Where Passion Meets Precision

PEER REVIEWED
COVER FEATURE
The Fludarabine Shortage and Its Ripple Pirtobrutinib and BTK Inhibitors in the
Effects: Navigating the Crisis CLL Treatment Landscape
Jose Tinajero, PharmD, BCOP; Amir Ali, A r s h e e t a K u m a r, P h a r m D ; G r a c e
P h a r m D , B C O P ; Ta m m y H a r u t u n y a n , P h a r m D Baek, PharmD, BCOP; and Chloe Siu,
c a n d i d a t e ; Te n y K h a c h a d o u r i a n , P h a r m D PharmD, BCPS, BCOP
c a n d i d a t e ; a n d M i c h a e l a M a h e r, P h a r m D
candidate Making Residency Research Projects
Patient Centered: How Retrospective
PRACTICE INSIGHTS Research Can Significantly Impact
Optimizing Oncological Care: The Influence of Cancer Care
AI on Insurance Approvals R y a n B e e c h i n o r, P h a r m D , B C P S , B C O P ;
B r i a n C o x , M B A , M S S F, F A C H E ; a n d A l b e r t o Cody Angerman, PharmD; and Aaron
Coustasse, DrPH, MD, MBA, MPH Steele, PharmD, BCOP

PATIENT FOCUS Practical Considerations of T-Cell

Advancement in Stem Cell Transplantation: Engagers in the Management of
Improving Outcomes for Patients With Relapsed/Refractory Multiple Myeloma
Matthew M. Lei, PharmD, BCOP;
Blood Cancer J a c k M a l e s p i n i , P h a r m D, B C O P ; E r i c a
Leen Alyaseen, PharmD candidate; Braxton Ta v a r e s , P h a r m D, B C P S , B C O P ; S a r a h
Park, PharmD candidate; Janet John, PharmD O’Neill, PharmD; Diana Cirstea, MD; and
candidate; Janice Thomas, PharmD candidate; E Bridget Kim, PharmD, BCPS, BCOP
Jessenia Amaro, PharmD candidate; Mollie
Schatz, PharmD candidate; and Sara Rogers,
PharmD, BCPS

CONFERENCE
Balancing Health Tech Innovation With
Safety: Navigating the Intersection of AI and
Patient Care
Alana Hippensteele CONTINUING EDUCATION

Intravenous (IV) Therapy 101: An Introduction to

Venous Catheters, IV Lines, and IV Administration
for Pharmacists and Pharmacy Technicians

APRIL 2024 | VOL. 6 NO. 3

 TABLE OF CONTENTS A P RI L 2024 VO LU M E 6 N U MBE R 3

15
ALSO IN THIS ISSUE C OV E R F E AT U R E
The Fludarabine Shortage and Its Ripple Effects:
6  PUBLISHER’S NOTE
 Navigating the Crisis
Empowering Oncology
Jose Tinajero, PharmD, BCOP; Amir Ali, PharmD, BCOP; Tammy Harutunyan, PharmD
Pharmacists: Driving Innovation candidate; Teny Khachadourian, PharmD candidate; and Michaela Maher, PharmD candidate
and Advancement Through
Pharmacist-Led Research
Mike Hennessy Jr

7  EDITORIAL ADVISORY BOARD


P R AC T I C E I N S I G H T S CONFERENCE
8  EDITOR’S NOTE
 40 HSSP Model Can Reduce 48 Unlocking the Potential
April Is Stress Awareness Financial Toxicity of Oral of Machine Learning and
Month: A Little Humbling Self- Oncology Treatment Language Models
Awareness May Go a Long Way Gillian McGovern, Assistant Editor in Oncology
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP,
Alana Hippensteele, Managing Editor
Pharmacy Practice in Focus: Oncology
editor in chief 42 Optimizing Oncological
Care: The Influence of AI 52 Balancing Health Tech
on Insurance Approvals Innovation With Safety:
Brian Cox, MBA, MSSF, FACHE; and Navigating the Intersection
PEER REVIEWED Alberto Coustasse, DrPH, MD, MBA, MPH of AI and Patient Care
Alana Hippensteele, Managing Editor
18 Pirtobrutinib and BTK Inhibitors
in the CLL Treatment Landscape
Arsheeta Kumar, PharmD; Grace Baek, PharmD,
PAT I E N T F O C U S C O N T I N U I N G E D U C AT I O N
BCOP; and Chloe Siu, PharmD, BCPS, BCOP
44 Advancement in Stem Cell 56 Intravenous (IV) Therapy
Transplantation: Improving 101: An Introduction to
24 Making Residency Research Outcomes for Patients With Venous Catheters, IV Lines,
Projects Patient Centered: How Blood Cancer and IV Administration for
Retrospective Research Can Leen Alyaseen, PharmD candidate; Pharmacists and Pharmacy
Significantly Impact Cancer Care Braxton Park, PharmD candidate; Janet Technicians
Ryan Beechinor, PharmD, BCPS, BCOP; Cody John, PharmD candidate; Janice Thomas, MiKaela Olsen, DNP, APRN-CNS, AOCNS,
Angerman, PharmD; and Aaron Steele, PharmD, PharmD candidate; Jessenia Amaro, FAAN
BCOP PharmD candidate; Mollie Schatz, PharmD
candidate; and Sara Rogers, PharmD, BCPS

28 Practical Considerations
of T-Cell Engagers in the
Management of Relapsed/
Refractory Multiple Myeloma
Matthew M. Lei, PharmD, BCOP; Jack Malespini,
PharmD, BCOP; Erica Tavares, PharmD, BCPS,
BCOP; Sarah O’Neill, PharmD; Diana Cirstea, MD;
and E Bridget Kim, PharmD, BCPS, BCOP

Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Pharmacy & Healthcare Communications, LLC, the editorial staff, or any member of the editorial advisory
board. Pharmacy & Healthcare Communications, LLC, is not responsible for accuracy of dosages given in articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement,
or approval of the products or services advertised or of their effectiveness, quality, or safety. Pharmacy & Healthcare Communications, LLC, disclaims responsibility for any injury to persons or property resulting
from any ideas or products referred to in the articles or advertisements.

Pharmacy Practice in Focus: Oncology™ is published by Pharmacy & Healthcare Communications, LLC, 2 Commerce Drive, Cranbury, NJ 08512. All rights reserved.
Editorial and advertising offices are at 2 Commerce Drive, Cranbury, NJ 08512. Email: [email protected]. Contents may not be reproduced without permission of the publisher.

4 pharmacytimes.com April 2024

 CONNECT WITH US
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 Publisher’s Note

Empowering Oncology Pharmacists:

Driving Innovation and Advancement
™

P U B L I S H I N G S TA F F Through Pharmacist-Led Research

T
ED I TO RI A L & PRO D U CTIO N
Editor in Chief Lisa E. Davis, PharmD, FCCP,
BCPS, BCOP
HE IMPACT PHARMACIST-LED RESEARCH on oncology pharmacy practice
Vice President, Content Laura Joszt, MA has had in the field of oncology is undeniable, with the Hematology/
Managing Editor Alana Hippensteele Oncology Pharmacy Association (HOPA) calling on pharmacists to
Assistant Managing Editor Aislinn Antrim contribute to cancer research to support these research practices. 1 This call by
Associate Editors Ashley Gallagher, HOPA has been reinforced with reviews that have demonstrated the need for
Assistant Editors Kennedy Ferruggia,
Gillian McGovern
oncology pharmacist participation in clinical research efforts. 2 Additionally,
Vice President, Copy Jennifer Potash although the rate of publication success for hematology/oncology research
Copy Chief Paul Silverman presented at pharmacy meetings is 17.5%, there is room for growth in this area. 3
Copy Supervisors Angie DeRosa, Nicole Canfora Lupo In the peer-reviewed insights paper on page 24, authors Ryan Beechinor,
Senior Copy Editors Cheney Baltz, Marie-Louise Best, PharmD, BCPS, BCOP; Cody Angerman, PharmD; and Aaron Steele, PharmD,
Kelly King
Substantive Editor Georgina Carson
BCOP, highlight strategies to enhance the impact of pharmacy research and the
Copy Editors Ron Panarotti, Yasmeen Qahwash likelihood of publication. Using a case study on daratumumab (Darzalex; Janssen
Creative Director, Publishing Melissa Feinen Biotech) administration optimization, the authors illustrate how implementing
Senior Art Director Marie Maresco research findings can lead to substantial cost savings and improved patient satis-
S AL E S faction, underscoring the transformative potential of pharmacist-driven research
Associate Director of Sales Colin Fishbein
in shaping clinical practice.
National Account Manager Tom Blackwell
Senior Vice President, Strategy
In the peer-reviewed literature review on page 18, authors Arsheeta Kumar,
Jeff Prescott, PharmD PharmD; Grace Baek, PharmD, BCOP; and Chloe Siu, PharmD, BCPS, BCOP,
Executive Assistant Amanda Siller
provide an overview of pirtobrutinib (Jaypirca; Eli Lilly and Company) and
Email: [email protected]
Bruton tyrosine kinase inhibitors in the current treatment landscape for chronic
G LO BA L A M BASSA D O R STRATEG I ES
Executive Director, Global Ambassador lymphocytic leukemia (CLL), discussing its epidemiology, mechanisms of
Strategies, Oncology Sharyn Foster development, clinical presentation, and treatment landscape evolution. In the
SAP Coordinator Erica Shemper
peer-reviewed literature review on page 28, authors Matthew M. Lei, PharmD,
O P E RAT I O N S & FIN A N CE
BCOP; Jack Malespini, PharmD, BCOP; Erica Tavares, PharmD, BCPS, BCOP;
Circulation Director Jon Severn
Vice President, Finance Leah Babitz, CPA
Sarah O’Neill, PharmD; Diana Cirstea, MD; and E. Bridget Kim, PharmD, BCPS,
Controller Katherine Wyckoff BCOP, discuss challenges in treating patients with relapsed or refractory multiple
CO R P O R AT E myeloma and highlight the promising activity of novel therapies, such as anti–B-
President & CEO Mike Hennessy Jr cell maturation antigen bispecific T-cell engagers, emphasizing the importance
Chief Financial Officer Neil Glasser, CPA/CFE
of supportive care strategies to optimize patient outcomes in the evolving
Chief Operating Officer Beth Buehler
treatment landscape.
Chief Data Officer Terric Townsend
Executive Vice President, Global Medical Affairs
In the cover story on page 15, authors Jose Tinajero, PharmD, BCOP; Amir Ali,
& Corporate Development Joe Petroziello PharmD, BCOP; Tammy Harutunyan, PharmD candidate; Teny Khachadourian,
Senior Vice President, Corporate Development PharmD candidate; and Michaela Maher, PharmD candidate, discuss the
Gil Hernandez
Senior Vice President, Content Silas Inman
significant drug shortages in oncology, particularly focusing on the shortage of
Senior Vice President, Human Resources & fludarabine, which is a crucial chemotherapy agent. They highlight the impact
Administration Shari Lundenberg of shortages on treatment strategies and patient care, emphasizing the need for
Senior Vice President, Mergers & Acquisitions,
pharmacists, regulatory bodies, and health care providers to collaborate, address
Strategic Innovation Phil Talamo
Executive Creative Director Jeff Brown these challenges, and explore innovative solutions.
The benefit of pharmacist-led research on oncology pharmacy practice is
Founder
Mike Hennessy Sr
significant, and Pharmacy Practice in Focus: Oncology aims to support this
1960-2021 effort with the publication of peer-reviewed papers, including original research,
literature reviews, and case reports. For pharmacists who are interested in
publishing their work, Pharmacy Practice in Focus: Oncology is interested in
reviewing that work and disseminating it to the field.
Mike Hennessy Jr
PRESIDENT & CEO
MJH LIFE SCIENCES®
FOR REFERENCES, GO TO PHARMACYTIMES.COM/PUBLICATIONS

6 pharmacytimes.com April 2024

 ADVISORY BOARD

E D I T OR I N C H I E F
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Clinical Professor, Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy
Clinical Pharmacist, Hematology-Oncology Banner – University Medical Center Tucson, University of Arizona Cancer Center

A S S O CI A T E E D I T ORS

Ryan Beechinor, PharmD, BCPS, BCOP Douglas Braun, PharmD Zahra Mahmoudjafari, PharmD, MBA,
Senior Pharmacist, Hematology/Oncology, Senior Pharmacy Director, BCOP, FHOPA
University of California, Davis American Oncology Network, LLC Clinical Pharmacy Manager, Hematology/
Comprehensive Cancer Center Blood and Marrow Transplant/Cellular
Assistant Professor, University of Therapy and PGY2 Oncology Residency
California, San Francisco School of Program Director, The University of
Pharmacy School of Pharmacy Kansas Cancer Center

BOARD OF EDITORIAL ADVISERS

Judith Alberto, MHA, RPh, BCOP Ryan Haumschild, PharmD, MS, MBA Christine Pfaff, RPh
Director of Clinical Initiatives, Director of Pharmacy Services, Senior Regional Director of Operations,
Community Oncology Alliance Emory Healthcare and Winship Cancer American Oncology Network, LLC
Institute
Britny Brown, PharmD, BCOP Christine Roussel, PharmD, BCOP, BCSCP
Clinical Associate Professor, University of Laly Havern, PharmD, MS, BCACP Senior Executive Director, Pharmacy,
Rhode Island College of Pharmacy Director, Specialty Health Solutions, Laboratory, and Medical Research,
Clinical Oncology Pharmacist, Smilow Oncology and Fertility, Walgreens Doylestown Health
Cancer Hospital Care Center at Westerly
Hospital Whitney Lewis, PharmD, BCOP
Shannon Hough, PharmD, BCOP
Clinical Pharmacy Specialist—Thoracic,
Senior Director, Clinical Programs,
Joshua Cox, PharmD, BCPS Head and Neck Medical Oncology, The
McKesson, supporting The US Oncology
Director of Pharmacy and Research, University of Texas MD Anderson Cancer
Network
Dayton Physicians Network Center
Adjunct Clinical Assistant Professor,
Julianne Darling, PharmD, BCOP University of Michigan College of
Ila M. Saunders, PharmD, BCOP,
Senior Manager of Education, NCODA Pharmacy
DipACLM, FHOPA
Sophia Zhang Humphreys, PharmD, MHA Associate Clinical Professor of Pharmacy
David DeRemer, PharmD, BCOP, FCCP, and Oncology Clinical Pharmacist - BMT/
Director, System Formulary Management
FHOPA Malignant Hematology, Moores Cancer
& Pharmacy Clinical Programs, Sutter
Clinical Professor, Department of Center, University of California, San Diego
Health
Pharmacotherapy and Translational
Research, University of Florida (UF) Jacob K. Kettle, PharmD, BCOP Scott A. Soefje, PharmD, MBA, BCOP,
College of Pharmacy Director, Ellis Fischel Cancer Center FCCP, FHOPA
Assistant Director, Experimental Service Line, University of Missouri Health Director, Pharmacy Cancer Care,
Therapeutics Group, UF Health Cancer Care Mayo Clinic
Center
Matthew M. Lei, PharmD, BCOP
Arianne Duong, PharmD, BCOP Clinical Pharmacy Specialist – Lymphoma,
Clinical Oncology Pharmacist, E DIT O R E ME R IT US
Massachusetts General Hospital
Fred Hutchinson Cancer Center Dan Steiber, RPh
Maya Leiva, PharmD, BCOP, APh Principal, Genesis Pharma Consultants
Heidi D. Finnes, PharmD, BCOP, FHOPA Hematology/Oncology Clinical Pharmacy
Director, Clinical Ambulatory Pharmacy Specialist, Schar Cancer Institute, Inova
Services, Mayo Clinic Health System
Assistant Professor of Pharmacy, Associate Professor of Hematology and
Mayo Clinic Alix School of Medicine Oncology - Pharmacy Practice, West
Coast University
Bryan P. Fitzgerald, PharmD, BCOP
Lead Advanced Practice Pharmacist,
Clinical Specialist in Oncology,
BASS Medical Group
University of Rochester Specialty Pharmacy
Clinical Pharmacy Leader (LRAT),
US Federal Government (HHS/ASPR)
Kirollos S. Hanna, PharmD, BCPS, BCOP,
FACCC Man Yee Merl, PharmD, BCOP
Director of Pharmacy, Minnesota Senior Clinical Pharmacy Specialist-
Oncology Oncology, Smilow Cancer Hospital -
Assistant Professor of Pharmacy, Yale New Haven Health
Mayo Clinic School of Medicine
April 2024 pharmacytimes.com 7
EDI TOR'S NOTE

April Is Stress Awareness Month: A Little

Humbling Self-Awareness May Go a Long Way
Li sa E . Dav i s , P h a r mD, FCC P, BCPS, BCO P, Ed ito r in Chief

T
A BOUT THE EDITOR he campaign for National Stress Awareness to initiate a new physical activity program or
Lisa E. Davis, PharmD, Month in April is under way, bringing maintain a regular one.
FCCP, BCPS, BCOP, attention to the negative impact of stress Our perceptions of the types and levels of
is the editor in chief
and advocating for strategies to better manage stress physical exercise that confer potential beneficial
of Pharmacy Practice
in Focus: Oncology . as essential components of mental and physical well- outcomes can be expanded upon. For example,
Davis holds positions being. Health care professionals work in stressful investigators who assessed vigorous intermittent
as a clinical pharmacist
environments and, if not experiencing and/or dealing lifestyle physical activity (VILPA) in self-reported
in early-phase clinical
trial and breast cancer with stressful situations themselves, are interacting nonexercising adults reported an association with
programs at the with patients and coworkers who are. Although the a reduced incidence of PA-related cancer. In this
University of Arizona stress response—elicited through interconnected prospective study of 22,398 participants followed
Cancer Center in
Tucson and as a clinical neuroendocrine, autonomic/metabolic, and immune up for a mean of 6.7 years, published in July 2023 in
professor of pharmacy systems—is central to survival, constant and/or JAMA Oncology, a minimum of about 3.5 minutes
practice and science repeated activation is detrimental to physical and of VILPA daily reduced total incident cancer risk by
at the University of
psychological health. 17% to 18% compared with no VILPA. Interestingly,
Arizona R. Ken Coit
College of Pharmacy. The effects of stress on physical disorders, heart greater than 90% of VILPA was accrued in sessions
Davis also sits on the disease, stroke, and mental health, among others, of up to 1 minute in duration. Participant activity
Hematology/Oncology
are well recognized, as are practical tips to combat was measured using wrist accelerometry recorders—
Pharmacy Association
Board of Directors and is stress and mitigate these effects, which we can feasible but beyond what could be captured
a member of the Cancer readily access through professional organizations, using exercise diaries or common smartwatches.
Prevention and Control the CDC, and numerous public resources. However, Confounding factors, such as sex, age, body mass
Program and scientific
review committee at the as individuals, we need to embrace these strategies index, lifestyle factors (eg, smoking, alcohol use,
University of Arizona that enable us to improve how we respond and etc) and established cardiovascular risk factors were
Cancer Center. adapt to stress, which is much easier to rationalize accounted for in the analyses. Thus, duration of daily
than operationalize. Many health professionals find VILPA was inversely associated with a reduced risk
that this humbling self-awareness promotes greater in incident and PA-related cancer risk, requiring only
understanding of and empathy for our patients as 4 to 5 minutes of VILPA daily to reduce cancer risk.1
we advise them regarding the importance of this With these data, a strategy of implementing
endeavor. VILPA may help to improve outcomes for cancer
One of the recommendations that can be survivors and/or patients undergoing active
challenging in advising patients with active cancer anticancer therapy. What remains unclear is whether
is that of incorporating regular exercise into their daily periods of VILPA will also help improve
daily lives. The impact of regular physical activity outcomes beyond cancer risk, such as stress and
in reducing one’s cancer risk has been established. stress-related complications. For patients and health
What may be less effectively conveyed are data care professionals, implementing VILPA could be a
supporting how a physically active lifestyle is much-needed answer to ongoing daily stress. To this
associated with improved outcomes for cancer end, health care professionals may similarly benefit
survivors, as is ongoing active therapy in the case from structured exercise interventions and support
of certain cancers. Notably, patients will be more programs, as it can be difficult to overcome the daily
successful and supported in these efforts through inertia of a busy work schedule, which paradoxically
structured exercise interventions and support may feel both incredibly active and sedentary. Again,
programs. Without this additional support, it may be humbling self-awareness may be a valuable tool
difficult for patients experiencing fatigue and other while progressing toward the goal of a less stressful,
FOR REFERENCES, GO TO
PHARMACYTIMES.COM/
PUBLICATIONS symptoms associated with active cancer treatments quotidian life.

