Bone Marrow X1 end of end of
(BM) Evaluation phase phase
Bone Marrow (BM) for end of end of
central flow MRD2 phase+ phase++
Bone Marrow (BM) for X2,7
Immunophenotyping
CSF cell count and X with with with each IT with each IT
cytospin each IT each IT
Absolute lymphocyte At end of each 12
count with T and B week maintenance
subset quantification cycle, and every 3
months after
completion of
therapy for 1 year
Peripheral Blood for Blinatumomab Cycle 1:Day
Pharmacokinetics (PK) 6
2 and Day 14
Peripheral Blood for • Prior to (Hour 0) start of Prior to start of
Immunogenicity first blinatumomab Maintenance
infusion (Cycle 1) Cycle 1 therapy
• End of Cycle 2$
Echocardiogram X
Pregnancy Test3 X
Testicular Biopsy X4 X5
1 BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse patients should
include morphology, immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis must be performed at a COG
approved cytogenetics lab and cases will be reviewed retrospectively by the COG Cytogenetics Committee. See Section
13.2 for details.
2 See Section 13.3 for details on shipping and handling
3 Female patients of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients

must use an acceptable method of birth control.

4 Patients with suspected testicular involvement at relapse (either isolated or with concurrent BM/CNS relapse) must have

biopsy performed at baseline.

5 Patients with definite or equivocal residual testiculomegaly at end of Block 1 must have a biopsy to determine whether TRT

is to be given during designated blocks of therapy (see Experimental Design Schema).

6
See lab manual on protocol webpage for sample collection and shipping details
7
Includes optional sample for CRLF2 expression for consenting patients (see Section 7.2 and Section 13.4).
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
$
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1.
+ Evaluation 1 ++ Evaluation 2
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain
other studies as indicated for good clinical care.

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7.1c HSCT
Observation Prior to 1-2 3 mo 6 mo 9 mo 1 yr. 2 3 4 5 At
transplant weeks Post- Post- Post- Post- yrs. yrs. yrs. yrs. subsequent
(Tx) after Tx Tx Tx Tx Post- Post- Post- Post- relapse
ANC> Tx Tx Tx Tx
500/µL
Bone X+++ X* X**
Marrow
(BM) for
central
MRD1
CSF cell X X
count and
cytospin
CBC, X X X X X X X X
differential,
platelets
BUN, X
Creatinine
LFT X X X X X X X
Pulmonary X
function test
Performance X X X X X X X X X X X
score
1 See
Section 13.3 for details on shipping and handling; (see Section 7.2)
+++pre-HSCT evaluation
*Day 30 (25-30)
**Day100 (+/- 3 weeks)
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain other studies as
indicated for good clinical care.

7.1d Salvage Therapy (Blinatumomab-S)

STUDIES TO BE Blinatumomab Blocks
OBTAINED
Hx/PE with VS/Wt Start of phase*
(BSA)
CBC/diff/plts weekly
Bilirubin, ALT, weekly
creatinine, BUN
Local Bone Marrow end of phase
(BM) Evaluation
Bone Marrow (BM) for pre-HSCT
central flow MRD2
CSF cell count and with each IT
cytospin
Peripheral Blood for Cycle 1: Day 2 and Day 14**
Pharmacokinetics (PK)
Peripheral Blood for • Prior to (Hour 0) start of first blinatumomab infusion (Cycle 1)
Immunogenicity • End of Cycle 2$
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
**See lab manual on protocol webpage for sample collection and shipping details
$
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1.

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7.1e Recommended Observations: Blinatumomab Blocks

The investigator is recommended to monitor the patient’s vital signs (body temperature,
heart rate and blood pressure) approximately every 4 hours during the first 12 hours after
the start of a cycle, and upon resumption after suspension for adverse event. On Day 2
and 3 vital signs should be measured once daily."

7.2 Research Studies

The following are correlative biology studies for which patient participation is optional. Please see
Section 13.0 for details on volumes of specimen collection and shipping information. Note: Patient
consent is required.
Study Summary of Sample and Timing
(see section for details)
Banking for Future Peripheral blood:
Research * • Baseline
(Section 13.1) • End Block 1
• End Block 2
• Relapse
Bone marrow:
• Baseline
• End Block 1
• Relapse
NOTE: This also includes the optional banking of residual
material from required bone marrow for central flow MRD
CRLF2 expression No separate specimen required – cell pellet from required
(Section 13.4) baseline central flow bone marrow will be used
Protein Cell Stress Peripheral blood:
(Section 13.6) • Day 1 of Block 1
o Before chemotherapy (Hour 0)
o After Chemotherapy (Hour 6 and Hour 24)
Blinatumomab Bone marrow:
Pharmacodynamics (PD) • End Block 1 (All patients)
(Section 13.5) • End Block 2 (LR patients on Arm D only)

Peripheral blood:
• Prior to (Hour 0) start of first blinatumomab
infusion
• During (Hour 6, Hour 12, Day 2, Day 7, Day 14,
Day 21) first blinatumomab infusion
•

* For cases with a limited amount of tissue available for analysis, please prioritize specimen for
tissue banking.
7.3 At Relapse
Patients who relapse and have consented to cell banking at time of enrollment should
have samples of bone marrow sent to the Molecular Reference Laboratory for cell
banking (see Section 13.1.)

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7.4 Follow-up
See COG Late Effects Guidelines for recommended post treatment follow-up:
http://www.survivorshipguidelines.org/

Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs)
schedule.
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY
CRITERIA

8.1 Criteria for Removal from Protocol Therapy

a) Treatment failure but not eligible to receive blinatumomab salvage
b) Treatment failure that receives blinatumomab salvage but does not achieve CR after 2
cycles of blinatumomab
c) Adverse events requiring removal from protocol therapy
d) Refusal of further protocol therapy by patient/parent/guardian.
e) Completion of planned therapy.
f) Physician determines it is in patient’s best interest.
g) Development of a second malignancy.
h) Second relapse at any site.
i) Repeat eligibility studies are outside the parameters required for eligibility (if applicable,
see Section 3.2 ).
j) Inevaluable
k) Found to be ineligible for HSCT (See Section 4.9.1)
l) Pre-Randomization (HR/IR or LR): Interval development of significant central
nervous system pathology that would preclude treatment with blinatumomab (see
Section 3.2.5.13 for definition).

Patients who are off protocol therapy are to be followed until they meet the criteria for Off
Study (see below). Follow-up data will be required unless consent was withdrawn.
8.2 Off Study Criteria
a) Death.
b) Lost to follow-up.
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at
recurrence).
d) Withdrawal of consent for any further data submission.
e) Tenth anniversary of the date the patient was enrolled on this study.

9.0 STATISTICAL CONSIDERATIONS

9.1 Statistical Design

9.1.1 Primary Endpoint
A primary objective (HR/IR Randomization) of AALL1331 is to compare disease-
free survival (DFS) of HR and IR relapse patients randomized to Block 2 and 3
chemotherapy (Control) vs. two blocks of blinatumomab (Experimental), followed
by allogeneic HSCT. DFS is defined as time from start of randomization to event
(treatment failure, relapse, second malignancy, death) or last follow-up for those

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who are event-free. DFS event date will be set at Day 1 if patients are deemed as
TF after randomization.
Another primary objective (LR Randomization) of AALL1331 is to compare DFS
of LR relapse patients randomized to chemotherapy alone (Control: Block 3,
Continuation 1, Continuation 2 and Maintenance) vs.
blinatumomab/chemotherapy (Experimental: blinatumomab, Continuation 1,
blinatumomab, Continuation 2, blinatumomab, Maintenance). DFS is defined as
time from start of randomization to first event (relapse, second malignant
neoplasm, remission death) or last follow up for those who are event-free.

9.1.2 Secondary Endpoints

A secondary objective (HR/IR Randomization) of AALL1331 is to compare
overall survival (OS) of HR and IR relapse patients randomized to Block 2 and 3
chemotherapy (Control) vs. two blocks of blinatumomab (Experimental),
followed by allogeneic HSCT. OS is defined as time from start of randomization
to death or last date of contact.

Another secondary objective (LR Randomization) of AALL1331 is to compare OS

of LR relapse patients randomized to chemotherapy alone (Control: Block 3,
Continuation 1, Continuation 2 and Maintenance) vs.
blinatumomab/chemotherapy (Experimental: blinatumomab, Continuation 1,
blinatumomab, Continuation 2, blinatumomab, Maintenance). DFS is defined as
time from start of randomization to first event (relapse, second malignant
neoplasm, remission death) or last follow up for those who are event-free.
9.1.3 Exploratory Endpoints
The exploratory endpoints associated with HR/IR Randomization are to compare
the rates of MRD positivity (>0.01%) at the end of Block 2 and 3 between
randomized arms for HR and IR relapse patients.
Other exploratory endpoints include estimating the CR rate, MRD negativity
(< 0.01%) rate and proportion that proceed to HSCT after treatment with
blinatumomab for treatment failure patients not previously receiving
blinatumomab, assessing the feasibility and safety of rapid taper of immune
suppression for subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-
HSCT with no aGVHD, and collecting biologic samples for the prospective
correlative biology studies described in Section 7.0.
Blinatumomab PK will be evaluated by summarizing blinatumomab steady state
concentrations and systemic clearance obtained from non-compartmental analysis.
In addition, a population PK approach using a non-linear mixed effect model will
also be used to assess blinatumomab PK. Exposure-response analyses will be
performed to explore associations among blinatumomab exposure, relevant
clinical covariates and clinical measures of saftery and efficacy.

9.2 Patient Accrual and Expected Duration of Trial

9.2.1 Stratification to be used in the randomization
All patients are assigned to Stratum 1 at enrollment. All HR/IR relapse patients
who do not meet the treatment failure criteria at the end of Block 1 will be eligible

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for HR/IR randomization and randomized equally between experimental

(blinatumomab) and control (chemotherapy) arms. The randomization will occur
upon recovery from Block 1 of therapy, and will be stratified by: 1) Risk Group
(HR vs. IR); 2) For HR patients, site of relapse (marrow vs. IEM); 3) For HR-
marrow patients, duration of first remission (< 18 months vs. 18-36 months from
diagnosis); 3) For HR-marrow patients, MRD level end Block 1 (< 0.1% vs. ≥
0.1%) to ensure balanced randomization within these subsets (see table below).

Stratum # Risk-Site CR1 mos MRD status

2 HR-Marrow < 18 MRD < 0.1%
3 HR-Marrow < 18 MRD ≥ 0.1%
4 HR-Marrow 18-36 MRD < 0.1%
5 HR-Marrow 18-36 MRD ≥ 0.1%
6 HR-IEM <18 -
7 IR - -
All late B-ALL marrow and late B-ALL IEM relapse patients with end Block 1
MRD < 0.1% will eligible for LR randomization and randomized equally between
experimental (blinatumomab) and control (chemotherapy) arms. The
randomization will occur upon recovery from Block 1 of therapy, and will be
stratified by: 1) site of relapse (marrow vs. IEM); and 2) MRD level at time of
randomization (< 0.01% vs. ≥ 0.01%) to ensure balanced randomization within
these subsets.

Stratum # Site CR1 mos MRD status

8 LR-Marrow ≥ 36 MRD < 0.01%
9 LR-Marrow ≥ 36 MRD ≥ 0.01% or MRD < 0.1%
with sensitivity 1/1000
10 LR-IEM ≥ 18 MRD < 0.01%
11 LR-IEM ≥ 18 MRD ≥ 0.01% or MRD < 0.1%
with sensitivity 1/1000

9.2.2 Sample size with power calculation

Sample size calculations driving this study are based on the two randomized
questions HR/IR Randomization and LR Randomization.
For HR/IR Randomization, approximately 170 evaluable HR/IR B-ALL patients
are to be randomized between experimental (blinatumomab) and control
(chemotherapy) arms after recovery from Block 1. As described in Section 9.3.1,
the test of the randomization question has a power of 80.0% at a one-sided
significance level of 2.5% to detect the desired improvement in 2-year DFS rate.
The 170 evaluable HR/IR B-ALL patients are expected to take 3 years to be
enrolled with the total rate of accrual to HR/IR Randomization to be 56 per year
after adjusting for approximate 10% refusal rate to randomization. This estimate is
based on the following estimates of annual accrual and dropout rate from past
studies AALL01P2, AALL02P2, AALL0433 and ADVL04P2:

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Early Early Late Late

marrow IEM marrow IEM
# entering study 60 5 44 28
Rate of MRD ≥ 0.1% - - 38% 12%
Rate of not dropping out prior
to block 2 (due to toxicity 70% 70% 90% 90%
and/or treatment failure)
# eligible for randomization 42 3 15 3
For LR randomization, approximately 206 evaluable LR B-ALL patients are to be
randomized between experimental (blinatumomab) and control (chemotherapy)
arms after recovery from Block 1. As described in Section 9.3.2, the test of the
randomization question has a power of 80.4% at a one-sided significance level of
5% to detect the desired improvement in 3-year DFS rate. The 206 evaluable LR
B-ALL patients are expected to accrue over 5.6 years with total rate of accrual to
LR Randomization to be 37 per year after adjusting for approximate 10% refusal
rate to randomization. This estimate is based on the following estimates of annual
accrual and dropout rate from past studies AALL01P2, AALL02P2, AALL0433
and ADVL04P2:

Late marrow Late IEM

# entering study 44 28
Rate of MRD < 0.1% 62% 88%
Rate of not dropping out prior to block 2 (due to
80% 80%
toxicity and/or treatment failure)
# eligible for randomization 22 20
Therefore, in order to enroll 170 and 206 evaluable patients for HR/IR and LR
Randomization respectively, a total of 195 early marrow/IEM and 403 late
marrow/IEM patients are expected be accrued at the beginning of the study.

9.3 Statistical Analysis Methods

9.3.1 HR/IR Randomization for HR and IR relapse patients
9.3.1.1 Primary endpoint: intent-to-treat DFS
The primary efficacy analysis for HR/IR Randomization will be an intent-
to-treat comparison of the DFS curves between the randomized arms based
on the Log-rank test. All HR/IR relapse patients who are not deemed as
treatment failures at the end of Block 1 will be eligible for HR/IR
Randomization. The randomization will occur upon recovery from Block
1 of therapy, and will be stratified as described in Section 9.2. From the
past studies of AALL01P2, AALL02P2 and ADVL04P2, the overall 2-
year DFS rate for HR/IR patients was approximately 45%. Although most
events are projected to occur within 2 years, events continue to occur in
subsequent years, and hence an exponential distribution is considered
more appropriate than a cure-rate model for comparing survival curves for

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this cohort of patients at the time of final analysis. Assuming a minimum

of 2 years of follow up, an estimate of 170 evaluable patients will need to
be randomized to achieve the goal of 18% improvement in 2-year DFS
rate with blinatumomab over the expected 2-year DFS rate of 45% with
chemotherapy backbone alone, with 80.0% power at a one-sided
significance level of 2.5%, which represents a 42.1% reduction in hazard
rate. The power calculations are based on the assumption of proportional
hazards and using the log rank test.
Interim analysis will be conducted to monitor for efficacy and futility. The
efficacy stopping boundaries to be used will be based on the O’ Brien-
Fleming spending function. The futility boundaries are based on testing
the alternative hypothesis at the 0.024 level.80 This monitoring rule can be
applied to any interim analysis schedule and maintains the overall
significance level of 0.025. Assuming exponential distribution and the
final analysis is performed at the 2 years after the completion of
enrollment, the expected maximum number of events to be observed is
estimated to be 109. The first interim analysis will be performed after 36
events have been observed. The cumulative power to detect the desired
improvement is approximately 78%. The sample of monitoring boundaries
for efficacy and futility with 3 interim analyses are given in the table
below.
Futility
Looks # of events Information Efficacy Boundary
Boundary
1 36 33% 3.731 -0.392
2 73 67% 2.504 0.280

3 109 100% 1.994 1.994

9.3.1.2 Secondary Endpoint: Intent-to-treat OS

From the past studies of AALL01P2, AALL02P2 and ADVL04P2, the 3-
year OS rate for HR/IR patients was approximately 48%, and most deaths
occurred within the first 3 years. Therefore, a cure-rate model with
exponential distribution assumed during the first 3 years followed by a flat
curve is considered for OS analysis. An interim OS analysis will be
conducted at the time of the final DFS analysis, i.e. when all the 170
randomized patients are followed up for 2 years. Assuming 17%
improvement in 3-year OS rate with blinatumomab over the expected 3-
year OS rate of 48% with chemotherapy backbone alone, approximate 70
deaths are to be observed by the time of the interim OS analysis. The
power to detect such improvement at a one-sided significance level of
2.5% is approximate 61% based on the log-rank test.
If DFS analysis meets its target level of improvement (i.e. one-sided p-
value < 0.025), the formal OS analysis will be performed at at 1 year after
the interim OS analysis, by which time approximate 74 deaths are to be

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observed. The power to detect the above desired improvement is

approximately 63%.

9.3.1.3 Secondary endpoint: MRD+ rates

MRD comparisons (using an MRD+ threshold of 0.01%) will be
performed at the end of Blocks 2 and 3 for marrow relapse patients
participating in HR/IR Randomization. From past experience with studies
AALL01P2, ADVL04P2, AALL07P1 and AALL0433, we anticipate that
over the 3 years of the study, there will be 56 patients per arm evaluable
for the MRD comparison at the end of Block 2 and 50 patients per arm
evaluable for the MRD comparison at the end of Block 3 (see table below
for derivation).

Early Late marrow with

Total
marrow MRD ≥ 0.1%

# randomized on HR/IR
61 24 85
Randomization (per arm)
Rate of not dropping out
63% 75%
prior to end Block 2
# evaluable for end Block 2
38 18 56
MRD testing
Rate of not dropping out
89% 88%
prior to end Block 3
# evaluable for end Block 3
34 16 50
MRD testing
Further, we anticipate that the rates of MRD ≥ 0.01% in the control arm
will be 67% (67% for early and 68% for late) at the end of Block 2 and
47% (43% for early and 55% for late) at the end of Block 3. A two-sample
Fisher’s exact test of proportions (one-sided, alpha = 5%) will be used to
test the hypothesis that the proportion of patients who are MRD+ on each
experimental arm (with blinatumomab) is smaller than the control arm
(without blinatumomab) at the end of Block 2 and 3. The corresponding
power to detect various degrees of reduction in MRD+ rates is shown in
the table below:

Expected # per % MRD+ Reduction in MRD+ rates

arm with (control (investigational arm)
successful MRD arm)
10% 15% 20% 25%
determination
End Block 2 56 67% 22.6% 41.8% 63.2% 81.2%
End Block 3 50 47% 19.2% 37.1% 59.5% 79.8%

9.3.1.4 Safety monitoring

According to the past study ALLR3, the cumulative toxic death rate of
Blocks 2 and 3 of chemotherapy was estimated to be 4% (1.6% for Block
2 and 2.7% for Block 3). The toxic death rate is expected to be lower in
the experimental arm than the control arm because the myelosuppressive

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cytotoxic chemotherapy blocks are replaced with targeted

immunotherapy. Therefore, toxic deaths will be closely monitored on all
patients enrolled to each arm of HR/IR Randomization separately through
blocks 2 and 3 of therapy. HR/IR Randomization will be temporarily
closed for detailed review and possible therapy modifications if the
number of toxic deaths in either arm is greater than or equal to that
specified in the table. The boundary of toxic death was computed based
on Pocock-type spending function at one-sided 20% significant level.

Information Pocock boundary Excessive

# evaluable
Looks of excessive toxic toxic death
patients
death rate
1 28 33% 4 14.29%

2 57 67% 5 8.77%

3 85 100% 7 8.24%

Either arm of HR/IR Randomization will be rejected for excessive toxicity

if the number of observed toxic deaths is greater than or equal to the
corresponding boundary at any interim analysis. The actual power (based
on exact binomial test) of declaring an arm too toxic are approximately
95.2%, 80.8%, 47.2% and 10.1% when the true toxic death rate is 13%,
10%, 7% and 4%, respectively.
In addition, occurred during Block 2 and 3 of chemotherapy the toxic
deaths and all toxicities of all grades between the two arms will be
monitored/compared during the study. If the toxic death rate or the rate for
any specific toxicity is significantly higher on the blinatumomab arm
compared to the control arm (ALLR3 backbone), the data will be reviewed
for possible suspension of the randomization and modification of therapy.
9.3.2 LR Randomization for LR relapse patients
9.3.2.1 Primary endpoint: intent-to-treat DFS from randomization
The primary efficacy analysis for LR Randomization will be an intent-to-
treat comparison of the DFS curves between the randomized arms based
on the Log-rank test. All late B-ALL marrow and IEM relapse patients
with end Block 1 MRD < 0.1% who are not deemed to be treatment
failures at the end of Block 1 or Block 2 will be eligible for LR
Randomization . For IEM patients, uninterpretable MRD (due to lack of
diagnostic marker) will be considered to be MRD negative. The
randomization will occur upon recovery from Block 2 of therapy, and will
be stratified as described in Section 9.2. Data from past studies suggest
that most events are to occur within 3 years, but events continue to occur
in subsequent years, and hence an exponential distribution is considered
more appropriate than a cure-rate model for comparing survival curves for
this cohort of patients at the time of final analysis. An estimate of 206
evaluable patients will be randomized 1:1 (103 evaluable patients per arm)
between randomized experimental (blinatumomab) and control
(chemotherapy) arms. Assuming a minimum of 3-years of follow up, this
sample size estimate is based on a goal of achieving a 11% improvement
in 3-year DFS rate with blinatumomab over the expected 3-year DFS rate

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of 73% with chemotherapy backbone alone, with 80.4% power at a one-

sided significance level of 5%, which represents a 44.6% reduction in the
hazard rate. The power calculations are based on the assumption of
proportional hazards and using the log rank test.
Interim analysis will be conducted to monitor for efficacy and futility. The
efficacy stopping boundaries to be used will be based on the O’ Brien-
Fleming spending function. The futility boundaries are based on testing
the alternative hypothesis at the 0.039 level.80 This monitoring rule can be
applied to any interim analysis schedule and maintains the overall
significance level of 0.05. Assuming exponential distribution and the final
analysis is performed at the 3 years after the completion of enrollment, the
expected maximum number of events to be observed is estimated to be 75.
The first interim analysis will be performed after 25 events have been
observed. The cumulative power to detect a difference is approximately
80%. The sample of monitoring boundaries for efficacy and futility with 3
interim analyses are given in the table below.
Looks # of Information Efficacy Boundary Futility
events Boundary

1 25 33% 3.202 -0.312

2 50 67% 2.140 0.288

3 75 100% 1.695 1.695

9.3.2.2 Secondary Endpoint: Intent-to-treat OS

From past studies suggest that most events for LR patients are to occur
within 4 years after randomization and the 4-year OS rate is estimated to
be 77%. Therefore, a cure-rate model with exponential distribution
assumed during the first 4 years followed by a flat curve is considered for
OS analysis for LR randomized patients. An interim OS analysis will be
conducted at the time of the final DFS analysis, i.e. when all the 206
randomized patients are followed up for 3 years. Assuming 10%
improvement in 4-year OS rate with blinatumomab over the expected 4-
year OS rate of 77% with chemotherapy backbone alone, approximate 36
deaths are to be observed by the time of the interim OS analysis. The
power to detect such improvement at a one-sided significance level of 5%
is approximate 60% based on the log-rank test.
If DFS analysis meets its target level of improvement (i.e. one-sided p-
value < 0.05), the formal OS analysis will be performed at 1 year after the
interim OS analysis, by which time approximate 37 deaths are to be
observed. The power to detect the above desired improvement is
approximately 61%.

9.3.2.3 Monitoring for severe toxicities and toxic deaths

According to the past study of ALLR3, the cumulative toxic death rate of
Block 3, Continuation and Maintenance chemotherapy was estimated to

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be 4% (2.7% for Block 3 and 1.5% for Continuation and Maintenance).

The toxic death rate is expected to be lower in the experimental arm than
the control arm because the myelosuppressive Block 3 is replaced with
targeted immunotherapy. Therefore, toxic deaths will be closely
monitored on all patients enrolled on to each arm of LR Randomization
separately from the start of Block 3 of therapy to the completion of
protocol therapy. LR Randomization will be temporarily closed for
detailed review and possible therapy modifications if the number of toxic
deaths in either arm is greater than or equal to that specified in the table
below. The boundary of toxic death was computed based on Pocock-type
spending function at one-sided 20% significant level.

Information Pocock Excessive toxic

#
boundary of death rate
Looks evaluable
excessive
patients
toxic death
1 34 33% 4 11.76%
2 69 67% 6 8.70%

3 103 100% 7 6.80%

Either arm of LR Randomization will be rejected for excessive toxicity if
the number of observed toxic deaths is greater than or equal to the
corresponding boundary at any interim analysis. The actual power (based
on exact binomial test) of declaring an arm too toxic are approximately
98.7%, 90.9%, 61.5% and 14.4% when the true toxic death rate is 13%,
10%, 7% and 4%, respectively.
In addition, occurred during Block 3, Continuation 2 (Week 1-5) and
Maintenance (Week 6-10) the toxic deaths and all toxicities of all grades
between the two arms will also be monitored/compared during the study.
If the toxic death rate or the rate for any specific toxicity is significantly
higher on the blinatumomab arm compared to the control arm, the data
will be reviewed for possible suspension of the randomization and
modification of therapy.

The potential for late adverse effects due to long term depletion of CD19+
normal lymphocytes following blinatumomab treatment is unknown. We
will monitor for lymphocyte recovery and late events related to delayed
recovery. Since HR/IR/TF patients go to HSCT soon after blinatumomab,
it would be difficult to make sense of lymphocyte recovery/late events
after blinatumomab for them. However, the LR patients that are
randomized to +/- blinatumomab and do not proceed to HSCT serve as an
excellent population to monitor for these delayed adverse effects. For all
LR patients, we will collect absolute lymphocyte counts
(ALC)/lymphocyte subset counts (total T and B cells) and data regarding
late infections and progressive multifocal leukoencephalopathy (PML)
after each 12-week maintenance cycle and every 3 months after
completion of therapy for 1 year. The peripheral B-cell recovery rates and
rates of late events by randomized arms will be monitored and compared

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descriptively between the two randomized arms every 6 months in the

biannual study progress report and DSMC report.

9.3.3 Pilot intervention for very high risk subset of HSCT recipients based on MRD and aGVHD

9.3.3.1 Primary endpoint

The primary endpoint of this non-randomized exploratory pilot
intervention (accelerated taper of immune suppression) is feasibility and
safety, with “success” defined as < 25% rate of Grade III-IV aGVHD and
< 5% rate of treatment-related mortality (TRM) associated with the
accelerated taper. We anticipate that 36 patients will meet the criteria to
receive the intervention. We will calculate the observed rates of Grade III-
IV aGVHD and TRM among this subset with 95% confidence intervals
and compare descriptively to our target rates.

9.3.3.2 Exploratory endpoint

As secondary endpoints, we will calculate the percent of patients able to
wean off immunosuppression without significant aGVHD (future
intervention group), DFS of intervention group (vs. similar pts in
ASCT0431 historical controls), rate of conversion from MRD+ to MRD-
among preMRD-/postMRD+ subset (correlated with DFS), aGVHD rates
post-intervention (correlated with DFS). These data will be analyzed
descriptively.

9.3.3.3 Safety monitoring

The toxic death and Grade 3+ GVHD rates will be closely monitored for
the subset of HSCT patients with MRD ≥ 0.01% pre- and/or post-HSCT
with no acute graft versus host disease (aGVHD) who undergo accelerated
taper of immune suppression during the study. According to past studies,
the cumulative toxic death rate was estimated to be 5% and the cumulative
incidence rate of Grade 3+ GVDH was approximately 25%.
The safety stopping boundaries to be used for toxic death and Grade 3+
GVHD, respectively, will be based on the Pocock-type spending function
at one-sided 20% significance level. Assuming 85% of evaluable HR/IR
patients will proceed to HSCT study and approximately 25% of them will
have MRD ≥ 0.01% pre- and/or post-HSCT with no evidence of aGVHD,
an estimate of 36 patients will be monitored in this subset. The intervention
(accelerated taper of immune suppression) will be temporarily closed for
detailed review and possible therapy modifications if the number of toxic
deaths or the number of Grade 3+ GVHD is greater than or equal to that
specified in the corresponding table below.

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Table for toxic death monitoring boundary:

Pocock boundary Excessive
# evaluable
Looks Information of excessive toxic toxic death
patients
deaths rate
1 12 33% 3 25.00%

2 24 67% 4 16.67%

3 36 100% 4 11.110%

The intervention will be rejected for excessive toxicity death if the number
of observed toxic deaths is greater than or equal to the corresponding
boundary at any interim analysis. The actual power (based on exact
binomial test) of declaring the intervention too toxic are approximately
88.5%, 71.1%, 41.6% and 10.9% when the true toxic death rate is 17%,
13%, 9% and 5%, respectively.
Table for Grade 3+ GVHD monitoring boundary:
Excessive
# evaluable Pocock boundary of
Looks Information toxicity
patients excessive toxicity
rate
1 12 33% 6 50.00%

2 24 67% 10 41.67%

3 36 100% 13 36.11%
The intervention will be rejected for excessive Grade 3+ GVHD if the
number of observed Grade 3+ GVHD is greater than or equal to the
corresponding boundary at any interim analysis. The actual power (based
on exact binomial test) of declaring the intervention too toxic are
approximately 96.4%, 80.5%, 45.9% and 13.2% when the true rate of
Grade 3+ GVHD is 49%, 41%, 33% and 25%, respectively.

See Appendix XII for guidelines for establishing organ stage and overall
grade of acute GVHD.

9.3.4 Treatment Failure (TF) patients who are non-randomly assigned to blinatumomab
Point estimate and the corresponding exact 95% confidence interval based on
Clopper-Pearson’s method will be provided to estimate the hematologic CR , the
rate of MRD < 0.01%, and the proportion treatment failure patients able to
proceed to hematopoietic stem cell transplant (HSCT).