8 pharmacytimes.com April 2024

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 F LUDA R A B I N E S HO RTAG E | C OV E R F E AT URE

The Fludarabine Shortage and Its Ripple Effects:

Navigating the Crisis
The significant surge in oncology drug shortages in 2023 particularly
affected essential chemotherapeutic drugs.
J o se Ti n a j ero, P h a rmD, B CO P; Ami r Ali , Phar mD, BCO P; Tammy Ha rutunya n , Pha rm D ca ndidate; Teny Khach adouria n , Pha rm D
can d i d ate; a n d M i ch ael a M ahe r, Phar mD c and i d ate

A BOUT THE AUTHORS

Jose Tinajero, PharmD,
BCOP, is a clinical
pharmacist specialist at
the City of Hope National
I n 2023, drug shortages were substantial,
leaving oncology patients without
treatment despite the myriad of drugs
being approved by the FDA annually. This has
been the highest rate of drug shortage since
immune depletion. 3 Allogeneic HCT
heavily relies on host immune depletion
to reduce the risk of allograft rejection.
With the addition of fludarabine in total
body irradiation (TBI), allograft rejection
Medical Center in Los
Angeles, California, and 2014, with no single cause at fault.1 However, decreases. Common conditioning regimens
his areas of specialization for the past decade, the United States has for allogeneic HCT requiring fludarabine
include cellular therapies, been experiencing these shortages, leading to include fludarabine, cyclophosphamide,
hematologic malignancies, detrimental impacts on health care.2 and TBI; fludarabine and TBI; and FCE
and hematopoietic stem cell
(fludarabine, cytarabine, etoposide). For
transplantation.
Overview of Drug Shortages autologous HCT, a fludarabine/melphalan
Amir Ali, PharmD, BCOP, Recently, product quality issues have been (flu/mel) combination is used. 3-5 With the
is a clinical pharmacist identified as the primary cause of drug addition of fludarabine to these regimens,
specialist at the University shortages. The lack of transparency on the lymphodepletion treatment yields a greater
of Southern California (USC)
part of the pharmaceutical industry raises persistence of CD4+ and CD8+ T cells. 6
Norris Comprehensive
Cancer Center and an unresolved questions for health systems and Additionally, fludarabine combinations
adjunct assistant professor pharmacies. Institutions have responded by used for R/R AML include FLAG
of pharmacy practice improving communication and amplifying (fludarabine, cytarabine, granulocyte colony-
at USC Alfred E. Mann the need for multidisciplinary collaboration stimulating factor), FLAG-Ida (FLAG and
School of Pharmacy and
to maintain a successful and expected idarubicin), and FLAG-Ida-Ven (FLAG-Ida
Pharmaceutical Sciences in
Los Angeles. quality of patient care. 2 and venetoclax).4 The potential clinical
implications of omitting or substituting
Tammy Harutunyan Impact on Fludarabine fludarabine in lymphodepletion before
is a class of 2025 One of the current chemotherapeutic drugs CAR T-cell therapy are uncertain but hold
PharmD candidate at the
experiencing a shortage, fludarabine, has the potential for profound impact on a
University of Southern
California Alfred E. Mann been identified by shortage trackers since treatment designed for curative purposes. The
School of Pharmacy and December 2021 with no complete resolution heightened demand for fludarabine persists
Pharmaceutical Sciences in to date. 3 Fludarabine monophosphate in the realm of allogeneic transplantation.
Los Angeles. is a purine analogue that is commonly Conventional and reduced-intensity
used for conditioning during allogeneic myeloablative regimens that feature
Teny Khachadourian
is a class of 2025 hematopoietic cell transplantation (HCT), fludarabine, such as flu/mel, busulfan/
PharmD candidate at the lymphodepletion for chimeric antigen fludarabine, and various conditioning
University of Southern receptor (CAR) T-cell therapy, and approaches, remain among the most widely
California Alfred E. Mann relapsed/refractory acute myeloid leukemia employed conditioning strategies in the
School of Pharmacy and
(R/R AML). Despite its use in a variety of United States.
Pharmaceutical Sciences in
Los Angeles. malignancies, there is a notable absence of
ongoing studies evaluating and providing Current Challenges and Proposed
Michaela Maher is a class of therapeutic alternatives. 3 Solutions
2025 PharmD candidate at The year 2023 has witnessed a
the University of Southern
California Alfred E. Mann
Significance of Fludarabine distressing record of scarcity, affecting
School of Pharmacy and A necessary step in having a successful 11 chemotherapy agents and a prostate-
Pharmaceutical Sciences in adoptive immune cell transfer is host specific membrane antigen targeted therapy,
Los Angeles.

April 2024 pharmacytimes.com 15

COVER F EATURE | FLU DARABIN E S H ORTAGE

highlighting the profound impact on cancer treatment. adverse events. Although the study was retrospective
This emphasizes the unprecedented nature of these and limited by sample size, it was the first to describe
shortages, signaling a critical challenge in maintaining intensive Ven-based regimens in the R/R setting
the expected level of patient care in oncological with different purine analogues. This study
practice. The surge in drug shortages is not an isolated emphasizes the need for larger studies to confirm
event but part of a broader trend affecting various these findings due to the small number of patients in this
therapeutic areas. Among the most vulnerable are retrospective analysis. 7
sterile injectable generic products, particularly those Shortages, particularly in oncology drugs, can lead
with a cost below $9 per dose, which are identified as to disturbances in the scheduling of chemotherapy
being at the highest risk. 2 Many older chemotherapy treatments, changes in the administered dose or regimen,
agents essential to cancer care fall within this category, and even missed doses due to the unavailability
posing a significant challenge. These shortages of alternative agents.7 As experts in medications,
stem from a convergence of factors, notably product pharmacists bring a wealth of knowledge in applied
quality issues with major suppliers. The situation therapeutics, insights into medication workflows, and
underscores a concerning lack of transparency within a keen awareness of the impact of shortages.8 Some
the pharmaceutical industry regarding the exact causes institutions have implemented local-level strategies
and contributing factors to these shortages. to address shortages, such as adopting pharmacy dose
According to the American Society of Health-System banding and rounding doses down to reserve vials. If a
Pharmacists, 56% of the drug shortages in 2022 had dose reduction exceeding 5% becomes necessary, these
unknown causes, emphasizing the complexity of adjustments are being implemented to optimize
the issue.1 In addition, supply/demand imbalances, vial allocation.
manufacturing issues, business decisions, and regulatory/ The administration of fludarabine based on adjusted
raw material problems collectively contribute to the body weight rather than actual body weight is also being
challenging landscape of drug shortages. The profound utilized, along with a shift in billing methodology from
impact of these shortages on public health is evident, as single-dose vials to a system based on dose delivery.
health care providers all over grapple with uncertainties in This method enables the distribution of split vials among
drug availability.1 In the past, the oncology field has faced patients, and clinical teams are encouraged to coordinate
similar challenges with drug shortages, prompting clinicians schedules for patients requiring fludarabine on the same
to pivot to alternative therapies when feasible. In addition, days to minimize drug wastage. Lastly, the stability
the Hematology/Oncology Pharmacy Association conducted of fludarabine, as determined by high-performance
a survey, revealing a 34% increase in oncology drug liquid chromatography, persists for 14 to 21 days at 2
shortages in 2019 compared with 2018. This underscores to 8 °C, which implies the possibility of preserving the
the problem severity, as the data show it affects 68% of reconstituted products for short-term use by patients.3
institutions surveyed.7
Pharmacist’s Role and Conclusion
Response to Shortages Although past shortages have presented acceptable
In the context of a critical shortage of fludarabine, a alternatives, the current challenge is distinct in that
retrospective study was conducted that focuses on the there is no sufficiently studied alternative regimen
impact of this shortage on the treatment landscape for available to replace the established standard of care:
diseases such as AML. The retrospective analysis led the fludarabine/cyclophosphamide regimen for CAR
by Tinajero et al delves into the descriptive analysis of T-cell therapy. Pharmacists can play a key role by
2 regimens: FLAG-Ida-Ven and CLIA-Ven (cladribine, urging the American Society for Transplantation and
cytarabine, idarubicin, venetoclax) for R/R AML Cellular Therapy to endorse treatment centers that
during the fludarabine shortage. The response rates include rationing plans for fludarabine. This aims to
for both regimens were 46% and 57%, respectively, maximize patient benefits and uphold the integrity
with measurable residual disease negative remissions of clinical trials. Simultaneously, they can advocate
achieved by 86% and 75%. However, the CLIA-Ven with suppliers and regulatory agencies to prevent
group demonstrated potentially higher toxicity, with future drug shortages and contribute by formulating
a higher incidence of grade 3 or 4 nonhematologic algorithms to manage the currently restricted supplies.

16 pharmacytimes.com April 2024

 F LUDA R A B I N E S HO RTAG E | C OV E R F E AT URE

This involvement aims to provide an institutional cohorts. Investigators must address differential
approach to patient care that is clear and confounder misclassification to avoid increasing
consistent. 3 bias in estimates when controlling for potential
Pharmacists are pivotal in ensuring that innovative confounders.9
solutions are implemented to sustain clinical trials
and clinical care during drug shortages. The impact REFERENCES
of these shortages extends beyond drug availability, 1. Drug shortages statistics. American Society of Health-
affecting the ability to maintain a consistent and System Pharmacists. Accessed March 5, 2024. https://
effective patient response. The current surge in www.ashp.org/drug-shortages/shortage-resources/drug-
oncology drug shortages demands urgent attention shortages-statistics
and innovative solutions. This not only jeopardizes 2. Tucker N. Oncology drug shortages persist, calling for
the accessibility of essential medications but also solutions. Targeted Oncology. April 4, 2023. Accessed
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care. There are political and organizational strategies oncology-drug-shortages-persist-calling-for-solutions
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areas and engage in clinical research to offer effector cell therapy delivery. Transplant Cell Ther.
solutions for alternative interventions. Pharmacists 2022;28(11):723-726. doi:10.1016/j.jtct.2022.08.002
can also advocate for a comprehensive approach 4. Visani G, Tosi P, Zinzani PL, et al. FLAG
that engages drug manufacturers, the FDA, and (fludarabine+high-dose cytarabine+G-CSF): an effective
health care providers, underscoring the urgency for and tolerable protocol for the treatment of ‘poor risk’ acute
collaborative efforts to address the underlying causes myeloid leukemias. Leukemia. 1994;8(11):1842-1846.
and implications of drug shortages in oncological 5. ​​van Besien K, Kunavakkam R, Rondon G, et al.
practice.2 Fludarabine-melphalan conditioning for AML and
Regulatory bodies now acknowledge the use of MDS: alemtuzumab reduces acute and chronic GVHD
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treatments for specialized areas including leukemias doi:10.1016/j.bbmt.2009.01.021
and lymphomas. However, when new treatment 6. Ramos CA, Rouce R, Robertson CS, et al. In vivo
indications rely on time-related events like treatment fate and activity of second- versus third-generation
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comparisons with external controls. Randomized lymphomas. Mol Ther. 2018;26(12):2727-2737.
controlled trials have traditionally been the gold doi:10.1016/j.ymthe.2018.09.009
standard for regulatory approval, but they are 7. Jackson GH. Use of fludarabine in the treatment of
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gained interest as a supplement to randomized S62-S67. doi:10.1038/sj.thj.6200392
experiments, with the 21st Century Cures Act 8. Tinajero J, Ngo D, Lee B, et al. AML-408 comparing
sparking discussions in the United States. One intensive purine analogues regimens with cladribine and
potential application of RWD is creating external fludarabine: CLIA-Venetoclax vs FLAG-Ida-Venetoclax
untreated comparator cohorts for single-arm for relapsed and refractory acute myeloid leukemia
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therapies show substantial early benefits, making Leuk. 2023;23(suppl 1):S298-S299.
it ethically challenging to withhold treatment, or doi:10.1016/S2152-2650(23)01056-X
when the patient pool is too small for sufficient 9. Ammar MA, Tran LJ, McGill B, et al. Pharmacists
outcomes in an internal untreated group. However, leadership in a medication shortage response:
integrating trial data with nonexperimental data illustrative examples from a health system response
introduces confounding concerns, requiring careful to the COVID-19 crisis. J Am Coll Clin Pharm.
consideration of confounder measurement in both 2021;4(9):1134-1143. doi:10.1002/jac5.1443

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Pirtobrutinib and BTK Inhibitors

in the CLL Treatment Landscape
A r she e ta Kum ar, P harm D; G r ac e B ae k, PharmD, BC OP; and C hloe S iu, PharmD, BC PS , BC OP

AUTHORS PR É C I S

Arsheeta Kumar, PharmD, is This review discusses the prevalence, mechanisms of development, and evolving treatment
a PGY-2 oncology pharmacy landscape in chronic lymphocytic leukemia, highlighting the emergence of Bruton tyrosine kinase
resident at the Fred inhibitors in 2013 as improved treatment options over traditional chemoimmunotherapy.
Hutchinson Cancer Research
Center and University of
INTRODUCTION
Washington Medicine in
Seattle, Washington.
Chronic lymphocytic leukemia (CLL) is a hematologic malignancy originating in B cells
Grace Baek, PharmD, BCOP, and is the most common type of leukemia in the United States, with 20,700 new diagnoses
is a clinical hematology/ and 4440 deaths estimated in 2024.1 CLL develops through various mechanisms, all
oncology pharmacist at the ultimately leading to the clonal expansion of mature B lymphocytes that typically express
Fred Hutchinson Cancer CD5, CD23, and CD19. Most patients with CLL have an indolent disease course—up
Research Center and to 70% are asymptomatic with incidental lymphocytosis at diagnosis. In these cases,
University of Washington observation is recommended until the patients meet indications for treatment. Symptomatic
Medicine in Seattle, patients may present with B symptoms (fever, night sweats, unintentional weight loss),
Washington. cytopenia, and enlarged lymph nodes. Treatment also is required for patients with CLL-
related complications such as significant/refractory cytopenia, progressive/symptomatic
Chloe Siu, PharmD, bulky disease, or end organ dysfunction.
BCPS, BCOP, is a clinical The treatment landscape for CLL has evolved since the introduction of Bruton tyrosine
hematology/oncology kinase inhibitors (BTKis) in 2013.2 Historical practice utilized traditional chemoimmu-
pharmacist at the Fred notherapy (CIT) such as the FCR regimen (fludarabine, cyclophosphamide, rituximab
Hutchinson Cancer Research [Rituxan; Genentech]) for the treatment backbone. Results from the phase 3 CLL-8 trial
Center and University of (NCT00281918) demonstrated long-term progression-free survival (PFS) and overall
Washington Medicine in survival (OS) in fit patients with untreated CLL, but these benefits did not translate well to
Seattle, Washington. patients with 17p deletion (del[17p]) or unmutated IGHV.3 Moreover, FCR was associated
with prolonged myelosuppression and elevated risk of secondary malignancies.4 These ad-
verse effects (AEs) led to the use of bendamustine (Bendeka; Teva) and rituximab (BR) in
DI SC LOSURES patients older than 65 years, based on results of the phase 3 CLL10 trial (NCT00769522),
None.
which demonstrated noninferior efficacy and improved safety with BR.4 Despite these
developments, overall prognosis among high-risk patients remained poor.5 Genomic testing
and further study of mutations allowed for the advent of targeted therapy with BTKis,
BCL2 inhibitors, obinutuzumab, and PI3K inhibitors.
Del(17p) results in mutation of the tumor suppressor TP53 gene and is associated with
worse response rates, PFS, and OS.6 Accordingly, current guidelines stratify treatment
based on presence of this genetic aberration. First-line therapy for patients with or with-
out del(17p)/TP53 consists of acalabrutinib (Calquence; AstraZeneca) with or without
obinutuzumab (Gazyva; Genentech), venetoclax (Venclexta; AbbVie and Genentech) plus
obinutuzumab, zanubrutinib (Brukinsa, BeiGene USA), or ibrutinib (Imbruvica; Pharmacy-
clics). Though CIT is additionally recommended in patients without del(17p) or TP53, it is
not preferred for use in these patients because several clinical trials demonstrated inferior
response rates.7-10 In patients with del(17p), BTKi therapy may be seen in clinical practice
more often than venetoclax, given the fixed duration of venetoclax-based therapy compared
with indefinite BTKi duration. In the second- or third-line setting, acalabrutinib, zanubruti-
nib, and venetoclax with or without rituximab are preferred regimens. More recently,
pirtobrutinib (Jaypirca; Eli Lilly and Company) received FDA indication for use in patients
with relapsed/refractory (R/R) CLL who have previously received a BCL2 inhibitor and
a covalent BTKi.11 Overall, BTKis have been established as a mainstay in treatment for

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TABLE 1. Efficacy of BTKis

Clinical trial Regimens Setting Median follow-up (months) ORR OS
RESONATE-2 15
Ibrutinib vs chlorambucil
89 92% vs 37% 7-year OS 78%

ELEVATE-TN19 Acalabrutinib monotherapy vs

acalabrutinib +obinutuzumab, 90% vs 96%, 83% 88% vs 93%, 88%
First-line CLL/SLL 47
chlorambucil +obinutuzumab (respectively) (respectively)

SEQUOIA17 Zanubrutinib vs
26 98% vs 89% 94% vs 94%
bendamustine +rituximab

RESONATE14 Ibrutinib vs ofatumumab 12-month OS 90%

74 42.6% vs 4.1%
vs 81%
R/R CLL/SLL
ELEVATE-RR21 Acalabrutinib vs ibrutinib
41 81% vs 77% Median not reached

ALPINE18 Zanubrutinib vs ibrutinib 12-month OS 95%

15 78% vs 63%
vs 84%
BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; ORR, overall response rate; OS, overall survival; R/R, relapsed/refractory; SLL, small
lymphocytic lymphoma.

patients with CLL and are generally given as continuous frequencies of AEs, given their reduced off-target kinase
therapy until disease progression and/or intolerance. phosphorylation. A classwide effect is lymphocytosis, a
treatment-related transient rise in absolute lymphocyte
BT K INH I BI TORS count within hours to weeks after initiation caused by efflux
BTK, a key step in the B cell receptor (BCR) signaling of malignant cells from lymph nodes.22 Other common
cascade, is overexpressed in several B-cell malignancies, toxicities include diarrhea, bleeding, fatigue, nausea,
including CLL. First- and second-generation BTKis bind rash, headache, dizziness, and cytopenia. Incidences
covalently and irreversibly to Bruton kinase, which disrupts of grade 3 or greater infections across all agents range
upstream signaling pathways that drive cell proliferation from 13% to 18%. Grade 3 or greater bleeding occurred
and stimulation of the tumor microenvironment.12 The in 2% and 3% of patients receiving acalabrutinib and
first BTKi, ibrutinib, was initially approved for patients zanubrutinib, respectively, an improvement from the 7%
with CLL in 2014 based on the phase 1/2 PCYC-1192- incidence rate seen with ibrutinib in the 8-year follow-
CA trial (NCT02195869), with further support from the up of RESONATE-2.8,16,17 The phase 3 ALPINE trial
phase 3 RESONATE (NCT01578707) and RESONATE-2 (NCT03734016) revealed a lower cumulative incidence of
(NCT01722487) trials. These latter studies established atrial fibrillation/flutter (5.2% vs 13.3%) with zanubrutinib
improved OS with ibrutinib in both previously treated and compared with ibrutinib, but there were similar rates of
treatment-naive patients, with long-term data demonstrating any-grade hypertension (21.9% vs 19.8%) and a higher
sustained benefit across predefined subgroup analyses incidence of neutropenia (22.8% vs 18.2%).18 In the
(advanced stage, bulky disease, high-risk genetic features, ELEVATE-RR trial, there were fewer incidences of atrial
etc).13-16 Despite the promising efficacy results, ibrutinib’s fibrillation/flutter (9.4% vs 16%) and hypertension (9.4% vs
clinically significant AE profile led to the development of 23.2%) in the acalabrutinib arm compared with the ibrutinib
second-generation BTKis acalabrutinib and zanubrutinib. arm.8,21 Ibrutinib is also associated with significantly higher
In the frontline setting, zanubrutinib exhibited higher rates of bleeding, diarrhea, arthralgia, muscle spasms,
event-free survival and overall response rate (ORR) back pain, contusion, and grade 3 or greater hypertension,
when compared with BR in the phase 3 SEQUOIA whereas patients on acalabrutinib experienced more
trial (NCT03336333).17 For patients with R/R disease, headache, cough, and grade 3 or greater fatigue. Additional
zanubrutinib also showed superior ORR and 2-year toxicities are summarized in Table 2.23-27
PFS compared with ibrutinib.18 Likewise, acalabrutinib Overall, these data confirm that ibrutinib’s increased
monotherapy demonstrated improved PFS compared with off-target kinase activity translates to a higher frequency
obinutuzumab-chlorambucil in the ELEVATE-TN trial of AEs. Although all BTKis bind off-target kinase HER4,
(NCT02475681) of treatment-naive patients, as well as it is theorized that ibrutinib’s additional binding of HER2
noninferior PFS compared with ibrutinib in the ELEVATE- contributes to cardiac toxicity because both kinases are
RR trial (NCT02477696) for patients receiving subsequent- expressed in the heart.28 Ibrutinib’s other off-target path-
line therapy.19-21 Efficacy results are summarized in Table 1. ways—PI3K, CSK, and TEC—are also hypothesized to
Though ibrutinib, acalabrutinib, and zanubrutinib share cause cardiac AEs such as atrial fibrillation. Acalabrutinib
similar toxicities, the second-generation BTKis have lower and zanubrutinib bind to these off-target kinases to a lesser

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TABLE 2. Comparison of All-Grade BTKi Adverse Events (CLL/SLL)23,24-27

Adverse event Ibrutinib36 Acalabrutinib37 Zanubrutinib38 Pirtobrutinib29
Hematologic toxicities
Neutropenia +++ + +++ +
Anemia ++ ++ ++ ++
Thrombocytopenia +++ ++ + +
+, 20%-39%; ++, 40%-50%; +++, > 50%
Nonhematologic toxicities
Fatigue +++ ++ + +++
Infections ++ +++ + +++
Bruising +++ ++ ++ +++
Diarrhea +++ +++ ++ ++
Cough + + + ++
Muscle spasms + + + ++
Dyspnea + + NR +
Nausea ++ ++ + +
Vomiting ++ ++ + +
Hypertension + + + +
Upper respiratory tract infection +++ +++ +++ +
Abdominal pain ++ – – +
Musculoskeletal pain ++ ++ + +
Headache + +++ + +
Atrial fibrillation/flutter + + + +
Peripheral edema ++ + - –
Constipation ++ ++ + –
Pyrexia ++ + + –
Dizziness ++ + – –
Rash ++ ++ +++ –
+, < 10%-19%; ++, 20%-30%; +++, > 30%
BTKi, Bruton tyrosine kinase inhibitor; NR, not reported; CLL, chronic lymphocytic leukemia.

extent, and thus they have fewer unintended effects given P IRTOBR U T INIB
higher selectivity for BTK.29 Pirtobrutinib is a next-generation BTKi approved by the
Lastly, acquired resistance to BTKis is important to con- FDA for patients with R/R mantle cell lymphoma (MCL)
sider because of worse clinical outcomes such as decreased and, most recently, approved for patients with R/R CLL.
OS and PFS in this patient population.30 Acquired ibrutinib Mechanistically, pirtobrutinib has a few key differences
resistance can occur in up to 38% of patients and most com- from previously approved BTKis. It is a reversible,
monly develops through a C481S residue mutation, which noncovalent inhibitor with a unique binding site. Although
prevents irreversible inhibition of BTK. This leads to inad- all BTKis exert their action in the adenosine triphosphate
equate, reversible BTK inhibition, which is due to the short pocket, pirtobrutinib is a back-pocket inhibitor that binds
half-life of ibrutinib and thus the insufficient suppression to an area away from C481, which allows it to overcome
of the BCR signaling pathway.31,32 Because all 3 covalent resistance conferred by the C481S mutation.34 Pirtobrutinib
BTKis target the C481 binding site, a C481S mutation in a additionally has a longer half-life of 20 hours compared
patient taking ibrutinib would thus have conferred resis- with that of other BTKis (4-6 hours), which theoretically
tance to acalabrutinib and zanubrutinib as well. This limits leads to more continuous inhibition of BTK compared
clinical utility of these first- or second-generation BTKis with first-generation inhibitors.34 Thus, despite being a
after disease progression.33 reversible inhibitor, the favorable pharmacokinetic profile

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TABLE 3. Comparison of BTKis23-27

Ibrutinib23 Acalabrutinib24 Zanubrutinib25 Pirtobrutinib26
Place in therapy First-, second-, and third-line therapy for CLL R/R CLL after prior BTKi
(CLL) therapy
Dose 420 mg once daily 100 mg twice daily 160 mg twice daily or 200 mg once daily
320 mg once daily
Dose forms 140-, 280-, 420-mg tablets 100-mg tablets 80-mg capsules 50-, 100-mg tablets
70-, 140-mg capsules
Pharmacokinetics • Metabolism: CYP3A4 • Metabolism: CYP3A4 • Metabolism: CYP3A4 • Metabolism: CYP3A4
• Half-life: 4-6 hours • Half-life: 1.4 hours • Half-life: 2-4 hours • Half-life: 19 hours
Renal dose No No No Yes
adjustment? Not studied in patients with CrCl Not studied in patients Not studied in patients Reduce to 100 mg once daily
< 25 mL/min or on dialysis with CrCl < 29 mL/min with CrCl < 15 mL/min or for eGFR 15-29 mL/min, not
or on dialysis on dialysis studied in patients with CrCl <
15 mL/min or on dialysis
Hepatic dose Yes No No No
adjustment? Reduce dose for Child-Pugh Not studied in patients with
classes A and B severe hepatic impairment
Avoid use in Child-Pugh class C
Drug interactions Reduce to 280 mg once daily with Reduce to 100 mg Reduce to 100 mg once If cannot be avoided, reduce
with CYP3A moderate CYP3A inhibitors once daily with daily with moderate to 150 mg twice daily with
inhibitors Avoid use with strong CYP3A moderate CYP3A CYP3A inhibitors strong CYP3A inhibitors
inhibitors inhibitors Avoid use with strong
Avoid use with strong CYP3A inhibitors
CYP3A inhibitors
Drug interactions Avoid use with strong CYP3A Avoid use with strong Avoid use with moderate Avoid use with moderate and
with CYP3A inducers inducers CYP3A inducers. If and strong CYP3A strong CYP3A inducers
cannot be avoided, inducers If cannot be avoided, increase
increase to 200 mg to 300 mg once daily
twice daily
Populations to • Extensive cardiovascular • History of migraine or • C481 mutation • Development of resistance
consider avoiding disease history headache disorder mutations (non-C481S BTK
use • Poorly controlled atrial • C481 mutation mutations)39
fibrillation/flutter
• At high risk of bleeding
• C481 mutation
BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; R/R, relapsed/refractory.

of pirtobrutinib allows for higher peak concentrations and ström macroglobulinemia, and follicular lymphoma.35 After
better plasma drug retention. a median follow-up of 6 months, ORR was 63% in all
Pirtobrutinib information is summarized in Table 2 and patients. In the CLL/small lymphocytic lymphoma (SLL)
Table 3.23-27 The dose of pirtobrutinib is 200 mg by mouth efficacy cohort, 247 patients received pirtobrutinib after
once daily, continued until disease progression or unaccept- prior treatment with a BTKi, with a median of 3 prior thera-
able toxicity. Pirtobrutinib is metabolized by CYP3A4 and pies. The ORR was 82.2% when including partial responses
shares similar drug interactions with prior BTKis. AEs are also in patients with lymphocytosis (73.3% when excluding
similar, including cytopenia, infection, bleeding, fatigue, ar- patients with lymphocytosis). After a median follow-up of
thralgia, and diarrhea, as well as transient lymphocytosis.23 19.4 months, median PFS was 19.6 months. Twelve-month
Initial FDA approval for pirtobrutinib was based on OS was 86%, and 18-month OS was 80.5%. The most
the results of the multicenter phase 1/2 BRUIN study common any-grade AEs were infection (71%), neutropenia
(NCT03740529), which evaluated 773 patients with pre- (32.5%), and bleeding (42.6%), with most grade 3 or higher
treated B-cell malignancies, including CLL, MCL, Walden- events being infection or neutropenia. Incidence of atrial

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fibrillation or flutter was 3.8%. Fewer than 3% paradigm. BRUIN-CLL-314 (NCT05254743) is

of patients discontinued pirtobrutinib because of an ongoing phase 3 trial comparing pirtobrutinib
treatment-related AEs, suggesting overall prom- with ibrutinib in patients with treatment-naive
ising tolerability.34 or R/R CLL, which may help further elucidate
Pirtobrutinib has demonstrated strong evi- safety differences between the 2 agents.38
dence for R/R lymphoid malignancies, which Although pirtobrutinib efficacy after intolerance
led to FDA approval in R/R CLL. National to acalabrutinib and zanubrutinib in CLL has
Comprehensive Cancer Network guidelines for been demonstrated in BRUIN, there remains a
CLL/SLL currently recommend pirtobrutinib use lack of head-to-head trials directly comparing
after intolerance or progression with previous the efficacy of these 3 BTKis. Additional nonco-
BTKis because use in the first-line setting is yet valent, reversible BTKis such as nemtabrutinib
to be established.36 are being evaluated in phase 1 studies.28 BTK
degrader molecules such as first-in-class agent
CONCLUSIO NS AND FUT URE NX-2127 are also under investigation, and they
D I R E CTI ONS may provide an option for heavily pretreated
BTKis are a mainstay in CLL treatment, with patients with R/R disease, including those who
patient-specific considerations ultimately driving previously received pirtobrutinib.38-40 These
physicians’ choice of agent. Selection depends agents, along with pirtobrutinib, will continue to
on AEs, comorbidities, ease of administration, change the CLL treatment landscape in terms of
prior lines of systemic therapy, drug-drug both safety and efficacy.
interactions, cost, and resistance profile. In
patients with a history of cardiovascular disease
and atrial fibrillation/flutter, ibrutinib should R EF ER EN CES
1. Key statistics for chronic lymphocytic leukemia. American
be avoided if possible. The ELEVATE-RR Cancer Society. Updated January 17, 2024. Accessed
trial notably excluded patients on concomitant March 14, 2024. https://www.cancer.org/cancer/types/
anticoagulation, whereas the SEQUOIA trial chronic-lymphocytic-leukemia/about/key-statistics.html
2. Rozkiewicz D, Hermanowicz JM, Kwiatkowska I,
did not. Zanubrutinib had a lower risk of Krupa A, Pawlak D. Bruton’s tyrosine kinase inhibitors
hemorrhage in this patient population when (BTKIs): review of preclinical studies and evaluation of
compared with ibrutinib, so it may be preferred clinical trials. Molecules. 2023;28(5):2400. doi:10.3390/
molecules28052400
over acalabrutinib. Given acalabrutinib’s 3. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions
unique toxicity of headaches, caution is advised after FCR chemoimmunotherapy in previously
in patients with a history of severe migraine untreated patients with CLL: updated results of the
CLL8 trial. Blood. 2016;127(2):208-215. doi:10.1182/
or headache disorders. Zanubrutinib causes blood-2015-06-651125
more neutropenia compared with other BTKis, 4. Eichhorst B, Fink AM, Bahlo J, et al; German CLL Study
though it has not been directly compared with Group (GCLLSG). First-line chemoimmunotherapy
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pirtobrutinib; this is an important consideration cyclophosphamide, and rituximab in patients with
in patients with a history of febrile neutropenia. advanced chronic lymphocytic leukaemia (CLL10): an
All 4 BTKis interact with CYP3A4 inhib- international, open-label, randomised, phase 3, non-
inferiority trial. Lancet Oncol. 2016;17(7):928-942.
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is a concern with all 4 BTKis as well, which cyclophosphamide and rituximab chemoimmunotherapy
in chronic lymphocytic leukemia: current evidence and
are only available as brand-name medications. controversies. Ther Adv Hematol. 2017;8(3):99-105.
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TP53 disruption in chronic lymphocytic leukemia patients
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for a 30-month course in the relapsed setting.37 2023;37(4):914-918. doi:10.1038/s41375-023-01845-9
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9. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab
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10. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib
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previously treated chronic lymphoid leukemia. 29. Estupiñán HY, Berglöf A, Zain R, Smith CIE.
N Engl J Med. 2014;371(3):213-223. Comparative analysis of BTK inhibitors and
doi:10.1056/NEJMoa1400376 mechanisms underlying adverse effects. Front
15. Munir T, Brown JR, O’Brien S, et al. Final analysis Cell Dev Biol. 2021;9:630942. doi:10.3389/
from RESONATE: up to six years of follow-up on fcell.2021.630942
ibrutinib in patients with previously treated chronic 30. Stephens DM, Byrd JC. Resistance to Bruton
lymphocytic leukemia or small lymphocytic tyrosine kinase inhibitors: the Achilles heel of
lymphoma. Am J Hematol. 2019;94(12):1353- their success story in lymphoid malignancies.
1363. doi:10.1002/ajh.25638 Blood. 2021;138(13):1099-1109. doi:10.1182/
16. Barr PM, Owen C, Robak T, et al. Up to 8-year blood.2020006783
follow-up from RESONATE-2: first-line ibrutinib 31. Woyach JA, Ruppert AS, Guinn D, et al.
treatment for patients with chronic lymphocytic BTKC481S-mediated resistance to ibrutinib
leukemia. Blood Adv. 2022;6(11):3440-3450. in chronic lymphocytic leukemia. J Clin
doi:10.1182/bloodadvances.2021006434 Oncol. 2017;35(13):1437-1443. doi:10.1200/
17. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib JCO.2016.70.2282
versus bendamustine and rituximab in 32. Thompson PA, Tam CS. Pirtobrutinib: a
untreated chronic lymphocytic leukaemia and new hope for patients with BTK inhibitor-
small lymphocytic lymphoma (SEQUOIA): a refractory lymphoproliferative disorders.
randomised, controlled, phase 3 trial. Lancet Blood. 2023;141(26):3137-3142. doi:10.1182/
Oncol. 2022;23(8):1031-1043. blood.2023020240
doi:10.1016/S1470-2045(22)00293-5 33. Aslan B, Kismali G, Iles LR, et al. Pirtobrutinib
18. Brown JR, Eichhorst B, Hillmen P, et al. inhibits wild-type and mutant Bruton’s tyrosine
Zanubrutinib or ibrutinib in relapsed or kinase-mediated signaling in chronic lymphocytic
refractory chronic lymphocytic leukemia. N leukemia. Blood Cancer J. 2022;12(5):1-12.
Engl J Med. 2023;388(4):319-332. doi:10.1056/ doi:10.1038/s41408-022-00675-9
NEJMoa2211582 34. Mato AR, Woyach JA, Brown JR, et al.
19. Sharman JP, Egyed M, Jurczak W, et al. Pirtobrutinib after a covalent BTK inhibitor in
Acalabrutinib with or without obinutuzumab versus chronic lymphocytic leukemia. N Engl J Med.
chlorambucil and obinutuzumab for treatment- 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
naive chronic lymphocytic leukaemia (ELEVATE- 35. Mato AR, Shah NN, Jurczak W, et al.
TN): a randomised, controlled, phase 3 trial. Pirtobrutinib in relapsed or refractory B-cell
Lancet. 2020;395(10232):1278-1291. doi:10.1016/ malignancies (BRUIN): a phase 1/2 study. Lancet.
S0140-6736(20)30262-2 2021;397(10277):892-901. doi:10.1016/S0140-
20. Sharman JP, Egyed M, Jurczak W, et al. 6736(21)00224-5
Efficacy and safety in a 4-year follow-up of the 36. Shanafelt TD, Borah BJ, Finnes HD, et al. Impact
ELEVATE-TN study comparing acalabrutinib of ibrutinib and idelalisib on the pharmaceutical
with or without obinutuzumab versus cost of treating chronic lymphocytic leukemia at
obinutuzumab plus chlorambucil in treatment- the individual and societal levels. J Oncol Pract.
naive chronic lymphocytic leukemia. Leukemia. 2015;11(3):252-258. doi:10.1200/JOP.2014.002469
2022;36(4):1171-1175. doi:10.1038/s41375-021- 37. Woyach JA, Wierda WG, Coombs CC, et al.
01485-x BRUIN CLL-314: A phase III open-label,
21. Seymour JF, Byrd JC, Ghia P, et al. Detailed safety randomized study of pirtobrutinib (LOXO-
profile of acalabrutinib vs ibrutinib in previously 305) versus ibrutinib in patients with chronic
treated chronic lymphocytic leukemia in the lymphocytic leukemia/small lymphocytic
ELEVATE-RR trial. Blood. 2023;142(8):687-699. lymphoma. Blood. 2022;140(suppl 1):12427-
doi:10.1182/blood.2022018818 12428. doi:10.1182/blood-2022-157589
22. Herman SEM, Niemann CU, Farooqui M, et 38. Reiff SD, Mantel R, Smith LL, et al. The BTK
al. Ibrutinib-induced lymphocytosis in patients inhibitor ARQ 531 targets ibrutinib-resistant
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analyses from a phase II study. Leukemia. 2018;8(10):1300-1315. doi:10.1158/2159-8290.
2014;28(11):2188-2196. doi:10.1038/leu.2014.122 CD-17-1409
23. Jaypirca. Prescribing information. Eli Lilly; 39. Jebaraj BMC, Müller A, Dheenadayalan RP,
2023. Accessed March 14, 2024. https:// et al. Evaluation of vecabrutinib as a model
www.accessdata.fda.gov/drugsatfda_docs/ for noncovalent BTK/ITK inhibition for
label/2023/216059Orig1s000Corrected_lbl.pdf treatment of chronic lymphocytic leukemia.
24. Mato AR, Wierda WG, Ai WZ, et al. NX-2127- Blood. 2022;139(6):859-875. doi:10.1182/
001, a first-in-human trial of NX-2127, a Bruton’s blood.2021011516
tyrosine kinase-targeted protein degrader, in 40. Wang E, Mi X, Thompson MC, et al. Mechanisms
patients with relapsed or refractory chronic of resistance to noncovalent Bruton’s tyrosine
lymphocytic leukemia and B-cell malignancies. kinase inhibitors. N Engl J Med. 2022;386(8):735-
Blood. 2022;140(suppl 1):2329-2332. 743. doi:10.1056/NEJMoa2114110

April 2024 pharmacytimes.com 23

 PEER REV IEWED | RE S I D E N CY R E S E A RC H P ROJECTS

Making Residency Research Projects Patient

Centered: How Retrospective Research Can
Significantly Impact Cancer Care
R y a n B eec hi nor, P harm D, B CP S, B COP ; Co dy Angerman, PharmD; and Aaron St eele, PharmD, BC OP

AUTHORS PR É C I S

Ryan Beechinor, PharmD, Through recognizing the importance of research in the scope of pharmacy practice by national
BCPS, BCOP, is a senior pharmacy organizations, research can become a prominent role and responsibility of pharmacy.
pharmacist at the University
of California (UC), Davis
Comprehensive Cancer INTRODUCTION
Center and an assistant
professor at the University SCHOL ARSHIP IN ON C O LO GY PH A R M ACY PR AC T I C E
of California, San Francisco In 2016, the American College of Clinical Pharmacy Board of Regents published a white
School of Pharmacy. paper titled “The Importance of Research and Scholarly Activity in Pharmacy Training.”
It highlighted the importance of pharmacist-led research and described some barriers to
Cody Angerman, PharmD , is a engaging in high-quality, impactful research that pharmacists face.1 Currently, most first
PGY2 oncology resident at the postgraduate year (PGY1) or second postgraduate year (PGY2) residency programs rely
UC Davis Medical Center in on retrospective designs for their residency projects. However, current residency project
Sacramento, California. publication rates are dismal, with estimates of successful publication between 1.8% and
4.3%.2,3 This is compounded by results from Stranges et al, who found that residents who
Aaron Steele, PharmD, BCOP,
publish their PGY1 or PGY2 research project are twice as likely to continue to publish
is a senior pharmacist in the
within 5 years after residency as those who do not publish their research projects.4
Department of Pharmacy at
Therefore, to get more pharmacists involved in peer-reviewed publications, it is important
the UC Davis Medical Center
that the design and/or content of their research be publishable. However, it is vital that
in Sacramento, California.
the importance of research be recognized in the scope of pharmacy practice by national
pharmacy organizations, which can facilitate incorporation of research among prominent
roles and responsibilities of pharmacy.
The scope of practice for hematology/oncology pharmacists, published by the
DI SC LOSURES Hematology/Oncology Pharmacy Association, calls on pharmacists to “contribute to cancer
Ryan Beechinor, PharmD, BCPS, research by leading clinical studies, reporting important observations from practice, and
BCOP, reports having received supporting investigational drug service programs.”5 This has been reinforced by other
funding/compensation for reviews highlighting the unique role pharmacists play in patient care; these reviews
consulting and/or research emphasized the need for oncology pharmacist participation in clinical research efforts.6
activities from the following Data on rates of publication success from hematology/oncology abstracts presented at
entities that are unrelated to this major pharmacy meetings are more encouraging at 17.5%, but this is far from satisfactory.7
content: AbbVie, Aptitude Health, In this paper, we describe a successful pharmacy-led research project and highlight the
Children’s Oncology Group, The
Dedham Group, Eunice Kennedy
factors that made this project publishable.
Shriver National Institute of Child
Health and Human Development, ID E N TIFY IN G AN E N VI R O N M E N T F O R A PU B LI S H A B LE R E S E A R C H PR OJ E C T
IQVIA, Melinta Therapeutics, One of the ways to ensure a pharmacy-led research project is publishable is to base the
National Institutes of Health, project on a change that happens in clinical practice.1,8,9 This can be a new drug approval,
Oncology Reimbursement indication, or administration method. A project becomes more valid and thus more likely
Management, Pfizer, and Trinity to be published when it creates a dynamic whereby different institutions have different
Life Sciences. All remaining practices about use. In the project that we will describe, the research question benefited
authors report no conflicts of from having both of these factors: A new administration method was made available, which
interest.
led to heterogeneity in practices across cancer centers.
In 2015, the intravenous (IV) formulation of daratumumab (Darzalex; Janssen Biotech)
became the first FDA-approved anti-CD38 antibody for use in patients with previously
treated multiple myeloma.8 In 2019, based on the results of the phase 3 CASSIOPEIA
(NCT02541383) and MAIA (NCT02252172) trials, it received FDA approval for
newly diagnosed multiple myeloma in the transplant-eligible and transplant-ineligible
populations.9 However, due to the relatively high frequency of infusion-related reactions

24 pharmacytimes.com April 2024

 PEER REV IEWED | RE S I D E N CY R E S E A RC H P ROJECTS

(IRRs) following IV administration of daratumumab in This intervention aims to reduce unnecessary clinic
the phase 2 data, most of the phase 3 protocols utilized a visits, improve symptom control, and enhance overall
6-hour observation time post infusion.10 Additionally, long patient well-being.
observation times led to increased burden of resources for
chair times, patient admittance to the hospital to finish the A N E X A M PLE F R O M T H E LI T E R AT U R E
infusion, creative strategies such as splitting the dose over In 2023, Maples et al published a seminal paper about
2 days, and subsequent decreased patient satisfaction. optimization of daratumumab administration, “Eliminating
The manufacturer of daratumumab, Janssen Biotech, the Monitoring Period With Subcutaneous Daratumumab:
having observed the incidence of IRRs with IV A Single-Center Experience,” in Blood Cancer Journal.19
daratumumab, in 2016 began engaging with the FDA The authors described a 2-step process by which they first
to develop a formulation of the agent combined with used a 2-hour observation period for the first 29 patients
recombinant human hyaluronidase for subcutaneous and reported that the IRR rate was less than 10%. They
injection.11 This led to the FDA approval of daratumumab went on to remove the observation period for 35 patients;
and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech) results showed that no serious IRR occurred in the zero-
in 2020, based on the results of the phase 3 COLUMBA hour observation period group and no patients required
(NCT03277105) trial.12 Although the trial showed a lower hospitalization. Only 1 patient reported an injection site
incidence of IRRs compared with the IV formulation of reaction (not an IRR) in this group. Authors concluded that
daratumumab, the supplementary appendix indicated that patients can safely receive subcutaneous daratumumab
investigators still used a 6-hour observation time after the without an observation period, as this contributes toward
first dose and as deemed necessary by the investigator for cost savings and increased infusion bed availability.19
subsequent injections (although, notably, this was absent
from the prescribing information).12,13 However, the lack I M PLE M E N T I N G T H E R E S U LTS AT U C DAV I S H E A LT H
of clarity in terms of observation times with the use of Based on the report of Maples et al, UC Davis, as well
subcutaneous daratumumab led to differing institutional as the other health system campuses UC-wide, has
standards, with some centers recommending a 4-hour adapted practices to a zero-hour observation period
observation and some only 1 hour.14,15 This led to several for subcutaneous daratumumab starting with cycle 1.
retrospective analyses, which aimed to shorten the duration We estimate that removing the minimum mandatory
of observation time.16-18 observation time of 4 hours per patient, as was shown in
Maples et al, and treating approximately 60 new patients
IDENTIFYIN G A N IN TERVE N TION FOR A P UB L ISHAB LE annually will save more than 240 hours of observation
RES EAR C H PROJEC T time. Based on our internal analysis of the costs associated
Most retrospective research projects have a disease state with observation time, we estimate this will save our
end point (eg, efficacy and/or safety). Retrospective health system $225,000 per year. These savings can be
studies are fraught with confounding bias, mostly reallocated into chair time for other patients.
stemming from their nonrandomized nature, which leads to In line with the report by Maples et al, implementation
a lack of generalizability. A third strategy that can increase of a zero-hour observation period likely has led to
the chance of pharmacy-led research being published is to increased patient satisfaction through expedited discharge,
focus the intervention on something more patient focused. as well as increased revenue through scheduling other
This way, if the interaction leads to better quality of life medications in place of the observation time. Importantly,
for the patient (eg, cost and/or time saved), this will be this does not apply to the IV formulation of daratumumab,
generalizable to the entire population of patients which still requires observation post administration.
with cancer. We have provided 4 examples of such
interventions below:
• An intervention that optimizes the amount of time a TABLE. Premedication Protocol for SC Administration of
patient spends in their home (eg, a regimen typically Daratumumab19
given in the inpatient setting, testing whether it can Drug Precycle 1 SC Precycle 2 SC Precycle 3 SC
be given in the outpatient setting with similar daratumumab daratumumab daratumumab
efficacy/safety). Acetaminophen 650 mg 650 mg -
• An intervention that improves the time required for
treatment (eg, testing rapid infusions of anticancer Diphenhydramine 50 mg 50 mg -
medications, which can reduce chair time).
• An intervention that seeks to ease the burden of
Montelukast 10 mg - -
caregivers and/or families. The current body of
literature in oncology inadequately addresses these
profound aspects, despite the well-established Dexamethasonea 20-40 mg 20-40 mg 20-40 mg
understanding of the psychosocial and emotional
effects on caregiver experiences. SC, subcutaneous.
• An intervention aimed at remotely monitoring and a
Antimyeloma therapy; for patients without an infusion-related reaction; all
managing common symptoms experienced by patients premedications are given orally 30 minutes prior to the first injection; no
with cancer, such as pain, nausea, and fatigue. postmedications are given; protocol used by Maples et al.