The toxic death will be closely monitored for TF patients who are non-randomly
assigned to blinatumomab. According to past studies, an approximate 60 (10%) of
enrolled patients will be deemed as TF, and the cumulative toxic death rate is
estimated to be 6%. The safety stopping boundaries to be used for toxic death will
be based on the Pocock-type spending function at one-sided 20% significance

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level. The intervention for TF patients will be temporarily closed for detailed
review and possible therapy modifications if the number of toxic deaths is greater
than or equal to that specified in the corresponding table below,
Table for toxic death monitoring boundary:
# evaluable Pocock boundary of Excessive toxic
Looks Information
patients excessive toxicities death rate
1 12 33% 3 25.00%

2 24 67% 4 16.67%

3 36 100% 5 13.89%

4 48 33% 6 12.50%

5 60 67% 7 11.67%

The intervention will be rejected for excessive toxicity death if the number of
observed toxic deaths is greater than or equal to the corresponding boundary at any
interim analysis. The actual power (based on exact binomial test) of declaring the
intervention too toxic are approximately 85.9%, 67.1%, 39.1% and 12.9% when
the true toxic death rate is 15%, 12%, 9% and 6%, respectively.

9.3.5 Blinatumomab related reportable adverse event (RAE)

A reportable adverse event (RAE) with respect to blinatumomab is defined in
Section 5.2. The reporting period case report form (CRF) for each blinatumomab
course will specifically collect data regarding blinatumomab RAEs. Due to limited
experience with blinatumomab, very little information is available estimate the
expected incidence of blinatumomab RAEs. We will prospectively monitor the
blinatumomab RAE rate on monthly study committee calls, and will report the
blinatumomab RAE rate every 6 months in the biannual study progress report and
DSMC report. RAE rates ≥ 10% will be of particular concern and will prompt
discussion with the DSMC.

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9.4 Gender and Minority Accrual Estimates

The gender and minority distribution of the study population is expected to be:

Accrual Targets
Sex/Gender
Ethnic Category
Females Males Total

Hispanic or Latino 85 79 164

Not Hispanic or Latino 225 209 434
Ethnic Category: Total of AllParticipants 2 310 288 598
2
Racial Category
American Indian/Alaska Native 5 3 8
Asian 12 14 26
Black or African American 35 22 57
Native Hawaiian or Other Pacific Island 2 1 3
White 256 248 504
Racial Categories: Total of All Subjects 310 288 598
* These totals must agree
This distribution was derived from past studies on AALL01P2, AALL02P2, ADVL04P2
and AALL0433.

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10.0 EVALUATION CRITERIA

10.1 Common Terminology Criteria for Adverse Events (CTCAE)

This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI)
for toxicity and performance reporting. A copy of the CTCAE version 4.0 can be
downloaded from the CTEP website
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
Additionally, toxicities are to be reported on the appropriate case report forms.

Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE
v4.0 as referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to
version 5.0).

10.2 Response Criteria

See definitions in Section 3.3.

11.0 ADVERSE EVENT REPORTING REQUIREMENTS

11.1 Purpose
Adverse event (AE) data collection and reporting, which are required as part of every
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those
who will enroll in future studies using similar agents. Certain adverse events must be
reported in an expedited manner to allow for timelier monitoring of patient safety and care.
The following sections provide information about expedited reporting.

11.2 Determination of reporting requirements

Reporting requirements may include the following considerations: 1) whether the patient
has received an investigational or commercial agent; 2) the characteristics of the adverse
event including the grade (severity), the relationship to the study therapy (attribution), and
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated
with the event.

An investigational agent is a protocol drug administered under an Investigational New

Drug Application (IND). In some instances, the investigational agent may be available
commercially, but is actually being tested for indications not included in the approved
package label.

Commercial agents are those agents not provided under an IND but obtained instead from
a commercial source. The NCI, rather than a commercial distributor, may on some
occasions distribute commercial agents for a trial.

When a study includes both investigational and commercial agents, the following rules
apply
• Concurrent administration: When an investigational agent is used in
combination with a commercial agent, the combination is considered to be

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investigational and expedited reporting of adverse events would follow the

guidelines for investigational agents.
• Sequential administration: When a study includes an investigational agent
and a commercial agent on the same study arm, but the commercial agent is
given for a period of time prior to starting the investigational agent,
expedited reporting of adverse events that occur prior to starting the
investigational agent would follow the guidelines for commercial agents.
Once therapy with the investigational agent is initiated, all expedited
reporting of adverse events follow the investigational agent reporting
guidelines.

11.3 Expedited Reporting Requirements – Serious Adverse Events (SAEs)

To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI
requires that AEs be submitted according to the timeframes in the AE reporting tables
assigned to the protocol, using the NCI’s CTEP Adverse Event Reporting System (CTEP-
AERS).

Any AE that is serious qualifies for expedited reporting. An AE is defined as any

untoward medical occurrence associated with the use of a drug in humans, whether or not
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event
(experience) occurring at any dose that results in ANY of the following outcomes:
1) Death.
2) A life-threatening adverse drug experience.
3) An adverse event resulting in inpatient hospitalization or prolongation of existing
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part
of routine medical practice.
4) A persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions.
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening,
or require hospitalization may be considered a serious adverse drug experience
when, based upon medical judgment, they may jeopardize the patient or subject
and may require medical or surgical intervention to prevent one of the outcomes
listed in this definition.

11.4 Special Situations for Expedited Reporting

11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug
Any Serious Adverse Event that occurs more than 30 days after the last
administration of the investigational agent/intervention and has an attribution of a
possible, probable, or definite relationship to the study therapy must be reported
according to the CTEP-AERS reporting tables in this protocol.

11.4.2 Persistent or Significant Disabilities/Incapacities

Any AE that results in persistent or significant incapacity or substantial disruption
of the ability to conduct normal life functions (formerly referred to as disabilities),
congenital anomalies or birth defects, must be reported via CTEP-AERS if it

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occurs at any time following treatment with an agent under a NCI IND/IDE since
these are considered to be serious AEs

11.4.3 Death
Reportable Categories of Death

• Death attributable to a CTCAE term.

• Death Neonatal: A disorder characterized by cessation of life during the first
28 days of life.
• Sudden Death NOS: A sudden (defined as instant or within one hour of the
onset of symptoms) or an unobserved cessation of life that cannot be
attributed to a CTCAE term associated with Grade 5.
• Death NOS: A cessation of life that cannot be attributed to a CTCAE term
associated with Grade 5.
• Death due to progressive disease should be reported as Grade 5 “Neoplasms
benign, malignant and unspecified (incl cysts and polyps) - Other
(Progressive Disease)” under the system organ class (SOC) of the same
name. Evidence that the death was a manifestation of underlying disease (e.g.,
radiological changes suggesting tumor growth or progression: clinical
deterioration associated with a disease process) should be submitted.

Any death occurring within 30 days of the last dose, regardless of attribution to
the investigational agent/intervention requires expedited reporting within 24 hours.

Any death occurring greater than 30 days after the last dose of the investigational
agent/intervention requires expedited reporting within 24 hours only if it is
possibly, probably, or definitely related to the investigational agent/intervention.

11.4.4 Secondary Malignancy

A secondary malignancy is a cancer caused by treatment for a previous
malignancy (e.g., treatment with investigational agent/intervention, radiation or
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary
malignancy.

The NCI requires all secondary malignancies that occur following treatment with
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are
available to describe the event:
• Leukemia secondary to oncology chemotherapy
• Myelodysplastic syndrome
• Treatment related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) must
also be reported via the routine reporting mechanisms outlined in this protocol.

Second Malignancy:
A second malignancy is one unrelated to the treatment of a prior malignancy
(and is NOT a metastasis from the initial malignancy). Second

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malignancies require ONLY routine reporting via CDUS unless otherwise

specified.

11.4.5 Pregnancy, Fetal Death, and Death Neonatal

NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”,
or “Neonatal loss”, the Pregnancy Information Form, available at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional
medical information to 301-230-0159. The potential risk of exposure of the fetus
to the investigational agent(s) or chemotherapy agent(s) should be documented in
the “Description of Event” section of the CTEP-AERS report.

11.4.5.1 Pregnancy
Patients who become pregnant on study risk intrauterine exposure of the fetus to
agents that may be teratogenic. For this reason, pregnancy needs to be reported in
an expedited manner via CTEP-AERS as
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions SOC.

There is a possibility that the sperm of male patients treated on studies involving
possible teratogenic agents may have been damaged. For this reason, pregnancy
in partners of men on study needs be reported and followed in the same
manner as a patient pregnancy.

Pregnancy needs to be followed until the outcome is known. If the baby is born
with a birth defect or anomaly, then a second CTEP-AERS report is required.

11.4.5.2 Fetal Death

Fetal death, defined in CTCAE as “A disorder characterized by death in utero;
failure of the product of conception to show evidence of respiration, heartbeat, or
definite movement of a voluntary muscle after expulsion from the uterus, without
possibility of resuscitation”, needs to be reported expeditiously, as Grade 4
“Pregnancy, puerperium and perinatal conditions - Other (pregnancy loss)”. Do
NOT report a fetal death as a Grade 5 event since CTEP-AERS recognizes any
Grade 5 event as a patient death.

11.4.5.3 Death Neonatal

Neonatal death, defined in CTCAE as “A disorder characterized by cessation of
life occurring during the first 28 days of life” needs to be reported expeditiously,
as Grade 4 “General disorders and administration - Other (neonatal loss)” when
the death is the result of a patient pregnancy or pregnancy in partners of men
on study. Do NOT report a neonatal death resulting from a patient pregnancy or
pregnancy in partners of men on study as a Grade 5 event since CTEP-AERS
recognizes any Grade 5 event as a patient death.

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11.5 Reporting Requirements for Specialized AEs

11.5.1 Baseline AEs
Although a pertinent positive finding identified on baseline assessment is not an
AE, when possible it is to be documented as “Course Zero” using CTCAE
terminology and grade. An expedited AE report is not required if a patient is
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value,
diarrhea). The baseline AE must be re-assessed throughout the study and reported
if it fulfills expedited AE reporting guidelines.
a. If the pre-existing condition worsens in severity, the investigator must
reassess the event to determine if an expedited report is required.
b. If the AE resolves and then recurs, the investigator must re-assess the event
to determine if an expedited report is required.
c. No modification in grading is to be made to account for abnormalities
existing at baseline.

11.5.2 Persistent AEs

A persistent AE is one that extends continuously, without resolution between
treatment cycles/courses.

ROUTINE reporting: The AE must be reported only once unless the grade
becomes more severe in a subsequent course. If the grade becomes more severe
the AE must be reported again with the new grade.
EXPEDITED reporting: The AE must be reported only once unless the grade
becomes more severe in the same or a subsequent course.

11.5.3 Recurrent AEs

A recurrent AE is one that occurs and resolves during a cycle/course of therapy
and then reoccurs in a later cycle/course.
ROUTINE reporting: An AE that resolves and then recurs during a subsequent
cycle/course must be reported by the routine procedures.
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent
cycle/course does not require CTEP-AERS reporting unless:
1) The grade increases OR
2) Hospitalization is associated with the recurring AE.

11.6 Exceptions to Expedited Reporting

11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER)
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and
Potential Risks (CAEPR) that contains a list of events that are considered expected
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific
Adverse Event List (ASAEL).)

AEs listed on the SPEER should be reported expeditiously by investigators to the

NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in
parentheses after the event. If the CAEPR is part of a combination IND using
multiple investigational agents and has an SAE listed on different SPEERs, use the
lower of the grades to determine if expedited reporting is required.

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11.6.2 Special Situations as Exceptions to Expedited Reporting

An expedited report may not be required for a specific protocol where an AE is
listed as expected. The exception or acceptable reporting procedures will be
specified in the protocol. The protocol specific guidelines supersede the NCI
Adverse Event Reporting Guidelines. These special situations are listed under the
CTEP-AERS reporting Table A for this protocol.

11.7 Reporting Requirements - Investigator Responsibility

Clinical investigators in the treating institutions and ultimately the Study Chair have the
primary responsibility for AE identification, documentation, grading, and assignment of
attribution to the investigational agent/intervention. It is the responsibility of the treating
physician to supply the medical documentation needed to support the expedited AE reports
in a timely manner.

Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report
Form (CRF) within the study database.

11.8 General Instructions for Expedited Reporting via CTEP-AERS

The descriptions and grading scales found in the NCI Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on
the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All
appropriate treatment areas should have access to a copy of the CTCAE.

An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be
submitted electronically to NCI via CTEP-AERS at:
https://webapps.ctep.nci.nih.gov/openapps/plsql/gader_accept$.startup.

In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned
in must be entered into the electronic CTEP-AERS system by the original submitter of the
report at the site.

• Expedited AE reporting timelines are defined as:

o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete
expedited report within 5 calendar days of the initial 24-hour report.
o 7 Calendar Days - A complete expedited report on the AE must be submitted
within 7 calendar days of the investigator learning of the event.

• Any event that results in a persistent or significant incapacity/substantial disruption of

the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is
an IME, which based upon the medical judgment of the investigator may jeopardize
the patient and require intervention to prevent a serious AE, must be reported via

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CTEP-AERS if the event occurs following investigational agent administration.

• Any death occurring within 30 days of the last dose, regardless of attribution to an
agent/intervention under an NCI IND/IDE requires expedited reporting within 24
hours.
• Any death occurring greater than 30 days of the last dose with an attribution of
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires
expedited reporting within 24 hours.
CTEP-AERS Medical Reporting includes the following requirements as part of the report:
1) whether the patient has received at least one dose of an investigational agent on this
study; 2) the characteristics of the adverse event including the grade (severity), the
relationship to the study therapy (attribution), and the prior experience (expectedness) of
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization
or prolongation of hospitalization was associated with the event.

Any medical documentation supporting an expedited report (e.g., H & P, admission

and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to
the NCI. NOTE: English is required for supporting documentation submitted to the
numbers listed below in order for the NCI to meet the regulatory reporting timelines.
Fax supporting documentation for AEs related to investigational agents supplied under
a CTEP IND to: 301-230-0159 (back-up: 301-897-7404).
Also: Fax or email to COG for all IND studies (fax # 626-303-1768; email: COGCTEP-
[email protected]; Attention: COG CTEP-AERS Coordinator).
• ALWAYS include the ticket number on all faxed documents.
• Use the NCI protocol number and the protocol-specific patient ID
provided during trial registration on all reports.

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11.9 Reporting Table for Late Phase 2 and Phase 3 Studies – Table A
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an
IND/IDE within 30 Days of the Last Administration of the Investigational
Agent/Intervention 1

FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death.
2) A life-threatening adverse event.
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. This
does not include hospitalizations that are part of routine medical practice.
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR
312.32; ICH E2A and ICH E6.)
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.
Hospitalization Grade 1 Grade 2 Grade 3 Grade 4 & 5
Timeframes Timeframes Timeframes Timeframes
Resulting in
Hospitalization 7 Calendar Days
≥ 24 hrs 24-Hour Notification
Not resulting in 5 Calendar Days
Hospitalization Not Required 7 Calendar Days
≥ 24 hrs
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special Situations as
Exceptions to Expedited Reporting are listed below.
Expedited AE reporting timelines are defined as:
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour notification.
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning
of the AE.
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an

attribution of possible, probable, or definite require reporting as follows:

Expedited 24-hour notification followed by complete report within 5 calendar days for:
• All Grade 4, and Grade 5 AEs
Expedited 7 calendar day reports for:
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
• Grade 3 adverse events

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11.10 Protocol Specific Additional Instructions and Reporting Exceptions

• Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not
require expedited reporting.
• Any blinatumomab-related AE that results in interruption of dosing as described
in Section 5.2 requires expedited reporting.

11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated

pathway
The following are expedited reporting requirements for adverse events experienced by
patients on study who have not received any doses of an investigational agent on this
study.
Commercial reporting requirements are provided in Table B.
COG requires the CTEP-AERS report to be submitted within 7 calendar days of
learning of the event.

Table B
Reporting requirements for adverse events experienced by patients on study who
have NOT received any doses of an investigational agent on this study.
CTEP-AERS Reporting Requirements for Adverse Events That Occur During
Therapy With a Commercial Agent or Within 30 Days1

Attribution Grade 4 Grade 5

Unexpected Expected
Unrelated or Unlikely CTEP-AERS
Possible, Probable, CTEP-AERS CTEP-AERS
Definite
1
This includes all deaths within 30 days of the last dose of treatment with a
commercial agent, regardless of attribution. Any death that occurs more than 30 days
after the last dose of treatment with a commercial agent that can be attributed
(possibly, probably, or definitely) to the agent and is not due to cancer recurrence
must be reported via CTEP-AERS.

11.12 Routine Adverse Event Reporting

Note: The guidelines below are for routine reporting of study specific adverse events on
the COG case report forms and do not affect the requirements for CTEP-AERS reporting.
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF)
within the study database. For this study, routine reporting is split into two categories:
1. During all blinatumomab cycles as well as parallel control arm cycles, routine
reporting will include all toxicities of all grades (see table).
2. HSCT routine reporting will include All toxicities reported via CTEP-AERS and
all Grade 4 and higher non-hematological Adverse Events
3. During all other blocks of therapy, routine reporting will include all toxicities
reported via CTEP-AERS and all Grade 3 and higher non-hematological
Adverse Events (see table).

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ADVERSE EVENT REPORTING BY TREATMENT PHASE

ALL PATIENTS REPORTING REQUIREMENT
All toxicities reported via CTEP-AERS and all Grade
Block 1
3 and higher non-hematological Adverse Events
HR/IR
Arm A Arm B
(Control) (Experimental)
Blinatumomab: Cycle
Block 2 All toxicities of all grades
1
Blinatumomab: Cycle
Block 3 All toxicities of all grades
2
All toxicities reported via CTEP-AERS and all Grade
Bridging Therapy
3 and higher non-hematological Adverse Events
All toxicities reported via CTEP-AERS and all Grade
HSCT HSCT
4 and higher non-hematological Adverse Events
LR
Arm C Arm D
(control) (Experimental)
All toxicities reported via CTEP-AERS and all Grade
Block 2 Block 2
3 and higher non-hematological Adverse Events
Block 3 Blinatumomab cycle 1 All toxicities of all grades
All toxicities reported via CTEP-AERS and all Grade
Continuation 1 Continuation 1
3 and higher non-hematological Adverse Events
Continuation 2
(first 5 weeks – days Blinatumomab cycle 2 All toxicities of all grades
1-35)
Continuation 2
(last 3 weeks – days
36-53) All toxicities reported via CTEP-AERS and all Grade
Continuation 2
Maintenance 3 and higher non-hematological Adverse Events
(first 5 weeks – days
1-35)
Maintenance
(second 5 weeks – Blinatumomab cycle 3 All toxicities of all grades
days 36-70)
Maintenance All toxicities reported via CTEP-AERS and all Grade
Maintenance (all)
(remainder) 3 and higher non-hematological Adverse Events
TF-Salvage Therapy
Blinatumomab-S 1
All toxicities of all grades
Blinatumomab-S 2

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12.0 RECORDS AND REPORTING

See the Case Report Forms posted on the COG web site with each protocol under “Data
Collection/Specimens”. A submission schedule is included.

12.1 CDUS
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions
participating in this trial.

12.2 CTA/CRADA
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to
the provisions in the “Intellectual Property Option to Collaborator”
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained
within the terms of award, apply to the use of the Agent(s) in this study:

12.2.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can
Agent(s) be transferred or licensed to any party not participating in the clinical study.
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s)
and shall be maintained as such by the investigators. The protocol documents for
studies utilizing Agents contain confidential information and should not be shared or
distributed without the permission of the NCI. If a copy of this protocol is requested
by a patient or patient’s family member participating on the study, the individual
should sign a confidentiality agreement. A suitable model agreement can be
downloaded from: http://ctep.cancer.gov.

12.2.2 For a clinical protocol where there is an investigational Agent used in combination
with (an)other Agent(s), each the subject of different Collaborative Agreements, the
access to and use of data by each Collaborator shall be as follows (data pertaining to
such combination use shall hereinafter be referred to as "Multi-Party Data”):
a. NCI will provide all Collaborators with prior written notice regarding the
existence and nature of any agreements governing their collaboration with NCI,
the design of the proposed combination protocol, and the existence of any
obligations that would tend to restrict NCI's participation in the proposed
combination protocol.

b. Each Collaborator shall agree to permit use of the Multi-Party Data from the
clinical trial by any other Collaborator solely to the extent necessary to allow
said other Collaborator to develop, obtain regulatory approval or commercialize
its own Agent.

c. Any Collaborator having the right to use the Multi-Party Data from these trials
must agree in writing prior to the commencement of the trials that it will use
the Multi-Party Data solely for development, regulatory approval, and
commercialization of its own Agent.

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12.2.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as
appropriate and unless additional disclosure is required by law or court order as
described in the IP Option to Collaborator
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).
Additionally, all Clinical Data and Results and Raw Data will be collected, used and
disclosed consistent with all applicable federal statutes and regulations for the
protection of human subjects, including, if applicable, the Standards for Privacy of
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.

12.2.4 When a Collaborator wishes to initiate a data request, the request should first be sent
to the NCI, who will then notify the appropriate investigators (Group Chair for
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact
them.

12.2.5 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with
the guidelines and policies of the responsible Data Monitoring Committee (DMC),
if there is a DMC for this clinical trial.

12.2.6 Any manuscripts reporting the results of this clinical trial must be provided to CTEP
by the Group office for Cooperative Group studies or by the principal investigator
for non-Cooperative Group studies for immediate delivery to Collaborator(s) for
advisory review and comment prior to submission for publication. Collaborator(s)
will have 30 days from the date of receipt for review. Collaborator shall have the
right to request that publication be delayed for up to an additional 30 days in order
to ensure that Collaborator’s confidential and proprietary data, in addition to
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon
as possible and preferably at least three (3) days prior to submission, but in any case,
prior to presentation at the meeting or publication in the proceedings. Press releases
and other media presentations must also be forwarded to CTEP prior to release.
Copies of any manuscript, abstract and/or press release/ media presentation should
be sent to:

Email: [email protected]

The Regulatory Affairs Branch will then distribute them to Collaborator(s). No

publication, manuscript or other form of public disclosure shall contain any of
Collaborator’s confidential/ proprietary information.

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13.0 SPECIAL STUDIES AND SPECIMEN REQUIREMENTS

Enrollment on companion protocol AALL05B1 (Cell Banking for Relapsed ALL) is

ENCOURAGED, but NOT REQUIRED. Patients who do enroll on AALL05B1 only require
a single cell bank specimen (i.e. not separate AALL1331 and AALL05B1 specimens).

13.1 Banking for Future Research (optional)

NOTE: Enrollment on companion protocol AALL05B1 (Cell Banking for Relapsed
ALL) or APEC14B1 (Project: Every Child) is ENCOURAGED, but NOT
REQUIRED. Patients who do enroll on AALL05B1 or APEC14B1 only require a
single cell bank specimen (i.e. not separate AALL1331 and AALL05B1 or APEC14B1
specimens).

For cases with a limited amount of tissue available for analysis, please prioritize
specimen for tissue banking.

This study is designed to provide material for banking for the purpose of performing
retrospective studies to refine risk stratification, identify new targets for therapy, identify
biomarkers to predict response, and to link host polymorphisms with various disease
characteristics and toxicities. See Appendix VI for details.

Sample Collection Procedures

A Specimen Transmittal Form should accompany every shipment of specimen(s) to the COG
Reference Laboratory. Please complete one form per patient per shipment.

Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol
specific form.

Shipping Media (SM)

Samples for the Reference Laboratories are to be collected in shipping media (SM) in
special 15 mL conical tubes. The SM contains RPMI with EDTA as the anticoagulant.
These tubes will be prepared in the Molecular Reference Laboratory and shipped in batches
to each participating institution, where they can be stored frozen at -20°C until use. Tubes
are stable for 3 months if refrigerated and stable for 1 year if frozen. To request prepared
and pre-packaged sample shipping tubes, order tubes through the Biopathology Center kit
management system (use the link provided on the CRA Web page).

Please Note: The receiving institutions are strongly encouraged to make requests for
sample tubes well in advance of their first patient registration on AALL1331; it will not be
possible to expedite shipping because of prohibitive costs.

Bone Marrow/Peripheral Blood Collection Procedures for Reference Laboratories:

a. Collect BM/PB into a syringe and transfer the specimen immediately into the SM tube
with RPMI/EDTA.
b. Mix well. At least 2 mL and up to 5 mL of BM/PB can be placed in 1 SM tube. If you
don’t have SM tubes, you can place the BM into large purple EDTA tubes that are
commonly available in most hospitals. However, the viability of the cells is greatly
enhanced in the SM tubes.

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c. For BM, use multiple syringes and tubes as necessary. Reposition the BM aspirate needle
at least once during the diagnostic procedure to ensure the maximum quality of BM.
DO NOT SHIP SYRINGES.
d. Label each tube with COG registration number/Biopathology number, patient name and
date of birth, date, institution and type of specimen (bone marrow).
e. Samples are to be shipped at room temperature except for international samples that are
expected to be delayed for more than 48 hours – place a cold pack (not ice pack) in
shipment.
NOTE: For patients who are not having a diagnostic BM for medical reasons, and who
have an absolute blast count of at least 1,000/μL, 2 mL of PB at diagnosis may be submitted
for each 1 mL of required marrow and submitted to the Reference Laboratories instead of
diagnostic BM.

Reference Laboratory – Shipping Address (including Saturday delivery):

Molecular Laboratory
Julie Gastier-Foster, PhD
COG ALL Reference Laboratory
Nationwide Children’s Hospital
700 Children's Drive, C1961
Columbus, OH 43205
Contact Person: Yvonne Moyer
Phone: (614) 722-2866
Fax: (614) 722-2887
Email: [email protected]
All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery
before 10 am). Use the COG FedEx account number, which may be found at:
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf.
Notify Laboratory of each Saturday delivery

13.2 Local Bone Marrow: Central review of cytogenetics/FISH

Bone marrow aspiration to confirm relapse (and/or to detect potential marrow disease in
presumed isolated extramedullary relapse patients) is required for study entry.
Morphologic, immunophenotypic, & cytogenetic/FISH analysis should be performed by
the local institution. Cytogenetic analysis should include FISH for any cytogenetic
abnormalities known from the patient‘s original leukemia if applicable. All FISH should
be performed on uncultured directly harvested cells or unstimulated overnight cultured
cells if the former is not possible. FISH for abnormalities shown by cytogenetics to be
unique to the relapse specimen should also be done on directly harvested cells or
unstimulated overnight cultured cells if the former is not possible. Cytogenetic/FISH
analysis must be performed at a COG approved cytogenetics lab and cases will be reviewed
retrospectively by the COG Cytogenetics Committee.
Please see the following link for a list of COG approved cytogenetics labs:
https://members.childrensoncologygroup.org/Disc/cytogen/default.asp

Required Material:
a) Two original karyotypes of different cells from each abnormal clone or of two normal
cells when no abnormalities are found; full-size metaphase images of the karyotypes
cells.

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b) A completed COG Cytogenetics Reporting Form and FISH Form (if done). These
reporting forms are available on the AALL1331 protocol web page. Electronic
submission of the karyotypes/FISH images is required.

Shipping: The review materials on each case should be sent to the COG ALL Cytogenetic
Coordinators within 4 weeks of study entry. If the institution is west of the Mississippi
River, send these materials to Dr. Andrew Carroll (University of Alabama). If the
institution is east of Mississippi River (except Minnesota and Wisconsin, which go to Dr.
Carroll), send all materials to Dr. Nyla Heerema (The Ohio State University).

Western Laboratory – Shipping Address:

Dr. Andrew Carroll, Ph.D.
Ph.D. Department of Genetics
University of Alabama at Birmingham
720 20th St. So. Kaul Bldg. Room 314B
Birmingham, AL 35294
Phone: 205-934-0665
Fax: 205-934-1078
Email: acarroll@ uab.edu

Eastern Laboratory – Shipping Address:

Dr. Nyla Heerema, Ph.D.
Professor and Director of Cytogenetics
The Ohio State University
Division of Clinical Pathology
Hamilton Hall, Room 167
1645 Neil Ave. Columbus, OH 43210
Phone: 614-292-7815
Fax: 614-292-7072
Email: [email protected]

13.3 Bone Marrow for Central Flow-Immunophenotping and MRD (required)

Immunophenotyping will be done on fresh bone marrow specimens collected at study
entry (see Section 7.1). Minimal residual disease will be detected using 6 color flow
cytometry (Dr. Michael Borowitz, Johns Hopkins University) on fresh bone marrow
specimens collected during therapy at various designated time points (see Section 7.1).
For patients who have consented to specimen banking, residual material should be sent for
banking. See section Section 13.1 for details.
Sample Collection Procedures
A Specimen Transmittal Form should accompany every shipment of specimen(s) to the COG
Reference Laboratory. Please complete one form per patient per shipment.

Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol
specific form.
Shipping Media (SM)
Samples for the Reference Laboratories are to be collected in shipping media (SM) in
special 15 mL conical tubes. The SM contains RPMI with EDTA as the anticoagulant.

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These tubes will be prepared in the Molecular Reference Laboratory and shipped in
batches to each participating institution, where they can be stored frozen at -20°C until
use. Tubes are stable for 3 months if refrigerated and stable for 1 year if frozen. To
request prepared and pre-packaged sample shipping tubes, order tubes through the
Biopathology Center kit management system (use the link provided on the CRA Web
page).

Please note: The receiving institutions are strongly encouraged to make requests for
sample tubes well in advance of their first patient registration on AALL1331; it will NOT
be possible to expedite shipping because of prohibitive costs.

Bone Marrow Collection Procedures for Reference Laboratories:

a. Collect BM into a syringe and transfer the specimen immediately into the SM tube
with RPMI/EDTA.
b. Mix well. At least 2 mL and up to 5 mL of BM can be placed in 1 SM tube. If you
don’t have SM tubes, you can place the BM into large purple EDTA tubes that are
commonly available in most hospitals. However, the viability of the cells is greatly
enhanced in the SM tubes.
c. Use multiple syringes and tubes as necessary. Reposition the BM aspirate needle at least
once during the diagnostic procedure to ensure the maximum quality of BM. DO NOT
SHIP SYRINGES.
d. Label each tube with COG registration number/Biopathology number, patient name and
date of birth, date, institution and type of specimen (bone marrow).
e. Samples are to be shipped at room temperature except for international samples that are
expected to be delayed for more than 48 hours – place a cold pack (not ice pack) in
shipment.