April 2024 pharmacytimes.com 25

 PEER REV IEWED | RE S I D E N CY R E S E A RC H P ROJECTS

Additionally, it is still necessary to follow presented at major pharmacy association meetings.

J Oncol Pharm Pract. Published online March 27,
the premedication protocol for subcutaneous 2021. doi:10.1177/10781552211004700
daratumumab that Maples et al utilized 8. Sanchez L, Wang Y, Siegel DS, Wang ML.
(Table).19 For those working at a health Daratumumab: a first-in-class CD38 monoclonal
antibody for the treatment of multiple myeloma.
system that has not implemented the zero- J Hematol Oncol. 2016;9(1):51.
hour observation period for subcutaneous doi:10.1186/s13045-016-0283-0
daratumumab, it may be beneficial to 9. Darzalex (daratumumab) injection. Prescribing
information. Janssen Biotech Inc; 2023. Accessed
consider the potential cost- and time-saving March 14, 2024. https://www.janssenlabels.com/
benefits and review the publication by package-insert/product-monograph/prescribing-
Maples et al.19 information/DARZALEX-pi.pdf
10. Darzalex Faspro: postinjection observation time.
Janssen Scientific Affairs. Updated March 5,
C ON C LU SION S 2024. Accessed March 11, 2024. https://www.
We should strive to design our pharmacy janssenscience.com/products/darzalex-faspro/
medical-content/darzalex-faspro-postinjection-
projects to be more publishable using observation-time
the 3 criteria captured by Maples et al: 11. BLA multidisciplinary review and evaluation:
identifying a project based on a practice BLA 761145, Darzalex Faspro (daratumumab and
hyaluronidase-fihj). Center for Drug Evaluation and
change, generating a research question Research. April 12, 2020. Accessed March 11, 2024.
based on variation in clinical practice, and https://www.accessdata.fda.gov/drugsatfda_docs/
studying an intervention that is patient nda/2020/761145Orig1s000MultidisciplineR.pdf
12. Darzalex Faspro (daratumumab/hyaluronidase).
focused and applicable to many centers. Prescribing information. Janssen Biotech Inc; 2022.
These factors will have a positive influence Accessed March 14, 2024. https://www.janssenlabels.
on not only the research project’s being com/package-insert/product-monograph/prescribing-
information/DARZALEX+Faspro-pi.pdf
publishable but also the project’s overall 13. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous
impact. With this emphasis, residency versus intravenous daratumumab in patients
research projects have the potential with relapsed or refractory multiple myeloma
(COLUMBA): a multicentre, open-label, non-
to change practice while providing an inferiority, randomised, phase 3 trial. Lancet
invaluable opportunity for pharmacists to Haematol. 2020;7(5):e370-e380.
actively contribute to the advancement of doi:10.1016/S2352-3026(20)30070-3
14. Kim EB, O’Donnell E, Branagan AR, et al. Real-
the profession. world observations and practical considerations
of subcutaneous daratumumab administration in
multiple myeloma. Blood. 2021;138(suppl 1):5018.
REFEREN CE S doi:10.1182/blood-2021-153751
1. Deal EN, Stranges PM, Maxwell WD, et al; 15. Kye J, Patel S, Seyer M, et al. Safety of SC
American College of Clinical Pharmacy. The daratumumab in the treatment of plasma-cell
importance of research and scholarly activity disorders: a single-center experience. J Hematol
in pharmacy training. Pharmacotherapy. Oncol Pharm. 2023;13(2):1-6.
2016;36(12):e200-e205. doi:10.1002/phar.1864 16. Davis JA, Youngberg H, Gaffney K, Duco M, Hashmi
2. Weathers T, Ercek K, Unni EJ. PGY1 resident H. “Fast but not so furious”: short observation time
research projects: publication rates, project after subcutaneous daratumumab administration
completion policies, perceived values, and is both a safe and cost-effective strategy. Clin
barriers. Curr Pharm Teach Learn. 2019;11(6):547- Lymphoma Myeloma Leuk. 2022;22(8):e680-e684.
556. doi:10.1016/j.cptl.2019.02.017 doi:10.1016/j.clml.2022.03.006
3. O’Dell KM, Shah SA. Evaluation of pharmacy 17. Hughes DM, Henshaw L, Blevins F, et al. Standard
practice residents’ research abstracts and publication 30-minute monitoring time and less intensive
rate. J Am Pharm Assoc (2003). 2012;52(4):524-527. pre-medications is safe in patients treated with
doi:10.1331/JAPhA.2012.10224 subcutaneous daratumumab for multiple myeloma
4. Stranges PM, Vouri SM. Impact of resident research and light chain amyloidosis. Clin Lymphoma
publication on early-career publication success. Am Myeloma Leuk. 2022;22(8):566-568.
J Health Syst Pharm. 2016;73(12):895-900. doi:10.1016/j.clml.2022.03.003
doi:10.2146/ajhp150567 18. Soefje SA, Carpenter C, Carlson K, et al.
5. Scope of Hematology/Oncology Pharmacy Practice. Clinical administration characteristics of
Hematology/Oncology Pharmacy Association. 2013. subcutaneous and intravenous administration of
Accessed March 11, 2024. https://www.hoparx.org/ daratumumab in patients with multiple myeloma
documents/111/HOPA13_ScopeofPracticeBk1.pdf at Mayo Clinic infusion centers. JCO Oncol Pract.
6. Holle LM, Boehnke Michaud L. Oncology 2023;19(4):e542-e549. doi:10.1200/OP.22.00421
pharmacists in health care delivery: vital 19. Maples KT, Hall KH, Joseph NS, et al. Eliminating
members of the cancer care team. J Oncol Pract. the monitoring period with subcutaneous
2014;10(3):e142-e145. doi:10.1200/JOP.2013.001257 daratumumab: a single-center experience.
7. Wooten KM, Arnall JR, Bowser KM, et al. Blood Cancer J. 2023;13(1):29.
Publication rates of hematology/oncology abstracts doi:10.1038/s41408-023-00801-1

26 pharmacytimes.com April 2024

 Pharmacy Practice in Focus: Oncology ™
is a peer-reviewed ™

publication that provides a platform for sharing and discussing

research, best practices, and practice management in the field
of oncology pharmacy to support education and discussion.
COVER FEATURES
CONFERENCE COVERAGE
ASH HIGHLIGHTS
ASH
From Axatilimab to Zanubrutinib:
Ibrutinib Plus Venetoclax With MRD-Directed
Treatment Updates Abound
Duration of Treatment Is a New Standard-of-
D O U G L A S B R A U N , P H A R M D , C S P, R P H
Care Regimen for Previously Unmanaged CLL
ALANA HIPPENSTEELE
SABCS HIGHLIGHTS
From Capecitabine to Tucatinib:

Submissions are welcome for peer review and original research

ASH
Data Reveal New Treatment Options
Assessing Philadelphia-Like B-Cell ALL
for Patients
in a Largely Hispanic Population
D O U G L A S B R A U N , P H A R M D , C S P, R P H
AMIR ALI, PHARMD, BCOP; MELISSA

that are focused on the work and practice of pharmacy

M A R T I N E Z , P H A R M D C A N D I D AT E ; M A R YA M
S A H E B K A S H A F, P H A R M D C A N D I D AT E ; A N D
Z YA N YA R I Z Z O , P H A R M D C A N D I D AT E

SABCS

professionals.
Pausing Endocrine Therapy for Pregnancy Did
Not Increase Risk of Recurrence for Those
With HR+ Breast Cancer
ASHLEY GALLAGHER

SABCS
Tucatinib, Trastuzumab Combination
Improves Progression-Free Survival in HER2+
Locally Advanced or Metastatic Breast Cancer

Pharmacy Practice in Focus: Oncology publishes original

AISLINN ANTRIM

research, literature reviews, case reports, case descriptions, JANUARY 2024 | VOL. 6 NO. 1

and other informed commentary on a variety of topics.

Topics of interest include, but are not limited to:

• Advancements in immunotherapy • Pharmacist-led approaches to drug shortages

• Precision medicine • Workload metrics and position justification

• Targeted therapies • Overcoming scheduling delays: stories from the field

• Biomarker development • Updates in antibody-drug conjugates

• Biosimilars in oncology • Climate change impact on access to care

• Oral chemotherapy management • HER2-low and the breast cancer treatment landscape

• Artificial intelligence and big data • Transitions of care in gene therapy

• Quality improvement and patient safety • Updates in checkpoint inhibitors

To submit your work or learn more about collaborating with us, contact
Alana Hippensteele, managing editor, at [email protected]
 PEER REV IEWED | T- C E L L E N G AG E R S I N R / R M M

Practical Considerations of T-Cell Engagers in the

Management of Relapsed/Refractory
Multiple Myeloma
M a t t h e w M . Le i , Ph ar m D, B COP ; J ac k M al e s p i ni , P harm D, BCOP; Erica Tavares, PharmD, BC PS , BC OP; S arah O’Neill, PharmD;
Di ana Ci r s te a, M D; and E. Bridget Kim, PharmD, BC PS , BC OP

AUTHORS PR É C I S

Matthew M. Lei, PharmD, Integration of these agents requires supportive care considerations for cytokine release syn-
BCOP, is a clinical pharmacy drome, neurotoxicity, infection, and antigen-specific toxicities to ensure optimal care of patients
specialist—lymphoma in the with multiple myeloma receiving T-cell–engaging therapies.
Jon and Jo Ann Hagler Center
for Lymphoma at Massa-
chusetts General Hospital in A B ST R AC T
Boston.
The treatment of patients with relapsed/refractory (R/R) multiple myeloma (MM), particularly
Jack Malespini, PharmD,
those with triple-class refractory MM, poses a clinical challenge due to the low overall response
BCOP, is a clinical pharmacy
rates and historically poor prognosis with previously available therapies. Agents with novel mech-
specialist in the Department
anisms of action, such as anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T cells
of Pharmacy at Massachu-
and, more recently, anti-BCMA bispecific T-cell engagers (TCEs), have demonstrated promising
setts General Hospital in
activity for most of these patients. In this review, we aim to summarize the current landscape of
Boston.
TCEs for the treatment of patients with R/R MM, focusing not only on approved agents, such as
Erica Tavares, PharmD, BCPS, teclistamab-cqyv (Tecvayli; Janssen Biotech, Inc), elranatamab-bcmm (Elrexfio; Pfizer Inc), and
BCOP, is a clinical pharmacy talquetamab-tgvs (Talvey; Janssen Biotech, Inc), but also on supportive care strategies intended
specialist in the Department to inform clinicians on how to integrate these innovative therapies into patient care. Given avail-
of Pharmacy at Massachu- able evidence, the use of TCEs in MM must include a comprehensive approach to the monitoring,
setts General Hospital in prophylaxis, and treatment of infections and to the supportive care for potential adverse events,
Boston, Massachusetts. such as cytokine release syndrome and neurotoxicity, including immune effector cell–associated
Sarah O’Neill, PharmD, is a neurotoxicity syndrome, and antigen-specific on-target, off-tumor toxic effects. The advent of
clinical pharmacy specialist in TCEs marks a pivotal shift in the treatment of patients with R/R MM and underscores the role of
the Department of Pharmacy at health care providers, particularly pharmacists, in the management and mitigation of adverse
Massachusetts General Hospital events associated with TCE therapy to optimize patient outcomes within this evolving
in Boston. treatment landscape.

Diana Cirstea, MD, is an

INTRODUCTION
attending physician in the
Center for Myeloma at Mass
General Cancer Center in
Multiple myeloma (MM) is a complex hematologic malignancy characterized by the clonal
Boston.
proliferation of plasma cells and their interplay within the tumor microenvironment.1,2 The
E. Bridget Kim, PharmD, landscape of MM therapeutics has witnessed a paradigm shift with the advent of the
BCPS, BCOP, is a clinical T-cell engagers (TCEs) teclistamab-cqyv (Tecvayli; Janssen Biotech, Inc), elranatamab-
pharmacy specialist in the
bcmm (Elrexfio; Pfizer Inc), and talquetamab-tgvs (Talvey; Janssen Biotech, Inc).3-5
Department of Pharmacy
at Massachusetts General
Although TCEs can achieve high response rates in patients with relapsed/refractory
Hospital and in the Center (R/R) MM, optimal use of supportive care is necessary for cytokine release syndrome
for Myeloma at Mass General (CRS) and neurotoxicity, including immune effector cell–associated neurotoxicity
Cancer Center in Boston. syndrome (ICANS). 6 Furthermore, with the high incidence of severe infections,
particularly opportunistic infections such as Pneumocystis jirovecii pneumonia
(PJP) and cytomegalovirus (CMV), monitoring, prophylaxis, and prompt treatment for
infection are necessary to mitigate infection-related morbidity and mortality.7,8 It is also
DI SC LOSURES
important to optimize support measures for the on-target, off-tumor toxic effects (ie, oral
None. and nail toxicities) of talquetamab. This review aims to summarize the pivotal data that
led to the accelerated approval of these TCEs as well as important considerations for

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TABLE 1. FDA-Approved Dosing Regimens for Teclistamab, Elranatamab, and Talquetamab10-12

Teclistamab-cqyv Elranatamab-bcmm Talquetamab-tgvs
Indication Patients with R/R MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an IMiD, and an
anti-CD38 monoclonal antibody
Route of
SC
administration
Premedication Required 1-3 hours prior to all Required approximately 1 hour prior Required 1-3 hours prior to all doses
doses in step-up schedule (including to all doses in step-up schedule and within the step-up dosing schedule and
first treatment dose) and may be may be necessary in repeat step- may be necessary in repeat step-up
necessary in repeat step-up dosing up dosing or for subsequent doses dosing or for subsequent doses in patients
or for subsequent doses in patients in patients who experienced CRS: who experienced CRS: corticosteroid
who experienced CRS: corticosteroid corticosteroid (IV/oral dexamethasone (IV/oral dexamethasone 16 mg or
(IV/oral dexamethasone 16 mg or 20 mg or equivalent), H1 receptor equivalent), H1 receptor antagonist (IV/oral
equivalent), H1 receptor antagonist antagonist (oral diphenhydramine diphenhydramine 50 mg or equivalent),
(IV/oral diphenhydramine 50 mg or 25 mg or equivalent), and antipyretic and antipyretic (IV/oral acetaminophen
equivalent), and antipyretic (IV/oral (oral acetaminophen 650 mg or 650-1000 mg or equivalent)
acetaminophen 650-1000 mg or equivalent)
equivalent)
Step-up dosing • Recommended step-up dose 1 • Recommended step-up dose 1 and • Weekly schedule: step-up dose 1 and 2
phase and 2 and first treatment dose with 2 with in-hospital monitoring for 48 and first treatment dose
in-hospital monitoring for 48 hours hours and 24 hours, respectively • Biweekly schedule: step-up dose 1, 2,
following each dose and 3 and first treatment dose
• In-hospital monitoring for 48 hours
following each dose
Step-up dosing Day Dose Day Dose Day Weekly dose
schedule
1 Step-up dose 1 0.06 mg/kg SC 1 Step-up dose 1 12 mg SC 1 Step-up dose 1 1.01 mg/kg SC
4a Step-up dose 2 0.3 mg/kg SC 4a Step-up dose 2 32 mg SC 4a Step-up dose 2 0.06 mg/kg SC
7a First treatment 1.5 mg/kg SC 8a First treatment 76 mg SC 7a First treatment 0.4 mg/kg SC
dose dose dose
Day Biweekly dose
1 Step-up dose 1 1.01 mg/kg SC
4a Step-up dose 2 0.06 mg/kg SC
7a Step-up dose 3 0.4 mg/kg SC
10 a
First treatment 0.8 mg/kg SC
dose
Subsequent Weekly Weekly through week 24 Weekly or biweekly
doses Biweekly thereafter (CR for ≥6 months) Biweekly thereafter (responders only)
Maintenance Weekly: 1.5 mg/kg SC 1 week after Weekly: 76 mg SC 1 week after first Weekly: 0.4 mg/kg SC 1 week after first
dosing schedule first treatment dose and weekly treatment dose and weekly thereafter treatment dose and weekly thereafter
thereafter through week 24 (minimum of 6 days (minimum of 6 days between doses)
between doses)
Biweekly: 1.5 mg/kg SC every 2 weeks Biweekly: 0.8 mg/kg SC 2 weeks after
for patients who have achieved and first treatment dose and every 2 weeks
maintained a CR for ≥ 6 months Biweekly: 76 mg SC every 2 weeks thereafter (minimum of 12 days between
starting at week 25 (responders only) doses)
CR, complete response; CRS, cytokine release syndrome; H1, histamine type 1; IMiD, immunomodulatory drug; IV, intravenous; MM, multiple myeloma; R/R, relapsed/
refractory; SC, subcutaneous.
a
Refer to package inserts for time required between doses.

the use of these therapies. These considerations include antibodies that bind BCMA on plasma cells, plasmablasts,
monitoring and management of CRS, neurotoxicity, and and MM cells and CD3 on T cells, leading to cytolysis of
infection and tailored supportive care for select toxicities the BCMA-expressing cells.4,5 Talquetamab is a bispecific
with talquetamab. antibody that targets CD3 on T cells and G protein–coupled
receptor family C group 5 member D (GPRC5D).3 Although
TECL ISTA MA B, ELRA N ATAMAB , AN D TALQUE TAMAB GPRC5D exhibits heightened expression in malignant
Teclistamab and elranatamab are bispecific B-cell plasma cells vs normal plasma cells, it is pertinent to note
maturation antigen (BCMA)–directed T-cell engaging that the expression of GPRC5D is predominantly confined to

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malignant plasma cells. However, trace expression GPRC5D and results from cohort B have yet to be published.14
is detected in the skin and testes, possibly contributing to After six 28-day cycles (24 weeks), patients who
unintended on-target, off-tumor toxic effects.9 achieved a partial response or better lasting at least
The trials that led to the accelerated approvals based on 2 months were eligible to switch to a dosing interval of
response rates of teclistamab, elranatamab, and talquetam- once every 2 weeks. Of the 123 patients in cohort A, 50
ab were MajesTEC-1 (NCT04557098), MagnetisMM-3 patients switched to biweekly dosing, and of these patients,
(NCT04649359), and MonumenTAL-1 (NCT03399799), 40 improved or maintained their response for at least 6
respectively.3-5 Their FDA-approved indication is in adult months. The ORR was 61%, with 35% of patients having
patients with R/R MM who have previously received at achieved a CR or better. MRD negativity was achieved in
least 4 lines of therapy, including a proteasome inhibitor 89.7% of patients with a CR or better who were evaluable
(PI), an immunomodulatory drug (IMiD), and an anti-CD38 for MRD. The secondary end points of median duration of
monoclonal antibody (Table 1).10-12 response, progression-free survival, and overall survival had
not been reached at a median follow-up of 14.7 months.14,15
Teclistamab Extended follow-up approximately 15 months after the
The MajesTEC-1 phase 2 trial assessed the efficacy and last patient’s first dose with a data cutoff date of March 14,
safety of teclistamab in adult patients with R/R MM who 2023, have been reported (Table 2).
had received at least 3 prior lines of therapy, including an
IMiD, a PI, and an anti-CD38 antibody.5 The study enrolled Talquetamab
165 patients, with a median follow-up of 14.1 months at The MonumenTAL-1 trial assessed the efficacy and safety
the data cutoff of March 16, 2022, with a median duration of talquetamab with 2 dosing cohorts: weekly and every
on treatment of 8.5 months (range, 0.2-24.4). The patient other week.3 Patients either received talquetamab at
population exhibited high resistance to previous therapies, 405 μg/kg weekly or at 800 μg/kg every other week. The
and a substantial proportion had triple-class and penta-drug majority of patients were triple-class refractory across the
refractory disease. The overall response rate (ORR) was weekly dosing group (n = 143) and every-other-week dosing
63%, with 39.4% of patients achieving a complete response group (n = 145) and among those who had received prior
(CR) or better. The median time to first response was T-cell receptor therapy (n = 51). At the median follow-up
1.2 months, and negativity for minimal residual disease of 11.7 months for the group receiving the 405-μg/kg dose
(MRD) at any time point was reported in 81.5% of and 4.2 months for the group receiving the 800-μg/kg dose,
MRD-evaluable patients.13 Certain factors, including the ORR was 70% and 64%, respectively. For the group
extramedullary disease, International Staging System receiving the 405-μg/kg dose, the median time to response
stage III disease, and extensive bone marrow involvement, and to a CR were 0.9 (range, 0.2-3.8) and 9.3 months
correlated with lower response rates. Notably, patients (range, 1.7-17.1), respectively, and for the group receiving
with fewer previous lines of therapy demonstrated higher the 800-μg/kg dose, these were 1.2 (range, 0.3-6.8) and 2.3
response rates. Responses were sustained, with a median months (range, 2.1-6.8), respectively. The median duration
duration of 18.4 months (95% CI, 14.9-not estimable). The of response for those receiving the 405 μg/kg and 800-μg/
median progression-free survival was 11.3 months kg doses were 10.2 (95% CI, 3.0-NR) and 7.8 months
(95% CI, 8.8-17.1), with a median overall survival of 18.3 (95% CI, 4.6-NR), respectively.16
months (95% CI, 15.1-not reached [NR]).13 Extended follow-up with a data cutoff date of January 23,
Results from extended follow-up of approximately 2023, have been reported (Table 2).
2 years with a data cutoff date of January 4, 2023, have
been reported (Table 2). PR AC T I CA L C O N S I DE R AT I O N S
CRS and neurologic toxicity
Elranatamab CRS and neurologic toxicity, including ICANS, are
The phase 2 MagnetisMM-3 clinical trial evaluated the well-recognized complications associated with immune
efficacy and safety of elranatamab and included patients effector cell therapies such as bispecific TCEs. However,
with R/R MM who were refractory to at least 1 PI, 1 IMiD, the incidence, severity, and onset of CRS and neurologic
and 1 anti-CD38 antibody and relapsed or refractory to their toxicity for TCEs vs available CAR T-cell therapies differ—
last antimyeloma regimen.4 Of the 187 patients enrolled, specifically because TCEs are drugs with defined half-
123 patients were in cohort A (no prior BCMA-directed lives dosed intermittently.6,16 CRS and ICANS, which may
therapy) and 64 patients were in cohort B (prior BCMA- appear as fever, malaise, hypotension, respiratory distress,
directed therapy [antibody-drug conjugate or chimeric antigen and neurological manifestations (Table 2), require prompt
receptor (CAR) T-cell therapy]). Results from cohort A after identification, evaluation, and management.17 Furthermore,
approximately 15 months of follow-up have been reported, it is critical to consider a differential diagnosis in patients