NOTE: For patients who are not having a diagnostic BM for medical reasons, and who
have an absolute blast count of at least 1,000/μL, 2 mL of PB at diagnosis may be
submitted for each 1 mL of required marrow and submitted to the Reference Laboratories
instead of diagnostic BM.

Please note: Specimens will be shipped to the COG Reference Laboratory at Johns Hopkins
(Eastern) ONLY.

Reference Laboratory – Shipping Address (including Saturday delivery):

Michael Borowitz, MD, PhD

Flow Cytometry Laboratory, Johns Hopkins Medical Institutions
Weinberg Building – Room 2300
401 N. Broadway
Baltimore, MD 21287
Phone: 410-614-2968
Fax: 410-502-1493
Email: [email protected]

All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery
before 10 am). Use the COG FedEx account number, which may be found at:
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf.

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Notify Laboratory of each Saturday delivery at 410-614-2968 or via email at

[email protected]

13.4 Bone Marrow for CRLF2 expression (optional)

We will quantify surface CRLF2 expression by flow cytometry and correlate with outcome.
This assay will be done in conjunction with the immunophenotyping performed at study
entry in Dr. Mike Borowitz’s lab at Johns Hopkins University (see Section 13.3). For
details, refer to Appendix IX.
Sample Collection Procedures
NOTE: A separate specimen is NOT REQUIRED. Please note on the specimen
transmittal forms that accompany the required immunophenotyping specimen whether
the patient has consented for the optional CRLF2 expression assay.

13.5 Blinatumomab Pharmacodynamics (PD) (optional)

Immunopharmacologic testing will be performed using blood and bone marrow specimens
in consenting patients treated with blinatumomab during the first exposure to
blinatumomab in an effort to identify biomarkers of blinatumomab response. For details,
refer to Appendix X.

NOTE: All patients will be offered participation in this study at Block 1, prior to treatment
assignment/randomization. Bone marrow samples will be drawn on all consenting patients
at end Block 1. If the patient is subsequently randomized or assigned to treatment with
blinatumomab (Arm B, Arm D, or Salvage Therapy), the Block 1 bone marrow sample will
be analyzed and subsequent blood samples should be obtained. If the patient is randomized
to treatment on the control arm (Arm A or Arm C), the Block 1 bone marrow sample will
be destroyed and no further samples will be collected.

Sample Collection Procedures

A Specimen Transmittal Form should accompany every shipment of specimen(s) to the
Brown Laboratory. Please complete one form per patient per shipment.

Please note: The AALL1331 Specimen Transmittal Form should be used. This is a protocol
specific form.

Blood and marrow collection schedule (see Section 7.2)

• Bone Marrow (1 sample, 5-10mL in sodium heparin tube)

o End Block 1 (All patients)
o End Block 2 (LR patients on Arm D only)

• Blood during first blinatumomab cycle (7 samples, 3mL each in sodium heparin tubes)
o Day 1
- 0 hr (just prior to start of blinatumomab infusion)
- 6 hr
- 12 hr
o Day 2

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o Day 7
o Day 14
o Day 21

Samples should be shipped at room temperature.

Brown Laboratory – Shipping Address (including Saturday delivery):

Dr. Patrick Brown
Johns Hopkins Oncology
Cancer Research Building I, Room 262
1650 Orleans Street
Baltimore, MD 21231
Laboratory phone: 410-955-8688
Pager no: 410-434-0732
E-mail: [email protected]

All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery
before 10 am). Use the COG FedEx account number, which may be found at:
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf.

Saturday deliveries are permissible. If a Saturday delivery is required, please notify Dr.
Brown of the planned shipment via email ([email protected]) PRIOR to the time of
shipment and clearly mark the package “For Saturday Delivery”.

13.6 Protein Cell Stress Pathways (optional)

Note: Isolated extramedullary relapse patients are not eligible for this sub-study.

This study is designed to analyze two specific aims: 1) To determine if specific protein
expression profiles, as determined by reverse-phase protein lysate array (RPPA) analysis
and phospho-flow analysis, correlate with therapy response and 2) To determine if
alterations in specific cell stress proteins (such as the UPR) during chemotherapy can
identify low risk patients with “high risk” protein signatures. For details, refer to Appendix
XI.
Consenting patients will have peripheral blood samples (5mL for those ≥ 10kg, 3 mL for
those < 10 kg) collected at 0h (prior to start of Block 1 systemic chemotherapy), and at 2
time points after the initiation of therapy (6 hours (h) and 24h after the first dose of Block
1 systemic chemotherapy) to examine for changes in protein expression patterns. Blood
samples for RPPA using sucrose centrifugation and (if necessary) the lymphoblast
population will be isolated by either bead technology or flow cytometry. Sample collected
for phospho-flow will be analyzed directly from whole blood. Sorted lymphoblasts will be
made into lysates for RPPA analysis prior to freezing. Remaining samples will be frozen
as pellets for protein analysis.

Eligible samples:
Sample should be sent to the Horton lab only if the patient has an initial absolute blast
count of at least 1000 lymphoblasts/µL. To calculate the absolute blast percentage,
multiply the total WBC by the % peripheral blasts:

(WBC)(% blast)(1000) = absolute blast count/µL

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Example: If the patient has a WBC of 10 and 50% blasts, the absolute blast count is:
(10)(.5)(1000) = 5000/µL

If the initial % blasts is unknown, send samples only if the total WBC is more than 10,000
and notify the Horton lab of the % blast as soon as available (contact info provided below).

Sample Collection Procedures

A Specimen Transmittal Form should accompany every shipment of specimen(s) to the
Horton Laboratory. Please complete one form per patient per shipment. Please note: The
AALL1331 Specimen Transmittal Form should be used. This is a protocol specific form.

Sample collection time points:

Day 1, Hour 0 Day 1, Hour 6-8 Day 1, Hour 24
(before start of systemic
chemotherapy)
Peripheral • 3mL in CellSave •
3mL in CellSave • 3mL in CellSave
Blood Preservative Tube* Preservative Preservative
(Block 1 • 3mL in heparin tube Tube* Tube*
only) • 3mL in heparin • 3mL in heparin
tube tube
*CellSave tubes will be provided by the Horton lab to each institution upon IRB approval.
To obtain more CellSave tubes, contact the Horton lab at the numbers provided below. If
the CellSave tubes are not available, submit entire 6 mL sample in 2 heparin tubes. Note
that the sample integrity is greatly enhanced by the use of CellSave tubes.

Store samples in refrigerator until shipment, and use Thermosafe with ice pack (or
similar Styrofoam shipping containers with sufficient ice packs if these are not available at
your site.) These containers maintain biology samples at a constant temperature and are
strongly recommended for biology sample shipment, particularly in warm weather months.

Horton Laboratory – Shipping Address (including Saturday delivery):

Dr. Terzah Horton c/o Gaye Jenkins
Feigin Center, Room 760.01
1102 Bates St.
Baylor College of Medicine
Houston, TX 77030
Phone: (832) 824-4676 or (832) 824-4269
email [email protected].

All samples should be mailed by overnight carrier (Federal Express) PRIORITY (delivery
before 10 am). Use the COG FedEx account number, which may be found at:
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf.

The Horton lab can accept Saturday shipments if we are contacted ahead of time.
Please contact Gaye Jenkins or Dr. Horton (832-824-4676 or 832-824-4269) for
alternative address and shipping information for Saturday delivery.

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13.7 Blinatumomab Immunogenicity Assessment (Required)

(See lab manual on protocol webpage for sample collection and shipping details)
Blinatumomab is a novel protein therapeutic under clinical development. As outlined in
the Draft Guidance: Immunogenicity Assessment for Therapeutic Protein Products (Feb
2013) pre-specified immunogenicity sampling will be performed to evaluate and mitigate
risk
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM338856.pdf).
Blood samples for the assessment of blinatumomab immunogenicity will be collected to
determine whether anti-idiotype antibodies directed against blinatumomab have been
developed. Screening for these antibodies will be done by ELISA assay on ECL Basis
(electrochemiluminescence), and binding will be confirmed with a Biacore assay to
measure protein-protein interaction and binding affinity.
In a tiered approach patient samples are initially tested in a screening assay. Samples that
produce signals above a certain screening cut point (classified as “positive”) may be
subjected to a confirmatory assay. The screening assay is designed to minimize false
negatives, so positive screening assays need to be confirmed as positive. These are
performed using the same format as the screening assay. A comparison of patient serum in
the presence and absence of excess blinatumomab is used to confirm or deny the existence
of anti blinatumomab antibodies. The screening and confirmation assay in the context of
blinatumomab clinical studies will be performed according to an internal standardized
protocol using a validated assay.
Immunoassay-positive samples will be analyzed in a third step using a cell based
blinatumomab-mediated cytotoxicity assay to determine if the detected antibodies have
neutralizing properties. Detection of neutralizing anti-blinatumomab antibodies relies on a
validated bioassay measuring changes in the biologic activity of blinatumomab triggered
by the presence of the antibody.
Blood Serum samples for antibody testing are being collected on all patients randomized
to receiving blinatumomab for the measurement screening of anti-blinatumomab binding
antibodies. Samples testing positive for binding antibodies will also be tested for
neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity
and presence of immune complexes. The ‘cell-based assay’ for neutralizing antibody
detection tests patient sera in a model cell based system. This does not require patient cells
or additional serum to be collected. Both the screening and the neutralizing assays are well-
established at the Amgen Research Munich laboratory.
COG will be notified of any positive neutralizing antibody results to blinatumomab. If
results are not provided, no neutralizing antibodies to blinatumomab have been detected.
Patients who test positive for neutralizing antibodies to blinatumomab at the final
scheduled study visit will be asked to return for additional follow-up testing. This testing
is to occur approximately every three months starting from when the site has been notified
of the positive result, until: (1) neutralizing antibodies are no longer detectable or (2) the
subject has been followed for a period of at least one year (± 4 weeks) post administration
of blinatumomab. All follow-up results, both positive and negative will be communicated
to COG. More frequent testing (e.g. every month) or testing for a longer period of time
may be requested in the event of safety-related concerns. Follow-up testing is not required
where it is established that the subject did not receive blinatumomab. Patients who test

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positive for binding, non-neutralizing antibodies and have clinical sequelae that are
considered potentially related to an anti-blinatumomab antibody response may also be
asked to return for additional follow-up testing.

13.8 Blinatumomab PK (required)

Please see the Lab Manual posted on the protocol web page for sample collection and
shipping details

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14.0 RADIATION THERAPY GUIDELINES FOR ALL PATIENTS

Radiation therapy (RT) for patients on COG protocols can only be delivered at approved
COG RT facilities (per COG administrative policy 3.9).

Timing of protocol therapy administration, response assessment studies, and surgical

interventions are based on schedules derived from the experimental design or on established
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG
administrative Policy 5.14 (except where explicitly prohibited within the protocol).

14.1 General Guidelines

The objective of this protocol is to compare the benefits and risks of Blinatumomab in the
treatment of first relapse B-ALL. Patients eligible for this study will undergo risk
classification after an initial block of chemotherapy (Block 1). Risk classification and the
indications for irradiation will be based on site of first relapse, time to first relapse, MRD
status following Block1 chemotherapy and clinical response to chemotherapy (when
testicular leukemia is present at protocol entry).
Patients determined to be low risk (LR) after Block 1, will receive additional chemotherapy
(Block 2) post randomization to a control arm or an experimental arm. The experimental
arm includes blinatumomab. Both the control and experimental arms include maintenance
chemotherapy to complete the respective regimens. LR patients with testicular leukemia at
protocol entry will receive testicular irradiation (2400cGy) during Block2 if they do not
have a clinical complete response after Block1. LR patients with CNS leukemia at protocol
entry will receive cranial irradiation (1800cGy) during maintenance chemotherapy.
Intermediate Risk (IR) and High Risk (HR) patients will be randomized to a control arm
or an experimental arm. The experimental arm includes blinatumomab. Both arms will
proceed to protocol-specified hematopoietic stem cell transplant (HSCT). Selected patients
that do not respond to Block1 and HR and IR patients that do not respond to the control
arm will receive blinatumomab in a separate treatment arm and may proceed to HSCT
depending on their response to Blinatumomab provided they do not have a history of CNS
leukemia (CNS3) at or after protocol entry. IR/HR patients with testicular leukemia at
protocol entry will receive testicular irradiation (2400cGy) during Block 2 (control arm) or
the first cycle of Blinatumomab (experimental arm) if they do not have a complete response
after Block1. IR/HR patients with testicular leukemia who have a complete clinical
response to Block 1 will receive supplemental testicular irradiation (600cGy) sequentially
with total body irradiation (TBI). IR/HR patients with CNS leukemia at protocol entry will
receive supplemental cranial irradiation (600cGy) sequentially with TBI. Supplemental
irradiation refers to irradiation of any site performed sequentially with TBI.
Treatment failure (TF) patients are select patients that do not respond to block1 and HR
and IR patients that do not respond to the control arm. They will receive Blinatumomab in
a separate treatment arm and may proceed to HSCT depending on their response to
Blinatumomab provided they do not have a history of CNS leukemia (CNS3) at or after
protocol entry. They may also receive testicular or cranial irradiation therapy when
indicated. TF patients after block1 will receive testicular irradiation (2400cGy) during their
first course of Blinatumomab. TF patients with testicular leukemia who have a complete

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clinical response to Block1 will receive supplemental testicular irradiation (600cGy)

sequentially with total body irradiation (TBI). TF patients after block2 with CNS leukemia
at protocol entry will receive supplemental cranial irradiation (600cGy) sequentially with
TBI.
Because there is no consensus on fractionated TBI or supplemental irradiation regimens,
the radiation therapy guidelines for this study were designed to promote protocol
participation and match guidelines used at the majority of approved transplant institutions
and evolved from guidelines developed for other COG protocols. Questions about these
guidelines should be directed to the radiation therapy coordinator or principal investigator.
Complete clinical response refers only to the testes. Supplemental irradiation refers to
irradiation of any site performed sequentially with TBI.

14.1.1 Required Benchmark and Questionnaires

Radiation therapy will be administered using photons or electrons according to
treatment site. All centers administering TBI must have completed the the TBI
benchmark available at IROC RI (QARC) website: www.IROCRI.QARC.org.
Benchmark materials and questionnaires may be obtained from the Quality
Assurance Review Center (www.qarc.org) and must be submitted before a patient
treated on this protocol can be evaluated. The calibration of therapy units used in
this protocol must be verified by IROC Houston (RPC)
(http://irochouston.mdanderson.org).

14.2 Indications for Radiation Therapy

14.2.1 Total Body Irradiation
TBI is indicated as part of the preparative regimen for IR/HR patients undergoing
HSCT.
14.2.1.1 Supplemental cranial irradiation is indicated for HSCT patients with a
history of CNS leukemia at protocol entry and shall be given
sequentially.
14.2.1.2 Supplemental testicular irradiation is indicated for HSCT patients with
the diagnosis of testicular leukemia and complete response after Block1
and shall be given sequentially. Those with testicular leukemia and
without complete response after Block1 will not require supplemental
testicular irradiation because they will have already received 2400cGy
earlier in the regimen.
14.2.1.3 Patients who require irradiation to extra-medullary sites other than
brain and testes should contact the Study Chair.
14.2.2 Cranial Irradiation
LR patients with a history of CNS leukemia at protocol entry should receive cranial
irradiation. Cranial irradiation will be given between the first and second 12 week
blocks of Maintenance chemotherapy. This corresponds to Week 40 for LR
patients treated on the control arm and Week 54 for LR patients treated on the
experimental arm. IR/HR patients will receive supplemental cranial irradiation
sequentially with TBI prior to HSCT. Exceptions to the use of cranial irradiation
include concerns about additional effects due to patient age, history of prior cranial

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irradiation and history or imaging evidence of CNS toxicity including

leukoencephalopathy, stroke and necrosis.
14.2.3 Testicular Irradiation
Patients with persistent testicular leukemia at the end of Block 1 will receive 2400
cGy of testicular radiation during either Block 2 chemotherapy (for LR patients
and HR/IR patients randomized to the control arm) or during blinatumomab (for
HR/IR patients randomized to the experimental arm and TF patients after Block 1).
Prior testicular irradiation will not be a contraindication to supplemental testicular
irradiation on this protocol.

14.3 Timing
14.3.1 All patients who might require irradiation should be seen in consultation by a
radiation oncologist in advance of treatment. The purpose of the consultation is to
participate in planning the sequence of treatment and to determine the need for
extra medullary (cranial, testicular and other) and supplemental irradiation in
conjunction with HSCT.
14.3.2 The timing of TBI and supplemental irradiation will be determined in part by the
TBI fractionation regimen. Supplemental irradiation should precede TBI and be
performed during weekdays.
14.4 Emergency Irradiation
There may be instances when radiation therapy has been administered prior to enrollment
on this protocol because of potentially life-threatening or function-threatening
extramedullary involvement. Although it is not expected that prior treatment would make
total body irradiation contraindicated, it should be considered when describing to the
patient or parent the potential complications of treatment on this protocol.
14.5 Equipment and Methods of Delivery
Treatment Site Photons Electrons
TBI Any Energy
Cranial Irradiation 4 or 6MV
Testicular Irradiation Any Energy Any Energy
Any energy for photons or electrons can be used as long as the skin and target dose
requirements are met.
14.6 Treatment Volumes
14.6.1 Total Body Irradiation
The entire body will be treated including the head and feet in one field. Care should
be taken to insure that the patient is entirely within the 90% isodose line of the
beam and not in the penumbra region.
14.6.2 Cranial Irradiation
The treatment site consists of the entire brain and intracranial subarachnoid volume
as well as the optic nerves and the posterior halves of the optic globes. The caudal
border shall be the C2/3 vertebral interspace.
14.6.3 Testicular Irradiation
The treatment site consists of the testes in the scrotal sac.

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14.7 Target Dose

14.7.1 Dose Definition
Photon and electron dose is to be specified in centigray (cGy)-to-muscle.
14.7.2 Prescribed Dose, Fractionation and Dose Rate for TBI
TBI may be administered with either of the following two regimens:
• 1200 cGy administered over 3 consecutive treatment days (Days -7, -6, -
5) at 200cGy BID
• 1200 cGy administered over 4 consecutive treatment days (Days -8, -7, -
6, -5) at 150cGy BID
Allowable but not preferred TBI regimen:
• 1320 cGy given over 4 consecutive treatment days (Days -8, -7, -6, -5) at
165cGy BID

Important considerations for TBI:

• Effort should be made to avoid interruptions in TBI administration
• The inter-fraction interval shall be no less than 5 hours between treatments
(start to start)
• A mid-plane dose rate of between 6 and 15cGy per minute is required

14.7.3 Prescribed Dose and Fractionation for Cranial Irradiation

14.7.3.1 LR patients will receive 1800cGy administered in 10 daily fractions

of 180cGy during Maintenance chemotherapy.

14.7.3.2 IR/HR patients will receive 600cGy administered in 3 daily fractions

of 200cGy immediately before TBI

14.7.4 Prescribed Dose and Fractionation for Testicular Irradiation (testicular leukemia
at protocol entry)

14.7.4.1 LR patients will not receive testicular irradiation if a complete

clinical response is observed after Block1.
14.7.4.2 LR patients will receive 2400cGy testicular irradiation administered
in 12 daily fractions of 200cGy during Block 2 if a complete clinical
response is not observed after Block 1.
14.7.4.3 IR/HR patients will receive 600cGy administered in 3 daily fractions
of 200cGy immediately before TBI if complete clinical response is
observed after Block 1.
14.7.4.4 IR/HR patients will receive 2400cGy testicular irradiation
administered in 12 daily fractions of 200cGy During Block 2 if a
complete clinical response is not observed after Block1.
14.7.5 Prescribed dose and fractionation for testicular irradiation (testicular leukemia
not present at protocol entry)

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14.7.5.1 Supplemental testicular irradiation of 400cGy in 1 or 2 daily fractions

prior to or during TBI may be administered according to institutional
preference but is not required.

14.8 Treatment Technique

14.8.1 TBI
Supine and prone, lateral decubitus, upright seated and standing positions are
allowed. Treatment will be delivered with equally weighted parallel opposed
portals. Each treatment will include both fields. All treatment techniques and
patient positions should meet the criteria on dose, dose rate, and dose uniformity.
Beam spoilers or other equally effective devices may be used to increase skin
dose to meet the dose uniformity requirements. Changes in patient positioning
after the patient has started TBI must be documented. Changes in lung blocking
and dose recalculation should be reported.
14.8.2 TBI - Lung Shielding
Lung shielding is mandated to restrict the lung dose (see Section 14.9.1). Lung
shielding to achieve dose reduction should conform to the following guidelines:
• The lateral edges will be 1.0 – 1.5 cm inside the inner border of the ribs;
• The inferior edges will be 1.0 – 1.5 cm superior from the dome of the apex of
the diaphragm;
• The superior borders will be 1.0 – 1.5 cm below the clavicles;
• The medial border 2.0 – 2.5 cm lateral to edges of the thoracic vertebral
bodies.
• No contouring of the lung shields will be done around the hilum unless there
is residual hilar adenopathy in which case the margins around the hilar
abnormality will be 1.0 – 1.5 cm. When utilized, lung blocks should be
employed for sequential treatments starting with the first treatment.
• Compensatory electron boost of the portion of the chest wall shielded by the
lung blocks is not required.

14.8.3 Cranial Irradiation

Supine treatment is recommended with immobilization appropriate for the age of
the child. Two opposed lateral equally weighted photon beams are preferred. The
fields shall extend at least 1 cm beyond the periphery of the scalp. Customized
field-shaping is required with blocks that are at least 5 HVL thick. Alternatively, a
multi-leaf collimator may be used provided the leaf width is less than or equal to
5 mm.
Lens sparing techniques are encouraged with 1 of 2 techniques:
• Angling of the 2 lateral fields in the anterior direction (RAO/LAO) using
the lateral canthus markers to “flatten” the beam edge. Shielding blocks
are used to block the anterior halves of the eyes, the nose, and mouth.
• Set the central axes of the horizontal cranial beams so that they are aligned
to the lateral canthi (half-beam blocking technique). The anterior edges of
the beams are defined by an external block or by an independently
controlled collimator and meet at a point 1 cm anterior to the frontal lobe

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meninges. Shielding blocks cover the anterior halves of the eyes and
protect the nose and mouth.

14.8.4 Testicular Irradiation

The patient shall be treated in the supine position. Field shaping for photons and
electrons will be done with either customized cerrobend blocking or multi-leaf
collimation. The testes may be supported posteriorly and, if possible, extended
caudally in order to minimize perineal irradiation. The penis should be excluded
from the field.
14.9 Organs at Risk
14.9.1 Normal tissue sparing for TBI
Restricting the lung dose to < 800 cGy is required on this protocol. This
requirement applies to both AP/PA and lateral treatments.. Institutions are
allowed to use their preferred method of beam attenuation to achieve the dose
reduction to lungs. The lung dose shall be reported as reference point C for lateral
treatments and reference point D for AP/PA treatments (see Section 14.10.1.2).
It should be reported on the TBI Summary form.
14.9.2 Normal tissue sparing for cranial irradiation
• Lens sparing techniques, as outlined in Section 14.8.3, are encouraged.

14.9.3 Normal tissue sparing for testicular irradiation

• Techniques for sparing perineum and penis are outlined in Section 14.8.4.

14.10 Dose Calculation and Reporting

14.10.1 Dose calculations for TBI

14.10.1.1 Suggested Methods for Dose Calculations for TBI

The TBI percent depth dose (PDD) or Tissue Maximum Ratio
(TMR) and output factors may be measured under TBI treatment
conditions for a range of phantom sizes to establish the database
for TBI beam-on time calculations and to validate the calculation
method. Measurements of entrance and exit dose at the center of a
phantom equivalent to the size of the typical patient are performed
and compared to the calculated dose. If differences are found,
additional correction factors should be introduced to the calculation
method. The prescription point is defined as the point along the
longitudinal axis of the patient at the mid-plane at the level of the
umbilicus (Point E below). Tissue inhomogeneity correction is not
required in the calculation of dose to the prescription point.
14.10.1.2 Dose Calculations and Measurements to Selected Anatomical
Reference Points for TBI
Prescription Point:
The following reference points will be determined:
The calculated and measured doses to selected anatomical points
should be submitted to IROC RI as part of the quality assurance
documentation:

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(Point A - Head) This reference point is defined along the

longitudinal axis of the skull at the greatest mid-separation
(immediately superior to the nasal bridge). The depth should be
taken as midway between the entrance and exit points of the
opposed radiation beams.
(Point B – Neck) This reference point is defined along the patient’s
longitudinal axis at the level of C3/C4 (approximate mid-neck, but
chosen for the thinnest mid-separation of the neck). The point is
taken to be midway between the entrance and exit point of the
beam.
(Point C - Mid-mediastinum) For APPA: The point is in the center
of the chest along the sagittal plane midway between the anterior
and posterior surfaces (Usually at the level of the carina). For
opposed laterals: this point is located midway between the entrance
and exit points of the beams at the level of the carina. Calculations
at this reference point should include lung shielding if present.
(Point D – Mid-Lung) APPA only: This reference point is centered
in the middle of the right or left lung (both medial/lateral and
cephalocaudad directions). The depth should be taken as midway
between the entrance and exit points of the opposed radiation
beams. Calculations at this reference point should include lung
shielding if present.
(Point E – Umbilicus) This is the PRESCRIPTION POINT. This
point is located along the patient’s longitudinal axis at the level of
the umbilicus and midway between the entrance and exit points of
the opposed beams.
(Point F – Hip or Pelvis) This reference point is defined at the level
approximately 1 cm superior to pubic symphysis midway between
the entrance and exit points of the beam.
(Point G - Knee) This reference point is defined along the midline
in the mid-plane of the knee at the level of the patella.
(Point H -Ankle) This reference point is defined along the midline
at the mid-plane of the ankle at the level of the lateral malleolus.
14.10.1.3 Lung Dose Calculation
Tissue heterogeneity must be accounted for in the calculation of
dose to lung. The preferred method is use of CT to enable use of
CT numbers in the calculation. Alternatively, other methods as
developed by the participating institution may be used. Lung
density value estimates, based on methods adopted by treating
institutions, may be incorporated into the dose calculation. The
methodology used by each participating institution for lung dose
determination will be evaluated as part of the benchmark approval
process.
14.10.2 Dose Uniformity and Treatment Site Coverage

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14.10.2.1 TBI Dose Uniformity and Treatment Site Coverage

The TBI fields should be set up to cover the patient’s entire body
without any part of the patient extending into the penumbra region.
The dose difference between the prescription point and each
reference point (see separate guidance for lung dose in section
14.9.1) shall be within ± 10% of the prescribed dose. The calculated
dose to the lung shall be in accordance with the lung dose
requirements specified in Section 14.9. To limit overall total lung
dose to < 800 cGy, partial transmission lung blocks can be used.
For AP/PA treatments the lung blocks may be placed in both AP
and PA fields or alternatively in just the AP or PA field alone.
14.10.2.2 Cranial Irradiation Dose Uniformity and Treatment Site Coverage
The prescription point for the cranial treatment is at or near the
center of the field. Regardless of the location of the central axis,
the dose should be prescribed at the center of the cranial volume
–midway between the points of maximum separation. The
variations of dose within the treatment site shall be within +7%, -
5% of the dose to the prescription point.
14.10.2.3 Testicular Irradiation Dose Uniformity and Treatment Site
Coverage
The scrotum should be treated with en face electrons with the
prescription depth covered by the 90% isodose. If electron beam
is used for testicular irradiation, the prescription should include
the beam energy and the dose coverage. Photon irradiation is
allowed.
14.10.3 Tissue heterogeneity
There shall be no required correction for tissue heterogeneity for the cranial and
testicular treatment.
14.10.4 Interruption of therapy
Excluding weekends and holidays, supplemental cranial irradiation, testicular
irradiation and fractionated TBI should be continuous. All efforts should be
made not to have treatment delay or interruption. Once patients have begun
testicular treatment, they should immediately proceed to TBI for
transplantation. If interruptions occur, the radiation therapy coordinator should
be notified.
14.11 Quality Assurance Documentation and Review
There are no on-treatment review or image submission requirements for this study. A post-
treatment review will be conducted by IROC RI. Questions regarding the dose calculations
or documentation should be directed to the COG Protocol Dosimetrist at the IROC RI
address noted below:
Within 1 week of the completion of radiotherapy, the following data shall be submitted:
• TBI Summary Form for Total Body Irradiation.
• Measured and/or calculated doses for the TBI reference points.
• A copy of the radiotherapy record including the prescription, and daily and
cumulative doses for all treated sites including TBI and supplemental sites (cranial,
testicular).

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• The "RT-2 Radiotherapy Total Dose Record" forms must be completed for cranial
and testicular irradiation.
• If the treatment technique differs from an approved benchmark, a new benchmark
must be completed and approved.

Data should be sent to:

IROC Rhode Island (QARC)
640 George Washington Highway, Building B, Suite 201
Lincoln, RI 02865-4207
Phone: (401) 753-7600
Fax: (401) 753-7601
E-mail: [email protected]

Contact for questions regarding dose calculations or documentation

COG Protocol Dosimetrist
IROC Rhode Island (QARC)
640 George Washington Highway, Building B, Suite 201
Lincoln, RI 02865-4207
Phone: (401) 753-7600
Fax: (401) 753-7601

14.12 Definitions of Deviation in Protocol Performance

14.12.1 TBI
14.12.1.1 Deviations for prescription dose
Deviations for TBI Dose
Variation Acceptable:
• The dose to the prescription point and to any of the reference points
(except points C and D lung dose points) differs from the protocol
specified dose by >10% or <15%.
Deviation Unacceptable:
• The dose to the prescription point and to any of the reference points
(except points C and D lung dose points) differs from the protocol
specified dose by >15%.
14.12.1.2 Deviations for TBI Dose Rate
• A dose rate exceeding 15cGy/min will be considered as an
unacceptable deviation.
14.12.1.3 Deviations for Lung Dose
• The dose to the lungs (reference points C and D) that is <700 cGy
or > 900 cGy will be considered an unacceptable deviation.
14.12.2 Deviations for Cranial Irradiation Dose
Variation Acceptable:
• The dose to the prescription point differs from the protocol specified dose
by > 6 but ≤ 10%.