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TABLE 2. Updated Efficacy and Select Safety Data From Registrational Trials for Teclistamab, Elranatamab, and
Talquetamab
Teclistamab-cqyv5,13,51 Talquetamab-tgvs3,52,54 Elranatamab-bcmm4,14,15,54
Targets BCMAxCD3 GPRC5DxCD3 BCMAxCD3
Clinical trial MajesTEC-1 MonumenTAL-1 (NCT03399799) MagnetisMM-3 (NCT04649359)
(NCT04557098)
N = 165 N = 339a N = 123
Median follow-up 23 months Weekly-dose cohort: 18.8 months Approximately 15 months after
Every-2-week cohort: 12.7 months last patient’s first dose
Prior TCR cohort: 14.8 months
Efficacy ORR, % 63.0 Weekly-dose cohort: 70.7 61.0
Every-2-week cohort: 75.7
Prior BCMA-directed Prior TCR cohort: 50.0 Prior BCMA-directed therapyb:
therapy: 45.3
40.0
CR or better, % 45.5 Weekly-dose cohort: 33.6 31.7
Every-2-week cohort: 38.7
Prior TCR cohort: 35.3
DOR, months 21.6 (16.2-NE) Weekly-dose cohort: 9.5 (6.7-13.3) NR
(95% CI) Every-2-week cohort: NR (13.0-NE)
Prior TCR cohort: 11.9 (4.8-NE) 15-month DOR rate (%): 71.5
Median PFS, months 11.3 (8.8-17.1) Weekly-dose cohort: 7.5 (5.7-9.4) NR
(95% CI) Every-2-week cohort: 11.9 (8.4-NE)c
Prior TCR cohort: 5.1 15-month PFS rate (%): 50.9
Median OS, months 21.9 (15.1-NE) NR NR
(95% CI)
12-month OS rate (%): 15-month OS rate (%): 56.7
Weekly-dose cohort: 76.4
Every-2-week cohort: 77.4
Prior TCR cohort: 62.9
Safety All-grade CRS 72.1 (0.6) Weekly-dose cohort: 79 (2.1) 57.7 (0)
(grades 3-4), % Every-2-week cohort: 74.5 (0.7)
Prior TCR cohort: 76.5 (2.0)
ICANS, % 3.0 Weekly-dose cohort: 10.7 3.4
Every-2-week cohort: 11
Prior TCR cohort: 2.9
BCMA, B-cell maturation antigen; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; GPRC5D, G protein–coupled receptor
family C group 5 member D; ICANS, immune effector cell–associated neurotoxicity syndrome; NE, not estimable; NR, not reached; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival; TCR, T-cell redirection.
a
288 patients received talquetamab 0.4 mg/kg weekly (n = 143) or 0.8 mg/kg every other week (n = 145), and the third cohort with 51 patients who had
received prior TCR therapy received either talquetamab 0.4 mg/kg weekly or 0.8 mg/kg every other week.
b
Pooled analysis of patients from MagnetisMM-1 (n = 13), MagnetisMM-3 (n = 64), and MagnetisMM-9 (n = 9).
c
61% of patients were censored at the time of analysis.

experiencing CRS or ICANS, given the possibility of an is necessary to minimize the time between when the
underlying infection or other medical condition that may medication order is placed and drug administration.
mimic CRS or ICANS. Infection-related symptoms, such CRS and ICANS are systemic inflammatory respons-
as fever, malaise, confusion, or respiratory distress, may es mediated by the overactivation of a patient’s immune
overlap with those observed in CRS and ICANS. Thus, system after treatment with immune effector cell therapy
a workup for infection, which may include blood and caused by activation of T lymphocytes, monocytes, and
urine cultures and chest radiography, should be conducted macrophages, leading to the downstream production of
if fever is present. Educating patients and nurses with interferon-γ, IL-6, and IL-10.18 This immune activation is
respect to the signs and symptoms of CRS and ICANS is observed during the step-up dose phase or with the first
crucial for prompt and effective care. Furthermore, in the treatment dose of TCEs. In clinical practice, the effective
case of anticytokine therapy with tocilizumab (Actemra; management of CRS and ICANS requires timely interven-
Genentech), communication within the medical team tion and selection of appropriate therapeutic agents based

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on the severity of the syndrome.6 Health care centers utilize Management of CRS
preventive measures to mitigate CRS and ICANS, including CRS may be graded in terms of severity based on the
premedications, step-up doses, and inpatient monitoring. presence of fever, hypotension, and/or hypoxia. For
Pharmacologic agents come into play if patients experience the management of low-grade CRS, an antipyretic and
signs of CRS or ICANS, including antipyretics, antiepilep- intravenous hydration act as primary interventions. The
tic drugs, corticosteroids, tocilizumab, and anakinra antipyretic is administered to alleviate mild symptoms
(Kineret; Swedish Orphan Biovitrum AB).17 before considering more specific interventions, such as
tocilizumab or other pharmacologic agents for moderate
Monitoring, risk stratification, and prophylaxis for CRS to severe cases of CRS. Tocilizumab, an IL-6 receptor
and ICANS inhibitor, can also be considered if fever persists with grade
Recommendations on hospitalization to monitor CRS 1 CRS despite adequate supportive care. IL-6 is notable as a
and ICANS are present in the package insert of available cytokine commonly found at elevated levels in individuals
TCEs.10-12 The duration of hospitalization may vary experiencing CRS, with its increased concentrations often
for each TCE based on how institutions implement the associated with the severity of the syndrome.6 Tocilizumab
recommended minimum timing between step-up doses can be repeated every 8 hours if there is no improvement of
and the first treatment dose. Because institutional resource CRS signs and symptoms but is limited to 3 doses within
constraints and site-of-care cost considerations may limit 24 hours and a maximum of 4 total doses.25 Furthermore,
the wider availability and use of these agents, strategies to it has been demonstrated that IL-6 can be blocked without
address these constraints are emerging, such as outpatient affecting the therapeutic activity of T cells mediated by
monitoring and administration of TCEs, use of prophylactic CD3 bispecific treatment, also suggesting benefit with
agents for CRS, and risk stratification for CRS. earlier use of cytokine blockade, possibly prophylactically,
Outpatient CAR T-cell infusion and monitoring have been to mitigate CRS.18
described by multiple centers, and experiences on outpatient A recent analysis provided a detailed overview of CRS
step-up dosing with TCEs for patients with MM are grow- events observed in patients from the MajesTEC-1 trial. Of
ing, highlighting the resources needed to educate patients the 165 total patients, tocilizumab was used in 60 patients
and the medical team regarding the necessary procedures (36.4%) and steroids in 14 patients (8.5%). There were
for patient monitoring, symptom triage, and provider 195 CRS events reported (in 119 patients), and 68 of the
assessment.19-22 Of note, implementation of TCEs at institu- events were managed with tocilizumab and 127 were not.
tions that do not routinely administer CAR T-cell infusions Fewer events managed by tocilizumab were followed by a
may be a challenge because resources may vary drastically subsequent event vs events for which tocilizumab was not
compared with authorized CAR T-cell treatment centers. used (19.1% vs 49.6%, respectively). Forty-five patients
Given the diversity of patient needs across institutions, received tocilizumab for their first CRS event, of whom 9
the implementation of policies and procedures for moni- (20%) had a subsequent CRS event compared with 46 of 74
toring patients receiving TCEs will vary. Efforts from care patients (62.2%) who were not managed with tocilizumab
staff performing patient follow-ups and assisting in patient for their first CRS event and had a subsequent event.26
triage may be accompanied by tools such as remote vitals
monitoring and rationale for TCE administration times that Management of ICANS
take into account the median time to onset of CRS. Early Available TCEs are associated with a lower incidence
engagement of the multidisciplinary care team is key. Fur- and severity of ICANS compared with available CAR
thermore, prophylactic strategies, such as with tocilizumab, T-cell therapies. However, prompt evaluation, diagnosis,
may attenuate the incidence and severity of CRS, which and management of ICANS remain vital in the care of
may further increase the feasibility of outpatient step-up patients receiving these therapies. ICANS is graded using
dosing and monitoring.23,24 Although the use of tocilizumab the Immune Effector Cell–Associated Encephalopathy
for CRS prophylaxis is promising, tailored use may increase (ICE) score.16 The ICE score comprises several clinical and
the feasibility of this practice for institutions. Notably, there neurological parameters, including orientation, naming,
is currently a paucity of data on the utility of continued following commands, writing, and attention. Nonsedating
dexamethasone administration beyond its use as a premedi- antiepileptic drugs can be used for seizure management as
cation for CRS prophylaxis. indicated. In contrast to supportive care with CAR T-cell
Models for CRS risk stratification may aid clinical therapy, antiepileptic drugs are not added as standard
decision-making for more intensive monitoring or prophy- prophylaxis with TCEs.26
lactic measures for patients at higher risk of CRS, partic- Corticosteroids are a cornerstone in the treatment of
ularly grade 2 or higher. However, data on risk factors of ICANS, dexamethasone specifically because it has a greater
CRS with TCEs are still insufficient to build such models at central nervous system penetration compared with other
this time. corticosteroids.17 For example, dexamethasone doses may

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range from 10 mg daily for grade 1 ICANS to 10 mg every the need for immediate guidance, acknowledging that
6 hours for grade 2/3 ICANS. High-dose methylpredniso- recommendations may be updated to reflect new and
lone (1 mg/kg) can be considered for severe ICANS. There maturing data from TCE therapies targeting BCMA as
is discordance on the use of tocilizumab for treatment of well as other antigens (eg, GPRC5D, Fc receptor-like
ICANS without signs or symptoms of CRS due to the risk 5 [FcRH5]).33,34 This is because data are more mature for
that tocilizumab may exacerbate ICANS.26 Tocilizumab is a trials evaluating anti-BCMA TCEs compared with TCEs
monoclonal antibody that cannot cross the blood-brain bar- against non-BCMA antigens. Current data suggest that the
rier, thus blocking the IL-6 receptor in peripheral tissues.26 incidence and severity of infection may be lower with non–
Hypothetically, this can lead to a temporary increase in lev- anti-BCMA TCEs compared with anti-BCMA TCEs.6,33,34
els of IL-6, thereby increasing the risk of ICANS.27 Alterna- However, given the incidence of serious and fatal infections
tively, anakinra, an IL-1 receptor antagonist that can reach as well as opportunistic infections with anti-BCMA TCEs,
clinically relevant concentrations in the central nervous recommendations for the prevention and management of
system, may be a preferred adjunct to dexamethasone.28-30 infection for patients with MM receiving treatment with
TCEs may be broadly considered until more data are
The Risk Evaluation and Mitigation Strategy program available, at which time more detailed recommendations
Due to the serious safety concerns arising from the risk may be provided reflecting disease stage, TCE antigen, and
of CRS and ICANS, TCEs with approved indication TCEs used in combination therapy.6,33,34
for the treatment of MM are available only through the Accompanying these current recommendations is in-
restricted Risk Evaluation and Mitigation Strategy (REMS) terest in modifying the dose density or intensity—based
drug safety program.10-12 There are important REMS on available evidence—to decrease the risk for infection
considerations for MM bispecific antibodies for each of the that accompanies TCE therapies, such as by rationally
key participants, specifically prescribers, pharmacy/health increasing the dosing interval for patients with sustained
care settings, and wholesalers. Notably, there are no patient- disease response. For example, in the phase 2 portion of the
specific requirements for a REMS program. Teclistamab and MajesTEC-1 trial, patients who received teclistamab and
talquetamab are available under the same REMS program, achieved a CR or better for 6 months or more could switch
in contrast to elranatamab. Prescribers must be certified by from weekly dosing of 1.5 mg/kg subcutaneously to every
the program by enrolling and completing training, which 2 weeks; there was an additional option for a schedule of
is a 1-time requirement for each of the REMS programs. every 4 weeks if patients demonstrated sustained response
Certified prescribers must counsel patients on the risk of to the every-2-weeks schedule.5 Patients who switched
CRS/ICANS at therapy initiation and dispense a patient to every 2 weeks had a decreased incidence of new-onset
wallet card, which patients are advised to always carry grade 3 or higher infections and, importantly, maintained
with them to signify their current treatment with these their depth of response.13 For teclistamab, the option of a
bispecific antibodies. Pharmacy/health care settings must decreased dosing frequency of 1.5 mg/kg subcutaneous-
be enrolled, have a designated authorized representative for ly every 2 weeks for patients who have achieved a CR or
each site, and train relevant staff on REMS requirements. better for a minimum of 6 months has been approved by
For each dose dispensed, a REMS dispense authorization the European Commission and recently by the FDA.10 In
code must be generated in the portal for the respective addition, a schedule of every 2 weeks reflecting the doses
bispecific antibody, verifying the ordering provider’s REMS used in the MagnetisMM-3 trial is FDA approved for elra-
certification status. Wholesalers may only supply drug to natamab for patients who are responders (partial response
REMS-certified pharmacy/health care settings, which may or better) at week 25 and onward and who have maintained
not loan, borrow, or sell these agents to other sites.10-12 this response for at least 2 months.4,12
Also noteworthy are a meta-analysis (median follow-
Monitoring for and prophylaxis against infections up, 7.6 months; range, 1.7-14.9) and pooled analysis
Patients with MM have an increased risk of infection due (median follow-up, 6.1 months; range, 1.7-14.1) that
to immunodeficiencies that can be disease and treatment have described the prevalence, character, and severity of
related.31,32 With anti-BCMA TCEs, the risk and severity infections in patients with MM treated with TCEs.7,8
of infections have been more notable and persistent than In the meta-analysis that included 16 clinical trials
with other treatments in the MM armamentarium, which (1666 patients), with 12 trials evaluating bispecific and
necessitate considerations for infection prevention to trispecific TCEs as monotherapy (1477 patients) and 4 trials
decrease infection-related morbidity and mortality.7,8 evaluating TCEs in a combination therapy, the prevalence
Notably, the use of anti-BCMA TCEs is associated with of all-grade and grade 3 or greater infections was 56% and
significant incidences of PJP and CMV reactivation and 24%, respectively; of the reported infection events, 68%
infection. Expert recommendations on prevention of were microbiologically confirmed, which included viral
infections for patients with MM receiving TCEs address (49%), bacterial (45%), and fungal (6%). Sixty-five fatal

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TABLE 3. Summary of Expert Recommendations for Patients With MM Receiving TCEs on Infection Monitoring, Prophylaxis,
and Treatment34
Monitoring Prophylaxis Treatment Action with TCE
Hypogammaglobulinemia • Monitor • N/A • Monthly immunoglobulin • Maintain dosing during
immunoglobulin levels replacement therapy if immunoglobulin treatment
monthly IgG level < 400 mg/dL, ≥ 2
severe recurrent bacterial
infections, life-threatening
infection, or no sufficient
response to antibiotic
therapy
Neutropenia • Monitor ANC • Consider • Use G-CSF for grade≥ 3 • Withhold dose if ANC
throughout treatment antibacterial neutropenia < 0.5 × 109/L or during
or antifungal • Avoid G-CSF during period febrile neutropenia
prophylaxis if at risk for CRS
prolonged/chronic
neutropenia
despite G-CSF
Viral infection • Monitor patient • Use an antiviral • Depends on infectious • Maintain dosing during
symptoms and clinical against HSV/VZV agent prophylaxis
presentation for all patients • Temporarily hold during
• Screen for HBV before antiviral treatment until
treatment initiation clinical resolution
• CMV testing if
infection suspected
• EBV testing not
routine, but consider
Bacterial infection • Cultures and tests • Recommended • Depends on infectious • Maintain dosing during
depend on infection if prolonged agent prophylaxis
site neutropenia, high • Temporarily hold during
• Imaging for risk of infections, or antibacterial treatment
confirmation history of recurrent until clinical resolution
bacterial infections
• Prophylaxis with
levofloxacin until no
longer neutropenic
Fungal infection • Routine monitoring not • PJP prophylaxis for • Depends on infectious • Maintain dosing during
recommended all patients agent prophylaxis
• Temporarily hold during
antifungal treatment until
clinical resolution
ANC, absolute neutrophil count; CMV, cytomegalovirus; CRS, cytokine release syndrome; EBV, Epstein-Barr virus; G-CSF, granulocyte colony-stimulating factor;
HBV, hepatitis B virus; HSV, herpes simplex virus; MM, multiple myeloma; N/A, not applicable; PJP, Pneumocystis jirovecii pneumonia; TCE, T-cell engager; VZV,
varicella-zoster virus.

infections were reported. Furthermore, the median time to Twenty-eight deaths attributed to infection were reported.7
onset of infections was described for all-grade infections To date, several sets of expert recommendations address
(49-79 days) and severe infections (≥ 3 months). Two late considerations for hypogammaglobulinemia, infection
(≥ 12 months) fatal infections were reported in 1 study.8 (viral, bacterial, and fungal) monitoring and prophylaxis,
In the pooled analysis that included 11 clinical trials and vaccinations for patients with MM who are receiving
(1185 patients) evaluating a TCE as monotherapy, with therapy with TCEs, including recommendations from a
71.6% of patients with MM receiving an anti-BCMA TCE, panel of experienced investigators from the academic Con-
the prevalence of all-grade and grade 3 or greater infections sortium to Overcome Multiple Myeloma through Innovative
was 50% and 24.5%, respectively, with the risk of grade Trials, from a global expert panel, and from the European
3/4 infections higher with anti-BCMA TCEs vs non– Myeloma Network.6,33,34 Key considerations from these ex-
anti-BCMA TCEs (30% vs 11.9%, respectively). Oppor- pert recommendations are summarized below and described
tunistic infections were also reported, including CMV in Table 3.34
reactivation/infection, PJP, Candida esophagitis, ophthalmic Immunoglobulin replacement should be considered for
herpes simplex virus (HSV), and progressive multifocal patients who have severe hypogammaglobulinemia (IgG
leukoencephalopathy. The prevalence of PJP and CMV re- < 400 mg/dL), who have had 2 or more severe recurrent
activation and/or infection was 4.2% and 8%, respectively. infections by encapsulated bacteria regardless of IgG level,

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who have had a life-threatening infection, or who have inhaled or intravenous pentamidine is recommended for all
a documented bacterial infection with no or insufficient patients receiving treatment with a TCE, and the applicable
response to antibiotic therapy. Patients should be evaluated prophylactic agent should be guided by patient-specific
for monthly immunoglobulin replacement during the period characteristics (eg, allergy to sulfonamides, which precludes
of immunoparesis, in the absence of serious infections, until use of sulfamethoxazole-trimethoprim; glucose-6-phosphate
IgG levels are consistently more than 400 mg/dL. Due to dehydrogenase deficiency, which precludes use of dapsone)
the possible confusion between an infusion- or injection- and institutional guidelines.6,33,34
related reaction with supplemental immunoglobulin and Granulocyte colony-stimulating factor (G-CSF) is recom-
CRS, immunoglobulin supplementation should be deferred mended for patients with MM with severe neutropenia to
until after the risk of CRS with the TCE has subsided. The decrease the risk for neutropenia-related infections. How-
recommended dosage of current FDA-approved TCEs is ever, during periods of risk for CRS, such as during step-up
given until disease progression or unacceptable toxicity, dosing and the first treatment dose with TCEs, the use of
which may limit immunoparesis recovery, so the optimal G-CSF may be weighed with the potential for inducing
duration of immunoglobulin replacement remains unclear; cytokine production and exacerbating CRS.40,41 Patients
finite treatment duration with TCEs in the treatment of should be vaccinated according to recommendations, with
MM may provide additional insight (NCT05932680). emphasis on vaccinations for influenza, Streptococcus
Furthermore, recent experiences have continued to highlight pneumoniae, herpes zoster, SARS-CoV-2, and respiratory
the risk for severe hypogammaglobulinemia with BCMA- syncytial virus.42
directed TCEs and CAR T cells and the association of
immunoglobulin supplementation with a decreased risk of Unique toxicities mediated by GPRC5D on keratinized tissues
severe infection.35-37 Talquetamab has a unique set of on-target, off-tumor
Recommendations for monitoring for and prophylaxis toxicities due to GPRC5D protein expression in healthy
against viral infections, including HSV/varicella-zoster keratinized tissues, such as cells in the oral cavity of the
virus (VZV), CMV, Epstein-Barr virus, and hepatitis B tongue, salivary glands, tonsils, skin, and nails.43 In clinical
virus (HBV), should be considered. Prophylaxis against trials, these toxicities were commonly observed in more
HSV/VZV with acyclovir or valacyclovir is recommended than 50% of patients receiving talquetamab (Table 4).3,11
for patients with R/R MM on active therapy. CMV serolo- Specifically, any grade of oral toxicity, weight loss, skin
gies may be considered prior to initiating TCE therapy, with toxicity, and nail toxicity occurred at 80%, 62%, 62%, and
monitoring of CMV DNA copies considered serially (eg, 50%, respectively. Oral toxicities consisted of dysgeusia
every 3 months) or in case of suspected infection. Data are (49%), dry mouth (34%), dysphagia (23%), and ageusia
limited on the optimal frequency for serial monitoring of (18%). Some patients also experienced significant weight
CMV DNA copies, with practice varying between institu- loss of more than 10% of their initial weight (grade 2;
tions. HBV screening is recommended and HBV reactiva- 29%) and, in some cases, more than 20% of their initial
tion risk assessment is conducted for patients with chronic weight (grade 2; 2.7%). Skin toxicities included rash,
or past HBV infection in consideration for prophylaxis maculopapular rash, erythema, and erythematous rash. Nail
with entecavir, tenofovir, or lamivudine, whereas patients toxicities were nail and nail bed disorder, nail discoloration,
with active HBV infection should be managed according to dystrophy, hypertrophy, ridging, onycholysis, onychoclasis,
guidelines.38,39 Monitoring for reactivation of Epstein-Barr and onychomadesis. Although these were common, they
virus is not routinely recommended but may be considered were mostly low grade. However, these changes were
in cases of persistent fever and fatigue.40,41 permanent in some patients, with many reporting no
Prophylaxis with an antibacterial agent, such as levoflox- symptom resolution to baseline (oral toxicity, 65%;
acin, may be considered for patients during periods of pro- weight loss, 57%).11
longed neutropenia or for those with a history of recurrent Current management strategies of on-target, off-tumor
infections and a high risk for infection. Prophylaxis may cell effects of targeting GPRC5D focus on oral toxicity and
be continued until neutrophil recovery or when infectious weight loss, skin toxicity, and nail toxicity.44-48 Although
risk has decreased. General antibacterial prophylaxis is not mostly low grade, these unusual toxicities may significantly
recommended due to the risk for promoting antimicrobial impact patient experience and quality of life. Oral toxicities
resistance. Similarly, routine prophylaxis for fungal infec- can affect a patient’s ability to experience food taste and
tion, except for PJP, is not recommended, although it may texture, resulting in changes in diet or interest in food and
be considered in consultation with an infectious disease spe- further leading to weight loss and deterioration of overall
cialist for patients during periods of prolonged neutropenia, nutritional status. Real-world studies report skin and nail
during prolonged use of high-dose corticosteroids, or with a toxicities as relatively benign, painless, and self-limit-
history of fungal infections. Prophylaxis for PJP with either ing, with some patients reporting concerns with changes
sulfamethoxazole-trimethoprim, dapsone, atovaquone, or in nail appearance and nail loss.44,49 GPRC5D toxicity