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Deviation Unacceptable:
• The dose to the prescription point differs from the protocol specified dose
by >10%.
14.12.3 Deviations for Testicular Irradiation Dose
Variation Acceptable:
• The dose to the prescription point differs from the protocol specified dose
by > 6% but ≤ 10%.
Deviation Unacceptable:
• The dose to the prescription point differs from the protocol specified dose
by > 10%.

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APPENDIX I: SUPPORTIVE CARE

NOTE: For blinatumomab-specific supportive care guidelines, please refer to Section 5.2.3.

General Guidelines
Aggressive supportive care improves outcome. The following guidelines are intended to give general
direction for optimal patient care and to encourage uniformity in the treatment of this study population.
Notify Study Chair of any unexpected or unusually severe complications. Please also see the COG
Supportive Care Guidelines at: https://members.childrensoncologygroup.org/prot/reference_materials.asp

Blood Components
Blood products should be irradiated following current FDA guidelines found at:
http://www.fda.gov/OHRMS/DOCKETS/98fr/981218g2.pdf
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components
CAN/CSA-Z902-10 issued in February 2010 and available at: http://www.shopcsa.ca

Red Blood Cells (RBC)

Transfusion with RBC is indicated to correct severe or symptomatic anemia or acute blood loss. In the
setting of extreme hyperleukocytosis investigators should be mindful that peripheral red blood cells
(PRBC) may contribute to hyperviscosity.

Platelets
Transfusion with platelets is indicated to correct bleeding manifestations and may be indicated for severe
thrombocytopenia without bleeding particularly prior to an invasive procedure.

Infection Prophylaxis
Patients undergoing transplantation for ALL on this protocol are at high risk for infection. This risk may be
increased due to infections that occur during the intensive chemotherapy most patients will receive prior to
stem cell transplant on this protocol. Centers should be especially mindful of this as they choose anti-
bacterial, anti-fungal, anti-viral, and PCP prophylactic regimens. Aside from well established screening
approaches for CMV, centers may wish to consider routine screening for other viral pathogens such as
Adenovirus or HHV-6. Any prophylaxis regimen chosen must be the same for patients on both arms of the
protocol. Special considerations should be given for antifungal prophylaxis (see below).

Pneumocystis jiroveci
All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 2.5 mg/kg/dose
(maximum dose 160mg/dose) by mouth twice daily on 2 or 3 sequential days per week. For patients allergic
to or experiencing excessive myelosuppression with TMP/SMX, alternative prophylaxis with dapsone (2
mg/kg/day by mouth, maximum dose 100 mg/day), aerosolized pentamidine (300 mg/q month ≥ 5 years of
age), or atovaquone (4-24 month: 45 mg/kg/day; >24 months: 30mg/kg/day) by mouth may be considered.
For children in whom TMP/SMX, dapsone, atovaquone, and inhaled pentamidine cannot be administered,
IV pentamidine (4 mg/kg/dose IV every 2 to 4 weeks) should be given. (REF: Centers for Disease Control
and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell
transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the
American Society of Blood and Marrow Transplantation. MMWR 2000; 49(No. RR-10):1-125. Available
at http://www.cdc.gov/mmwr/PDF/rr/rr4910.pdf. Accessed November 24, 2010.) Please also see
https://members.childrensoncologygroup.org/prot/reference_materials.asp for COG Supportive Care
Guidelines.

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Varicella Vaccine
May be given to the siblings of patients in remission and stable at the physician’s discretion. Varicella
vaccination is not recommended for ALL patients during therapy.

Gamma globulin
If clinically indicated, IgG levels may be monitored throughout treatment. If the IgG level falls below
age-determined normal levels, IVIG at 400 mg/kg may be administered at the discretion of the
investigator. Note of IVIG administration should be recorded on data form.

Antifungals
Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently with vincristine
may increase the risk of neurotoxicity. Investigator caution is advised if azole antifungals are used.
Fluconazole and other azoles are expected to increase serum tacrolimus and sirolimus levels. Therefore,
dosages of sirolimus and tacrolimus should be adjusted accordingly. Due to extreme interactions with
sirolimus, voriconazole is contraindicated during sirolimus. Patients on voriconazole prior to transplant
should have another drug substituted for voriconazole prior to starting sirolimus therapy.

Hospitalization after High-Dose Cytarabine

Empiric hospitalization after Day 8 of Induction 3 (intensively-timed Capizzi-II) until there is evidence of
marrow recovery should be considered due to the risk of neutropenic sepsis; patients not hospitalized
should be monitored very closely.

Treatment of Established or Presumed Infections

Fever with Neutropenia

For patients with ANC < 500/μL and temperature between 38.0° and 38.5°C twice in 12 hours, or ≥ 38.5°C,
empiric parenteral broad spectrum antibiotics should be instituted after obtaining appropriate cultures. The
risk of sepsis is higher during Induction and while the peripheral neutrophil count is falling rather than
rising. Duration of therapy should be determined by site of infection (if identified), culture results, and
response to treatment. If fever and neutropenia persist, systemic antifungal therapy should be initiated after
3-5 days. When mucositis is present (especially following HD ARAC), alpha hemolytic streptococcal
infections should be suspected. It is recommended that empiric antibiotic coverage includes vancomycin or
clindamycin for coverage of potential gram-positive infections.

Use of G-CSF
G-CSF may be used for severe infections with neutropenia, but routine use is discouraged.

Filgrastim (G-CSF) at a dose of 5 micrograms/kg/day given IV or subcutaneously is required for recipients

of cord blood starting at Day +1 and continuing until patients are fully engrafted. G-CSF is generally not
necessary for BM/PBSC recipients and is not recommended, unless engraftment is delayed.

Primary Varicella Infection (Chickenpox)

Patients should be treated promptly with acyclovir 1500 mg/m²/day intravenously divided q 8 hours, and
monitored closely for the development of invasive systemic disease.

Empiric Management of Pulmonary Infiltrates

Pulmonary infiltrates should be evaluated with bronchoscopy and biopsy, lavage or open lung biopsy. If a
procedure cannot be tolerated, begin empiric antifungal therapy given the high likelihood of fungal disease
during Induction, Re-induction and periods of intensive chemotherapy (HDAraC). Empiric coverage should
include treatment for gram-negative and positive bacteria, Legionella (erythromycin), Pneumocystis

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(TMP/SMX), and fungi (amphotericin) pending culture results. If fungal pulmonary disease is documented,
surveillance radiographic imaging studies of the sinuses, abdomen/pelvis and brain are indicated. Surgical
excision of pulmonary lesions should be considered at the discretion of the treating physician. Treatment
of fungal infections with amphotericin B and/or other antifungal agents will be at the discretion of the
treating physician. Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently
with vincristine may increase the risk of neurotoxicity. Investigator caution is advised if azole antifungals
are used.

Management of Mucositis/Perirectal Cellulitis

Mucositis should be managed with IV hydration and hyperalimentation if indicated, effective analgesia,
broad-spectrum gram-positive and gram-negative antibiotic therapy and empiric antiviral and antifungal
therapy as indicated. Management of perirectal cellulitis should include broad-spectrum antibiotic therapy
with dual gram-negative coverage as well as anaerobic coverage (i.e. ceftazidime + aminoglycoside +
metronidazole; or piperacillin-tazobactam + aminoglycoside), Sitz baths, a strong barrier technique and
effective analgesia.

Constipation
As vincristine may cause severe constipation, prophylactic stool softeners/laxatives (per investigator‘s
discretion) are recommended during all phases in which VCR is given.

Guidelines During Induction

Patients may experience profound myelosuppression and immune suppression during this time. Since
steroids may mask fever as well as other components of the inflammatory response, sepsis during Induction
may be associated with very mild and subtle symptoms. Caregivers must also be made aware that patients
may experience very rapid clinical deterioration. This suggests the need for a supportive care network that
can recognize and respond to sudden changes in a patient‘s condition. In addition it should be noted that
serious toxic events may have an intestinal component. Patients with subtle GI symptoms should be
monitored very closely.

Tumor Lysis Syndrome

In this population with ALL, rapidly assess patients clinically and by appropriate laboratory parameters for
evidence of symptomatic hyperleukocytosis, tumor lysis syndrome, and coagulopathy. Suggested studies
to be obtained prior to initiating antileukemia therapy include complete blood count (CBC), prothrombin
and activated partial thromboplastin times, fibrinogen, D-dimer, and serum electrolytes, including
creatinine, BUN, uric acid, phosphorous, and calcium. Continued monitoring of these studies should be
carried out at suitable intervals until abnormalities have resolved or the risk has abated. Begin allopurinol
at a dose of 300 mg/m²/day in 3 divided doses and continue until peripheral blasts and extramedullary
disease are reduced. In some situations it may be appropriate to use rasburicase instead of allopurinol.
Hydrate at 2400-3000 mL/m²/day to maintain urine output > 100 mL/m²/hour until peripheral blasts and
extramedullary disease are reduced. Alkalinize urine with NaHCO3 20-40 mEq/L IV fluid to maintain urine
pH between 6.5 and 7.5. Alkalinization is not recommended when treating with rasburicase.

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APPENDIX II: THERAPY DELIVERY MAPS

APPENDIX II-A Block 1 (All patients)
Block 1 therapy is common to all patients on study
Patient COG ID number DOB
Block 1 lasts 4 weeks (28 days). Please see Section 4.2 for treatment details. This therapy delivery map is on two (2) pages.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

IT Age (yrs) Dose 1, 8 CNS1/2 ONLY a. Hx, PE [VS/Wt (BSA)]

Intrathecal Methotrexate (IT 1-1.99 8 mg
MTX) *For CNS2: Continue weekly until 2 clear csf b. CBC/diff/platelets
2-2.99 10 mg
3-8.99 12 mg
samples are obtained i.e. CNS1 c. Local BM evaluation%
≥9 15 mg Note age-based dosing d. BM forImmunophenotyping
e. CSF cell count, cytospin1
Intrathecal Triple Therapy (ITT): IT Age (yrs) Dose 1, 8, 15, 22 CNS3 ONLY f. Bilirubin, ALT & creatinine,
Methotrexate (MTX)/ 1-1.99 MTX:8mg, BUN
Hydrocortisone (HC)/Cytarabine HC: 8mg,
g. Echocardiogram
(ARAC) ARAC: 16mg Note age-based dosing
2-2.99 MTX: 10mg h. Pregnancy test
HC: 10 mg i. Testicular Exam & Testicular
ARAC: 20 mg biopsy, if indicated®
3-8.99 MTX: 12 mg
HC: 12 mg 1
Obtain with each IT/ITT
ARAC: 24 mg
≥9 MTX: 15 mg
See Section 7.0 for details.
HC: 15 mg
ARAC: 30 mg
Optional studies
MitoXANTRONE (MITOX) IV over 15-30 10 mg/m²/dose 1, 2 Administer through the tubing of a freely infusing
minutes solution of D5W or 0.9% NaCl
j Banking for future research
Dexamethasone (DEX) PO 10 mg/m²/dose 1-5, 15-19 Total Daily Dose 20 mg/m²/day divided BID k Protein cell stress pathways
Cap dose at 40 mg per day. l. CRLF2 expression
VinCRIStine (VCR) IV push over 1 1.5 mg/m² 1, 8, 15, 22 +Or infusion via minibag as per institutional m. BM sample for
minute+ policy. Maximum dose: 2mg Blinatumomab PD
Pegaspargase (PEG-ASP) IV over 1-2 2500 International 3, 17 Administer through the tubing of a freely infusing
hours units/m²/dose solution of D5W or 0.9% NaCl
See Section 7.2 for details.

OBTAIN OTHER STUDIES AS

REQUIRED FOR GOOD
PATIENT CARE

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APPENDIX II-A Block 1 (All patients)

Block 1 therapy is common to all patients on study
Patient COG ID number DOB
Ht _________cm Wt _________kg BSA _________m2
Date Due Date Day IT MTX ITT MITOX DEX VCR PEG-ASP Studies Comments (Include any held
Given CNS1/2 ONLY* CNS3 ONLY doses, or dose modifications)
____mg ____mg ____mg ___mg ____mg ____IU
Enter calculated dose above and actual dose administered below a-i, l$,j+
1 _____mg _____mg ____mg ____mg _____mg k¥
2 ____mg
3 ____IU
4
5
---

8 _____mg _____mg _____mg b, e, f

---

15 _____mg* _____mg ____mg _____mg b, e*, f

---

17 ____IU
---
19
22 _____mg* _____mg _____mg b, e*, f
---

29 b, c%, d,e^ f, i®,j+,

m
Begin next course based on Day 29 risk assignment and treatment randomization. IR/HR patients randomized to Arm A receive Block 2 therapy (Section 4.3,
APPENDIX II-B), IR/HR patients randomized to Arm B receive Blinatumomab Block-Cycle 1 therapy (Section 4.5, APPENDIX II-D). LR patients will be
randomized to Arm C (control arm) or Arm D (experimental arm). All LR patients (Arm C and Arm D) receive Block 2 therapy (Section 4.3, APPENDIX II-
B). Treatment failures post-Block 1 with M3 marrow without residual CNS disease (CNS1) are eligible for treatment with at least 2 blocks of Salvage Therapy
(Blinatumomab-S) (Section 4.7, APPENDIX II-I); treatment failures with residual CNS disease (CNS2/3), irrespective of marrow status will be off protocol
therapy. See Section 4.3 for further details on time frame for end-Block 1 evaluations and criteria to fulfill prior to subsequent therapy.
*For CNS2 patients, continue weekly until 2 clear CSF (CNS1) samples are obtained; can be a max of 4 (Weeks 1, 8, 15 and 22). If still unclear,
patients are treatment failures and will be off protocol therapy regardless of marrow status.
^
A diagnostic LP should be performed on Day 29 for CNS2 or CNS3 patients for whom clearance of CSF blasts has not yet been documented.
®
Testicular biopsy is only done in the setting of persistent testicular enlargement. Patients with persistent testicular leukemia at the end of Block 1 who are
deemed treatment failure (TF) will receive 2400 cGy of testicular radiation during Blinatumomab.
$
No separate specimen needed-cell pellet from required central flow MRD assays will be used (see Section 13.4 for complete details)..
¥
PB before and after chemotherapy on Day 1 of Block 1 (see Section 13.6) for complete details).
%
BM evaluation to confirm relapse and/or detect marrow disease in presumed isolated extramedullary relapse patients should include morphology,
immunophenotyping & cytogenetics/FISH. Cytogenetic/FISH analysis must be performed at a COG approved cytogenetics lab and cases will be reviewed
retrospectively
+Bone marrow: at Baseline and End Block 1. Peripheral blood: At Baseline and End Block 1. (See Section 13.1 for complete details)
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-B Block 2

Block 2 therapy is for all LR patients post Block-1 (Arm C and Arm D) and HR/IR Patient COG ID number DOB
patients randomized to the control arm (Arm A)
Block 2 lasts 4 weeks (28 days). Block 2 should begin after receipt of risk assignment according to timing outlined in Section 4.2. Patients can proceed with Block 2 without awaiting count recovery
(must be no later than 5 days after callback). Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 15 cyclophosphamide and etoposide. Please see Section 4.3 for treatment
details. This Therapy Delivery Map is on two (2) pages.

DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Dexamethasone (DEX) PO 3 mg/m²/dose 1-5 Total Daily Dose: 6 mg/m2/day, divided BID.
b CBC/diff/platelets
c Local BM evaluation
VinCRIStine (VCR) IV push over 1 1.5 mg/m²/dose 1 + Or infusion via minibag as per institutional policy d BM for MRD evaluation
minute+ Maximum dose: 2 mg e CSF cell count, cytospin1
Intrathecal Methotrexate (IT IT Age (yrs) Dose 8 CNS 1/2 ONLY f Bilirubin, ALT & creatinine,
MTX) 1-1.99 8 mg BUN
2-2.99 10 mg Note age-based dosing g Testicular Exam
3-8.99 12 mg
≥9 15 mg When IT therapy and ID MTX are scheduled for the same Optional studies
day, deliver the IT therapy within 6 hours of the beginning h Banking for future research
of the IV MTX infusion (hour -6 to +6, with 0 being the start i Bone Marrow for Blinatumomab
of the MTX bolus). PD (Arm D ONLY)
Intrathecal Triple Therapy IT Age (yrs) Dose 8, 22
1
(ITT): 1-1.99 MTX:8mg, CNS3 ONLY. Obtain with each IT/ITT
Methotrexate (MTX) HC: 8mg,
Hydrocortisone (HC) ARAC: 16mg Note age-based dosing. See Section 7.0 for details.
Cytarabine (ARAC) 2-2.99 MTX: 10mg
HC: 10 mg
ARAC: 20 mg
3-8.99 MTX: 12 mg See Section 7.2 for details.
HC: 12 mg
ARAC: 24 mg OBTAIN OTHER STUDIES AS
≥9 MTX: 15 mg REQUIRED FOR GOOD
HC: 15 mg PATIENT CARE
ARAC: 30 mg
Intermediate Dose IV over 36 hours 1000 mg/m²/dose 8 See Section 5.8 for admin guidelines.
Methotrexate (ID MTX)
Leucovorin (LCV) PO/IV 15 mg/m²/dose 10, 11 48 hours after the start of ID MTX infusion. See Section 5.8
& Appendix IV for admin guidelines
Pegaspargase (PEG-ASP) IV over 1-2 hours 2500 International units/m²/dose 9 or 10* *Administer 4 hours after completion of Day 8 IV MTX.
Cyclophosphamide (CPM) IV over 15-30 mins. 440 mg/m²/dose 15-19
Etoposide (ETOP) IV over 60-120 mins. 100 mg/m²/dose 15-19
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during Block 2 therapy. See Section 14.2 for details of TRT.

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APPENDIX II-B Block 2

Block 2 therapy is for all LR patients post Block-1 (Arm C and Arm D) and HR/IR Patient COG ID number DOB
patients randomized to the control arm (Arm A)
Ht _________cm Wt _________kg BSA _________m2
Date Date Day DEX. VCR IT MTX ITT ID MTX LCV PEG-ASP CPM ETOP Studies Comments (Include any
Due Given CNS1/2 ONLY CNS3 ONLY held doses, or dose
____mg ____mg ____mg ______mg ___mg ___mg ___IU ___mg ___mg modifications)
Enter calculated dose above and actual dose administered below
1 ____mg ____mg a, b, f
---

5
---

8 ____mg ____mg ____mg^ b, e, f

9 ____IU*
10 ____mg
11 ____mg
---

15 ____mg& ____mg& b, f
---

19
22 ____mg b, e#, f
---

29 b,c,d,f,g,h+,i
Following count recovery, HR/IR patients on Arm A receive Block 3 therapy (Section 4.4, APPENDIX II-C). HR/IR Treatment Failures post-Block 2 have the opt
of receiving 2 blocks of Salvage Therapy –(Blinatumomab-S) (Sections 4.7, 4.8, APPENDIX II-F, II-G). LR patients randomized to Arm C receive Block 3 therapy
(Section 4.4., APPENDIX II-C), and LR patients randomized to Arm D receive Blinatumomab Block 1: Cycle 1 therapy (Section 4.15, APPENDIX II-D).
^
All patients with M1 marrow must have ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 8 ID MTX. Day 8 treatment must begin no later than 14
days after risk assignment for patient to continue to receive protocol therapy.
& Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 15 cyclophosphamide and etoposide.
+ Peripheral blood: End Block 2 (See Section 13.1 for complete details)
*Administer 4 hours after completion of Day 8 IV MTX. (Day 9 or 10)
# CNS3 ONLY

See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-C Block 3

Block 3 therapy is for all HR/IR patients randomized to the control arm (Arm A), and LR patients Patient COG ID number DOB
randomized to the control arm (Arm C).
Block 3 lasts 4 weeks (28 days) and starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL. Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22
ID MTX. See Section 4.4 for treatment details. This Therapy Delivery Map is on two (2) pages.

DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Dexamethasone (DEX) PO (May be given IV) 3 mg/m²/dose BID 1-5 Total Daily Dose: 6 mg/m2/day, divided BID.
b CBC/diff/platelets
c Local BM evaluation
VinCRIStine (VCR) IV push over 1 minute+ 1.5 mg/m²/dose 1 +
Or infusion via minibag as per institutional policy d BM for MRD evaluation
Maximum dose: 2 mg e CSF cell count, cytospin1
Cytarabine (ARAC) IV over 3 hours 3000 mg/m²/dose Q12H 1, 2, 8, 9 f Bilirubin, ALT & creatinine,
BUN
Erwinia L-asparaginase IM 25, 000 International units/m²/dose 2, 4, 9, 11, 23 See Section 4.4 for administration guidelines.
(ERWINAZE) • On Days 2 and 9, Erwinia should be given 4 hours 1
Obtain with each IT/ITT
after last cytarabine infusions.
• On Day 23, Erwinia is to be given 4 hours after the See Section 7.0 for further details.
completion of the Day 22 MTX infusion.
Intermediate Dose IV over 36 hours 1000 mg/m²/dose 22 See Section 5.8 for admin guidelines.
Methotrexate (ID MTX)
Leucovorin (LCV) PO/IV 15 mg/m2/dose 24, 25 48 hours after the start of ID MTX infusion. See OBTAIN OTHER STUDIES AS
Section 5.8 for admin guidelines REQUIRED FOR GOOD
Intrathecal Methotrexate IT Age (yrs) Dose 1 All Patients When IT therapy and ID MTX are scheduled for the PATIENT CARE
(IT MTX) 1-1.99 8 mg same day, deliver the IT therapy within 6 hours of the
2-2.99 10 mg beginning of the IV MTX infusion (hour -6 to +6,
3-8.99 12 mg 22 CNS 1/2 ONLY with 0 being the start of the MTX bolus).
≥9 15 mg
Note age-based dosing
Intrathecal Triple Therapy IT Age (yrs) Dose 22 CNS3 ONLY
(ITT): 1-1.99 MTX:8mg,
Methotrexate (MTX) HC: 8mg, When ITT therapy and ID MTX are scheduled for the
Hydrocortisone (HC) ARAC: 16mg same day, deliver the ITT therapy within 6 hours of
Cytarabine (ARAC) 2-2.99 MTX: 10mg the beginning of the IV MTX infusion (hour -6 to +6,
HC: 10 mg with 0 being the start of the MTX bolus).
ARAC: 20 mg
3-8.99 MTX: 12 mg Note age-based dosing
HC: 12 mg
ARAC: 24 mg
≥9 MTX: 15 mg
HC: 15 mg
ARAC: 30 mg

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APPENDIX II-C Block 3

Block 3 therapy is for all HR/IR patients randomized to the control arm (Arm A), and LR patients Patient COG ID number DOB
randomized to the control arm (Arm C).

Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day DEX. VCR ERWINAZE ID MTX LCV ARAC IT MTX IT MTX ITT Studies Comments
Given All Patients CNS1/2 ONLY CNS3 ONLY (Include any held
____mg ____mg ____IU ___mg ____mg ____mg ____mg ______mg ______mg ______mg doses, or dose
modifications)
Enter calculated dose above and actual dose administered below
1 ____mg ____mg ____mg ____mg ____mg a, b, e, f
2 ____IU ____mg ____mg
3
4 ____IU
5
---
8 ____mg ____mg b, f
9 ____IU ____mg ____mg
---
11 ____IU
---
15 b, f
---
22 ____mg^ ____mg ____mg b, e, f
23 ____IU
24 ____mg
25 ____mg
---
29 b, (c, d)* f
Following count recovery ANC ≥ 500/µL and platelets ≥ 50,000/µL, HR/IR patients on Arm A proceed to HSCT as soon as possible (Section 4.9); see Section 4.10, Appendix II-H for
suggested bridging therapy in the event that HSCT is delayed. HR/IR Treatment Failures post-Block 3 have the option of receiving 2 blocks of Salvage Therapy –Blinatumomab-S (Sections
4.7, 4.8, APPENDIX II-F, II-G). LR patients randomized to Arm C receive Continuation 1 therapy (Section 4.11, Appendix II-H).
^ Await count recovery until ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22 ID MTX.
*HR/IR Patients ONLY.
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-D Blinatumomab Block - Cycle 1 (HR/IR Patients in Arm B )

This therapy is the 1st cycle of therapy with blinatumomab for the HR/IR patients randomized to the experimental arm (Arm B) Patient COG ID number DOB
Blinatumomab Block-Cycle 1 lasts 5 weeks (35 Days). For patients with M1 marrow, treatment begins when ANC ≥ 500/µL and platelets ≥ 50,000/µL and must begin no later than 14 days after risk assignment for
patient to continue to receive protocol therapy. For patients with M2 marrow, treatment begins without awaiting count recovery, and must be no later than 5 days after callback. See Section 4.5 for treatment details. This
Therapy Delivery Map is on one (1) page.

DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

Blinatumomab (BLIN) IV 15 micrograms/m²/day 1-28 a Hx, PE [VS/Wt (BSA)]

Dexamethasone (DEX) PO or IV 10 mg/m²/dose , 6-12 hours prior to 1 Start prior to blinatumomab therapy b CBC/diff/platelets
blinatumomab infusion, c BM (Local evaluation &
THEN MRD)
5 mg/m2 within 30 minutes of starting d CSF cell count, cytospin1
Blinatumomab infusion e Bilirubin, ALT &
Intrathecal Methotrexate IT Age (yrs) Dose 15, 29 CNS1/2 ONLY creatinine, BUN
(IT MTX) 1-1.99 8 mg f Peripheral blood for PK
2-2.99 10 mg Note age-based dosing g Peripheral blood for
3-8.99 12 mg Immunogenicity
≥9 15 mg
Intrathecal Triple Therapy IT Age (yrs) Dose 15, 29 CNS3 ONLY Optional studies
(ITT): 1-1.99 MTX:8mg, h Blinatumomab PD
Methotrexate (MTX) HC: 8mg,
Hydrocortisone (HC) ARAC: 16mg Note age-based dosing 1
Obtain with each IT/ITT
Cytarabine (ARAC) 2-2.99 MTX: 10mg
HC: 10 mg See Section 7.0 for further
ARAC: 20 mg details.
3-8.99 MTX: 12 mg
HC: 12 mg
OBTAIN OTHER STUDIES
ARAC: 24 mg
≥9 MTX: 15 mg
AS REQUIRED FOR
HC: 15 mg GOOD PATIENT CARE
ARAC: 30 mg
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during Blinatumomab Block – Cycle 1. See Section 14.2 for details of TRT.

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APPENDIX II-D Blinatumomab Block - Cycle 1 (HR/IR Patients in Arm B )

This therapy is the 1st cycle of therapy with blinatumomab for the HR/IR patients randomized to the experimental arm (Arm B) Patient COG ID number DOB

Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day BLIN DEX IT MTX ITT Studies Comments (Include any held doses, or dose modifications)
Given CNS1/2 ONLY CNS3 ONLY
____µg ____mg ______mg ______mg
Enter calculated dose above and actual dose administered below
1 ____µg ____mg a*, b, e, h+,g$
2 f&,h+
---
7 h+
8 b, e,
---
14 f&, h+
15 ____mg ____mg b, d, e
---
21 h+
22 b, e,
---
28
29 ____mg ____mg b, c, d, e
30-35 Rest Period
Following count recovery, start next cycle, Blinatumomab Block Cycle 2 (Section 4.6, APPENDIX II-E). Treatment failures will be taken off protocol therapy.
Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete details).

$ Prior to (Hour 0) first blinatumomab infusion (see Section 13.7 & lab manual for details)
&
See lab manual for collection and shipping details
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e

See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-E Blinatumomab Block - Cycle 2 (HR/IR Patients in Arm B)
This therapy is the 2nd cycle of therapy with blinatumomab for the HR/IR patients randomized to the experimental arm (Arm B) Patient COG ID number DOB
Blinatumomab Block-Cycle 2 lasts 5 weeks (35 Days) and begins when ANC ≥ 500/µL and platelets ≥ 50,000/µL. See Section 4.6 for treatment details. This Therapy Delivery Map is on one (1) page.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS
Blinatumomab (BLIN) IV 15 micrograms/m²/day 1-28 a Hx, PE [VS/Wt (BSA)]
Dexamethasone (DEX) PO or IV 10 mg/m²/dose , 6-12 hours prior to 1 Start prior to blinatumomab therapy b CBC/diff/platelets
blinatumomab infusion, c BM (Local evaluation & MRD)
THEN d CSF cell count, cytospin1
e Bilirubin, ALT & creatinine, BUN
5 mg/m2 within 30 minutes of starting f Peripheral blood for
Blinatumomab infusion Immunogenicity
Intrathecal Methotrexate IT Age (yrs) Dose 8, 29 CNS1/2 ONLY
(IT MTX) 1-1.99 8 mg
2-2.99 10 mg Note age-based dosing 1
Obtain with each IT/ITT
3-8.99 12 mg
≥9 15 mg See Section 7.0 for further details.
Intrathecal Triple IT Age (yrs) Dose 8, 29 CNS3 ONLY
Therapy (ITT): 1-1.99 MTX:8mg,
Methotrexate (MTX) HC: 8mg, OBTAIN OTHER STUDIES AS
Hydrocortisone (HC) ARAC: 16mg Note age-based dosing REQUIRED FOR GOOD PATIENT
Cytarabine (ARAC) 2-2.99 MTX: 10mg CARE
HC: 10 mg
ARAC: 20 mg
3-8.99 MTX: 12 mg
HC: 12 mg
ARAC: 24 mg
≥9 MTX: 15 mg
HC: 15 mg
ARAC: 30 mg
Ht _________cm Wt _________kg BSA _________m2
Date Due Date Day BLIN DEX IT MTX ITT Studies Comments (Include any held doses, or dose
Given CNS1/2 ONLY CNS3 ONLY modifications)
____µg ____mg ______mg ______mg
Enter calculated dose above and actual dose administered below
1 ____µg ____mg a*, b, e
---

8 ____mg ____mg b, d, e
---

15
---

22 b, e
---

28
29 ____mg ____mg b, c, d, e,f$
30-35 Rest Period
Following count recovery, patients will proceed to HSCT (Section 4.9). See Section 4.10, Appendix II-H for suggested bridging therapy in the event that
HSCT is delayed. Treatment failures will be taken off protocol therapy.
$
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details
&
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e See lab manual for collection and shipping details
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-F Blinatumomab-S:Cycle 1 (Treatment Failure)

This therapy is the 1st cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients Patient COG ID number DOB
classified as treatment failures who have not previously had blinatumomab on study.
Blinatumomab-S: Cycle 1 lasts 5 weeks (35 Days). See Section 4.7 for treatment details. This Therapy Delivery Map is on two (2) pages.

DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Blinatumomab IV 5 micrograms/m²/day 1-7
b CBC/diff/platelets
(BLIN)
c CSF cell count,
15 micrograms/m²/day 8-28 cytospin1
d Bilirubin, ALT &
Dexamethasone PO or IV 10 mg/m²/dose , 6-12 hours prior to blinatumomab 1 Start prior to blinatumomab creatinine, BUN
(DEX) infusion, therapy e Local BM evaluation
f BM for MRD- pre
THEN HSCT
g Peripheral blood for PK
5 mg/m2 within 30 minutes of starting Blinatumomab h Peripheral blood for
infusion Immunogenicity
Intrathecal IT Age (yrs) Dose 15
Methotrexate (IT 1-1.99 8 mg Note age-based dosing Optional studies
MTX) 2-2.99 10 mg i Blinatumomab PD
3-8.99 12 mg
≥9 15 mg
1
Obtain with each IT/ITT

See Section 7.0 for further

details.

OBTAIN OTHER
STUDIES AS
REQUIRED FOR GOOD
PATIENT CARE

Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation during the 1st cycle of Blinatumomab-S therapy. See Section 14.2 for details of TRT.

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APPENDIX II-F Blinatumomab-S:Cycle 1 (Treatment Failure)

This therapy is the 1st cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients Patient COG ID number DOB
in the HR/IR randomization classified as treatment failures who have not previously had blinatumomab
on study.

Ht _________cm Wt _________kg BSA _________m2

Date Date Day BLIN DEX IT MTX Studies Comments (Include any held
Due Given doses, or dose modifications)
____µg ____mg ______mg
Enter calculated dose above and actual dose administered below
1 ____µg ____mg a*, b, d, i+,h$
2 g&
---

7 i+
8 b, d
---

14 g&, i+
15 ____mg b, c, d, i+
---

21 i+
22 b, d
---

28
29 b, d, e, f+++
30-35 Rest Period
See Section 4.7.6 for criteria for proceeding to HSCT (Section 4.9) or to Blinatumomab-S: Cycle 2 (Section 4.8, APPENDIX II-G)
+
Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete
details).
$ Prior to (Hour 0) first blinatumomab infusion. In cases where blinatumomab treatment will not continue to Cycle 2, collect additional sample at end of Cycle 1. (see Section
13.7 and lab manual for details)
&
See lab manual for collection and shipping details
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
+++ Pre-HSCT evaluation
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-G Blinatumomab-S: Cycle 2 (Treatment failure)

This therapy is the 2nd cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients Patient COG ID number DOB
classified as treatment failures who have not previously had blinatumomab on study.
Blinatumomab-S: Cycle 2 lasts 5 weeks (35 Days) and starts when ANC ≥ 500/µL and platelets ≥ 50,000/µL. See Section 4.8 for treatment details. This Therapy Delivery Map is on two (2) pages.
.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Blinatumomab IV 15 micrograms/m²/day 1-28
b CBC/diff/platelets
(BLIN)
c Local BM evaluation
d CSF cell count, cytospin1
Dexamethasone PO or IV 10 mg/m²/dose , 6-12 hours prior to 1 Start prior to blinatumomab e Bilirubin, ALT & creatinine,
(DEX) blinatumomab infusion, therapy BUN
f BM for MRD- pre HSCT
THEN g Peripheral blood for
Immunogenicity
5 mg/m2 within 30 minutes of
starting Blinatumomab infusion
Intrathecal IT Age (yrs) Dose 8, 29
Methotrexate (IT 1-1.99 8 mg Note age-based dosing 1
Obtain with each IT/ITT
MTX) 2-2.99 10 mg
3-8.99 12 mg See Section 7.0 for further
≥9 15 mg details.

OBTAIN OTHER STUDIES

AS REQUIRED FOR GOOD
PATIENT CARE

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APPENDIX II-G Blinatumomab-S: Cycle 2 (Treatment failure)

This therapy is the 2nd cycle of therapy with Salvage Therapy (Blinatumomab-S) for the HR/IR patients Patient COG ID number DOB
classified as treatment failures who have not previously had blinatumomab on study.

Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day BLIN DEX IT MTX Studies Comments (Include any held doses, or dose
Given ______mg modifications)
______µg ______mg
Enter calculated dose above and actual dose administered below
1 ____µg _____mg a*, b, e
---

8 ____mg b, d, e
---

15 b, e
---

22 b, e
---

29 ____mg b, c, d, e,g$,
f+++
30-35 Rest Period
See Section 4.8.5 for criteria for proceeding to HSCT (Section 4.9) or to Bridging Maintenance Therapy Section 4.10, Appendix II-H. Patients
with M2/M3 marrow after Blinatumomab-S: Cycle 2 will be taken off protocol therapy.
$
In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
+++ Pre-HSCT evaluation
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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Appendix II-H Bridging Maintenance Therapy: Optional (HR/IR patients

and TF patients that are eligible for HSCT) Patient COG ID number DOB
This therapy is only for HR/IR patients awaiting stem cell transplant therapy due to stem cell
source or facility scheduling issues causing a lag time > 2 weeks after count recovery. Bridging
therapy can be given for a maximum of 6 weeks, but does not need to be given the full 6 weeks if
patient is ready for HSCT earlier.
This therapy lasts for a maximum of 6 weeks (42 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL. See Section 4.10 for treatment
details. This therapy delivery map is on one (1) page.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

VinCRIStine (VCR) IV push over 1 minute+ 1.5 mg/m²/dose 1, 22 + Or infusion via minibag as per institutional policy.
b CBC/diff/platelets
c BM for MRD evaluation
Maximum dose: 2 mg
d BUN/creatinine
e LFTs
Mercaptopurine (MP) PO 75 mg/m²/dose 1-42
Methotrexate (MTX) PO 20 mg/m²/dose 1, 8, 15, 22, 29, 36 See Section 7.1c for Follow up
observations.
Ht _________cm Wt _________kg BSA _________m2
Date Due Date Given Day VCR MP PO MTX Studies Comments (Include any held doses, or
____mg ___mg ______mg dose modifications)
Enter calculated dose above and actual dose administered below
1 _____mg _____mg _____mg a, b, c, d,e
---
8 _____mg
---
15 _____mg
---
22 _____mg ______mg
---
29 _____mg
---
36 _____mg
---
42
43 c1
1
Bone marrow for MRD evaluation must be repeated prior to the start of HSCT.
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-I Continuation1/2 (All LR patients)

This therapy is for all LR patients and is the same for Continuation 1 and Continuation 2. Patient COG ID number DOB
Continuation lasts 8 weeks and is given twice, for a total of 16 weeks. Begin when ANC ≥ 500/µL and platelets ≥ 50,000/µL. Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL
prior to beginning Day 22 ID MTX. See Section 4.11 for treatment details. This therapy delivery map is for one cycle of Continuation and is on two (2) pages.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS
a Hx, PE [VS/Wt (BSA)]
Dexamethasone (DEX) PO 3 mg/m²/dose 1-5 Total Daily Dose: 6 mg/m2/day, divided BID.
b CBC/diff/platelets
c CSF cell count, cytospin1
VinCRIStine (VCR) IV push over 1 minute+ 1.5 mg/m²/dose 1 +
Or infusion via minibag as per institutional policy d Bilirubin, ALT &
Maximum dose: 2 mg creatinine, BUN
Methotrexate (MTX) PO 20 mg/m²/dose 8, 15, 29, 36
Intermediate Dose IV over 36 hours 1000 mg/m²/dose 22 CNS3 ONLY
Methotrexate (ID MTX) 1
Methotrexate (MTX) PO 25 mg/m/dose Q6H 22 CNS1/2 ONLY Obtain with each IT/ITT

Mercaptopurine (MP) PO 75 mg/m²/dose 1-42 See Section 7.0 for further

details
Leucovorin (LCV) IV/PO 15 mg/m²/dose Q6H 24, 25 Begin 48 hrs after the START of ID MTX infusion.
Leucovorin (LCV) PO 10 mg/m2/dose Q6H 24 Begin 48 hrs after the START of day 22 Methotrexate
Cyclophosphamide (CPM) IV over 30-60 minutes 300 mg/m²/dose 43, 50 See Section 4.11 and Appendix IV for administration OBTAIN OTHER STUDIES
guidelines.
Etoposide (ETOP) IV over 60-120 minutes 150 mg/m²/dose 43, 50 AS REQUIRED FOR GOOD
PATIENT CARE
Thioguanine (TG) PO 40 mg/m2/dose 43-49
Cytarabine (ARAC) IV/SQ 50 mg/m²/dose 44-47, 51-54
Intrathecal Methotrexate IT Age (yrs) Dose 1, 43 CNS1/2 ONLY
(IT MTX) 1-1.99 8 mg
2-2.99 10 mg Note age-based dosing
3-8.99 12 mg
≥9 15 mg
Intrathecal Triple Therapy IT Age (yrs) Dose 1, 43 CNS3 ONLY
(ITT): 1-1.99 MTX:8mg,
Methotrexate (MTX) HC: 8mg, Note age-based dosing
Hydrocortisone (HC) ARAC: 16mg
Cytarabine (ARAC) 2-2.99 MTX: 10mg
HC: 10 mg
ARAC: 20 mg
3-8.99 MTX: 12 mg
HC: 12 mg
ARAC: 24 mg
≥9 MTX: 15 mg
HC: 15 mg
ARAC: 30 mg

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APPENDIX II-I Continuation1/2 (All LR patients)

This therapy is for all LR patients and is the same for Continuation 1 and Continuation 2. Patient COG ID number DOB
Enter Cycle #: _____ Ht _________cm Wt _________kg BSA _________m2
Date Date Day DEX. MP VCR PO PO MTX ID MTX LCV ETOP CPM TG ARAC IT MTX ITT Studies Comments
Due Given MTX CNS1/2 CNS3 ____mg CNS1/2 CNS3 (Include any held
ONLY ONLY ONLY ONLY doses, or dose
___mg __mg ___mg ___mg ___mg ____mg ___mg ___mg ___mg ___mg ___mg ___mg modifications)

Enter calculated dose above and actual dose administered below

1 ___mg ___mg __mg ___mg ___mg a, b, c,d
2
3
4
5
----

8 ___mg b,d
---

15 ___mg b,d
----

22^ ____mg ____mg b,d

----

24 ____mg
25 ____mg
---

29 ___mg b,d
---

36 ___mg b,d
----

42
43^ ___mg ___mg ___mg ___mg ___mg b, c,d
44 ___mg
---

46
47
---

48
49
50 ___mg ___mg b, d
51 ___mg
---

53
54
---

56 b,d
Following Continuation 1, upon count recovery, LR patients randomized to Arm C will receive Continuation 2 therapy (Section 4.11, APPENDIX II-I), LR patients randomized to Arm D will receive
Blinatumomab Block: Cycle 2 therapy (Section 4.16, APPENDIX II-N),
Following Continuation 2, upon count recovery, LR patients randomized to Arm C will receive Maintenance Cycle 1 therapy (Section 4.12, Appendix II-J), LR patients randomized to Arm D will receive
Blinatumomab Block: Cycle 3 therapy (Section 4.16, APPENDIX II-N),
^ Await count recovery to ANC ≥ 500/µL and platelets ≥ 50,000/µL prior to beginning Day 22 and Day 43 therapy. See Section Section 4.11 for details
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.
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Appendix II-J Maintenance Cycle 1 (All LR patients)

This Maintenance therapy is for all LR patients (Arm C and Arm D ) Patient COG ID number DOB
Maintenance Cycle 1 lasts for 12 weeks (84 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL. See Section 4.12 for treatment details. This
therapy delivery map is for Maintenance and is on two (2) pages.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Dexamethasone (DEX) PO 3 mg/m²/dose BID 1-5, 29-33, & 57-61 Total Daily Dose: 6 mg/m2/day, divided BID.
b CBC/diff/platelets
c CSF cell count, cytospin1
VinCRIStine (VCR) IV push over 1 1.5 mg/m²/dose 1, 29, 57 + Or infusion via minibag as per institutional policy. d Bilirubin, ALT & creatinine, BUN
minute+ Maximum dose: 2 mg e Absolute lymphocyte count with T and
Mercaptopurine (MP) PO 75 mg/m²/dose 1-84 B subset quantification.2
f Peripheral blood for Immunogenicity
Methotrexate (MTX) PO 20 mg/m²/dose 8, 15, 22, 29, 36, 43,
50, 57, 64, 71, 78 1
Obtain with each IT/ITT
Intrathecal IT Age (yrs) Dose 1 CNS1/2 ONLY 2
To be done at the end of each 12 week
Methotrexate (IT MTX) 1-1.99 8 mg
maintenance cycle and every 3 months after
2-2.99 10 mg Note age-based dosing
completion of therapy for 1 year.
3-8.99 12 mg
≥9 15 mg
Intrathecal Triple IT Age (yrs) Dose 1 CNS3 ONLY See Section 7.0 for further details.
Therapy (ITT): 1-1.99 MTX:8mg,
Methotrexate (MTX) HC: 8mg,
Hydrocortisone (HC) ARAC: 16mg Note age-based dosing
Cytarabine (ARAC) 2-2.99 MTX: 10mg
HC: 10 mg
ARAC: 20 mg
3-8.99 MTX: 12 mg
HC: 12 mg
ARAC: 24 mg
≥9 MTX: 15 mg
HC: 15 mg
OBTAIN OTHER STUDIES AS
ARAC: 30 mg
REQUIRED FOR GOOD PATIENT CAR

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Appendix II-J Maintenance Cycle 1 (All LR patients)

This Maintenance therapy is for all LR patients (Arm C and Arm D) Patient COG ID number DOB
Ht _________cm Wt _________kg BSA _________m2
Date Due Date Day DEX. VCR MP MTX IT MTX ITT Studies Comments (Include any held
Given CNS1/2 ONLY CNS3 ONLY ______mg doses, or dose modifications)
____mg ____mg ___mg ______mg ______mg
Enter calculated dose above and actual dose administered below
1 _____mg _____mg _____mg ______mg ______mg a, b, c, d,f$
2
3
4
5
----

8 ______mg
----

15 ______mg
----

22 ______mg
----

29 _____mg _____mg ______mg a, b, d

30
31
32
33
----

36 ______mg
----

43 ______mg
-----

50 ______mg
-----

57 _____mg _____mg ______mg a, b, d

58
58
60
61
----

64 ______mg
-----

71 ______mg
-----

78 ______mg
----

84 a, b, d, e
85 Following Maintenance Cycle 1 therapy, CNS3 patients ONLY will receive CNS directed therapy with chemoradiation (Section 4.13, APPENDIX II-K). All other
patients on Arm C and Arm D will continue with Maintenance Post-Cycle 1 therapy (Section 4.14, APPENDIX II-L)
$ Arm D ONLY. Prior to start of Maintenance therapy for eligible patients (see Section 13.7 and lab manual for details)
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-K Maintenance Chemoradiation-CNS Directed Therapy (LR Patients)

This therapy is for all CNS3 patients ONLY and is given between 1st and 2nd cycles of Maintenance
therapy. Patient COG ID number DOB
This CNS directed therapy lasts 3 weeks (21 days). See Section 4.13 for treatment details. This Therapy Delivery Map is on one (1) page
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

Dexamethasone (DEX) PO 5 mg/m²/dose 1-7, 15-21 Total Daily Dose: 10 mg/m2/day, divided a Hx, PE [VS/Wt (BSA)]
BID. b CBC/diff/platelets
c Bilirubin, ALT & creatinine,
VinCRIStine (VCR) IV push over 1 minute+ 1.5 mg/m²/dose 1, 8, 15 + Or infusion via minibag as per
BUN
institutional policy d Absolute lymphocyte count with
T and B subset quantification.2
Maximum dose: 2 mg
Pegaspargase (PEG-ASP) IV over 1-2 hours 2500 International units/m²/dose 1 Administer through the tubing of a freely
infusing solution of D5W or 0.9% NaCl
See Section 7.0 for further details.
Cranial Radiotherapy: Patients with CNS3 and isolated CNS relapse will receive cranial radiation during Maintenance, between Blocks 1 and 2. See
Section 14.1 for details of cXRT. OBTAIN OTHER STUDIES
AS REQUIRED FOR GOOD
PATIENT CARE
Enter Cycle #: _____ Ht _________cm Wt _________kg BSA _________m2
Date Due Date Day DEX. VCR PEG-ASP Studies Comments (Include any held doses, or dose
Given ____mg ____mg ____IU modifications)
Enter calculated dose above and actual dose administered below
1 ________mg ________mg _______IU a, b, c
2
3
4
5
6
7
8 ________mg
---

15 ________mg ________mg
16
17
18
19
20
21 d
22 Following chemoradiation, patients will receive Maintenance Post-Cycle 1 therapy (Section 4.14, APPENDIX II-L) when count parameters are met.
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-L Maintenance Post Cycle 1 (All LR patients)

Patient COG ID number DOB
This therapy is for all LR patients (Arm C and Arm D )

Maintenance Post Cycle 1 is given in 12 week cycles based on dose modifications for low counts and platelets. See Section 4.14 and Section 5.9 for details. This therapy delivery map is on two (2)
pages.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Dexamethasone (DEX) PO 3 mg/m²/dose BID 1-5, 29-33, & 57-61 Total Daily Dose: 6 mg/m2/day, divided BID.
b CBC/diff/platelets
c CSF cell count, cytospin1
VinCRIStine (VCR) IV push over 1 minute+ 1.5 mg/m²/dose 1, 29, 57 + Or infusion via minibag as per institutional policy d Bilirubin, ALT & Creatinine, BUN
Maximum dose: 2 mg e Absolute lymphocyte count with T
Methotrexate (MTX) PO 20 mg/m²/dose 1 CNS3 ONLY and B subset quantification2
Mercaptopurine (MP) PO 75 mg/m²/dose 1-84
1
Methotrexate (MTX) PO 20 mg/m²/dose 8, 15, 22, 29, 36, 43, 50, Obtain with each IT/ITT
2
57, 64, 71, 78 To be done at the end of each 12 week
Intrathecal IT Age (yrs) Dose 1 CNS1/2 ONLY maintenance cycle and every 3 months
Methotrexate (IT MTX) 1-1.99 8 mg after completion of therapy for 1 year.
2-2.99 10 mg Note age-based dosing
3-8.99 12 mg See Section 7.0 for further details.
≥9 15 mg
OBTAIN OTHER STUDIES AS
REQUIRED FOR GOOD
PATIENT CARE

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APPENDIX II-L Maintenance Post Cycle 1 (All LR patients)

Patient COG ID number DOB
This therapy is for all LR patients (Arm C and Arm D)

Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day DEX. VCR MTX (PO) MTX (PO) MP IT MTX Studies Comments (Include any held doses, or
Given CNS3 ONLY _____mg CNS1/2 ONLY dose modifications)
____mg ____mg ____mg _____mg ______mg
Enter calculated dose above and actual dose administered below
1 ____mg _____mg ______mg _____mg ______mg a, b, c, d
2
3
4
5
----

8 ______mg
----

15 ______mg
----

22 ______mg
----

29 ____mg _____mg ______mg a, b, d

30
31
32
33
----

36 ______mg
----

43 ______mg
-----

50 ______mg
-----

57 ____mg _____mg ______mg a, b, d

58
59
60
61
----

64 ______mg
-----

71 ______mg
-----

78 ______mg
----

84 a, b, d, e
85 Maintenance cycles are repeated in 12 week cycles based on dose modifications for low counts or low platelets until 2 yrs from start of Block 1 therapy for both
male and female patients.
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-M Blinatumomab Block - Cycle 1 (LR Patients in Arm D )

This therapy is the 1st cycle of therapy with blinatumomab for the LR patients randomized to Arm D
Patient COG ID number DOB

This cycle lasts 5 weeks (35 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50 000/µL.. See Section 4.15 for treatment details. This Therapy Delivery Map is on one (1) page.

DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

Blinatumomab (BLIN) IV 15 micrograms/m²/day 1-28 a Hx, PE [VS/Wt (BSA)]
Dexamethasone (DEX) PO or IV 10 mg/m²/dose , 6-12 hours prior to 1 Start prior to blinatumomab therapy b CBC/diff/platelets
blinatumomab infusion, c CSF cell count, cytospin1
THEN d Bilirubin, ALT & creatinine, BUN
e Peripheral blood for PK
5 mg/m2 within 30 minutes of starting f Peripheral blood for
Blinatumomab infusion Immunogenicity
Intrathecal Methotrexate IT Age (yrs) Dose 8, 29 CNS1/2 ONLY
(IT MTX) 1-1.99 8 mg Optional studies
2-2.99 10 mg Note age-based dosing g Blinatumomab PD
3-8.99 12 mg
≥9 15 mg
Intrathecal Triple IT Age (yrs) Dose 8, 29 CNS3 ONLY
Therapy (ITT): 1-1.99 MTX:8mg, 1
Obtain with each IT/ITT
Methotrexate (MTX) HC: 8mg,
Hydrocortisone (HC) ARAC: 16mg Note age-based dosing See Section 7.0 for further details.
Cytarabine (ARAC) 2-2.99 MTX: 10mg
HC: 10 mg
ARAC: 20 mg
3-8.99 MTX: 12 mg
HC: 12 mg
ARAC: 24 mg OBTAIN OTHER STUDIES AS
≥9 MTX: 15 mg REQUIRED FOR GOOD PATIENT
HC: 15 mg CARE
ARAC: 30 mg
Testicular Radiotherapy: Patients with persistent testicular disease will receive testicular radiation. See Section 14.2 for details of TRT.

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APPENDIX II-M Blinatumomab Block - Cycle 1 (LR Patients in Arm D )

This therapy is the 1st cycle of therapy with blinatumomab for the LR patients randomized to Arm D
Patient COG ID number DOB

Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day BLIN DEX IT MTX CNS1/2 ITT CNS3 ONLY Studies Comments (Include any held doses, or dose
Given ______µg ______mg ONLY ______mg modifications)
______mg
Enter calculated dose above and actual dose administered below
1 ____µg _______m a*, b, d, g+,f$
g
2
---
e& g+
7 g+
8
---
____mg ____mg b, c, d,
14 e& g+
15 b, d
---

21 g+
22
---
b, d
28
29 ____mg ____mg b, c, d
30-35 Rest Period
36 Following Blinatumomab Block: Cycle 1, patients receive Continuation 1 therapy (Section 4.11, APPENDIX II-I) when count parameters are
met.
+
Peripheral blood: Prior to (Hour 0) and during (Hour 6, Hour 12, Day 2, Day 7, Day 14, Day 21) first blinatumomab infusion (see Section 13.5 for complete details).
$ Prior to (Hour 0) first blinatumomab infusion (see Section 13.7 and lab manual for details)
&
See lab manual for details
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX II-N Blinatumomab Block - Cycle 2 and 3 (LR Patients in Arm D)

This therapy is Cycles 2 and 3 of therapy with blinatumomab for the LR patients randomized to Arm D Patient COG ID number DOB

Blinatumomab Block: Cycles 2 & 3; each last 5 weeks (35 days) and starts when peripheral counts recover to ANC ≥ 500/µL and platelets ≥ 50,000/µL. See Section 4.16 for treatment details.
This Therapy Delivery Map is on one (1) page.
DRUG ROUTE DOSAGE DAYS IMPORTANT NOTES OBSERVATIONS

a Hx, PE [VS/Wt (BSA)]

Blinatumomab (BLIN) IV 15 micrograms/m²/day 1-28
b CBC/diff/platelets1
c Bilirubin, ALT & creatinine, BUN
d Peripheral blood for Immunogenicity

1
Dexamethasone (DEX) PO or IV 10 mg/m²/dose , 6-12 hours prior to 1 Start prior to blinatumomab Obtain with each IT/ITT
blinatumomab infusion, therapy See Section 7.0 for further details.
THEN
5 mg/m2 within 30 minutes of starting OBTAIN OTHER STUDIES AS
Blinatumomab infusion REQUIRED FOR GOOD PATIENT CARE

Enter Cycle #_________ Ht _________cm Wt _________kg BSA _________m2

Date Due Date Day BLIN DEX Studies Comments (Include any held doses, or dose modifications)
Given
____µg ______mg
Enter calculated dose above and actual dose administered below
1 ____µg ______mg a*, b, c
---

8 b, c
---

15 b, c
---

22 b, c
---

28
29 b, c,d$
30-35 Rest Period
36 Following Blinatumomab Block Cycle 2: LR B-ALL patients randomized to Arm D will receive Continuation 2 (Section 4.11, APPENDIX II-I) when
count parameters are met.
Following Blinatumomab Block Cycle 3: LR B-ALL patients randomized to Arm D will receive Maintenance Cycle 1 therapy- (Section 4.12, Appendix
II-J) when count parameters are met.
$
Obtain at End Cycle 2. In cases where blinatumomab treatment will not continue to Cycle 2, collect sample at end of Cycle 1. See Section 13.7 and lab manual for details
*See recommended vital sign monitoring for Blinatumomab blocks in Section 7.1e
See Section 5.0 for Dose Modifications for Toxicities and Appendix I for Supportive Care Guidelines.

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APPENDIX III: MERCAPTOPURINE DOSING GUIDELINES

MERCAPTOPURINE 75 mg/m2

Daily Dose (d) for 7 days

Body Surface Area (m²)* Cumulative Weekly Dose
(1 tablet = 50 mg)
0.36 - 0.40 ½ tab / d x 6; 1 tab / d x 1 200 mg/wk
0.41 - 0.45 ½ tab / d x 5; 1 tab / d x 2 225 mg/wk
0.46 - 0.49 ½ tab / d x 4; 1 tab / d x 3 250 mg/wk
0.50 - 0.54 1 tab / d x 4; ½ tab / d x 3 275 mg/wk
0.55 - 0.59 1 tab / d x 5; ½ tab / d x 2 300 mg/wk
0.60 - 0.64 1 tab / d x 6; ½ tab / d x 1 325 mg/wk
0.65 - 0.69 1 tab / day 350 mg/wk
0.70 - 0.73 1 tab / d x 6; 1½ tab / d x 1 375 mg/wk
0.74 - 0.78 1 tab / d x 5; 1½ tab / d x 2 400 mg/wk
0.79 - 0.83 1 tab / d x 4; 1½ tab / d x 3 425 mg/wk
0.84 - 0.88 1½ tab / d x 4; 1 tab / d x 3 450 mg/wk
0.89 - 0.92 1½ tab / d x 5; 1 tab / d x 2 475 mg/wk
0.93 - 0.97 1½ tab / d x 6; 1 tab /d x 1 500 mg/wk
0.98 - 1.02 1½ tab / day 525 mg/wk
1.03 - 1.07 1½ tab / d x 6; 2 tab / d x 1 550 mg/wk
1.08 - 1.11 1½ tab / d x 5; 2 tab / d x 2 575 mg/wk
1.12 - 1.16 1½ tab / d x 4; 2 tab / d x 3 600 mg/wk
1.17 - 1.21 2 tab / d x 4; 1½ tab / d x 3 625 mg/wk
1.22 - 1.26 2 tab / d x 5; 1½ tab / d x 2 650 mg/wk
1.27 - 1.30 2 tab / d x 6; 1½ tab / d x 1 675 mg/wk
1.31 - 1.35 2 tab / day 700 mg/wk
1.36 - 1.40 2 tab / d x 6; 2½ tab / d x 1 725 mg/wk
1.41 - 1.45 2 tab / d x 5; 2½ tab / d x 2 750 mg/wk
1.46 – 1.49 2 tab / d x 4; 2½ tab / d x 3 775 mg/wk
1.50 – 1.54 2½ tab/ d x 4; 2 tab / d x 3 800 mg/wk
1.55 – 1.59 2½ tab/ d x 5; 2 tab / d x 2 825 mg/wk
1.60 – 1.64 2½ tab/ d x 6; 2 tab / d x 1 850 mg/wk
1.65 – 1.69 2½ tab/ d 875 mg/wk
1.70 – 1.73 2½ tab/ d x 6; 3 tab / d x 1 900 mg/wk
1.74 – 1.78 2½ tab/ d x 5; 3 tab / d x 2 925 mg/wk
1.79 – 1.83 2½ tab/ d x 4; 3 tab / d x 3 950 mg/wk
1.84 – 1.88 3 tab/ d x 4; 2½ tab / d x 3 975 mg/wk
1.89 – 1.92 3 tab/ d x 5; 2½ tab / d x 2 1000 mg/wk
1.93 – 1.97 3 tab/ d x 6; 2½ tab / d x 1 1025 mg/wk
1.98 – 2.02 3 tab/ d x 7 1050 mg/wk
2.03 – 2.07 3 tab/ d x 6; 3½ tab / d x 1 1075 mg/wk

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2.08 – 2.11 3 tab/ d x 5; 3½ tab / d x 2 1100 mg/wk

2.12 – 2.16 3 tab/ d x 4; 3½ tab / d x 3 1125 mg/wk
2.17 – 2.21 3½ tab/ d x 4; 3 tab / d x 3 1150 mg/wk
2.22 – 2.26 3½ tab/ d x 5; 3 tab / d x 2 1175 mg/wk
2.27 – 2.30 3½ tab/ d x 6; 3 tab / d x 1 1200 mg/wk
2.31 – 2.35 3½ tab/ d x 7 1225 mg/wk
2.36 – 2.40 3½ tab/ d x 6; 4 tab / d x 1 1250 mg/wk
2.41 – 2.45 3½ tab/ d x 5; 4 tab / d x 2 1275 mg/wk
2.46 – 2.49 3½ tab/ d x 4; 4 tab / d x 3 1300 mg/wk
2.50 – 2.54 4 tab/ d x 4; 3½ tab / d x 3 1325 mg/wk
2.55 – 2.59 4 tab/ d x 5; 3½ tab / d x 2 1350 mg/wk
2.60 – 2.64 4 tab/ d x 6; 3½ tab / d x 1 1375 mg/wk
2.65 – 2.69 4 tab/ d x 7 1400 mg/wk
2.70 – 2.73 4 tab/ d x 6; 4½ tab / d x 1 1425 mg/wk
2.74 – 2.78 4 tab/ d x 5; 4½ tab / d x 2 1450 mg/wk
2.79 – 2.83 4 tab/ d x 4; 4½ tab / d x 3 1475 mg/wk
2.84 – 2.88 4½ tab/ d x 4; 4 tab / d x 3 1500 mg/wk
2.89 – 2.92 4½ tab/ d x 5; 4 tab / d x 2 1525 mg/wk
2.93 – 2.97 4½ tab/ d x 6; 4 tab / d x 1 1550 mg/wk
2.98 – 3.00 4½ tab/ d x 7 1575 mg/wk
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated on actual BSA with no maximum
dose.

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APPENDIX IV: THIOGUANINE DOSING GUIDELINES

THIOGUANINE 40 mg/m2
*Patients exceeding a BSA of 3 m2 should have their TG doses calculated on actual BSA with no maximum dose.
Body Surface Area Daily Dose (d) for 7 days Cumulative Weekly
(m²)* (1 tablet = 40 mg) Dose
0.27 – 0.3 Use oral compounded suspension
0.31 – 0.34 Use oral compounded suspension
0.35 – 0.38 Use oral compounded suspension
0.39 – 0.41 Use oral compounded suspension
0.42 – 0.45 Use oral compounded suspension
0.46 – 0.48 Use oral compounded suspension
0.49 – 0.54 ½ tab / d x 7 140 mg/wk
0.55 – 0.61 ½ tab / d x 6; 1 tab / d x 1 160 mg/wk
0.62 – 0.68 ½ tab / d x 5; 1 tab / d x 2 180 mg/wk
0.69 – 0.75 ½ tab / d x 4; 1 tab / d x 3 200 mg/wk
0.76 – 0.82 1 tab / d x 4; ½ tab / d x 3 220 mg/wk
0.83 – 0.89 1 tab / d x 5; ½ tab / d x 2 240 mg/wk
0.9 – 0.96 1 tab / d x 6; ½ tab / d x 1 260 mg/wk
0.97 – 1.04 1 tab / d x 7 280 mg/wk
1.05 – 1.11 1 tab / d x 6; 1½ tab / d x 1 300 mg/wk
1.12 – 1.18 1 tab / d x 5; 1½ tab / d x 2 320 mg/wk
1.19 – 1.25 1 tab/ d x 4; 1½ tab / d x 3 340 mg/wk
1.26 – 1.32 1½ tab / d x 4; 1 tab / d x 3 360 mg/wk
1.33 – 1.39 1½ tab / d x 5; 1 tab /d x 2 380 mg/wk
1.4 – 1.46 1½ tab / d x 6; 1 tab / d x 1 400 mg/wk
1.47 – 1.54 1½ tab /day 420 mg/wk
1.55 – 1.61 1½ tab / d x 6; 2 tab / d x 1 440 mg/wk
1.62 – 1.68 1½ tab / d x 5; 2 tab / d x 2 460 mg/wk
1.69 – 1.75 1½ tab / d x 4; 2 tab / d x 3 480 mg/wk
1.76 – 1.82 2 tab / d x 4; 1½ tab / d x 3 500 mg/wk
1.83 – 1.89 2 tab / d x 5; 1½ tab / d x 2 520 mg/wk
1.9 – 1.96 2 tab / d x 6; 1½ tab / d x 1 540 mg/wk
1.97 – 2.04 2 tab / day 560 mg/wk
2.05 – 2.11 2 tab / d x 6; 2½ tab / d x 1 580 mg/wk
2.12 – 2.18 2 tab / d x 5; 2½ tab / d x 2 600 mg/wk
2.19 – 2.25 2 tab / d x 4; 2½ tab / d x 3 620 mg/wk
2.26 – 2.32 2½ tab / d x 4; 2 tab / d x 3 640 mg/wk
2.33 – 2.39 2½ tab / d x 5; 2 tab / d x 2 660 mg/wk
2.4 – 2.46 2½ tab / d x 6; 2 tab / d x 1 680 mg/wk
2.47 – 2.54 2½ tab / d 700 mg/wk
2.55 – 2.61 2½ tab / d x 6; 3 tab / d x 1 720 mg/wk
2.62 – 2.68 2½ tab / d x 5; 3 tab / d x 2 740 mg/wk
2.69 – 2.75 2½ tab / d x 4; 3 tab / d x 3 760 mg/wk
2.76 – 2.82 3 tab / d x 4; 2½ tab / d x 3 780 mg/wk
2.83 – 2.89 3 tab / d x 5; 2½ tab / d x 2 800 mg/wk
2.9 – 2.96 3 tab / d x 6; 2½ tab / d x 1 820 mg/wk
2.97 – 3 3 tab / d x 7 840 mg/wk

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APPENDIX V: YOUTH INFORMATION SHEETS

INFORMATION SHEET REGARDING RESEARCH STUDY

(for children from 7 through 12 years of age)

A trial to compare 2 ways to treat children with B-Lymphoblastic Leukemia (B-ALL)

that has come back (relapsed) after the first treatment
1. We have been talking with you about your illness, B-ALL. You have received treatment for this B-
ALL before. After doing tests, we have found that the cancer has come back in your bone marrow,
brain or spinal cord, or testes. B-ALL that has come back after the first treatment is called relapse.

2. We are asking you to take part in a research study because you have B-ALL that has relapsed. A
research study is when doctors work together to try out new ways to help people who are sick. In this
study we are trying to learn more about how to treat B-ALL when it has come back after the first time
it was treated. During this study, we want to test whether the relapsed B-ALL responds better to
combination chemotherapy or a new drug called blinatumomab. The treatment that you get will
depend on a process called random assignment. Random assignment is a lot like flipping a coin and
you will have an equal chance of getting both treatment options.

3. Children and teens who are part of this study will be treated with either combination chemotherapy or
a new drug called blinatumomab. It is possible that some children will get radiation to their brain or
testes, depending on where the leukemia is found. Some children will also get a stem cell transplant.

4. Sometimes good things can happen to people when they are in a research study. These good things
are called “benefits.” We hope that a benefit to you of being part of this study is having the leukemia
go away for as long as possible. But we don’t know for sure if there is any benefit of being part of this
study.

5. Sometimes bad things can happen to people when they are in a research study. These bad things are
called “risks.” The risks to you from this study are that you might experience more side effects from
the combination chemotherapy or blinatumomab. Another risk is that the therapy on this study might
not be as effective as other options. Other things may happen to you that we don’t yet know about.

6. Your family can choose to be part of this study or not. Your family can also decide to stop being in
this study at any time once you start. There may be other treatments for your illness that your doctor
can tell you about. Make sure to ask your doctors any questions that you have.

7. We are asking your permission to collect additional blood. We want to see if there are ways to tell
how the cancer will respond to treatment. These samples would be taken when other standard blood
tests are being performed, so there would be no extra procedures. You can still be treated on this
study even if you don't allow us to collect the extra blood samples for research.

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INFORMATION SHEET REGARDING RESEARCH STUDY

(for teens from 13 through 17 years of age)

A trial to compare 2 ways to treat children with B-Lymphoblastic Leukemia (B-ALL)

that has come back (relapsed) after the first treatment

1. We have been talking with you about your illness, B-ALL. You have received treatment for this B-
ALL before. After doing tests, we have found that the cancer has come back in your bone marrow,
brain or spinal cord, or testes. B-ALL that has come back after the first treatment is called relapse.

2. We are asking you to take part in a research study because you have B-ALL that has relapsed. A
research study is when doctors work together to try out new ways to help people who are sick. In this
study we are trying to learn more about how to treat B-ALL when it has come back after the first time
it was treated. During this study, we want to test whether the relapsed B-ALL responds better to
combination chemotherapy or a new drug called blinatumomab. The treatment that you get will
depend on a process called random assignment. Random assignment is a lot like flipping a coin and
you will have an equal chance of getting both treatment options.

3. Children and teens who are part of this study will be treated with either combination chemotherapy or
a new drug called blinatumomab. It is possible that some children will get radiation to their brain or
testes, depending on where the leukemia is found. Some children will also get a stem cell transplant.

4. Sometimes good things can happen to people when they are in a research study. These good things
are called “benefits.” We hope that a benefit to you of being part of this study is having the leukemia
go away for as long as possible. But we don’t know for sure if there is any benefit of being part of this
study.

5. Sometimes bad things can happen to people when they are in a research study. These bad things are
called “risks.” The risks to you from this study are that you might experience more side effects from
the combination chemotherapy or blinatumomab. Another risk is that the therapy on this study might
not be as effective as other options. Other things may happen to you that we don’t yet know about.

6. Your family can choose to be part of this study or not. Your family can also decide to stop being in
this study at any time once you start. There may be other treatments for your illness that your doctor
can tell you about. Make sure to ask your doctors any questions that you have.

7. We are asking your permission to collect additional bone marrow. We want to see if there are ways to
tell how the cancer will respond to treatment. These samples would be taken when other standard
tests are being performed, so there would be no extra procedures. You can still be treated on this
study even if you don't allow us to collect the extra samples for research.

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APPENDIX VI: ADDITIONAL INFORMATION FOR BANKING FOR FUTURE RESEARCH

CORRELATIVE BIOLOGY STUDY

a) Rationale
The ability to collect leukemic and normal tissue samples for future research, and to link these samples to
patient characteristics and outcomes, has been critical to recent seminal discoveries regarding the molecular
basis of de novo ALL and relapsed ALL, and the relationship of specific molecular lesions with outcomes
and response to targeted therapies. In the context of this protocol, we will seek consent from participants to
provide material for banking for the purpose of performing retrospective studies to refine risk stratification,
identify new targets for therapy, identify biomarkers to predict response, and to link host polymorphisms
with various disease characteristics and toxicities.

b) Aims and methods

These studies will be performed as stand-alone biology studies subject to review and approval in accordance
with the NCTN policies. The following are general descriptions of the types of studies planned.

• Leukemia genomic studies

Modern genomic studies of high risk ALL have identified novel genetic alterations in ALL that are
associated with treatment failure. In particular, high frequencies of mutations have been described in
genes involved in B lymphocyte development (EBF1, IKZF1, PAX5) and signaling (BTLA, CD200,
RAS) and in cell cycle regulation (CDKN2A/B, RB, TP53).81 Limited genomic analyses of paired
diagnosis and relapse ALL samples have also shed light upon the early origin and clonal nature of such
leukemia-associated mutations.82,83 Other yet-undiscovered mutations likely contribute the
pathogenesis of this heterogeneous group of malignancies, and comprehensive prospective evaluation
of the genetic landscape of relapsed ALL has not been performed. We hypothesize that integration of
genomic profiling data will provide important insights regarding the molecular pathogenesis of relapsed
ALL and may identify potential therapeutic targets or identify novel mechanisms of resistance within
the context of the agents employed.84-86

We hypothesize that high-throughput genome-wide profiling via multiple non-overlapping techniques

provide a comprehensive genetic and epigenetic “fingerprint” and will identify key alterations that
contribute to the pathogenesis and progression of relapsed ALL. We further hypothesize that integration
of these approaches will allow discovery of alterations that may also be present in de novo ALL and
could ultimately be used for initial risk stratification and new treatment approaches.

Consenting patients will submit bone marrow and/or peripheral blood samples at study entry and, if
applicable, at second relapse to the central COG Tissue Bank at Nationwide Children’s Hospital for
storage of viably cryopreserved cells and for isolation nucleic acids, including DNA and RNA. Nucleic
acids isolated from relapse specimens will be stored for potential use for genomic profiling, which will
include single nucleotide polymorphism (SNP) arrays, array-based gene expression profiles and/or
quantitative RT-PCR-based gene expression analyses, methylation arrays, and/or comprehensive
sequencing approaches (e.g., RNA-seq, whole exome sequencing), depending on currently available
technologies and funding sources. Banked specimens subsequently will be distributed from the
reference laboratories to the laboratories performing the individual correlative biology studies. Results
from these correlative biology studies may ultimately facilitate (a) enhanced refinement of risk
stratification for patients with relapsed ALL, (b) detection of previously-unsuspected subset specificity
of blinatumomab, and (c) generation of additional hypotheses with respect to the underlying biology of
relapsed ALL.
• Host polymorphism studies
There is substantial evidence that both inherited germline constitutional and somatically-acquired ALL-

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specific genomic variation may contribute to variations in response.87-96 Blood samples obtained
during remission are requested specifically for the purpose of providing constitutional (germline) DNA
from each patient. Several efforts are anticipated for study of how genomic variation (SNPs, copy
number variations, DNA methylation and insertions/deletions) in the constitutional DNA may be
associated with phenotypes in ALL. The phenotypes could include those related to probability of cure,
response, adverse events or classification. Techniques for interrogation of DNA variation are constantly
evolving, and thus these techniques vary but may include candidate polymorphism testing (eg, via
Taqman, GoldenGate, or PCR/RFLP assays), candidate gene sequencing (eg, via next-generation
technologies coupled with exon capture) or whole-genome sequencing (eg, via next-generation
technologies, with or without capture).

• MRD by next generation sequencing (NGS)

Next-generation sequencing (NGS) offers the potential for highly sensitive and standardized detection
of minimal residual disease (MRD) in ALL. In comparison to current PCR methods, NGS assays do
not require the laborious generation and validation of patient-specific primers, resulting in improved
turn-around time and reduced cost, and may provide improved specificity by direct enumeration of
leukemia-derived sequences. Current flow cytometric methods for MRD detection rely on relatively
subjective assessments by trained interpreters and are about 1 log less sensitive than PCR-based
methods. To determine the suitability of NGS methods for routine MRD assessment in a clinical trial
setting, we will sequence the variable regions of IGH in pretreatment and post-treatment samples. Both
the presence and the frequency of the MRD clone relative to the total IGH repertoire will be noted.

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APPENDIX VII-A CLINICAL SITE MANAGEMENT OF OUT-PATIENT TREATMENT USING

CTEP-SUPPLIED BLINATUMOMAB

• PREPARED IV INFUSION BAGS MAY NOT BE CHANGED BY THE STUDY SUBJECT

• PREPARED INFUSION BAGS OR INTACT VIALS MUST NOT BE TRANSPORTED TO
ANOTHER LOCATION BY THE STUDY SUBJECT

AGENT PREPARATION AND ADMINISTRATION OPTIONS

• Prepare all out-patient infusion bags at the registering/treating NCTN Network institution.
Study subjects should return to the registering/treating institution for all infusion bag
changes.

• For study subjects that cannot return to the registering/treating institution every 48-hours
for infusion bag exchanges, the next preference would be for another NCTN Network
institution that is participating on the trial and is closer to the subject’s home take
over responsibility for the study subject’s protocol participation. In such cases, transfer of
the subject’s protocol registration to another participating investigator and institution
should be considered.

• If transferring the subject’s protocol registration to another participating investigator and

trial site within the NCTN Network is not feasible, use of a local outpatient infusion
center could be considered.

a. First preference would be for all infusion bags to be prepared by the

registering/treating institution and shipped via overnight courier delivery service in
a 2o to 8oC pre-qualified shipping container to the local out-patient infusion center.

b. The prepared infusion bags are stored at the local outpatient infusion center. The
infusion center would perform each infusion bag change.

c. If the local outpatient infusion center will not administer prepared infusion bags
admixed by the registering/treating institution, the registering/treating institution
may provide intact vials of blinatumomab to the local outpatient infusion center,
with infusion bags prepared and administered by the local outpatient infusion center
staff.

d. In either case, the local outpatient infusion center would be managed as a satellite
pharmacy of the registering/treating institution (see evaluation criteria below).

e. If physical transport of intact vials of blinatumomab from the registering/treating

institution to the local infusion center by registering/treating institution or local
infusion center staff is not possible, CTEP will allow shipment of the vials from the
registering/treating institution to the local infusion center via overnight courier
delivery service in a 2o to 8oC pre-qualified shipping container.

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• If an outpatient infusion center is not an option, use of a home health care service provider
can be considered.

Note: If a home health care agency is being considered to prepare and change the blinatumomab
infusion bag, the drug company that provides blinatumomab will cover the costs associated with
a home health care agency providing these services.

a. The first preference would be for all outpatient infusion bags to be prepared by the
registering/treating institution and shipped via overnight courier delivery service in
a 2o to 8oC pre-qualified shipping container to the servicing home health care
agency.

b. The prepared infusion bags are stored by the home health care agency and each
individual infusion bag transported to the subject’s home by the home health care
service nursing staff under refrigerated storage conditions for each infusion bag
change.

c. If home health care agency will not administer prepared infusion bags admixed by
the registering/treating institution, the registering/treating institution may provide
intact vials of blinatumomab to the home health care agency, with infusion bags
prepared and administered by the home health care agency staff.

d. In either case, the home health care agency would be managed as a satellite
pharmacy of the registering/treating institution (see evaluation criteria below).

e. If physical transport of intact vials of blinatumomab from the registering/treating

institution to the home health care agency by registering/treating institution or home
health care agency staff is not possible, CTEP will allow shipment of the vials from
the registering/treating institution to the home health care agency via overnight
courier delivery service in a 2o to 8oC pre-qualified shipping container.

5. If all options above are not feasible, shipping the prepared infusion bags directly to
patient’s home via overnight courier delivery service for administration by home
healthcare agency staff is acceptable.
a. The prepared infusion bags are to be shipped in a 2o to 8oC pre-qualified shipping
container containing one infusion bag per box. Example, if you are making 2 x 48
hour infusion bags, each infusion bag will be shipped in a separate 2o to 8oC pre-
qualified shipping container. The number of infusion bags that may be prepared
and shipped is dependent on the duration the shipping container used is qualified to
maintain 2o to 8oC temperature.
b. Patients should NOT open the shipping container upon arrival. Shipping containers
are to be stored in a secured area away from reach of children or pets.
c. Shipping containers must only be opened by the home health care service staff at
the time of the infusion bag change. Only one shipping container should be opened
at a time. If cold-chain management of the prepared infusion bag has been

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interrupted by opening of the shipping container or storage of the prepared infusion

bag in the shipping container exceeds the duration of the qualified time the
container will maintain 2o to 8oC temperature, the infusion bag should not be used.

The home health care service staff should immediately contact the registering/treating
institution site pharmacy as indicated on the shipment form. Within 1 business day, the
registering/treating institution site should send an email to the COG Industry Sponsored
Trials office at [email protected] with a copy to PMB/CTEP at
[email protected] to report all such occurrences of prepared, unusable
infusion bags shipped to a patient’s home.

d. Form documenting the time of packaging in the shipping container, duration of time
the container will maintain 2o to 8oC temperature and verification that cold-chain
management was maintained prior to administration must be included in each
shipping container and returned to registering/treating institution for documentation
purposes. (See Appendix VII-B)

e. Home health care service staff is to use GCP guidelines.

EVALUATION OF POTENTIAL SATELLITE PHARMACY SITES

When the registering/treating institution is considering use of a local infusion center or home
health care agency as a satellite pharmacy, the following must be assessed by the
registering/treating institution in relation to the suitability of the local infusion center or home
health care agency:

• Ability to appropriately store (temperature and security) the intact agent vials and/or
prepared infusion bags.
• Ability to provide documentation of controlled and monitored temperature storage
conditions while the IND agent is in the local infusion center or home health care agency
possession.
• Availability of appropriately trained staff to prepare doses in compliance with USP <797>
guidelines and the protocol, to label infusion bags according to the protocol instructions
and to store agent doses under appropriate controlled temperature conditions.
• For home health care agency services, the ability to transport each prepared dose
individually to the subject’s home under appropriate controlled storage conditions or the
ability to assess and confirm that cold-chain management of prepared infusion bags
shipped to the subject’s home is maintained prior to administration.
• Availability of appropriately trained staff to administer the prepared doses and perform the
infusion bag changes according to the protocol.
• Methods for proper disposal of the waste, empty vials, IV bags, etc. are in place.
• Plan for return of unused intact vials to the registering/treating institution is in place.
• Source documentation to confirm agent administration must be maintained by the local
infusion center or home health care agency and must be provided to the registering/treating
institution for incorporation into the patient’s medical/research records and for audit
purposes.
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• Plan for handling missed doses is in place.

• Agent accountability must be maintained via use of the NCI Drug Accountability Record
Form (DARF). The originating site must keep a Control DARF and the local infusion
center or home health care agency would be required to maintain a Satellite DARF if
receiving and storing supplies of intact vials or receiving and storing infusion bags prepared
by the registering/treating institution. Maintenance of a Satellite DARF is not required by
home health care agency staff for prepared infusions bags shipped to the subject’s home.
• The DARF must be provided to the registering/treating institution for record keeping
purposes and audits.
• Documentation of IRB coverage for the protocol must be maintained. The IRB of record
for the site must be informed that the study subject may receive therapy administered by a
non-research site (i.e., the local infusion center or home health care agency).

TRAINING FOR ALL PARTICIPATING SITES

The Lead Network Group for the trial must work with participating sites to:

a. Implement a training process for participating NCTN Network sites regarding

blinatumomab preparation and administration. Documentation of participating site
training must be submitted via RSS as a protocol specific requirement at the time of
site activation for participation on the trial

b. Develop a plan for participating NCTN Network sites to assess and train local
outpatient infusion centers or home health care agency for patient treatment if required
and document training of such sites

c. Have a training manual available for local outpatient infusion centers or home health
care agencies on the clinical trial, appropriate agent preparation, handling and
administration requirements and appropriate record keeping requirements

d. Create a definitive written communication plan for use between registering/treating

institution and the local outpatient infusion centers or home health care agency on an
ongoing basis during subject’s treatment regimen, including emergency contact
information for the registering/treating institution and investigator

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APPENDIX VII-B SHIPMENT OF BLINATUMOMAB IV BAG FROM SITE/PHARMACY TO

PATIENT’S HOME

To be completed by Site/Pharmacy:
From: (Investigator Name, Address) To Patient: (Patient Initials, Study ID No) Protocol No.:
_________________ ; ____________________
Patient Initials Study ID Number

Prepare shipment of IV bag at 2°C to 8°C in validated/pre-qualified insulated shipper as per manufacturer
instructions (see shipping container instructions). Please take care to use the applicable instructions for
summer or winter package preparation, respectively.

IV Bag number Date of packaging Time of packaging packed by

[DD/MMM/YYYY] [hh:mm] (initials)

Please tick the boxes and fill in the information below when preparing the IV bag shipment!
□ Validated/pre-qualified shipping container duration of time 2°C to 8°C temperature is
maintained: ___________________________ hours
□ Cooling elements for provided box used according to manufacturer’s instruction

Confirmed by:
(print name, signature) (date)

To be completed by Ambulant/Home Care Service Provider:

Shipment box unopened and content intact? YES 

NO 

IF NO, please comment_

Date and time shipment box opened:

(date) (time)
Confirmed by:
(print name, signature) Amb. Care Service (date)
Note: If content is not intact, please do not use IV bag and inform site immediately!
If time box opened minus time of packaging exceeds the time duration the shipping
container maintains 2°C to 8°C, please do not use IV bag and inform site
immediately!

CONFIDENTIAL

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APPENDIX VIII: ADDITIONAL INFORMATION FOR MRD CORRELATIVE BIOLOGY

STUDY

a) Rationale
Minimal residual disease is known to be a powerful prognostic factor in childhood ALL.1-5,12,20-22 Although
the majority of work has been done in newly diagnosed ALL patients, several studies using both polymerase
chain reaction methods13,14,16-18 and flow cytometry19,23 have shown that MRD is highly predictive of second
marrow relapse.

Flow cytometric MRD results will be used for the following purposes in this study:
• For late B-ALL marrow and late B-ALL IEM patients, we will use end-Block 1 flow cytometric MRD
levels of < 0.1% vs. ≥ 0.1% to define low risk group vs. intermediate risk group, respectively. The low
risk group will be eligible for LR randomization. The intermediate risk group will be eligible for HR/IR
Randomization.
• For the LR patients participating in LR randomization, we will use end-Block 2 MRD levels of < 0.01%
vs. ≥ 0.01% as a randomization stratification criteria to ensure balanced randomization.
• For the IR and HR patients participating in HR/IR Randomization, we will use end-Block 1 MRD levels
of <0.1% vs. ≥ 0.1% as a randomization stratification criteria to ensure balanced randomization.
• For HR/IR Randomization patients proceeding to HSCT, we will use the end-Block 3/pre-HSCT MRD
level, the peri-engraftment MRD level and the day +100 MRD level to determine eligibility for rapid
tapering of immunosuppression.
• In HR/IR Randomization, we will use flow cytometric MRD+ rates at the end of Blocks 2 and 3 as a
secondary efficacy objective.

b) Technique
Aliquots of fresh bone marrow specimens at study entry and during therapy at various designated time
points (see study schema and TDMs) will be adjusted to suitable cell concentrations and stained with the
following combinations of monoclonal antibodies in 6-color immunofluorescence:

Tube 1: CD20-FITC/CD10-PE/CD38-PerCP-Cy5.5/CD58-APC/CD19-PE-Cy7/CD45-APC-Cy7
Tube 2: CD9-FITC/CD13-PE+CD33-PE/CD34-PerCP-Cy5.5/CD10-APC/CD19-PE-Cy7/CD45-APC-
Cy7

After incubation, samples will be lysed with ammonium chloride, fixed with 0.25% ultra pure
formaldehyde, and washed once before analysis. Samples will be run on a Becton Dickinson FACSCanto.
A minimum of 750,000 events will be collected, and data will be analyzed by software developed by Dr.
Brent Wood, University of Washington that facilitates the hierarchical gating strategy useful for identifying
phenotypically aberrant cells. In cases in which the above panels are not informative for detecting abnormal
cells, additional markers including but not limited to CD15 and TdT will be added to the panel to help
identify MRD populations. In addition, if the administration of blinatumomab creates difficulties in
identifying leukemic cells by virtue of CD19 expression, cytoplasmic CD79a and/or CD22 will be used to
aid gating.

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APPENDIX IX: ADDITIONAL INFORMATION FOR CRLF2 CORRELATIVE BIOLOGY

STUDY

a) Rationale
Recent genomic studies of ALL have identified genomic alterations of CRLF2, which encodes the thymic
lymphopoietin receptor (TSLPR) and which results in upregulation of CRLF2 as an important contributor
to leukemic pathogenesis.3-5,7 Upregulation may occur by gene alterations, most often fusing CRLF2 to
either P2RY8 or IGH@, as well as rarely, a CRLF2 point mutation (F232C),3-5,7 though there may also be
as yet unrecognized mechanisms. In addition, patients with whose blasts show upregulated CRLF2 typically
also have simultaneous activating mutations in kinase genes including IKZF1, JAK1 and JAK2, and as a
result have abnormalities in signal transduction networks.3,4,7 Our results suggested high risk children with
overexpressed CRLF2 as detected by PCR have very poor outcome irrespective of whether structural
rearrangements can be identified,8 while other studies have suggested that this is only true of patients with
P2RY8-CRLF2 translocations.2,9 Moreover, in our studies CRLF2 did not appear to be prognostically
significant in standard risk patients.8 However, virtually nothing is known about CRLF2 overexpression in
the relapse setting, and whether its expression has continued prognostic significance in this already poor-
risk group of patients. In addition, because of the underlying kinase abnormalities in this patient population,
these patients are potentially ideal candidates for treatment with novel signal transduction inhibitors.
Assessing CRLF2 expression may help to identify patients who might be candidates for specific therapy in
trials that may be developed as these agents mature.

b) Technique
In conjunction with the immunophenotyping performed at study entry as a baseline for flow cytometric
MRD testing, we will also quantify surface TSLPR expression and correlate with outcome.

c) Specific Aims
Aims:
1) To determine if the frequency of high CRLF2 expression (which correlates with CRLF2
genomic lesions) is higher in the first marrow relapse B-ALL patient population than in the
initial diagnosis B-ALL patient population.
2) To determine if first marrow relapse B-ALL patients with high CRLF2 expression have an
inferior outcome to those without high CRLF2 expression.
d) Power calculations
Aim 1: Comparison of the frequency of CRLF2 expression among B-ALL patients in first marrow
relapse to that in newly diagnosed B-ALL patients.
From past COG studies for newly diagnosed B-ALL, it is estimated that 10% of standard risk (SR) and
21% of high risk (HR) patients will relapse. Assuming there are 2/3 SR and 1/3 HR newly diagnosed
patients, it is estimated that around 49% and 51% of patients in first relapse will be NCI SR and HR,
respectively. Given that about 7% and 12% of the SR and HR patients have high level CRLF2 expression
via flow cytometery, the overall rate of high CRLF2 expression (which correlates with genomic lesions)
in newly diagnosed B-ALL patients is about 10%.
The following table provides the power to detect a difference in rates of high CRLF2 expression between
newly diagnosed and 1st relapse B-ALL patients when the rate of high CRLF2 expression of the 1st
relapse patients is 13%, 15%, 18% and 20% (i.e. RR=1.3, 1.5, 1.8 and 2.0), respectively. The power
calculations are based on a one-sample exact test at 5% significance levels (one-sided). A total of 426
B-ALL marrow relapse ALL patients [180 early (CR1<36 months) and 246 late (CR1 ≥36 months)]
were considered in this power calculation.