April 2024 pharmacytimes.com 35

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TABLE 4. Unique Toxicities of Talquetamab Mediated by GPRC5D on Keratinized Tissues

Oral toxicitya Weight lossa Skin toxicitya Nail toxicityb
Any grade (grades 3-4), % 80 (2.1) 62 (2.7) 62 (0.3) 50 (0)
Toxicity types Dysgeusia, 49% Grade 2 (≥ 10% loss of Rash Nail/nail bed disorder
Dry mouth, 34% initial weight): 29% Maculopapular rash Nail discoloration
Dysphagia, 23% Grade 3 (≥ 20% loss of Erythema Nail dystrophy
Ageusia, 18% initial weight): 2.7% Erythematous rash Nail hypertrophy
Nail ridging
Onycholysis
Onychoclasis
Onychomadesis

Median onset (range), days 15 (1-634) 67 (6-407) 25 (1-630) 50.5 (6-316)

Median time to resolution (range), 43 (1-530) 50 (1-403) 33 74 (15-247)

days

Patients without symptom resolution 65 57 Not reported Not reported

to baseline, %

GPRC5D, G protein–coupled receptor family C group 5 member D.

a
Safety information per prescribing information.11
b
Safety information per supplemental appendix from Chari et al.3

management for taste alterations include food texture and emphasize that the integration of these therapies into patient
flavor experimentation and adequate hydration. Salivary care requires supportive care considerations for CRS and
substitutes, such as salt mouth rinse, artificial saliva neurotoxicity, infection, and antigen-specific toxicities.
spray, and corticosteroid mouth wash (eg, dexamethasone These efforts will remain important not only as available
oral solution), for dry mouth have been reported to good TCEs are investigated in combination with other therapies
effect.44 Ongoing vitamin and nutritional support may be (eg, anti-CD38 monoclonal antibodies, IMiDs, cereblon
necessary throughout treatment with talquetamab, with dose E3 ligase modulators, CAR T cells, T-cell costimulatory
modification and dose withholding as necessary. Support- molecules, and other TCEs) but also as TCEs targeting
ive measures for skin and nail toxicities include the use of multiple tumor antigens (eg, trispecific TCEs) or other
heavy moisturizers and lotions and topical corticosteroids to novel antigens (eg, FcRH5) become available.
control inflammation, irritation, and redness; oral corti- Furthermore, although questions remain about the optimal
costeroids may be considered for severe events.44 Patient sequencing of not only TCEs and CAR T-cell therapies but
education and early detection and intervention are key to also antigen targets (BCMA, GPRC5D, and FcRH5), avail-
managing these adverse events long term. able data demonstrate that TCEs retain efficacy in patients
previously treated with CAR T cells and suggest that patients
Safety considerations: Vial sizes/concentrations, stability, who have progressed on or were refractory to a TCE may
and administration have a blunted response to CAR T cells.50-54 As broad efforts to
There are several practical considerations for safely implement TCEs into clinical practice continue, challenges and
preparing, storing, and administering teclistamab, opportunities will remain because of ongoing investigation of
elranatamab, and talquetamab. Highlighted in TCEs in earlier lines of therapy. Considerations for agent-spe-
Table 5 are some key differences from each product’s cific toxicity management, including CRS, neurotoxicity, and
prescribing information.10,12 antigen-specific toxicities, are evolving alongside emerging
real-world experiences. Importantly, strategies to facilitate
C O NCLUSION safe outpatient step-up dosing of TCEs may allow broader
The emergence of TCEs, such as teclistamab, elranatamab, availability and access to these therapies. The integration
and talquetamab, marked a watershed moment in the of evolving supportive care strategies remains a focus in the
therapeutic armamentarium for R/R MM, offering promise care of patients with MM. This becomes particularly import-
for patients navigating the available complex treatment ant as we aim to incorporate T-cell–engaging therapies into
options. In this review, we have summarized the pivotal earlier lines of treatment, with the goal of inducing deeper,
data that led to the approval of these therapies while more durable responses while pursuing the possibility of
highlighting their efficacy and safety. Furthermore, we curing patients with MM.

36 pharmacytimes.com April 2024

 PEER REV IEWED | T- C E L L E N G AG E R S I N R / R M M

TABLE 5. Teclistamab, Elranatamab, and Talquetamab Vial Sizes, Concentrations, and Stability10-12
Teclistamab-cqyv
No. of syringes/dose
Dose Vial size Concentration Stability
(maximum 2 mL/syringe)
0.06 mg/kg 1
30 mg/3 mL 10 mg/mL 20 hours RT or RF
0.3 mg/kg 1, 2, or 3 depending on weight

1.5 mg/kg 153 mg/1.7 mL 90 mg/mL 1 or 2 depending on weight

Elranatamab-bcmm
No. of syringes/dose
Dose Vial size Concentration Stability
(maximum 2 mL/syringe)
12 mg
44 mg/1.1 mL
32 mg 40 mg/mL 4 hours RT or RF 1
76 mg 76 mg/1.9 mL
Talquetamab-tgvs
No. of syringes/dose
Dose Vial size Concentration Stability
(maximum 2 mL/syringe)
0.01 mg/kg 1
3 mg/1.5 mL 2 mg/mL
0.06 mg/kg 24 hours RT or RF 1, 2, or 3 depending on weight
0.4 mg/kg 1
40 mg/mL 40 mg/mL
0.8 mg/kg 1 or 2 depending on weight
RF, refrigerated; RT, room temperature.

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April 2024 pharmacytimes.com 39

P RACTICE INSIGHTS | FIN AN C IAL TOXIC IT Y

HSSP Model Can Reduce Financial Toxicity of

Oral Oncology Treatment
PAPs in this model can significantly reduce OOP costs regardless of the
pharmacy setting.
G i l li an M cG overn , As s i s tant Ed i to r

™
D espite significant treatment advances
and the expanded use of precision
medicine and novel oral oncology
agents, cancer continues to be one of the
most expensive diseases to treat. High out-
fall into 1 of 3 categories: manufacturer-
funded co-pay cards or vouchers, which are
available to commercially insured patients;
manufacturer free drug programs, which
are also funded by manufacturers but have
of-pocket (OOP) costs of oral oncology strict income eligibility requirements; and
agents and other therapies—which often charitable foundations or grant programs,
cost $10,000 per month or more—can place which can help cover expenses such as travel
financial burdens on both patients with cancer costs, mortgage payments, and pet care as
and their families or caretakers, contributing well as connect patients with resources to
to financial toxicity. address financial hardships. Further, the
Financial toxicity can also result in patients model includes liaisons, monthly refill calls,
and caretakers making decisions that can frequent clinical pharmacist assessments, and
impact treatment adherence. To continue to direct communication between the pharmacy
afford treatment, patients and caretakers may and health care team.
skip doses to stretch out treatment over a “PAPs can significantly reduce OOP
longer time, or reduce expenditure on food, costs for oral oncolytic [therapies], and the
clothing, and leisure activities, affecting integrated care model of HSSP is optimally
quality of life. Some patients turn to long- positioned to access PAP funds for patient
term strategies—such as refinancing housing benefit,” Stutsky said. “The integrated,
or borrowing money—to offset the cost of patient-centered model of HSSPs allows
cancer treatment. The burden of these efforts direct communication between the pharmacy
can induce stress, anxiety, and depression and health care team to identify patients with
in patients, hindering their quality of high co-pays and secure FA sooner than if
life and potentially extending to the these patients were filling prescriptions at
patients’ caregivers. a nonintegrated pharmacy,” Stutsky said.
“Recent literature cites rising OOP costs “We wanted to explore the impact of the
and negative effects of financial toxicity HSSP model on reducing financial burden in
on [patients with cancer]; however, this has the patient population filling oral oncolytic
not been the experience with many patients [therapies].”
filling oral oncolytics through health-system To describe the impact of PAPs on OOP
specialty pharmacies [HSSPs],” said Martha costs for patients with cancer who filled
Stutsky, PharmD, BCPS, director of clinical oral oncology agents through HSSPs, a
outcomes at Shields Health Solutions. retrospective analysis of prescription fill data
Through HSSPs, patient assistance was conducted. The study included adult
programs (PAPs) help alleviate prescription and pediatric patients who attend oncology
costs by providing financial support; clinic visits and received 3 or more fills of an
however, finding and identifying available oral oncology agent through an HSSP from
PAPs, screening for eligibility requirements, January 1, 2020, to September 30, 2022.
and enrolling patients into programs to access A total of 33,697 medication fills for 3084
the necessary financial assistance (FA) can patients were recorded. The average OOP cost
be a lengthy, complex process. PAPs can per fill varied depending on the medication,

40 pharmacytimes.com April 2024

 F I N A N C I A L TOX I C I T Y | P R AC T I CE I N S I G HTS

and the median was skewed significantly because the clinic, these patients are followed through the
of high outliers. Approximately 81% (n = 27,137) process by the HSSP regardless of the location of
of the distinct fills were associated with an OOP their fill.”
cost less than $5, and of those patients who had an Shields Care is an HSSP that works with health
OOP cost of less than $5, approximately 89% had system partners to manage prior authorization
FA secured. by embedding pharmacy liaisons into specialty
Further, patients with government insurance clinics. The Shields model identifies FA for
filling brand medications received FA 92% of patients in the health system regardless of whether
the time, compared with a rate of 83% for fills their pharmacy location is within the health
for generic medications. In contrast, 81% of system.
patients in the nongovernment group filling brand “[This model] was created to address
medications had FA secured, compared with 49% inadequate specialty patient outcomes
of patients filling generic medications. According secondary to limited access, insurance barriers,
to the authors of the retrospective analysis, these financial toxicity, poor adherence, low patient
data highlight the role of manufacturer support in engagement, and patient/provider dissatisfaction
lowering OOP costs for brand medications as well in the specialty pharmacy marketplace. Health
as the significance of grant funding and PAPs for systems are uniquely positioned to provide
government-insured patients who receive generic unparalleled patient care because the patient,
medications. prescribers, nurses, support staff, and specialty
Pharmacy liaisons, who ideally are embedded pharmacy team are all colocated, use a shared
within specialty clinics, also provide support EMR, and have integrated workflows and direct
through therapy enrollment processes, assessing communication,” Stutsky said.
financial needs, directly coordinating with drug Although financial toxicity continues to be a
delivery, and monitoring patients’ adherence to problem within cancer care, the implementation
therapies. In addition, an integrated model can of PAPs can help reduce the burden, and
help identify potential risk early (at the time of HSSPs—such as in that of the Shields model—are
the first fill) and can include outreach to a PAP created to optimize PAP funds. Reducing the
targeted toward solving the problem prior to the OOP costs for patients with cancer can increase
clinical outcomes being compromised, according accessibility to medication while potentially
to the authors of the retrospective analysis. improving treatment adherence and clinical
“In an integrated HSSP model, the pharmacy outcomes. According to Stutsky, the next steps to
liaison is often the first member of the interdisciplinary addressing financial toxicity within oral oncology
health care team to speak to the patient about the involve enabling patient access to these programs;
cost of their medication and to inform them about however, long-term strategies will require more
options for assistance,” Stutsky said. “As the expert effort because more complex strategies must
in accessing available funding, the liaison navigates be developed.
patients through the enrollment process to reduce “PAPs and facilitating patient access to these
delays to starting therapy.” programs is an interim solution to the issue of
According to Stutsky, an additional advantage financial toxicity in oral oncology,” Stutsky
of pharmacy liaisons within integrated HSSPs said. “However, long-term strategies to solve
is the ability to identify FA for patients within the problem include policy changes—including
the health system, regardless of the pharmacy at Medicare Part D benefit design—and addressing
which they fill. the high cost of these medications.”
“If a prescription is transferred to an external
pharmacy due to insurance mandates or other REFERENCE
reasons, the Shields liaison still coordinates the 1. Stutsky M, Lindner C. The challenge of financial
PAP with the patient and works with the external toxicity in cancer care: a focus on oral oncology.
pharmacy to ensure that the patient receives their Shields Health Solutions. October 5, 2023. Accessed
medication in a timely manner,” Stutsky said. January 4, 2024. https://www.shieldshealthsolutions.
“Because the liaison has visibility to the electronic com/wp-content/uploads/2023/10/Shields_
medical record [EMR] and communication with WP_2023_OncologyFinTox_10.5.23.pdf

April 2024 pharmacytimes.com 41

P RACTICE INSIGHTS | IN S U RAN C E AP P ROVALS & A I

Optimizing Oncological Care: The Influence of AI

on Insurance Approvals
Successful integration demands overcoming various hurdles.
B r i an C ox, M BA, MS S F, FACH E ; and Alb e r to Co u s tas se , Dr P H, MD, MBA, MPH

A BOUT THE AUTHORS

Brian Cox, MBA, MSSF,
FACHE, is the director of
hospital operations and
IT/CIT at Baptist Health
W ithin the United States,
oncological treatments represent
a considerable portion of the
health care landscape, in terms of both their
prevalence and associated costs. The year
periods, with patients enduring delays of up
to 4 months before receiving approval.6,7 The
administrative intricacies associated with
obtaining insurance authorization for such
treatments profoundly affect patient care,
System in New Albany,
Indiana. 2022 witnessed 1.9 million new cancer cases which helps to emphasize the urgent need for
and over 600,000 cancer-related deaths, streamlined and efficient processes.4,8
Alberto Coustasse, signaling the pressing need for efficient
DrPH, MD, MBA, MPH, is strategies in managing and addressing AI Intervention in Streamlining
a professor in the Health
Informatics Program in
challenges in oncology.1 Authorization Processes
the Management and The financial weight of cancer care is Recent strides in artificial intelligence (AI)
Health Care Administrative striking, with the total national expenditure offer promising solutions to expedite and
Division at the Lewis on cancer care reaching approximately enhance the PA and insurance approval
College of Business at $208.9 billion in 2020. This substantial cost processes. For example, Health Care
Marshall University in South
encompasses direct medical expenses and Service Corporation (HCSC) implemented
Charleston, West Virginia.
indirect costs such as productivity loss due to AI and observed a resulting 1400 times
illness and premature death.2,3 These figures faster processing rate for PA requests in
underscore the critical need to optimize 2022. This breakthrough significantly
oncological processes to ensure timely and reduced processing times and enabled more
accessible patient care. efficient triaging of requests. 9,10 However, it
should be noted that the AI tools at HCSC
Challenges in Oncological only approve or forward the PA to a hands-on
Treatment Authorization clinician reviewer and never deny claims. 9
Managing prior authorization (PA) and Studies suggest that using AI-based systems
insurance approvals in oncology has always to standardize clinical data submissions and
presented a considerable challenge. These integrate electronic health records using the
intricate processes involve numerous Fast Healthcare Interoperability Resources
stakeholders and can cause significant data standard can optimize these processes
delays, ultimately impeding patients’ further.10 Standardization initiatives aim
access to critical treatments. 4 Studies to alleviate administrative burdens and
have demonstrated that these delays have expedite treatment access for patients
a considerable impact, with essential with cancer. Strategies such as developing
services such as imaging and chemotherapy specialty-oriented, tool-based approaches
experiencing an average delay of 2 weeks. 4 and incorporating national clinical guidelines
Additionally, some reports have shown that into decision-making processes can also
patients may abandon their recommended improve the efficiency and effectiveness of
treatment plans due to the time-consuming the authorization process.4,8
and often complicated PA process. 5
Furthermore, specific treatments, such as Financial Implications and
proton beam therapy, encounter remarkably Administrative Burdens
high initial denial rates, reaching up to 60%. The financial strain imposed on health care
These denials lead to prolonged waiting institutions by the PA process has been

42 pharmacytimes.com April 2024

 I N S UR A N C E A PPR OVA L S & A I | P R AC T I CE I N S I G HTS

substantial, with estimates indicating an annual cost 3. Financial burden of cancer care. National Cancer Institute.
of nearly $500,000 per institution for obtaining PA for Updated August 2023. Accessed December 14, 2023.
radiation treatment–related services. 11 Administrative https://progressreport.cancer.gov/after/economic_burden
hurdles, especially those related to PA policies, have 4. Chino F, Baez A, Elkins IB, Aviki EM, Ghazal LV, Thom
significantly impeded clinical access to specific B. The patient experience of prior authorization for cancer
therapies, resulting in financial constraints within the care. JAMA Netw Open. 2023;6(10):e2338182. doi:10.1001/
health care system. 8 jamanetworkopen.2023.38182
Addressing the challenges and optimizing AI integration 5. Smith AJB, Mulugeta-Gordon L, Pena D, et al. Prior
in oncological treatment processes necessitates overcoming authorization in gynecologic oncology: an analysis of clinical
various hurdles. Ensuring AI systems’ seamless integration impact. Gynecol Oncol. 2022;167(3):519-522. doi:10.1016/j.
and interoperability with existing health care infrastructures ygyno.2022.10.002
is paramount to their effective operation. Additionally, 6. Yu NY, Sio TT, Mohindra P, et al. The insurance approval
comprehensive data standardization across health care process for proton beam therapy must change: prior
facilities is crucial to unlocking the full potential of AI authorization is crippling access to appropriate health care. Int
in streamlining authorization processes and ultimately J Radiat Oncol Biol Phys. 2019;104(4):737-739. doi:10.1016/j.
enhancing patient care.12 ijrobp.2019.04.007
Burnout among providers due to the PA process is also an 7. Chiang JS, Yu NY, Daniels TB, Liu W, Schild SE, Sio TT.
expected outcome, even for providers in training. A study of Proton beam radiotherapy for patients with early-stage and
313 radiation and medical oncology trainees found that 71% advanced lung cancer: a narrative review with contemporary
reported a concern for the quality of care declining, and clinical recommendations. J Thorac Dis. 2021;13(2):1270-
77.1% also reported decreased enthusiasm for their chosen 1285. doi:10.21037/jtd-20-2501
profession as a result of the PA process.13 8. Gupta A, Khan AJ, Goyal S, et al. Insurance approval for
proton beam therapy and its impact on delays in treatment. Int
The Path Forward: Addressing Challenges and J Radiat Oncol Biol Phys. 2019;104(4):714-723. doi:10.1016/j.
Optimizing AI Integration ijrobp.2018.12.021
Ensuring fairness and accuracy in AI algorithms is 9. Diamond F. How HCSC is using AI to speed up prior
crucial. To achieve this, national clinical leaders and authorization. Fierce Healthcare. July 17, 2023. Accessed
patient representatives should evaluate and certify December 14, 2023. https://www.fiercehealthcare.com/payers/
the algorithms. Additionally, including patient hcsc-using-augmented-and-artificial-intelligence-quicken-
representatives in the review board guarantees that the speed-prior-authorization
AI algorithms effectively incorporate patient needs, 10. Lenert LA, Lane S, Wehbe R. Could an artificial intelligence
concerns, and values. This rigorous process ensures that approach to prior authorization be more human? J Am Med
expert-level decisions are made transparently and fairly. 10 Inform Assoc. 2023;30(5):989-994. doi:10.1093/jamia/ocad016
The integration of AI has the potential to significantly 11. Bingham B, Chennupati S, Osmundson EC. Estimating
improve traditional methods of analyzing medical data the practice-level and national cost burden of treatment-
for cancer detection and treatment.14 Collaborative efforts related prior authorization for academic radiation oncology
among stakeholders, technology developers, and regulatory practices. JCO Oncol Pract. 2022;18(6):e974-e987.
bodies are pivotal in accelerating standardized AI solutions doi:10.1200/OP.21.00644
in oncology. These concerted endeavors catalyze improved 12. Williams E, Kienast M, Medawar E, et al. A standardized
authorization processes, ultimately enhancing patient access clinical data harmonization pipeline for scalable AI application
to timely and effective treatments. deployment (FHIR-DHP): validation and usability study. JMIR
Med Inform. 2023;11:e43847. doi:10.2196/43847
REFERENCES 13. Kim H, Srivastava A, Gabani P, Kim E, Lee H, Pedersen KS.
1. Cancer facts & figures 2022. American Cancer Society. Oncology trainee perceptions of the prior authorization process:
Accessed December 14, 2023. https://www.cancer.org/research/ a national survey. Adv Radiat Oncol. 2021;7(2):100861.
cancer-facts-statistics/all-cancer-facts-figures/cancer-facts- doi:10.1016/j.adro.2021.100861
figures-2022.html 14. Cox B, Coustasse A, Gupta M, Kimble C. AI is revolutionizing
2. Mariotto AB, Enewold L, Zhao J, Zeruto CA, Yabroff KR. oncology with a quantum leap in cancer treatment. Pharmacy
Medical care costs associated with cancer survivorship Times. October 16, 2023. Accessed December 14, 2023. https://
in the United States. Cancer Epidemiol Biomarkers Prev. www.pharmacytimes.com/view/ai-is-revolutionizing-oncology-
2020;29(7):1304-1312. doi:10.1158/1055-9965.EPI-19-1534 with-a-quantum-leap-in-cancer-treatment

April 2024 pharmacytimes.com 43

PATIENT F OCUS | S C T

Advancement in Stem Cell Transplantation:

Improving Outcomes for Patients With
Blood Cancer
Advances, challenges, and promising innovations emerge.
Le e n A lya se en , P h a rmD cand i d ate ; Brax to n Par k, Phar mD ca n didate; Ja n et John , Pha rm D ca n didate; Ja n ice T h om a s, Ph a rm D
can d i date ; J es se n ia Ama ro, Phar mD cand i d ate ; M o lli e Sc hatz, Ph a rm D ca ndidate; a n d Sa ra Rogers, Ph a rm D, BCPS