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Rate of high CRLF2 expression in relapse B-ALL

Significance
pts Power (%)
Level
(baseline rate = 10% among newly diagnosed pts)
5% 13% 60.0
15% 92.4
18% 99.9
20% 100.0

Aim 2: Comparison of EFS in first marrow relapse B-ALL patients with high level CRLF2 expression
vs. those without high level CRLF2 expression.
It is anticipated that a total of 180 early (CR1<36 months) and 246 late (CR1 ≥36 months) marrow B-
ALL patients will be enrolled to AALL1331. According to past studies, the 3-year EFS of early and late
marrow relapse patients are approximately 26% and 65%, respectively, giving an overall 3-year EFS of
about 48%. Assuming the above rates of high-level CRLF2 expression and minimum 2 years of follow-
up, the table gives powers for comparing EFS between patient groups with and without high level
CRLF2 expression. The power calculations are based on the one-sided log-rank test at the 5%
significance level.
CRLF2 high rate for Sample Size 3-year EFS rates
Significance
1st relapsed pre-B CRLF2 Power
Level CRLF2- CRLF2+ CRLF2-
pts +
0.05 0.13 55 371 0.18 0.52 100.0
0.13 55 371 0.20 0.52 99.9
0.13 55 371 0.23 0.52 99.8
0.13 55 371 0.26 0.51 99.0
0.13 55 371 0.30 0.51 96.3
0.13 55 371 0.33 0.50 88.8
0.13 55 371 0.36 0.50 77.7
0.13 55 371 0.39 0.49 55.1
0.15 64 362 0.18 0.53 100.0
0.15 64 362 0.20 0.53 100.0
0.15 64 362 0.23 0.52 99.9
0.15 64 362 0.26 0.52 99.6
0.15 64 362 0.30 0.51 97.5
0.15 64 362 0.33 0.51 93.5
0.15 64 362 0.36 0.50 81.2
0.15 64 362 0.39 0.50 65.0
0.18 77 349 0.18 0.55 100.0
0.18 77 349 0.20 0.54 100.0
0.18 77 349 0.23 0.53 100.0
0.18 77 349 0.26 0.53 99.9
0.18 77 349 0.30 0.52 99.1
0.18 77 349 0.33 0.51 95.7
0.18 77 349 0.36 0.51 88.8
0.18 77 349 0.39 0.50 69.6

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0.20 85 341 0.18 0.56 100.0

0.20 85 341 0.20 0.55 100.0
0.20 85 341 0.23 0.54 100.0
0.20 85 341 0.26 0.54 100.0
0.20 85 341 0.30 0.53 99.6
0.20 85 341 0.33 0.52 97.8
0.20 85 341 0.36 0.51 90.6
0.20 85 341 0.39 0.50 72.1

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APPENDIX X: ADDITIONAL INFORMATION FOR BLINATUMOMAB

PHARMACODYNAMICS CORRELATIVE BIOLOGY STUDY

a) Rationale
For patients with relapsed/refractory ALL, response patterns to blinatumomab are essentially binary. Some
patients have a striking response, with a systemic cytokine release syndrome (CRS, most notably IL-6)
accompanying clearance of leukemic blasts and culminating in an MRD-negative remission, and others do
not respond.10,11,97 For patients that have received blinatumomab in the setting of MRD positivity (i.e., with
very low tumor burden), response rates are generally higher and significantly less likely to be associated
with CRS.4,5 Attempts to correlate responses with various peripheral blood parameters (such as ALC and
T-cell subset quantitation) have been largely unsuccessful in either setting, although the patient numbers
have been limited.3

The bone marrow microenvironment contains various immunologic components that have been shown to
either enhance or suppress cytotoxic T-cell effector response to tumor antigens. The bone marrow serves
as a reservoir of memory T-cells with heightened antigen specificity compared to peripheral blood memory
T-cells, and the bone marrow microenvironment is capable of effectively priming naïve T-cell responses.98-
100
However, the bone marrow is also a reservoir for suppressive regulatory CD4/CD25/FOXP3+ T-cells
(T regs).101 Comparative studies of bone marrow vs. peripheral blood in patients with myeloma have shown
that marrow-infiltrating lymphocytes (MILs) are more effectively activated and expanded and are more
capable of tumor-specific cytotoxicity than peripheral blood lymphocytes (PBLs).102 In addition, bone
marrow contains myeloid-derived suppressor cells (MDSCs) that have been shown to preferentially capture
and present tumor associated antigens to T regs, resulting in tumor tolerance, and preventing the capture
and presentation of these antigens by dendritic cells to activate tumor-specific cytotoxic effector T-cells.103
IL-6 is among the key mediators that skews the marrow T-cell repertoire from T regs to cytotoxic effector
T-cells.104

As has been suggested by previous studies, lymphocyte populations and cytokine profiles in the peripheral
blood may also provide insight into responses3 and adverse effects11. Since our study will include more
patients than any blinatumomab trial to date, our study may be particularly well-suited to detect these
associations.

b) Hypotheses and specific aims

The overall objective of this correlative study is to generate new knowledge regarding the mechanisms that
determine the observed heterogeneity of clinical responses to blinatumomab in relapsed ALL, for which
there are currently no biomarkers. While this study is preliminary and will not by itself establish biomarkers
of blinatumomab response, it may identify putative biomarkers that can then be evaluated for validation in
future studies.

We hypothesize that the balance of enhancing vs. suppressive components of the cytotoxic T-cell effector
response in the bone marrow microenvironment may be playing a particularly important role in determining
the presence or absence of clinical response to blinatumomab. Specifically, we hypothesize that the bone
marrow of patients that respond to blinatumomab (i.e., achieve complete continuous remission after
treatment with blinatumomab) will be characterized by a relative predominance of cytotoxic
memory/effector T-cells and a paucity of T regs and MDSCs, while the opposite pattern will be
characteristic of the bone marrow of non-responders (i.e., those that relapse after treatment with
blinatumomab).

• Specific Aim 1: To determine if the balance of enhancing vs. suppressive components of the
cytotoxic T-cell effector response in the bone marrow microenvironment at baseline correlates with
disease free survival (DFS) in relapsed ALL patients treated with blinatumomab.

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We further hypothesize that lymphocyte populations and cytokine profiles in the peripheral blood at
baseline and at post-treatment time points (hours 6 and 12 on day 1, and once on days 2, 7, 14 and 21) may
also provide insight into adverse effects and clinical response, and so we will collect peripheral blood for
flow cytometric characterization of lymphocyte subsets (including T-cell subsets as above, as well as
circulating normal B-cells) and isolate plasma for multiplex cytokine profiling (including IL-6, IL-2R, IL-
8, IL-10, MCP-1, MIP-1B, and INF-γ).

• Specific aim 2: To determine if peripheral blood patterns of lymphocyte subsets and cytokines,
both at baseline and at post-treatment time points, correlates with incidence of blinatumomab-
related reportable adverse events (see section 5.2.1), and DFS in relapsed ALL patients treated with
blinatumomab.

c) Methods
• Processing, cryopreservation and quality control

Refer to Section 13.5 for specimen collection and shipment. All blood and marrow samples will first
be centrifuged to allow isolation of plasma. Plasma will be stored in 250 uL aliquots and stored at -80
C for subsequent batched assays. Cell pellets will be diluted in HBSS and centrifuged over Lymphocyte
Separation Medium (LSM) to isolate mononuclear cells, then suspended in cryoprotectant solution and
viably cryopreserved in liquid nitrogen in aliquots of 10e6 cells for subsequent batched assays. Assays
will be performed as cohorts of five patients have provided a complete set of samples.

The Brown laboratory routinely processes blood and marrow specimens from cooperative group
clinical trials and performs a wide variety of assays using plasma and viably cryopreserved cells.
Samples are generally received in the laboratory within 48 hours of collection and processed
immediately. Plasma and cells are sufficiently stable in transport under these conditions for the
proposed assays. The flow cytometric assays are routinely performed in the Pardoll laboratory, which
is collaborating on this project and has provided the processing protocol described above.

• Multiparameter flow cytometric measurement of lymphocyte subsets and MDSCs

Vials of viably cryopreserved marrow and blood cells will be thawed and washed and viable cells
counted by trypan blue exclusion. Cells will then be stained with isotype controls and the following
antibody panels, and analyzed in triplicate by flow cytometry
o For lymphocyte subsets: CD3, CD4, CD8, CD19, CD20, CD45RO, CD45RA, HLADR, CD27,
CD62L, CD25, CD28 and CD127.
o For MDSCs (marrow only): Lin, HLA-DR, CD33, CD11b, CD14, CD15

The endpoint for this assay will be the relative percentage and absolute number (in cells/uL) and of
each of the following:
o T regs
o Naïve T-cells
o Memory T-cells (central vs. effector)
o Activated T-cells
o B-cells
o Monocytic MDSC (marrow only)
o Granulocytic MDSC (marrow only)

• Cytokine profiling in marrow and blood plasma

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Vials of frozen plasma will be thawed and a panel of cytokines will be quantitated in triplicate using a
custom cytometric bead array kit (custom BD CBA) designed to measure the following: IL-6, IL-2R,
IL-8, IL-10, MCP-1, MIP-1B, and INF-γ. Isotype controls will serve as negative controls, and standard
curves will be generated using control cytokine solutions.

The endpoint for this assay will be levels of each cytokine in pg/mL.

• Rationale for selection of methods and laboratories

The methods described above are performed routinely in the Brown (processing and
cryopreservation) and Pardoll (flow cytometric measurement of lymphocytes, MDSCs and
cytokines) laboratories, and are likely to optimize the chances that the proposed studies will be
successful.

d) Analysis and Statistical Considerations

• Specific Aim 1:

We will calculate ratio (R) of enhancing to suppressive components in bone marrow microenvironment
for each patient as follows:

R = (# Memory T-cells + # Activated T-cells) / (# T regs + # MDSC)

We will use logistic regression to model outcome (no relapse vs. relapse) as a function of R. The
Benjamin-Hochberg procedure will be used to control for multiple comparisons.

The anticipated result is that R is negatively correlated with risk of relapse (i.e., a higher ratio of
enhancing to suppressive components will reduce risk of relapse). If this anticipated result is seen,
multivariate analysis that includes known associations with relapse (duration of first remission, MRD,
etc.) will be performed to determine whether the marrow microenvironment ratio adds anything
independent to known predictors of relapse in blinatumomab-treated patients.

This analysis will be performed on the entire cohort of patients treated with blinatumomab, and also
separately on the HR/IR cohort and on the LR cohort.

We anticipate that a total of 156 evaluable patients will be treated with blinatumomab on this study
(Section 9.2), of which 72 will be HR/IR and 84 will be LR. We assume that we will have 90%
compliance with submission of the marrow sample. We assume that about 10% of submitted samples
will fail analysis for technical reasons. Thus, we expect that our sample size for R will be 127 (59
HR/IR and 68 LR).

Since we are proposing to use standard assays (flow cytometric quantification of marrow cell subsets)
in a novel way (calculation of enhancing vs. suppressive components), we do not have a priori
knowledge of the expected range of observed ratios. As such, these studies are exploratory and
definitive power calculations are not possible. However, if we assume the log(R) follows a Gaussian
distribution with a mean of 0 and standard deviation of 1 (i.e., a standard normal distribution), and
assuming an overall relapse rate of 50% for the trial, a sample size of 127 will have 80% power to
detect an effect size of 0.5, using a 2-sided significance level of 0.05. For example, if we assume patients
who eventually relapse have a mean R of 1 (log(R)=0), then we would be able to detect that patients
who do not eventually relapse have a mean R of >3.16 (log(R)=0.5) or a mean R of <0.316 (log(R)=-

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0.5). This effect size is not unreasonable to expect. These calculations are based on methods from Hsieh,
et al. Statist. Med. 17, 1623-1634 (1998).

The relationships between the ratios and rates of relapse will be described, and subsequent studies will
be designed to validate these findings prospectively in the context of future clinical trials.

• Specific Aim 2:

There are 12 variables to be determined for each blood sample (7 samples per patient):
1) Total T-cell number
2) CD4 count
3) CD8 count
4) Memory T-cell count
5) Activated T-cell count
6-12) Level of each of 7 individual cytokines

For each of the 12 variables, we will determine the baseline value (BV; hour 0) and the maximal change
value (MCV; value at the post-treatment timepoint for which the variable has increased or decreased to
the greatest degree). For the MCV, a landmark approach will be used in which all cases are followed
for 21 days, and the maximal change observed up to that point will be used to predict outcome from
that point forward for all patients who are still observable up to that landmark time point.

There are 2 outcomes of interest:

1) Presence or absence of blinatumomab-related reportable adverse event
2) No relapse vs. relapse

As a first level analysis, we will use logistic regression to model each of the 2 outcomes as a function
of each of the 12 variable’s BV, and each of the 12 variable’s MCV. The Benjamin-Hochberg procedure
will be used to control for multiple comparisons.

The anticipated results are:

1) BV of some subsets of T-cell counts (memory T-cells, e.g.) are positively correlated with the risk of
blinatumomab-related reportable adverse events, and negatively correlated with risk of relapse.
2) MCV of a subset of cytokines (IL-6 and INF-γ, e.g.) is positively correlated with the risk of
blinatumomab-related reportable adverse events, and negatively correlated with risk of relapse.

Subsequent levels of analysis will attempt to characterize combinations of T-cell subset counts and
cytokine levels that may perform better than individual variables in modeling the outcomes of interest.

If any of the anticipated results are seen with respect to the relapse outcomes, multivariate analysis that
includes known associations with relapse (duration of first remission, MRD, etc.) will be performed to
determine whether any of the T-cell subset/cytokine variables adds anything independent to known
predictors of relapse in blinatumomab-treated patients.

This analysis will be performed on the entire cohort of patients treated with blinatumomab, and also
separately on the HR/IR cohort and on the LR cohort.

We anticipate that a total of 156 evaluable patients will be treated with blinatumomab on this study
(section 9.2), of which 72 will be HR/IR and 84 will be LR. We assume that we will have at least 90%

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compliance with submission of the blood samples, and that about 10% of submitted samples will fail
analysis for technical reasons. Thus, we expect that our sample size will be 127 (59 HR/IR and 68 LR).

Since we are proposing to use standard assays (flow cytometric quantification of blood T-cell subsets
and cytokines) in a novel way (combining variables to model risks of adverse events and relapse after
treatment with blinatumomab), we do not have a priori knowledge of the expected ranges of values for
most variables. As such, these studies are exploratory and definitive power calculations are not possible.

However, some estimates based on specific assumptions are possible. If we assume that the baseline
value for memory T-cell count for the entire study population follows a Gaussian distribution with a
mean of 500/uL and a standard deviation of 100/uL, and we assume an overall relapse rate of 50% for
the trial, a sample size of 127 will have 80% power to detect an effect size of 50/uL, using a 2-sided
significance level of 0.05. For example, if we assume patients who eventually relapse have a mean BV
memory T-cell count of 500, then we would be able to detect that patients who do not eventually relapse
have a mean BV T-cell count of >550/uL, or a mean BV T-cell count of <450/uL. This effect size is
not unreasonable to expect. These calculations are based on methods from Hsieh, et al. Statist. Med.
17, 1623-1634 (1998).

The relationships between the variable(s) and rates of adverse events/relapse will be described, and
subsequent studies will be designed to validate these finding prospectively in the context of future
clinical trials.

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APPENDIX XI: ADDITIONAL INFORMATION FOR PROTEIN CELL STRESS PATHWAYS

CORRELATIVE BIOLOGY STUDY

a) Rationale
Many excellent studies have focused on gene expression profiles in ALL.51,52 However, changes in protein
cell stress pathways and deregulated signal transduction pathways, have been much less well studied in
ALL. There is an unmet need to learn more about chemotherapy-induced proteins expression changes in
order to determine if specific proteins or protein clusters can help predict response to therapy. Specific
protein expression patterns are likely to correlate with disease-free survival (DFS) and will enable us to
identify specific populations at risk for relapse. Since it is very difficult to salvage patients after second
relapse, one of the goals of this study is to determine which patients classified as low risk based on timing
and site of relapse (Section 9.2) would benefit from being risk stratified instead into the high risk group.
This would improve DFS in all patients with relapsed ALL. Relevant protein expression profiles will be
validated in future COG trial for patients with relapsed ALL and (if the increase in correct risk assignment
increases to meets statistical specifications) will be used, in conjunction with molecular classification
systems, as an adjunct for risk assignment.

b) Hypotheses and specific aims

We hypothesize that activation of cell stress pathways and signal transduction pathways deregulated in
ALL will correlate with DFS, and that the expression of specific proteins or proteins clusters will identify
patients classified as low risk patients that would benefit from more intensive therapy. We have two
specific aims to address these hypotheses:
1. To determine if specific protein expression profiles, as determined by reverse-phase protein
lysate array (RPPA) and phosphoflow cytometry, correlate with clinical outcome (DFS)
2. To determine if alterations in specific groups of cell stress proteins can be used to generate a
“high-risk” protein expression signature that identifies patients stratified to the low-risk group
(based on time and site of relapse) that would benefit from stratification into the high-risk
group.

c) The contributions that the proposed study will make to the current knowledge base
Little is known about the changes in cell stress proteins during chemotherapy. This analysis will contribute
greatly to our current knowledge base by 1) determining if specific proteins or protein clusters correlate
with response therapy, 2) increasing our knowledge about lymphoblast response to standard relapse
chemotherapy, 3) allowing a better understanding of the biology-defined ALL subgroups, aiding the
development of targeted therapies, and 4) allowing for the development of protein expression risk-
classifiers that could be validated and utilized, along with gene expression profiling, to aid in risk
stratification in subsequent relapsed clinical trials.

d) Relevant preclinical data

1. RPPA The Kornblau lab has analyzed two cohorts of adult AML using RPPA. The first, with
539 samples from 258 patients, was probed with 51 antibodies. the second, with 747 samples
from 539 patients, was probed with 194 antibodies 105,106 These samples demonstrated that there
were recurrent patterns of protein expression that correlated with outcome. Recent studies have
shown that the analysis of RPPA and single cell network profiling by phosphoflow to can be
analyzed using recently developed computational methods to provide a combined protein
expression predictor.107
2. Phosphoflow cytometry: Studies have demonstrated that phosphoflow analyses can be
predictive of outcome in pediatric acute leukemia. As an example, Redell et al. identified that
responsiveness to IL-6 in pediatric AML was associated with superior survival.108

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e) Relevant data from previous clinical studies

1. RPPA: Our preliminary data shows that we can reliably assess post-chemotherapy protein
activation. Using a test set of 32 validated RPPA antibodies, we assessed changes in protein
expression in 27 COG pediatric leukemia patients following induction chemotherapy. We have
determined that 1) CellSave tubes preserve protein expression profiles post-treatment, as shown
by the relative stability of actin expression, but a decrease in p-AKT; and 2) that we can detect
the heterogeneous patterns of changes in protein expression over time, including changes in
AKT, m-TOR, MAPkinase and the FOXO3 pathway following treatment (Horton, Kornblau,
personal communication).
2. Phosphoflow: Based upon phosphoflow studies from phase 1 COG and adult trials using these
assays,109,110 we anticipate that we can reliably identify signaling upregulation at baseline and
during therapy using shipped specimens. In an institutional study of adults with AML treated
with sirolimus and chemotherapy, inhibition of phosphorylated S6 correlated with clinical
responses (Perl 2012).

f) The comparability of the methods proposed to those previously used, and the likelihood that
the resulting data will be able to be compared with existing data. Analysis of RPPA is currently
being performed using the same methods in AAML1031, and so these results should be directly
comparable. Analysis of signal transduction networks will use identical methods to those piloted
in ADVL1011 and ADVL1114, and so these should be comparable as well.

g) The reason for selection of the assay methodology.

1. RPPA is a technique which can quantitate protein expression from over 1000 patient samples
on a single slide using validated antibodies.111 The sample requirements are quite small; analysis
of protein panels can be accomplished with as little as 200,000 cells per patient. This is the only
assay able to provide detailed analysis of protein expression with this number of cells. This
technique is also relatively resistant to protein degradation during shipping time. Blood is
collected into CellSave preservation tubes, which we have shown can stabilize protein
expression for up to 72 hours (Horton et al manuscript in review).
2. Similarly, phosphoflow cytometry is a very sensitive and reproducible technique, analyzing
signal transduction abnormalities and the level of the single cell. Phosphoflow can also be used
to analyze samples both at baseline and following chemotherapy treatment.109

h) The stability of the samples used for analysis:

Although no formal studies have been performed to determine stability, samples collected locally over the
past 15 years from the Horton laboratory were examined by RPPA. There were no statistically significant
differences in expression patterns or protein intensity based on the age of the sample (Kornblau, personal
communication).

i) Technical performance characteristics

1. Antibody validation: RPPA antibodies have gone through extensive testing prior to inclusion
on the array,88 including both analytic validation, and assay validation with clinically relevant
samples.94 Antibodies validated for RPPA demonstrate specificity of signal and, in the case of
phosphorylation or cleavage sensitive antibodies, context-specific validation performed in
baseline and stimulated samples.87 Validation steps have included: 1) antibody specificity as
determined by immunoblot, 2) appropriate induction of phosphorylation/cleavage in response
to known inducing agents, 3) correlation of RPPA signal with immunoblot expression (R>0.5),
4) acceptable sigmoidal curve fit of signal with sample dilution (analyzed using Super-Curve),
5) variable slope normalization112 and, in cases of high background, 6) topographical
normalization. Slides with unacceptable variances will be redone. RPPA has acceptable intra-
assay and inter-assay variability, with intra-assay coefficients of variation (COV) of 6-15% and

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established inter-assay reproducibility. We have established standard operating procedures

(SOPs) for sample processing, cell sorting and RPPA, and laboratory staff in both the Horton
and Kornblau labs are experienced with the procedure.
b. Minimizing sample variability: based on prior testing samples received within 72h of
collection from the patient have very similar protein expression patterns. (Horton, manuscript
in preparation). Samples for RPPA will be collected in CellSave preservation tubes and mailed
by FedEx courier to maintain protein integrity.

j) A description of the positive and negative controls

Controls will include normal adult and pediatric bone marrow, ALL cell lines, and ALL cells
stimulated with chemotherapy as described .105,106,113

k) The experience that the investigators have with the assay

1. The Horton Laboratory will be collaborating with Dr. Steve Kornblau who has extensive
experience with RPPA analysis of leukemia samples.105,106,113
2. The Tasian laboratory has extensive experience with phosphoflow cytometry analyses of
primary patient leukemia specimens and of xenografted pediatric ALL and AML specimens.114-
117

l) The methods of scoring and plan for analysis

a. Overview: Statistical analyses will be performed in a stepwise manner. First, we will analyze dynamic
changes in protein activations following chemotherapy in all patients. The purpose is to discover natural
groupings based on proteomic data only and to analyze the response of different biologically relevant signal
transduction pathways during treatment. Second, we will examine protein clustering stratified by risk group
and genetic subtype using supervised clustering analysis. Third, once clinical outcome data become
available, we will analyze differences between treatment groups as they relate to DFS. This analysis will
include unsupervised clustering methods.105,106,113 Finally, we will generate a classifier(s) that best correlates
with clinical outcome for the group as whole. While the primary objective of the study is DFS, we will also
examine classifiers stratified by CR and relapse after study completion.

b. Statistical analysis: Supercurve algorithms were used to generate a single value from the 5 serial
dilutions.1 Loading controls2 and topographical normalization3 procedures will account for protein
concentration and background staining variations. Analysis using unbiased clustering, perturbation
bootstrap clustering and principle component analysis was then performed as previously described.4 We
(SM Kornblau, KR Coombes (MDACC) and A. Qutub (Rice University) have developed a
novel modification of the Gap statistic, named “stability Gap” for selecting the optimal number of patient
clusters from the range of possible clusters118 This will be utilized to select the optimal number of
clusters for comparison in outcomes analysis. Analysis typically places samples into 3-7 clusters for further
analysis.
Comparison of the protein levels between paired samples will be done by performing paired t-
tests. Association between protein expression levels and categorical clinical variables will be assessed in
R using standard t tests, linear regression or mixed-effects linear models. Association between continuous
variable and protein levels will be assessed by using Pearson and Spearman correlation and linear
regression. Bonferroni corrections were performed to account for multiple statistical parameters for
calculating statistical significance. The Kaplan-Meier method was used to generate the survival
curves. Univariate and multivariate Cox proportional hazard modeling will be performed to investigate
association with survival with protein levels as categorized variables using Statistica version 10 software
(StatSoft, Tulsa, OK).

Other methods of analysis may include: Hierarchical Clustering, Principal Component Analysis
(PCA), Self-Organizing Maps (SOM) and other class discovery methods.119 Cluster stability will be

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accessed using reproducibility measures, including GAP,120 and Stability Gap (manuscript in preparation),
as well as robustness and discrepancy indices.121 Differentially expressed proteins will be found using
paired t-test as well as repeated measures, mixed effect ANOVA and ANOVA with contrasts. To determine
if dynamic changes in specific protein pathways predict chemoresistance, we will use different regression
and classification methods: Self Organizing Maps(SOM) (when no outcome is used), class prediction
methods such as logistic regression, Support Vector Machine,122 Random Forest,123 Binary Tree Prediction,
Bayesian Compound Covariate Predictor, and Discriminant analysis
(http://linus.nci.nih.gov/techreport/Manual32.pdf).

Correlation of protein data with clinical variables

For Specific Aim 1, we will determine if there is a protein classifier prognostic for clinical outcome. After
assignment of each patient to a risk group (based on time and site of relapse, n=403 low-risk, n=195 high-
risk), samples will be stratified based on risk group and supervised clustering analysis will be performed
based on clinical outcome variables (DFS).

For Specific Aim 2, we will determine which patients classified as low-risk (based on time and site of
relapse) that would benefit from the more intensive chemotherapy given to high-risk patients (i.e.,
reassignment to the high risk group). Following the generation of a risk-based protein expression classifier
from all low-risk patients, further testing of the putative classifier will be based on performance
characteristics using predefined cutpoints using ROC curves. Comparisons will be made using the AUC of
ROC curves between standard risk stratification (time and site of relapse), MRD response, and the putative
protein expression classifiers. Model overfitting and biased assessment of model performance will be
minimized using bootstrap clustering as previously described 105ROC curves will be generated for each
stratification group, as well as for combinations of groups. Since attainment of CR following subsequent
relapse is suboptimal,124,125 and DFS is guarded following subsequent relapse, protein expression classifiers
that maximize specificity with adequate sensitivity will be prioritized for further characterization.

m) The sites performing the correlative studies.

RPPA analysis will be performed in the Kornblau laboratory (MD Anderson Cancer Center, Houston TX)
in collaboration with Dr. Horton. Phosphoflow analysis will be performed in the Tasian laboratory
(Children’s Hospital of Philadelphia).

n) Maintenance of quality control/assurance

Quality control will be maintained as previously described (Section i).105,106,113

o) Marker prevalence:
Since the methods will analyze multiple proteins (RPPA) and signal transduction pathways (phosphoflow),
the prevalence of each marker will vary.

p) Estimate what proportion of patients on a therapeutic trial will have available sample for
correlative study analysis; discuss possible biases.
Based on prior samples obtained for RPPA analysis from patients enrolled on the Phase 3 COG AML trial
AAML1031, we estimate 40% of enrollments will provide an evaluable sample. As the most common
reasons for sample dropout include technical issues (20% sample dropout due to sample quality, 40% due
to samples not being drawn at site, 10% due to delays in shipping), lack of consent (10-15%), and
insufficient lymphoblasts in peripheral blood to qualify for the study (20%). The latter 20% will have a
bias toward high-risk disease and early marrow relapse.

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q) Specify how any cutpoints will be determined

Specific aim 1: Performance characteristics and cutpoints will be made by comparison of AUC for ROC
curves of available classifiers including standard risk stratification (time to and site of relapse) and MRD
status. Since the objective of this study is to improve DFS, and DFS are can be estimated by both the hazard
ratio and probability of relapse. These numbers will become available from AALL0433, AALL01P2,
AALL04P2 and AALL07P1 prior to trial completion. In order to identify patients likely to relapse, without
increasing the risk of overtreating patients that require minimal therapy to achieve DFS, we will choose
classifiers that maximize the true positive rate (sensitivity) while maintaining adequate specificity using
statistically meaningful and clinically relevant cutpoints.

Specific aim 2: To determine if alterations in specific cell stress proteins can be used to generate a “high-
risk” protein expression signature that identifies patients stratified to the low-risk (based on time and site
of relapse) group that would have benefited from stratification into the high-risk group. For analysis of
clinical utility, assumptions are usually made based on prior clinical trials for a similar pediatric relapsed
ALL cohort. However, previous relapsed ALL COG studies have used different risk assessments, making
a priori cutpoint determination challenging. Therefore, we will present basic principles for determining
cutpoints for protein expression classifiers.
To aid in determining specific cutpoints, data from the recently completed AALL0433 clinical trial will be
used to determine the prevalence of relapse and DFS in a similar LR population.
Since our aim is to improve the detection of true high risk patients misclassified into the low-risk
group, we are interested in both the sensitivity and specificity of a putative protein classifier. The clinical
usefulness of a protein expression classifier is dependent the proportion of low-risk patients that relapse
(which can be estimated from the AALL0433 trial), as well as the proportion of low-risk patients with the
“high-risk” putative classifier (determined by this study). Depending on the change in DFS for those
correctly identified as having a “high-risk” protein classifier, the relative risks that can be used to identify
the clinical usefulness can be estimated. Once these estimates are known, we can estimate both absolute
risk reduction and decrease in relative risk of a low-risk patient with a “high-risk” classifier. Our goal would
be to identify a classification signature that outperforms the current method of risk stratification (time and
site of relapse) and/or allowed for an absolute risk reduction of at least 5% in the low-risk group.

r) Specify the statistical power of the correlative study

Sample size for basis of power calculations:

Based on power size calculations (Section 9.2.2), we anticipate that the study will enroll 598 patients,
including 195 high-risk and 403 low-risk patients (based on time and site of relapse). Based on sample
retrieval rate of 36% (see Section p), we will have 215 patients for protein expression analysis. For specific
aim 1, all evaluable patients with usable sample would be considered for analysis (n=215). For the second
aim, patients in the low-risk group (n=403) would be eligible if we receive usable sample. Based on sample
recruitment in AAML1031 (36%), we expect to collect usable sample for 145 of the 403 evaluable patients.
Although all sample set are required to have a 0h sample, about 82% of samples have the full data set (i.e.
sufficient material for RPPA (CellSave preservation tubes) and phospho-flow (heparin tubes) at 0h, 6h, and
24h). For measures of changes over time, we anticipate that we will have 176 patient sets for SA1 and 118
patients for SA2. If the unfolded protein response is of interest, we expect that 90% of patients will have
sufficient material for transcript analysis (n=193 for SA1, n=130 for SA2).
A summary of sample size data is provided in Table XI-1:

In addition to determining the effect sizes (defined as the difference in the corresponding mean outcomes
over a common standard deviation) of assays between treatment groups, we will also compare protein
classifiers with clinical outcome (MRD status and EFS). For the analysis of data across time (0h, 6h and
24h) we do not know a priori the most relevant time points to compare. Short-term differences could have
returned to baseline by 24h, and may be most accurately estimated by changes between 0h and 6h. Long-

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term differences would be best measured by 0h-24h comparison. Complex changes, such as increase at 6h
and decreases by 24h (seen with NF-κB after chemotherapy) are best measured using all three time points
as descriptors. However, for simplicity we have provided the affect sizes for changes from 0h to 24h in
Table XI-1.

Table XI-1: Effect-size differences based on sample size for protein cell stress pathways
1. RPPA and phospho-flow Samples size (max) Effect size *
studies
Baseline and change at 24h by 135 (67/tx group) 0.488
treatment arm (blinatumomab
therapy vs non-blinatumomab 110 (55/tx group) 0.539
therapy; randomized patients only)
Baseline and change at 24h by All patients:
MRD response (rate of MRD >= 215 (84 MRD >=0.1%/ 131 MRD 0.393
0.1%: 62% for high-risk, 28% for < 0.1%) for baseline comparisons.
low-risk; 39% overall)
176 (69 MRD >=0.1%/107 MRD < 0.435
0.1%) for changes over time.

Low-risk:
145 (41 MRD >=0.1%/ 104 MRD
< 0.1%) for baseline comparisons. 0.520

118 (33 MRD >=0.1%/85 MRD <

0.1%) for changes over time. 0.579

Baseline and change at 24h by 3- 135 (86 no event/ 49 with event) for 0.505
year DFS for randomized patients baseline changes.
(estimated 3-year DFS 64%)
110 (70 no event/ 40 with event) 0.560
For changes over time.
Assumptions: alpha = 0.05, beta = 0.2.Abbreviations: grp= group, tx = treatment
* With this effect size, the study will have at least 80% power at 2-sided significance level of 0.05 to
detect such difference given the corresponding sample size.

s) Corrections for multiple comparisons

We will use the Benjamini-Hochberg correction to account for multiple comparisons.126

t) Discuss how the results will have an impact on future studies.

This contribution will significantly impact future studies because it will add protein cell stress markers to
the armamentarium of genetic mutations currently used to assess relapse risk, increasing the power of risk
stratification, and identifying patients most likely to relapse and those most likely to benefit from therapies
that target deregulated cell signaling pathways in relapsed ALL.

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APPENDIX XII: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR

ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS
HOST DISEASE (GVHD)

Reporting Requirements for Acute GVHD in COG Studies

In an attempt to standardize reporting of acute GVHD, the COG Stem Cell Transplantation Committee has
adopted a modification of guidelines that were originally developed at the University of Michigan.

Table 1 outlines standard criteria for GVHD organ staging. However, confounding clinical syndromes (such
as non-GVHD causes of hyperbilirubinemia) may make staging GVHD in a given organ difficult. In
addition, timing of organ specific symptoms affects whether that symptom is more or less likely to be true
GVHD. Please refer to Tables 2 and 3 to assist you in deciding whether to attribute these clinical findings
to GVHD, especially in situations where a biopsy is not possible. For additional help, please see the text
which follows the tables. Table 4 reviews the approach to assessing GVHD as acute, chronic, or the overlap
between the two.

Finally, engraftment syndrome will be reported separately from the GVHD scoring presented below.
Engraftment Syndrome
A clinical syndrome of fever, rash, respiratory distress, and diarrhea has been described, just prior
to engraftment in patients undergoing unrelated cord blood and mismatched transplantation. If, in
the judgment of the local investigator, a patient experiences this syndrome, details of the event
should be reported when requested in the study CRFs.

Modified Glucksberg Staging Criteria for Acute Graft versus Host Disease

Table 1 Organ Staging (See tables and text below for details)
Stage Skin Liver (bilirubin) Gut (stool output/day)
0 No GVHD rash < 2 mg/dL Adult: < 500 mL/day
Child: < 10 mL/kg/day

1 Maculopapular rash 2-3 mg/dL Adult: 500–999 mL/day

< 25% BSA Child: 10 -19.9 mL/kg/day
Or persistent nausea,
vomiting, or anorexia, with
a positive upper GI biopsy.
2 Maculopapular rash 3.1-6 mg/dL Adult: 1000-1500 mL/day
25 – 50% BSA Child: 20 – 30 mL/kg/day

3 Maculopapular rash 6.1-15 mg/dL Adult: > 1500 mL/day

> 50% BSA Child: > 30 mL/kg/day

4 Generalized >15 mg/dL Severe abdominal pain with

erythroderma plus or without ileus, or grossly
bullous formation and bloody stool (regardless of
desquamation > 5% BSA stool volume).

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For GI staging: The “adult” stool output values should be used for patients > 50 kg in weight. Use
3 day averages for GI staging based on stool output. If stool and urine are mixed, stool output is
presumed to be 50% of total stool/urine mix (see Section 3.2).

For stage 4 GI: the term “severe abdominal pain” will be defined as:
(a) Pain control requiring institution of opioid use, or an increase in on-going opioid use, PLUS
(b) Pain that significantly impacts performance status, as determined by the treating MD.

If colon or rectal biopsy is +, but stool output is < 500 mL/day (< 10 mL/kg/day), then consider as
GI stage 0.

There is no modification of liver staging for other causes of hyperbilirubinemia

Overall Clinical Grade (based on the highest stage obtained):

Grade 0: No stage 1-4 of any organ
Grade I: Stage 1-2 skin and no liver or gut involvement
Grade II: Stage 3 skin, or Stage 1 liver involvement, or Stage 1 GI
Grade III: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI
Grade IV: Stage 4 skin, liver or GI involvement

Table 2 Evaluating Liver GVHD in the Absence of Biopsy Confirmation (See Table 3.0 below)

Establishing liver GVHD with no skin or GI GVHD

No Skin/GI GVHD Assume no liver GVHD, unless proven by biopsy
Day 0-35
No Skin/GI GVHD If NO other etiology identified, NO If other etiology identified or
Day 36-100 improvement with stopping improves with stopping hepatotoxic
hepatotoxic medications/TPN: drugs/TPN:
Stage as liver GVHD Do not stage as liver GVHD

Establishing liver GVHD with skin or GI GVHD and other cause of hyperbilirubinemia
Skin and/or GI GVHD Worsening bilirubin level (includes Stable or improving bilirubin after
present worsening just prior to onset of skin diagnosis of skin or GI GVHD,
or GI tract GVHD) OR stable irrespective of treatment:
elevated bilirubin despite resolution Do not stage as liver GVHD
of non-GVHD cause of increased
bilirubin:
Stage as liver GVHD

Changing liver GVHD stage with other cause of hyperbilirubinemia

Skin and GI GVHD Liver GVHD staging is carried forward without increase in stage until other
stable, improving, or disease process resolves (e.g., if TTP is diagnosed in the presence of stage 2
absent liver GVHD, the liver GVHD stage 2 is carried forward despite rising
bilirubin level until TTP is resolved. If there is no liver GVHD – stage 0 –
and new onset TTP, the stage 0 is carried forward until TTP is resolved).

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Skin and/or GI GVHD Liver GVHD is staged according to the Glucksberg criteria. The
worsening elevated bili is attributed to GVHD alone.

Thus, when skin or GI GVHD is worsening, there is no downgrading of

liver GVHD staging for other causes of hyperbilirubinemia. (e.g., if TTP is
diagnosed in the presence of stage 2 liver GVHD and worsening skin or GI
GVHD, the liver is staged according to the actual bilirubin level even if
some of the rise in bilirubin is attributed to TTP).

Similarly, even if there is no liver GVHD at onset of a new process, (such

as TPN cholestasis), but skin or GI GVHD worsen during that process, then
liver GVHD is diagnosed and staged according to the height of the
bilirubin.

There is one exception to this: the diagnosis of TTP, with high LDH and
unconjugated bilirubin precludes the diagnosis and staging of new liver
GVHD in the absence of a confirmatory liver biopsy.

Table 3 Evaluating GI GVHD in the Absence of Biopsy Confirmation (See Table 4.0 below)

Establishing GI GVHD with new onset diarrhea and no skin or liver GVHD
No Skin/liver GVHD Assume no GI GVHD, unless proven by biopsy
Day 0 through
engraftment
No Skin/liver GVHD NO other etiology of diarrhea Any other etiology of diarrhea
Engraftment through identified: identified:
day 100 Stage as GI GVHD Do not stage as GI GVHD

Establishing GI GVHD with pre-existing diarrhea and skin or liver GVHD

Skin and/or liver GVHD Worsening diarrhea (includes Improving diarrhea after the
present worsening just prior to onset of skin diagnosis of skin or liver GVHD
or liver GVHD) OR persistent (irrespective of treatment) OR
diarrhea despite resolution of non- persistent diarrhea without resolution
GVHD cause: of underlying non-GVHD cause:
Stage as GI GVHD Do not stage as GI GVHD

Differentiating Acute GVHD, Chronic GVHD, and Overlap Syndrome

There is often confusion differentiating acute from chronic GVHD, especially in the setting of reduced
intensity transplants, DLI and new prophylactic treatments. The NIH Working Group recently published
new classifications for GVHD:

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Table 4 Acute GVHD, Chronic GVHD, and Overlap Syndrome

Category Time of Symptoms Presence of Acute Presence of Chronic
after HCT or DLI GVHD features GVHD features
Acute GVHD
Classic acute GVHD ≤100 d Yes No
Persistent, recurrent, or >100 d Yes No
late-onset acute GVHD

Chronic GVHD
Classic chronic GVHD No time limit No Yes
Overlap syndrome No time limit Yes Yes

• Scoring of acute GVHD may need to occur past day 100. In particular, patients should continue to
be scored for acute GVHD when classic acute GVHD symptoms (maculopapular rash, nausea,
vomiting, anorexia, profuse diarrhea - particularly if bloody and ileus) persist past day 100 or if
identical symptoms previously scored as acute GVHD resolve and then recur within 30 days during
immunosuppression taper but past day 100.

• Those patients being scored as having acute GVHD should NOT have diagnostic or distinctive
signs of chronic GVHD.

• Patients with both acute and chronic symptoms should be diagnosed as having Overlap
Syndrome and scored according to their chronic GVHD score.

Further Explanation of Criteria presented in Tables 2 and 3

1.0 Assessment of Skin GVHD

1.1 Presence or Absence of Skin GVHD: Skin GVHD will be considered present if a rash characteristic
of acute GVHD develops after allogeneic marrow transplantation involving more than 25% of the
body surface not clearly attributable to causes such as drug administration or infection. The extent of
the body surface area involved can be estimated by the “Rule of Nines”. In estimating the extent of
skin GVHD, the area involved is calculated for individual anatomic areas, such as the arm or leg, and
then the total is derived from a simple summation. Areas that are non-blanching should not be
considered involved regardless of the overlying color of the rash (red, brown, etc.). Limited
distribution erythema (with the exception of palms and soles) in the absence of associated rash
elsewhere on the body will not be considered GVHD.

2.0 Assessment of Liver GVHD

2.1 Assessing for the Presence or Absence of Liver GVHD

A. Hyperbilirubinemia (total bilirubin > 2.0 mg/dL) in the absence of other signs of acute GVHD in
the skin or GI tract:

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i) Day 0-35: If hyperbilirubinemia alone is present with no other signs of acute GVHD in other
organ systems, acute GVHD will not be diagnosed based solely on laboratory abnormalities.
Acute GVHD will be diagnosed if findings on histopathology studies of liver from a biopsy or
autopsy are confirmatory.

ii) Day 35-100: If hyperbilirubinemia (must be conjugated bilirubin) is not improving or is

exacerbated (especially if serum alkaline phosphatase is increased), in the absence of acute
GVHD in other organ systems, no other etiologies are identified, and does not improve with
discontinuation of hepatotoxic drugs, acute GVHD will be diagnosed. However, it is
distinctly unusual to develop ascites or a coagulopathy in the early stages of acute GVHD of
the liver alone. In the absence of histopathology studies of liver from a biopsy or autopsy
specimen, ascites or a coagulopathy secondary to liver dysfunction will be considered to
indicate the presence of another disease process (e.g. veno-occlusive disease). Recommended
non-invasive studies to define an etiology for hyperbilirubinemia are:

a. Imaging of liver (CT or ultrasound)

b. Hepatitis screen (only if ALT is elevated)
c. PT
d. Blood cultures
e. Review of medication list for potentially hepatotoxic drugs
f. Review of risk factors for viral liver infection (HSV, CMV, VZV, adenovirus, EBV,
HBV, and HCV)
g. Hemolysis screen

B. Pre-existing hyperbilirubinemia clearly attributed to an etiology other than acute GVHD in the
presence of signs of acute GVHD in other organ systems.

i) If pre-existing non-GVHD liver disease (documented clinically, by lab assessment, or by

imaging studies) is stable or improving at the onset of signs of acute GVHD in other organs,
then acute GVHD of the liver will not be considered to be present unless proven by liver
biopsy or autopsy.

ii) If hyperbilirubinemia worsens several days before or at the time of onset of signs of acute GVHD
in other organ systems, GVHD will be considered to be present unless histopathology studies
of liver are available and negative on a biopsy during that time interval or autopsy results
exclude GVHD.

iii) If hyperbilirubinemia persists and is not improving after resolution of a pre-existing non-GVHD
liver disease process (e.g. localized infection of liver, systemic sepsis, biliary tract obstruction)
when signs of acute GVHD are present in other organ systems or no other intervening cause
has been diagnosed, then acute GVHD will be considered to be present in the absence of a new,
clearly identifiable cause of non-GVHD liver disease or unless a liver biopsy or autopsy
specimen is negative.

C. Prior acute GVHD in liver with new onset of a disease process that exacerbates pre-existing or
recently resolved hyperbilirubinemia:

i) If an etiology other than acute GVHD is clearly identified as causing or exacerbating

hyperbilirubinemia and acute liver GVHD has been diagnosed and has been stable, improving, or
resolved, then the liver will not be restaged for acute GVHD until the resolution or stabilizing of
the concurrent disease process (i.e., the liver stage prior to the onset of the new disease process will

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be carried forward until the new disease process resolves). Example: Acute GVHD of the liver and
gut is diagnosed on day 20. Treatment of acute GVHD results in falling bilirubin levels to liver
stage 1. Sepsis or TTP develops with transient worsening of the hyperbilirubinemia. The liver stage
is not increased, despite a higher bilirubin level, because the cause of worsening hyperbilirubinemia
is attributed to sepsis or TTP.

ii) If an etiology other than acute GVHD is clearly identified as causing or exacerbating
hyperbilirubinemia in the presence of already worsening acute liver GVHD or GVHD of the skin
or GI tract is simultaneously worsening, then the liver GVHD will be staged according to the actual
bilirubin level, even though another cause of hyperbilirubinemia is present.

3.0 Assessment of GVHD of the Gastrointestinal Tract

3.1 Assessing for the Presence or Absence of GVHD of the Gastrointestinal Tract

A. Diarrhea (> 500 mL/day in adults or > 10 mL/kg in pediatric patients) in the absence of other signs
of acute GVHD in other organ systems

i) Day 0-engraftment: If diarrhea alone is present without other signs of acute GVHD in other
organ systems, acute GVHD will not be considered present. Diarrhea will be attributed to acute
GVHD if histopathology studies of gastrointestinal tract from a biopsy or autopsy are
diagnostic.

ii) Engraftment-day 100: If diarrhea persists and is not improving, is exacerbated, or develops de
novo in the absence of acute GVHD in other organ systems, histopathology studies of gut
biopsies or from autopsy specimens are not available, and no other etiologies are clearly
identified, acute GVHD will be considered to be the cause. A stool specimen should be
examined to rule out infectious causes (e.g. rotavirus, adenovirus, and C. difficile toxin). It is
recommended, if at all possible, that biopsies be obtained for diagnostic purposes.

B. Pre-existing diarrhea clearly attributed to an etiology other than acute GVHD in the presence of
signs of acute GVHD in other organ systems:

i) If pre-existing diarrhea caused by a process other than GVHD has been documented clinically
or by lab assessment and is stable or improving at the onset of signs of acute GVHD in the skin
or liver, then acute GVHD of the intestine will not be considered to be present in the absence
of biopsy confirmation or autopsy report.
ii) If diarrhea or gastrointestinal symptoms are already present, but worsen significantly at the
time of onset of signs of acute GVHD in the skin or liver, GVHD will be considered present,
unless biopsy or autopsy are negative.
iii) If diarrhea persists after resolution of a pre-existing disease process with signs of acute
GVHD present in other organ systems, GVHD will be considered present, unless biopsy or
autopsy are negative.

C. Prior or present acute GVHD in other organ systems with new onset of diarrhea:

If diarrhea is clearly attributable to an etiology other than acute GVHD (e.g., infection) and a
history of acute GVHD exists or acute GVHD is present in other organ systems and is stable, then
the gastrointestinal tract will not be evaluable for acute GVHD until the resolution or stabilizing of

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the other disease process (e.g., infection) in the absence of biopsy or autopsy confirmation.

D. Persistent anorexia, nausea or vomiting in the absence of signs of acute GVHD in other organ
systems:

Persistent anorexia, nausea or vomiting in the absence of other known causes of these
symptoms will be considered stage 1 acute GVHD if confirmed by endoscopic biopsy.

If a biopsy is not possible (e.g. secondary to thrombocytopenia) but the clinical findings
are compatible with acute GVHD, then the patient will be treated and recorded as having
acute GVHD.

3.2 Staging of the Gastrointestinal Tract for the Severity of Acute GVHD

The severity of gastrointestinal tract GVHD will be staged according to modified Glucksberg criteria.
To minimize errors caused by large day-to-day variation, diarrhea volume is measured as an average
over 3 days and reported as the volume in milliliters per day. When urinary mixing is noted the stool
volume will be considered half of the total volume unless nursing staff is able to give a better estimate
from direct observation. Abdominal cramps are considered significant for staging if the severity results
in a clinical intervention (e.g. analgesia, fasting, etc.). Blood in the stools is considered significant if
the blood is visible or hematochezia/ melena is present and not clearly attributed to a cause other than
GVHD (e.g. epistaxis/ hemorrhoids).

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APPENDIX XIII: CTEP AND CTSU REGISTRATION PROCEDURES

CTEP REGISTRATION PROCEDURES

CTEP Investigator Registration Procedures

Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy
require all investigators participating in any NCI-sponsored clinical trial to register and to renew
their registration annually.

Registration requires the submission of:

• a completed Statement of Investigator Form (FDA Form 1572) with an original signature
• a current Curriculum Vitae (CV)
• a completed and signed Supplemental Investigator Data Form (IDF)
• a completed Financial Disclosure Form (FDF) with an original signature

Fillable PDF forms and additional information can be found on the CTEP website at
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please
contact the CTEP Investigator Registration Help Desk by email at
<[email protected]>.

CTEP Associate Registration Procedures / CTEP-IAM Account

The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM)
application is a web-based application intended for use by both Investigators (i.e., all physicians
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in
the conduct of NCI-sponsored clinical trials).

Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account.

Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP
Investigator Registration Procedures above for information on registering with CTEP as an
Investigator, which must be completed before a CTEP-IAM account can be requested.)

An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials
Support Unit) websites and applications, including the CTSU members’ website.

Additional information can be found on the CTEP website at

<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact
the CTEP Associate Registration Help Desk by email at <[email protected]>.

CTSU REGISTRATION PROCEDURES

This study is supported by the NCI Cancer Trials Support Unit (CTSU).

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Requirements for AALL1331 Site Registration:

• CTSU IRB Certification (for sites not participating via the CIRB)
• CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI
CIRB)

Submitting Regulatory Documents:

Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office,
where they will be entered and tracked in the CTSU RSS.
CTSU Regulatory Office
1818 Market Street, Suite 1100
Philadelphia, PA 19103
Phone: 1-866-651-2878
Fax: 215-569-0206
E-mail: [email protected] (for regulatory document submission only)

Checking Your Site’s Registration Status:

Check the status of your site’s registration packets by querying the RSS site registration status page
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of
regulatory approval from the CTSU Regulatory Office.)
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username
and password
 Click on the Regulatory tab at the top of your screen
 Click on the Site Registration tab
 Enter your 5-character CTEP Institution Code and click on Go

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APPENDIX XIV: POSSIBLE DRUG INTERACTIONS

The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or
their Parents should be encouraged to talk to their doctors before starting any new medications, using
over-the-counter medicines, or herbal supplements and before making a significant change in diet.

Cyclophosphamide

Drugs that may interact with cyclophosphamide

• Allopurinol
• Chloramphenicol
• Cyclosporine
• Digoxin
• Etanercept
• Hydrochlorothiazide
• Indomethacin
• Nevirapine
• Pentostatin
• Warfarin

Food and supplements that may interact with cyclophosphamide*

• St. John’s Wort
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants”
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Cyclosporine

Drugs that may interact with cyclosporine

• Antibiotics
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
• Citalopram, clozapine, escitalopram, fluoxetine, fluvoxamine, lurasidone, nefazodone,
paliperidone, quetiapine, thioridazine, ziprasidone
• Antifungals
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, amphotericin
• Anti-inflammatory, arthritis, or pain medications
• Aspirin, celecoxib, hydroxychloroquine, ibuprofen, indomethacin, ketorolac, leflunomide,
naproxen, meloxicam, oxaprozin, sulindac, tofacitinib, tolmetin
• Anti-rejection medications
• Mycophenolate, sirolimus, tacrolimus
• Antiretrovirals and antivirals

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• Atazanavir, boceprevir, darunavir, delavirdine, efavirenz, etravirine, fosamprenavir,

indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tipranavir
• Anti-seizure medications
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Cholesterol medications
• Atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, fenofibrate,
gemfibrozil, colesevelam
• Heart medications
• Aliskiren, amiodarone, dronedarone, carvedilol, digoxin, diltiazem, eplerenone, verapamil,
captopril, enalapril, lisinopril, ramipril
• Kidney medications
• Acetazolamide, amiloride, spironolactone, triamterene
• Some chemotherapy (be sure to talk to your doctor about this)
• Many other drugs, including the following:
• Ambrisentan, bosentan, sitaxentan, aprepitant, allopurinol, colchicine, danazol,
dexamethasone, fluoxymesterone, methyltestosterone, oxandrolone, mifepristone,
natalizumab, pimozide, butabarbital, secobarbital, ivacaftor, octreotide

Food and supplements that may interact with cyclosporine*

• Alfalfa
• Black cohosh
• Echinacea
• Grapefruit, grapefruit juice, Seville oranges, star fruit
• Red Yeast Rice
• St. John’s Wort
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Cytarabine (by vein)

Drugs that may interact with cytarabine

• Clozapine, digoxin, flucytosine, leflunomide

Food and supplements that may interact with cytarabine*

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

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Dexamethasone

Drugs that may interact with dexamethasone

• Antibiotics
• Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin,
rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
• Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone,
nefazodone, quetiapine
• Antifungals
• Caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
• Arthritis medications
• Leflunomide, tofacitinib
• Anti-rejection medications
• Cyclosporine, sirolimus, tacrolimus
• Antiretrovirals and antivirals
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild,
telaprevir, tipranavir
• Anti-seizure medications
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Heart medications
• Amiodarone, amlodipine, dronedenarone, verapamil
• Some chemotherapy (be sure to talk to your doctor about this)
• Some oral contraceptives or birth control medications
• Many other drugs, including the following:
• Aprepitant, artemether/lumefantine, aspirin, deferasirox, ibuprofen, ivacaftor, lomitapide,
mifepristone, natalizumab, nimodipine, praziquantel, warfarin

Food and supplements that may interact with dexamethasone*

• Echinacea
• St. John’s Wort
• Grapefruit, grapefruit juice, Seville oranges, star fruit
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Etoposide

Drugs that may interact with etoposide

• Antibiotics
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
• Aripiprazole, clozapine, nefazodone
• Antifungals
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole

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• Arthritis medications
• Leflunomide, tofacitinib
• Anti-rejection medications
• Cyclosporine, tacrolimus
• Antiretrovirals and antivirals
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tipranavir
• Anti-seizure medications
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Heart medications
• Amiodarone, dronedenarone, verapamil
• Some chemotherapy (be sure to talk to your doctor about this)
• Many other drugs, including the following:
• Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide,
mifepristone, natalizumab, pimozide, sitaxentan

Food and supplements that may interact with etoposide*

• Echinacea
• Glucosamine
• St. John’s Wort
• Grapefruit, grapefruit juice, Seville oranges, star fruit
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Fludarabine

Drugs that may interact with fludarabine

• Clozapine, leflunomide, natalizumab, pentostatin, tofacitinib

Food and supplements that may interact with fludarabine*

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

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Leucovorin

Drugs that may interact with leucovorin

• Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone)

Food and supplements that may interact with leucovorin*

• Folic acid
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Methotrexate (by mouth or by vein)

Drugs that may interact with methotrexate

• Some antibiotics (amoxicillin, Bactrim, chloramphenicol, ciprofloxacin, penicillin, piperacillin,

tetracycline)
• Some anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, naproxen, ketorolac)
• Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole)
• Several other specific agents, including the following: amiodarone, clozapine, cyclosporine,
eltrombopag, leflunomide, phenytoin, pimecrolimus, probenecid, pyrimethamine, retinoids,
theophylline, warfain

Food and supplements that may interact with methotrexate*

• Alcohol
• Echinacea
• Some vitamins, including those that contain folic acid or high doses of vitamin C
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Mercaptopurine

Drugs that may interact with mercaptopurine

• Artiritis medications: leflunomide, tofacitinib
• Other medications, such as allopurinol, azathioprine, clozapine, febuxostat, natalizumab, olsalazine,
sulfasalazine, warfarin

Food and supplements that may interact with mercaptopurine*

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

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Mitoxantrone

Drugs that may interact with mitoxantrone

• Aripiprazole
• Clozapine
• Cyclosporine
• Dofetilide
• Leflunomide
• Natalizumab
• Pimozide
• Tofacitinib

Food and supplements that may interact with mitoxantrone*

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Mycophenolate mofetil

Drugs that may interact with mycophenolate mofetil

• Antacids such as aluminum hydroxide, magnesium hydroxide
• Arthritis medications such as leflunomide, tofacitinib
• Some antibiotics and antiviral medications (be sure to talk to your doctor about this)
• Some heartburn medications including esomeprazole, lansoprazole, omeprazole, pantoprazole
• Other medications such as cholestyramine, natalizumab, oral contraceptives (“birth control”),
probenecid, rifabutin, rifampin, rifapentine, sevelamer

Food and supplements that may interact with mycophenolate mofetil*

• Echinacea
• Vitamins and supplements containing magnesium
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Pegaspargase

Drugs that may interact with pegaspargase

• Leflunomide, natalizumab, tofacitinib

Food and supplements that may interact with pegaspargase*

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

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Tacrolimus

Drugs that may interact with tacrolimus

• Antibiotics
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
• Citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, nefazodone, paliperidone,
quetiapine, thioridizine, ziprasidone
• Antifungals
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
• Anti-inflammatory, arthritis, or pain medications
• Leflunomide, tofacitinib
• Anti-rejection medications
• Cyclosporine, sirolimus
• Antiretrovirals and antivirals
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tipranavir
• Anti-seizure medications
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Heart medications
• Amiodarone, dronedenarone, disopyramide, procainamide, sotalol, verapamil
• Kidney medications
• Amiloride, spironolactone, triamterene
• Stomach and reflux medications
• Dexlansoprazole, esomeprazole, lansoprazole, omeprazole
• Some chemotherapy (be sure to talk to your doctor about this)
• Many other drugs, including the following:
• Ambrisentan, bosentan, sitaxentan, aprepitant, colchicine, dexamethasone, mifepristone,
natalizumab, pimozide

Food and supplements that may interact with tacrolimus*

• Echinacea
• St. John’s Wort
• Grapefruit, grapefruit juice, Seville oranges, star fruit
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Thioguanine.
Drugs that may interact with thioguanine*
• Arthritis medications: leflunomide, tofacitinib
• Other medications, such as allopurinol, clozapine, natalizumab, olsalazine, sulfasalazine

Food and supplements that may interact with thioguanine**

• Echinacea

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**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Thiotepa
Drugs that may interact with thiotepa*

• Arthritis medications like leflunomide or tofacitinib

• Other medications like bupropion, clozapine, efavirenz, methadone, promethazine, or natalizumab

Food and supplements that may interact with thiotepa**

• Echinacea
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

Vincristine
Drugs that may interact with vincristine
• Antibiotics
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin
• Antidepressants and antipsychotics
• Aripiprazole, nefazodone, trazodone
• Antifungals
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
• Arthritis medications
• Leflunomide, tocilizumab, tofacitinib
• Anti-rejection medications
• Cyclosporine, tacrolimus
• Antiretrovirals and antivirals
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir,
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir,
tenofovir, tipranavir
• Anti-seizure medications
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone
• Heart medications
• Amiodarone, digoxin, dronedenarone, propranolol, verapamil
• Some chemotherapy (be sure to talk to your doctor about this)
• Many other drugs, including the following:
• Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide,
warfarin

Food and supplements that may interact with vincristine*

• Echinacea
• St. John’s Wort
• Grapefruit, grapefruit juice, Seville oranges, star fruit
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or
dried herbs. All forms should be avoided.

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