A BOUT THE AUTHORS

Leen Alyaseen is a class
of 2024 PharmD candidate
in the Department of
Pharmacy Practice, Irma
T he development of stem cell
transplantation (SCT), also referred
to as hematopoietic SCT, is a critical
landmark in medicine. SCT gives patients
another chance at life when fighting such
SCT evolves based on the research and
technological developments that are key
to the field’s advancement and the
possibility of application in cancer
clinics.1,2 Further, SCT is becoming more
Lerma Rangel School of blood cancers as leukemia, lymphoma, and personalized with immunotherapy and
Pharmacy, Texas A&M
University in Kingsville.
multiple myeloma (MM).1 This technique genome-editing therapies.
is carried out by stem cell infiltration into
Braxton Park, Janet the patient’s circulation, and is intended Clinical Application
John, Janice Thomas, to replace cancerous or damaged cells to SCT is recommended for patients who are
Jessenia Amaro, and Mollie facilitate average blood cell production and in remission and can tolerate intensive
Schatz are class of 2027
PharmD candidates in the
enhance immunity. chemotherapy; SCT is done during the
Department of Pharmacy Cancer therapies like chemotherapy consolidation phase. During this process,
Practice, Irma Lerma Rangel and radiotherapy are effective for treating the remaining leukemic cells, including
School of Pharmacy, Texas many types of cancer, offering significant normal cells, are killed from the patient’s
A&M University in Kingsville. potential for disease management and overall bone marrow, and are replaced with the
Sara Rogers, PharmD,
survival improvement. SCT provides an transfused stem cells the transfusion of
BCPS, is a clinical assistant alternate solution for patients who do not stem cells. The new stem cells replenish
professor of precision respond to traditional methods of treatment the healthy stem cells in the bone marrow,
medicine and ambulatory or who have a relapse after such therapies.1 promoting the production of new red blood
care at Irma Lerma Rangel Using stem cells along with the infusion of cells, white blood cells, and platelets. 3,4
College of Pharmacy, Texas
A&M University in Kingsville;
healthy (or “normal”) undifferentiated stem Allogeneic transplants, the most common
a clinical specialist at cells ensures the elimination of cancerous among patients with leukemia, utilize
Texas A&M Physicians cells and regeneration of bone marrow healthy blood-forming cells from a family
Clinic; and a cofounder of simultaneously1,2; this results in increased member who is human leukocyte antigen
the American Society of protection for the patient from typical (HLA)–matched, umbilical cord blood,
Pharmacovigilance
in Houston.
illnesses and boosts their immune response or an unrelated donor. Previous exposure
to disease. to leukemic cells will assist the newly
Recently, SCT in oncology has become transplanted immune system in
more effective, less toxic, and more recognizing and assailing any remaining
accessible. The innovation of haploidentical cancerous cells, known as the
transplantation using donors with partial graft-vs-leukemia effect. 4
matching has enlarged the pool of donors, Lymphoma is a type of cancer that begins
relieving the stress of finding a match in the lymphatic system; the malignant
and hastening transplants.2 Also, the strict lymphomas include Hodgkin lymphoma
protocols and supportive care regimens (HL) and non-HL.5 Chemotherapy is
have drastically minimized complications usually the first-line therapy for aggressive
associated with the procedure, making the lymphomas, but 20% to 30% of patients with
technique tolerable and efficient. non-HL and 15% of patients with HL relapse
At the heart of technology innovation, after the first therapy.6 Follicular lymphoma,

44 pharmacytimes.com April 2024

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the most common indolent non-HL, is usually considered stem cell leads to the rejection of the graft by the host’s
incurable and exhibits a high incidence of relapse.7 immune system. 10 This is not an issue in ASCT, as the
SCT is considered for those failing first-line therapy.7 donor cells are the same as the recipient stem cells.
Two approaches to treating recurrent follicular lymphomas Allogeneic embryonic stem cells (ESCs) transplanted
include autologous SCT (ASCT) and allogeneic SCT in mice with healthy immune systems vs those that are
(alloSCT).7 A study (NCT00137995) conducted before the immunocompromised showed destruction within 7 to
widespread use of rituximab (Rituxan; Genentech) compared 10 days, with a lower cell survival time in the second
chemotherapy with chemotherapy followed by ASCT.7 round of injections. 10 The presence of surface proteins
The study demonstrated higher 2-year progression-free on the ESCs triggers the attack of donor ESCs by the
survival (PFS) rates for purged (hematopoietic stem cells recipient’s immune system. 10 Antibodies in the body
[HSCs] without contaminated cancer cells) and unpurged cause hyperacute immune rejections involving systemic
(unpurified HSCs) stem cells (58% and 55%, respectively) inflammatory responses shortly after transplantation. 10
compared with chemotherapy alone (26%).7 Additionally, HLA mismatch leads to acute rejection within 7 days
overall survival at 4 years was notably higher in the purged of the procedure, whereas chronic rejection means a
and unpurged stem cells (71% and 77%, respectively) than mismatch in the minor histocompatibility complex
chemotherapy alone.7 results in long-term graft rejection and
alloSCT has a lower rate of relapse but a higher rate of graft-vs-host diseases. 10
transplant-related mortality, especially in older patients.7 Chimeric antigen receptor (CAR) T-cell therapy has
To minimize this, a reduced intensity conditioned (RIC) provided positive results for B-cell malignancies such
alloSCT, was considered. Studies using the RIC allogeneic as lymphoma, with patients experiencing sustained
SCT process have been promising in older patients and in remissions.11 However, there are safety concerns about
those heavily pretreated (with chemotherapy or ASCT), how the activation and proliferation of CAR T cells are
showing a possibility for a cure. This treatment shows a uncontrolled once infused into the patient’s body.11 In some
5-year PFS rate of 50% to 85%.7 clinical trials, the 10-fold expansion of CAR T cells has
MM is a type of cancer that forms in plasma cells. In caused tumor lysis syndrome and fatal cytokine release
MM, the cells accumulate in the bone marrow and become syndrome.11 In addition, 10% of patients given CAR T-cell
cancerous, crowding out the healthy blood cells.8 There are therapy targeting the pan–B-cell antigen CD19 (CART-19)
several treatment options for MM, including chemotherapy, show evidence of relapse due to the inability of CAR T cells
immune modulator drugs, targeted therapies, stem cell transplant, to target and bind to mutant cancer cells that have lost their
and supportive care.8 The deciding factors for what form of antigens.11 To combat this, the recombinant engineering of
treatment to pursue include the disease stage, the patient’s switches specific to CART-19 has been a potential method to
health, and the genetic characteristics of the cancer cells.8 prevent the undesired release of cytokines.11 These antibody
SCT, and specifically usually ASCT, is commonly switches contain a tumor antigen–specific Fab molecule
considered the standard consolidation plan for patients with embedded with a new peptide that can bind to an antibody
newly diagnosed MM and some patients with a recurrence and generate an antigenic response.11 The Fab molecule
of the disease.9 ASCT is added to treat patients undergoing binds specifically to the switchable CAR T cell and forms a
high-dose chemotherapy (HDC) combined with ixazomib complex that can control the activities of the CAR T cells to
(Ninlaro; Takeda Pharmaceuticals), an oral proteasome a certain extent.11
inhibitor, and granulocyte colony-stimulating factors.9 Unlike the success story of B-cell stem cell therapy,
This combination of treatments is favorable with stem cell the use of CAR T-cell therapy for T-cell malignancies has
mobilization in approximately 89% of patients.9 The best major challenges relating to its procedure.12 As cancer has
patient candidates with MM for stem cell transplantation are a set pathway for infection of the T cell, the possibility of
in overall good health and can withstand HDC, respond well blast contamination of the newly replaced autologous T-cell
to initial treatment, have adequate stem cell reserves, are products is high.12 The contaminated CAR T cells would then
relatively young, and have stable comorbidities.8 be targeted for destruction, meaning that T-lineage antigens
are no longer being eliminated.12 Because of the antitumor
Challenges Behind SCT activity of allogeneic double-negative T cells (DNTs), it has
There is a need to address challenges with host immune been explored as the alternative treatment option against
rejection and procedure-related issues before stem T-cell acute lymphoblastic leukemia and peripheral T-cell
cell treatments are offered to patients as the first line lymphoma.12 In vitro studies and xenograft models showed
of therapy. The expression of foreign antigens on the that allogeneic DNTs could be made more potent in the

April 2024 pharmacytimes.com 45

PATIENT F OCUS | S C T

destruction of T-cell malignancies by transducing the DNTs regularly interspaced short palindromic repeats (CRISPR)
with a third-generation anti–CD4-CAR-DNT.12 technology to edit a protein called CD45, which sits on
the surface of CAR T cells and HSCs to protect them from
Recent Research Innovation leukocyte attacks.16 With the mutation, the CAR T-cell/stem
Stem cell therapy is a treatment of interest for cancer cell therapy has shown prolonged anticancer effects against
due to its reduced off-target effects and potential for acute myeloid leukemia, acute T-cell leukemia, and
enhancing the target specificity of traditional standards B-cell lymphoma.16
of care when used as carriers or in combination therapy.
These treatment strategies involve HSC and mesenchymal Conclusion
stem cell (MSC) transplantation. In hematologic oncology, the evolution of SCT and its
Specifically for blood cancers such as MM, leukemia, and accompanying treatments continue to show improvement
lymphoma, the derivation of exosomes from stem cells has in blood cancer therapy. In its current clinical setting,
shown promise in providing a modified route for delivering SCT therapies have offered many patients with leukemia,
anticancer drugs. To utilize the stem cells as carriers, they lymphoma, and MM a second chance at life. However,
must be primed with the drug of choice and other exogenous with innovation comes new challenges, such as antigen
materials to increase the acceptance of the stem cells into mismatching, that will require equally creative solutions.
the body.13 After priming, the stem cells can absorb the drug Recent innovations, like the development of paclitaxel
and package the drug molecules into their exosomes to be and CAR T-cell treatments, show the ongoing efforts to
released via exocytosis at the tumor site.13 Bonomi et al refine and reduce the risks associated with SCT. These
experimented with priming mesenchymal stromal cells with developments are just a glimpse into the fascinating future
paclitaxel to test for growth inhibition in MM and leukemia of SCT pharmaceutics, which can further expand the
cells in both in vitro and in vivo studies.14,15 When tested in therapeutic benefits of stem cell therapies in medicine.
vitro and in vivo on both human and mice leukemia cells,
the study found that the paclitaxel-primed cells inhibited
proliferation and reduced angiogenesis of leukemia cells.15
The anticancer drug–primed stem cells acted relatively REFERENCES
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Similar potent anticancer effects were seen when applied strategies to prevent and treat disease relapse after stem-cell
to MM cells, an aggressive form of hematologic cancer. transplantation. J Clin Oncol. 2021;39(5):386-396.
Additionally, observations showed proof of MM cell doi:10.1200/JCO.20.01587
growth suppression upon injection of the primed MSCs.14 2. La Rocca U. Donor specific anti-HLA antibodies in
Although further studies are needed to ensure the safety and Hematopoietic Stem Cell Transplantation. A stepwise
efficacy of drug-releasing stem cell exosomes, this treatment project to establish a better definition of their role and a
option, combined with other immunotherapies, can enhance desensitization strategy. Dissertation. Sapienza Universita di
antiangiogenic effects at target cells while maintaining the Roma. Accessed February 18, 2024. https://iris.uniroma1.it/
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cancers is combining it with CAR T-cell treatments to create Accessed February 24, 2024. https://siteman.wustl.edu/
a replenishing source of immune cells. CAR T cells have treatment/cancer-types/leukemia/blood-and-marrow-transplant-
been successful in anticancer applications; the cells are for-leukemia/
extracted from the patient, activated, and otherwise modified 4. Stem cell transplantation. Leukemia & Lymphoma Society.
before being transfused into the patient to act on the tumor Accessed February 24, 2024. https://www.lls.org/leukemia/
cells by targeting their antigens.13 However, the actions of acute-myeloid-leukemia/treatment/stem-cell-transplantation
the CAR T cells have a short duration due to their tendency 5. Matasar MJ, Zelenetz AD. Overview of lymphoma diagnosis
to differentiate into effector cells with limited anticancer and management. Radiol Clin North Am. 2008;46(2):175-198.
activity.13 By combining the CAR T cells with stem cells, doi:10.1016/j.rcl.2008.03.005
there would be longer-lasting sources of “blank canvas” 6. Zahid U, Akbar F, Amaraneni A, et al. A review of autologous
immune cells to draw from to create more CAR T cells; stem cell transplantation in lymphoma. Curr Hematol Malig
these, in turn, can prolong the anticancer activity at the Rep. 2017;12(3):217-226. doi:10.1007/s11899-017-0382-1
tumor site to prevent further growth and kill the cancer cells. 7. Norman JE, Schouten HC, Dreger P, Robinson SP. The role
Wellhausen et al embraced this approach and used clustered of stem cell transplantation in the management of relapsed

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follicular lymphoma in the era of targeted therapies. negative CD4-CAR-T cells. J Immunother Cancer.
Bone Marrow Transplant. 2019;54(6):787-797. 2023;11(9):e007277. doi:10.1136/jitc-2023-007277
doi:10.1038/s41409-018-0372-5 13. Chu DT, Nguyen TT, Tien NLB, et al. Recent progress
8. Gerecke C, Fuhrmann S, Strifler S, Schmidt-Hieber of stem cell therapy in cancer treatment: molecular
M, Einsele H, Knop S. The diagnosis and treatment mechanisms and potential applications. Cells.
of multiple myeloma. Dtsch Arztebl Int. 2016;113(27- 2020;9(3):563. doi:10.3390/cells9030563
28):470-476. doi:10.3238/arztebl.2016.0470 14. Bonomi A, Steimberg N, Benetti A, et al. Paclitaxel-
9. Bühler S, Akhoundova D, Jeker B, et al. Stem cell releasing mesenchymal stromal cells inhibit the growth of
mobilization with ixazomib and G-CSF in patients with multiple myeloma cells in a dynamic 3D culture system.
multiple myeloma. Cancers (Basel). 2023;15(2):430. Hematol Oncol. 2017;35(4):693-702.
doi:10.3390/cancers15020430 doi:10.1002/hon.2306
10. Li SC, Zhong JF. Twisting immune responses for 15. Pessina A, Coccè V, Pascucci L, et al. Mesenchymal
allogeneic stem cell therapy. World J Stem Cells. stromal cells primed with paclitaxel attract and kill
2009;1(1):30-35. doi:10.4252/wjsc.v1.i1.30 leukemia cells, inhibit angiogenesis and improve
11. Rodgers DT, Mazagova M, Hampton EN, et al. Switch- survival of leukemia-bearing mice. Br J Haematol.
mediated activation and retargeting of CAR-T cells 2013;160(6):766-778. doi:10.1111/bjh.12196
for B-cell malignancies. Proc Natl Acad Sci U S A. 16. Wellhausen N, O’Connell RP, Lesch S, et al. Epitope
2016;113(4):E459-E468. doi:10.1073/pnas.1524155113 base editing CD45 in hematopoietic cells enables
12. Fang KK, Lee J, Khatri I, Na Y, Zhang L. Targeting universal blood cancer immune therapy. Sci Transl Med.
T-cell malignancies using allogeneic double- 2023;15(714):eadi1145. doi:10.1126/scitranslmed.adi1145

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April 2024 pharmacytimes.com 47

CO N F ERENCE | ACC C AMC C BS

F E BRUA RY 2 8 – MA RCH 1 , 2024 | CAPITAL H ILTON IN WASHIN GTON , DC

Unlocking the Potential of Machine Learning and

Language Models in Oncology
Some terminology and history of these models can be beneficial for
oncology professionals.
A l an a H i ppe n ste el e, Ma nag i ng Ed i to r

A strength of using machine learning (ML) in

oncology is its potential to extract data from
unstructured documents, explained Will Shapiro,
vice president of data science at Flatiron Health, during a
session at the Association of Cancer Care Centers’ (ACCC)
Shapiro noted that terminology can pose challenges for
professionals in health care as they begin diving into terms
that contain a wealth of knowledge based on decades of
research and thousands of dissertations. Terms such as LLM,
natural language processing (NLP), generative AI, AI, and
50th Annual Meeting and Cancer Center Business Summit ML each represent an abundance of information that have
(AMCCBS) in Washington, DC. According to Shapiro, the helped us understand their potential today. Specifically,
ML team at Flatiron is focused on this endeavor in relation Shapiro noted that this collection of terms he highlighted
to oncology data and literature. is distinct from workflow automation, another term in the
“There’s a ton of really rich information that’s only in same field that often gets grouped with the others. Shapiro
unstructured documents,” Shapiro said during the session. noted that workflow automation is distinct in that there are
“We build models to extract things like metastatic status or well-known ways in which quality is evaluated.
diagnosis state, which are often not captured in any kind of “With something like generative AI—which is, I think,
regular, structured way.” one of the most hyped things out in the world right now—it’s
Shapiro explained that more recently, his ML team has so new that there really aren’t ways that we can think about
started working with large language models (LLMs). He quality,” Shapiro said during the session. “That’s why I think
noted this space has significant potential within health care. it’s really important to get educated and understand what’s
“[At Flatiron] we built out a tool at the point of care going on [around these terms].”
that matches practice-authored regimens to [National According to Shapiro, a lot of these terms get used
Comprehensive Cancer Network] guidelines,” Shapiro said. interchangeably, which can increase confusion. “I think
“That’s something that we’re really excited about.” that there’s a good reason for that, which is that there’s a
Notably, Shapiro explained that his background is not lot of overlap,” Shapiro said during the session. “The same
in health care; he worked for many years at Spotify, where algorithm can be a deep learning algorithm and an NLP
he built personalized recommendation engines using algorithm, and a lot of the applications are also the same.”
artificial intelligence (AI) and ML. “I really got excited Shapiro noted that one way of structuring these terms is to
about machine learning and AI in the context of building think of AI as a broad category that encompasses ML, deep
personalized recommendation engines [at Spotify],” Shapiro learning, and generative AI as nested subcategories. NLP,
said during the session. “[Although] personalizing music for however, contains some differences.
a place like Spotify is radically different from personalizing “There is an enormous amount of overlap between NLP
medicine, I think there are actually some core things that and AI. A lot of the major advances in ML and AI stemmed
really connect them, and I believe strongly that ML and from questions from NLP. But then there are also parts of
AI have a key role to play in making truly personalized NLP that are really distinct. [For example,] rules-based
medicine a reality.” methods of parsing text are not something that I will think

48 pharmacytimes.com April 2024

 AC C C A M C C B S | C O N F E R E NCE

about with AI, and I will [preface] this by saying that this predicting or doing 1 task,” Shapiro said. “But 1 thing that’s
is contentious,” Shapiro said during the session. “If you become really exciting, and kind of gets into the weeds
google this, there will be 20 different ways that people try to of LLMs, is this concept of taking a pretrained model and
structure this. My guidance is to not get too bogged down in fine-tuning it on labeled examples, which is a way to really
the labels but really try to focus on what the algorithm is, or increase the performance of a pretrained model.”
[what] the product is that you’re trying to understand.” Further, the “T” in ChatGPT stands for “transformer,”
According to Shapiro, 1 reason oncologists should care which is a type of deep learning architecture developed at
about these terms is that ChatGPT, the most famous LLM in Google in 2017. According to Shapiro, it was originally
use today, is used by 1 in 10 doctors in their practice, according described in a paper called “Attention Is All You Need.”
to a survey conducted in summer 2023. Shapiro noted that by “Transformers are actually kind of simple,” Shapiro said. “If
the time of the presentation at the ACCC AMCCBS meeting in you read about the history of deep learning, model architectures
February 2024, that number had likely increased. tended to get more and more complex, and the transformer
LLMs are also a type of language model. According to actually stripped away a fair amount of this complexity. But
Shapiro, the technical definition of a language model is a what’s been really game changing is how big they are, as
probability distribution over a sequence of words. they’re trained on the internet. So, things like Wikipedia,
“So, basically, given a chunk of text, [it’s] the probability Reddit—these huge corpuses of text—have billions of
that any word will follow the chunk that you’re looking at,” grammars, and they’re really, really expensive to train.”
Shapiro said during the session. “LLMs are essentially language Yet, the size of them has led to these incredible
models that are trained on the internet, so they’re enormous.” breakthroughs in performance and benchmarks that have
According to Shapiro, language models can also be used caused quite a bit of buzz recently, Shapiro explained. This
to generate text. For instance, in the example “My best attention raises the importance of becoming more educated
friend and I are so close, we finish each other’s ” it is in what these models are and how they work, especially in
not difficult for humans to finish this with the appropriate areas such as health care.
word in the blank, which would be “sentences.” Shapiro “With 10% of doctors using ChatGPT, it is something that
explained that this is very much how language models work. everyone really needs to get educated about pretty quickly. I
“Probabilistically, ‘sentence’ is the missing word [in also just think there are so many exciting ways that ML and
that example], which is very much at the core of what’s AI have a role to play in the future of oncology,” Shapiro
happening with a language model,” Shapiro said during the said during the session.
session. “In fact, autocomplete, which you probably don’t Shapiro added that, by using these models, there is the
even think about as you see it every day, is generative AI potential in oncology to conduct research pulled from
that’s an example [of a language model], and it’s one of the enormous patient populations, which can be made available
motivating examples of generative AI.” at scale. Additionally, there is the potential to summarize
To be clear in terms of definition, Shapiro noted that visit notes from audio recordings, to predict patient response
generative AI are AI models that generate new content. to a treatment, and to discover new drug targets.
Specifically, the “GPT” in ChatGPT (which is both an “There are huge opportunities in ML and AI, but there are
LLM and a generative AI) stands for generative pretrained also a lot of challenges and a lot of open questions. When
transformer. According to Shapiro, pretrained models can you see someone like Sam Altman, the CEO of OpenAI,
be understood as having a foundational knowledge, which going to Congress and asking it to be regulated, you know
contrasts with other kinds of models that just do a that there’s something to pay attention to,” Shapiro said during
single task. the session. “That’s because there are some real problems.”
“I mentioned my team works on building models that will Such problems include hallucinations, which consists
extract metastatic status from documents, and that’s all they of models inventing answers. Shapiro said what makes
do,” Shapiro said during the session. “In contrast, pretrained hallucinations by AI models even more pernicious is that
models can do a lot of different kinds of things. They can they come from a place of technological authority.
classify the sentiment of reviews, they can flag abusive “There’s an inherent inclination to trust them,” Shapiro
messages, and they probably are going to write the next 10 said during the session. “There’s a lot of traditional
Harry Potter novels. They can extract adverse events from considerations for any type of ML or AI algorithm around
charts and they can also do things that extract metastatic whether they are biased, whether they are perpetuating
status. So, that’s a big part of the appeal: 1 model can do a inequity, and whether data shifts affect their quality. For this
lot of different things.” reason, I think it’s more important than ever to really think
However, this can have a trade-off in terms of quality. closely about how you’re validating the quality of models.
“What we’ve found at Flatiron Health is that, generally, High-quality ground truth data, I think, is essential for using
purpose-built models can be much better at actually any of these types of ML or AI algorithms.”

VISIT PHARMACYTIMES.COM FOR REFERENCES.

April 2024 pharmacytimes.com 49

CO N F ERENCE | ACC C AMC C BS

Balancing Health Tech Innovation With Safety:

Navigating the Intersection of AI and Patient Care
Real safety concerns persist for patients in the rapid development of
AI technology.
A l an a H i ppe n ste el e, Ma nag i ng Ed i to r

I n the digital technology space, rapid product

development is key, explained Stephen V. Speicher,
MD, MS, senior medical director and head of health
care quality and patient safety at Flatiron Health during
a session at the Association of Cancer Care Centers 50th
I do think we’re the sole industry that is keeping fax machine
companies in business,” Speicher said during the session. “But
I can personally attest to the fact that as we’ve been building
out things like the [electronic health record (EHR)] and other
software devices, we’ve done so while keeping safety front
Annual Meeting and Cancer Center Business Summit in of mind. This has never been more important than right now
Washington, DC. With the rapidity of this development in in technological history.”1
the tech industry, consumer safety has not necessarily been a In product development in the tech industry, there is
significant consideration, Speicher explained.1 a concept known as the “hype cycle,” which Speicher
“You don’t have to be a tech guru to understand that explained is the actual technical term with a real
the early tech motto at Facebook was ‘to move fast and to methodology.1 Developed by the market research firm
break things,’” Speicher said during the session. “Although Gartner, the hype cycle follows the journey of new
this has led to a tremendous amount of digital technology technologies from introduction to the peak of inflated
in the space, as well as a multitrillion-dollar industry and expectations, through the trough of disillusionment, and
tremendous shareholder value, it has also created a culture ultimately to their plateau of productivity.1,2
where, historically at least, safety and quality have not been “In 2023 and 2024, Gartner puts artificial intelligence
front of mind, specifically on the consumer side.”1 [AI] at the peak of inflated expectations, which essentially
In the classic software development model, a team of means that it’s right now at the peak of the hype cycle,”
engineers, designers, and product managers work to design, Speicher said during the session. “I think we can all see
develop, and roll out software products to consumers as fast that in how AI is talked about in day-to-day conversations. I
as possible, according to Speicher. This process can take think, right now, if you were to ask any random person about
weeks or months, depending on the company—very different AI, they’re either going to say it is the savior that’s going
from the years or decades product development can take in to do everything possible to solve every single problem out
much more risk-averse industries, such as aerospace or drug there, or the AI robots are going to take over the world and
development.1 destroy us—there really is no in-between when we’re talking
“What that really led to is a culture where safety might not about AI.” 1
be front of mind, and it might be thought of as an ultimately According to Speicher, our current place in the hype cycle
secondary outcome for product development,” Speicher said is an optimal time to be thinking about quality and safety
during the session. “The biggest example of this can be seen and prioritizing those areas over rapid innovation. Speicher
in social media. In social media platforms, recent numbers explained that it is important for the health care industry to
have shown that Meta, the company that owns Facebook, understand now what the opportunities and risks are.1
Instagram, and WhatsApp, has approximately 4 billion daily “Health care, for the first time, is not behind in the use
active users at this point. So, with more than half of the of [current technology],” Speicher said during the session.
world’s population using one of these social media platforms “With 10% of physicians using ChatGPT, [according to a
every single day, you would hope that safety was really survey conducted in the summer of 2023], we need to stay
thought about as these things were being built out.”1 on top of safety and quality.”1
However, a recent systematic review showed that there is a A recent story published by Today exemplified the
70% increase in self-reported symptoms of depression among messaging the public is receiving around AI in a health care
groups that use social media frequently, Speicher explained. context, according to Speicher.1 “This [story] is actually
Yet, although consumer-facing digital technology does not have something that my mom sent me, as she is an avid watcher
the most ideal track record for safety, there is positive news of the Today show,” Speicher said during the session.
when it comes to the health care tech industry.1 “This story is of a young boy whose mom brought him
“Hopefully, this is not surprising, but we’ve been much to multiple doctors, and nobody could find the diagnosis.
more vigilant in our pursuit of safe and high-quality But she put his symptoms in ChatGPT, and they found the
technology in health care. But it may come at a cost because correct diagnosis—this is the messaging that [the public

52 pharmacytimes.com April 2024

 AC C C A M C C B S | C O N F E R E NCE

is] seeing, [which] is why we need to be having these equity, or it can be a movement away from equity and
conversations today about quality and safety.”1 toward greater inequities in health care,” Speicher
To effectively evaluate quality and safety regarding AI said. “So how do we think about that within our AI
tools in health care, there are 3 fundamental concerns to tools? Again, this goes back to our data example—
consider, Speicher explained. These, he said, are based on what happens if a model is based off data that are not
his understanding of how these tools are being inclusive, and we’re coming up with decisions and
built, his experience in other aspects of health care making conclusions that are really only relevant for a
information technology (IT), and what leading industry subset of the population and really shouldn’t be applied
experts are saying.1 to the broader population?”1
“The first area of crucial potential risk lies in The third and final concern Speicher noted regarding
the underlying foundational data infrastructure AI tools in health care is how these tools are being used,
that underpins these models,” Speicher said during and how to ensure that use is appropriate.1 “What I’ve
the session. “This is especially problematic as we learned working in health care IT is that these tools
think about health care data specifically. One of the are really only as safe as the way they’re being used
major moves in health care data is to this world of by clinicians,” Speicher said during the session. “The
interoperability where communication and data are example I like to use is a car. Of course, the car needs to
being transferred back and forth very seamlessly. be safe, the brakes need to work, the transmission needs to
[Although] that era is here, I would say it’s still fairly do whatever transmissions do—my example breaks down
nascent. That means data standards across the health really quickly because I don’t know cars very well—but,
care IT ecosystem are improving, but in their current ultimately, it’s the driver who dictates the overall safety
state, they still have a significant amount profile of the car. If you have a 16-year-old with a proven
of variability.”1 undeveloped prefrontal cortex vs someone a little older
According to Speicher, this is especially true in who is a little more risk averse—that’s who’s really
terms of historical data.1 “If you have an AI model dictating the safety of the product. In health care, it is
that’s learning relationships of hemoglobin to disease no different, and AI is no different.”1
progression for a patient, what happens if those According to Speicher, it is important to have full
hemoglobin values are inaccurate? The values are visibility for providers on how these tools work, what
incorrect, and the units are incorrect, and it is learning they are meant to do, and what they are not meant
from these historical data,” Speicher said during the to do. Further, Speicher noted that it is important
session. “Furthermore, these data standards [are] to understand ways to expedite workflows and not
proving to be really only applicable to Certified limit the critical thinking of physicians. However,
Health IT.”1 the problem of who makes sure all this happens is an
Health IT certification is overseen by the US federal additional consideration.1
government’s Office of the National Coordinator for “What’s really interesting to me is this may be one of
Health Information Technology (ONC).3 The ONC’s the very few topics where there’s a unanimous opinion
certification program ensures that Certified Health IT that regulation is actually quite important,” Speicher
meets the technological capability, functionality, and said during the session. “That being said, regulatory
security requirements adopted by the US Department of frameworks and health care IT is unique, and not
Health and Human Services (HHS).3 Speicher explained everything is regulated. There’s fragmentation on who
that health IT that is not certified may make claims regulates between the FDA, HHS, and other government
regarding the capabilities of its health technology, but agencies. Ultimately, and this is not going to surprise
it may not have the same standards for data quality that anybody, these things take a very long time to actually
Certified Health IT companies have.1 go through.”1
“The second area that I want to talk about is the In the meantime, these products are rapidly evolving
potential for bias [in AI tools in health care],” Speicher while regulatory bodies review them, Speicher
said during the session. “In the past few years, we’ve explained.1 “What we know about the current regulatory
seen a major push for understanding existing inequities landscape is that we have a few definitive inputs
in health care and making sure we are trying to on how we think about health care IT and AI in this
work toward a world of health equity for individuals space,” Speicher said during the session. “The first
regardless of race, gender, sexual orientation, income, thing we have is the Executive Order on the Safe, Secure,
and many other variables.” and Trustworthy Development and Use of Artificial
According to Speicher, like many things in Intelligence that was released by the White House [in
technology, AI can really move things in one direction October 2023], and we anticipate something coming out
or another. “It could be a movement toward improved from HHS in 2024 outlining in a little more detail what

April 2024 pharmacytimes.com 53

CO N F ERENCE | ACC C AMC C BS

this means specifically for health care.”1 important as health care professionals, providers, and
Then there is what is most relevant to Certified administrators to understand some of the basics of
Health IT, and that is the ONC’s Health Data, these tools and understand what questions you need
Technology, and Interoperability: Certification to start asking, and to have an appropriate level of
Program Updates, Algorithm Transparency, and skepticism,” Speicher said.1
Information Sharing (HTI-1) Final Rule. This rule The first question Speicher noted he would
basically builds from what the ONC was doing in recommend asking is about the use case.1 “I’d want
terms of clinical decision support. The HTI-1 also to understand where this [health tech] is incorporated
creates a new concept known as decision support into the workflow and how risky that part of the
intervention (DSI), with the ONC beginning to regulate workflow is,” Speicher said. “Are we talking about
what it calls predictive DSIs for the first time.1 treatment decisions or are we talking about diagnosis?
“[DSI] focuses on decision support that derives We have to understand how risky that part of the
relationships based on training data and calls out workflow is, and how skeptical we need to be of
the importance of source attributes with a really the tool.”1
strong focus on transparency,” Speicher said during Additionally, Speicher noted it is important to
the session. “This is the ONC’s attempt to really understand the data that are training that AI, and to ask
understand where AI is starting to come into EHR questions about the standards the health tech developer
products and other software products as well.”1 has for data quality.1 “Where are the data coming
State governments are looking to get involved in from, and what standards are in place,” Speicher said.
this regulation process, and some have started to “I [also would recommend asking] how often the model
produce their own rules. For example, in Georgia, is refreshed. We know that in health care, and specifically
a Senate bill aims to regulate not EHR or software in oncology, things change rapidly. So how are we
companies, but providers, according to Speicher. The making sure the most up-to-date information is
bill seeks to regulate the practice of medicine and the being put into this model and training this model
safe use of EHRs in practices in Georgia.1 to make sure we’re making the right decisions
“Clearly, they’re moving quickly, and there are for patients?”1
regulations on the horizon,” Speicher said. “But that being Speicher noted he would also recommend asking
said, these tools are being used actively by providers questions about how quality and safety issues
[now]. So where does that responsibility lie?”1 are addressed upon discovery of such concerns.
Speicher noted the relevance of a comment from Specifically, it is beneficial to ask who oversees
Fei-Fei Li, PhD, who calls out the fact that we quality and safety, and how they are assessing these
urgently need policymakers to fully understand tools prior to their use by clinicians.1
what AI is now, [which] is going to take a “The last question is this: What is the
multistakeholder approach.1 implementation plan for this [health tech]? Again,
“[Li explains that] there needs to be checks and going back to that safe use of the tool—how am I
balances [in this process],” Speicher said. “She going to make sure my end user, my providers, my
finishes with her biggest fear being waking up and clinicians, my nurses, whoever’s using this tool, are
hearing about the first reported death by suicide from using this appropriately?” Speicher said. “How am I
self-diagnosis of ChatGPT.”1 going to make sure they know how to use this, when to
Speicher explained that this is a relevant concern use it, and how to make sure it’s as safe as possible?”1
now, not in the future. If ChatGPT users listen to news
stories of the technology solving diagnosis challenges
that physicians cannot, and a user then puts their
symptoms into ChatGPT and it spits out a terminal References
1. Speicher SV. Deep dive 6: artificial and business intelligence
diagnosis, the patient may decide to take their life into
technology. Presented at: Association of Cancer Care Centers
their own hands. If the patient thinks ChatGPT is as 50th Annual Meeting and Cancer Center Business Summit;
good as a doctor’s opinion, if not better—because that February 28-March 1, 2024; Washington, DC.
is what the media is telling them—then suicide is a 2. Gartner hype cycle. Gartner. Accessed March 1, 2024.
real risk.1 https://www.gartner.com/en/research/methodologies/gart-
ner-hype-cycle
Speicher noted, however, that health care
3. Certification of health IT. Office of the National Coordinator
professionals do not need to be AI experts to safely for Health Information Technology. Updated July 17, 2023.
use AI health care tools and understand current Accessed March 1, 2024. https://www.healthit.gov/topic/
concerns about their use.1 “But I do think it’s really certification-ehrs/certification-health-it

54 pharmacytimes.com April 2024

 O PC | C O N F E R E NCE

ADVERTO R I A L

OPC Summer 2024: Connecting Oncology

Pharmacists With Cutting-Edge Insights and
Opportunities to Collaborate
This year’s event from June 20 to 21, 2024, in Austin, Texas, will offer
4.25 BCOP CE hours.
A l an a H i ppe n ste el e, Ma n ag i ng Ed i to r

O
ncology Pharmacists Connect (OPC) will Mahmoudjafari: This year, I have the privilege of
be held in Austin, Texas, from June 20 to serving as cochair of the conference. I am looking
21, 2024. Presented in partnership with forward to learning from and meeting with those in
Hematology/Oncology Pharmacy Association, the attendance.
event gathers data reported at the 2024 American
Society of Clinical Oncology (ASCO) Annual Pharmacy Times: With significant upcoming FDA
Meeting, with board-certified oncology pharmacy approvals and impactful updated data likely to be
(BCOP) continuing education (CE) sessions held on presented at the 2024 ASCO Annual Meeting, what
June 21 from 12 pm to 5 pm . is the value of OPC as an opportunity to discuss
these data and breaking news with colleagues?
Pharmacy Times ® sat down with OPC Cochair
Zahra Mahmoudjafari, PharmD, BCOP, FHOPA, Mahmoudjafari: The field is rapidly evolving, so
associate editor, Pharmacy Practice in Focus: meeting with others who are also acutely aware of
Oncology; clinical pharmacy manager, Hematology/ these shifts and are actively working to stay abreast
BMT/Cellular Therapeutics; and PGY2 oncology of these updates can be a helpful way to get up to
residency program director, University of Kansas speed.
Health System in Kansas City, Missouri, to learn
more about the event and what it will provide Pharmacy Times: What will OPC be offering in
attendees. Additionally, Mahmoudjafari addressed terms of CE and BCOP credits?
the value of meeting with a larger community of
pharmacists working together to develop solutions Mahmoudjafari: OPC is not only going to be
for responding clinically and operationally to offering CE for each of the sessions, but it will also
evidence reported at the 2024 ASCO Annual be offering 4.25 BCOP CE hours this year from
Meeting. practice management, annual conference, and BCOP
updates. Topics discussed will include precision
Pharmacy Times: What is unique about what OPC medicine, head and neck cancer updates, prevention
offers? and updates of venous thromboembolism, and
updates in acute leukemia.
Zahra Mahmoudjafari, PharmD, BCOP, FHOPA:
I appreciate the small conference feel of OPC. I also
really value the presentation style with panels as
opposed to a single speaker. It enriches the entire
experience, and you can learn from multiple key
stakeholders. Scan to review the agenda
and learn more about
Pharmacy Times: What is your involvement with the event.
OPC this year?

April 2024 pharmacytimes.com 55

CONTINUING EDUCATION
THIS ACTIVITY IS SUPPORTED BY MJH LIFE SCIENCES®, THE PARENT COMPANY OF AdvanCE.

Intravenous (IV) Therapy 101: An Introduction to

Venous Catheters, IV Lines, and IV Administration
for Pharmacists and Pharmacy Technicians
FACULTY EDUCATIONAL OBJECTIVES
MiKaela Olsen, DNP, APRN-CNS, AOCNS,
FAAN At the completion of this activity, the participant will be able to:
Clinical Program Director, Oncology • Recognize common types of venous access and catheters
Johns Hopkins Hospital and Johns Hopkins • Outline the benefits and complications associated with venous catheters and
Health System intravenous (IV) therapy
Baltimore, Maryland • Define types and appropriate use of IV tubing, filters, and administration devices

MEDICAL WRITING AND EDITORIAL SUPPORT TARGET AUDIENCE: Pharmacists and pharmacy technicians
Brianna Winters ACTIVITY TYPE: Knowledge
Senior Medical Writer LEARNER LEVEL: Foundational
Pharmacy Times Continuing Education™ RELEASE DATE: March 26, 2024
Cranbury, New Jersey EXPIRATION DATE: March 26, 2025
ESTIMATED TIME TO COMPLETE ACTIVITY: 1.0 hour
DISCLOSURES
FEE: This lesson is offered for free at www.pharmacytimes.org.
The following contributor has a relevant financial

A
relationship with a commercial interest to
disclose:
s pharmacy services expand, (eg, medications or fluids), to admin-
FACULTY pharmacists and pharmacy ister blood products, or to obtain blood
MiKaela Olsen, DNP, APRN-CNS, AOCNS,
FAAN
technicians need to have a specimens for analysis. Using VADs
Other (honorarium): Becton, Dickinson and working knowledge of the types of can reduce the number of venipuncture
Company
intravenous (IV) access, administra- attempts, which increase the patient’s risk
AdvanCE tion devices, tubing, and filters used in of infiltration, extravasation, phlebitis,
PLANNING STAFF treatment options. When compounding vein scarring and damage, thrombus, and
Jim Palatine, RPh, MBA; Maryjo Dixon, RPh,
MBA; Amy L. Morris, PharmD, BCOP; Morgan sterile IV products, pharmacy techni- hematomas, as well as resulting in diffi-
McCluskey Wirtz, PharmD, MBA; Angelica cians should be aware of the access site culty with future vascular access attempts
and medication compatibility to mini-
Archibald; Susan Pordon; Brianna Winters; Chloe
Taccetta; and Rebecca Green have no relevant and maintenance.1,2 Several factors must
financial relationships with commercial interests mize risk to the patient. Pharmacists be considered when selecting a VAD, such
to disclose.
may need to provide education to other as patient and treatment characteristics.
Medical reviewer Sneha Srivastava, PharmD, health care professionals on proper VADs are often used in conjunction
BCACP, CDCES, DipACLM, has the following
medication administration depending on with IV fluid administration devices that
financial relationship with a commercial interest
to disclose: the IV access, medication(s), and/or ad- make delivery of the solution or medi-
Speakers Bureau: Xeris Pharmaceuticals ministration set. An understanding of the cation more precise and easier. Infu-
An anonymous peer reviewer was part of the complexities of IV therapy will enable sion pumps have options ranging from
content validation and conflict resolution and pharmacists and pharmacy technicians nonelectric flow devices for low-risk
to best serve the needs of the end users,
has no relevant financial relationships with
commercial interests to disclose. infusions to electronic pumps, such as
including nursing staff and the patient. large volume infusion pumps and small
volume patient-controlled analgesia
Venous Access Devices (PCA) pumps. PCA pumps can provide
A venous access device (VAD) is a cath- improved pain control when compared
eter that is used to access the bloodstream with non-patient–controlled opioid injec-
through veins to administer IV therapy tions.3 When deciding which type of

AdvanCE is accredited by the Accreditation Council for Pharmacy

Education (ACPE) as a provider of continuing pharmacy education.
This activity is approved for 1.0 contact hour (0.10 CEU) under the
ACPE universal activity numbers 0659-0000-24-004-H99-P and
0659-0000-24-004-H99-T. The activity is available for CE credit through
March 26, 2025.

56 pharmacytimes.org April 2024

 www.pharmacytimes.org

tubing to use for IV infusions, consider the duration of the FIGURE 1. TYPES OF VASCULAR ACCESS DEVICES14
infusion, the volume, and the number of medications or solu-
tions being administered. Lastly, filters may be used either
during the preparation or delivery of a medication or solution.
Filters will remove bacteria, in-line precipitates, entrapped
air, or other contaminates, preventing harm from occurring
to the patient.4 The size of the filter determines what particles
are removed. Pharmacists and pharmacy technicians should
be aware of common medications requiring the use of a filter
as they are involved in preparation of these medications.
Pharmacists who prepare, dispense, and administer medica-
tions play a pivotal role in the recommendation, selection, use,
and management of VADs and need to work collaboratively to
make decisions that are best for the patient. Multidisciplinary
teams must work together to implement evidence-based
protocols for the management of patients with VADs to ensure
patient tolerance and compliance with their treatment.

VAD Catheter Types

VADs provide an important alternative to oral delivery of Types of vascular access devices: (a) Peripheral IV catheter, (b) US-guid-

medications, fluids, or nutrients. Some medications cannot be

ed peripheral IV catheter, (c) Midline catheter, (d) Non-tunneled central
venous catheter, (e) Tunneled central venous catheter, (f) Implanted port,
given by mouth due to patient intolerance or simply because (g) Peripherally inserted central catheter.

there is no oral formulation available, as is sometimes the Republished from Bompoint C, Castagna A, Hutt D, et al. Transplant
preparation. Kenyon M, Babic A, eds. In: The European Blood and Marrow
case with oncology medications. Additionally, VADs may Transplantation Textbook for Nurses: Under the Auspices of EBMT [inter-
net]. Springer; 2018. doi:10.1007/978-3-319-50026-3_4. Accessed March 5,
be used to deliver blood products and aspiration of blood for 2024. https://www.ncbi.nlm.nih.gov/books/NBK543669/figure/ch4.Fig1/

laboratory studies.
under the terms of the Creative Commons Attribution 4.0 International
License (http://creativecommons.org/licenses/by/4.0/).
VADs vary based on material, size, average dwell time,
number of lumens, power rating, insertion technique, and Peripheral VADs
complication rates. These physical characteristics as well Peripheral VADs are inserted into smaller veins in the extrem-
as duration of therapy, type of medication or solution being ities, external jugular veins, and scalp veins in neonates.5
infused, insertion site, and patient needs all play a role in Peripheral VADs are easier to place or remove, are of lower
selecting the best VAD. The Infusion Nursing Standards cost, and are less invasive and restrictive for patients.7,8 These
recommend multiple factors for consideration when choosing lines are ideal for short-term use and compatible with most
the appropriate VAD, including diluent and final osmolarity, medications or solutions.9-11 Lastly, peripheral access offers a
infusate pH, method of administration, infusion rate and pres- lower risk of infection.12 One study showed catheter-related
sure, pharmacologic effect of the medication on the vein (eg, bloodstream infections occurred 3 times more for central
vasoconstriction or vasodilation), number of infusion thera- catheters compared with peripheral catheters.13 Some periph-
pies, and anticipated duration of therapy.5 eral VADs are also power rated for high-speed injections of
There are 2 main types of venous access based on the type contrast during imaging tests, however, cannot be used for
of vein that the line resides in: peripheral and central. Periph- hemodynamic monitoring such as central venous pressure
eral VADs are usually placed in the hand or arm in small veins (CVP). Refer to the manufacturer’s instructions for use to
while central VAD catheters reside in large (central) veins determine if VADs are power rated.
such as the superior vena cava or inferior vena cava. These
central VADs are inserted in the upper arm, the neck, upper Placement
chest, or the groin.6 From a pharmacy perspective, it is impor- FIGURE 1 depicts types and placement of various periph-
tant to differentiate between peripheral and central VADs and eral and central VADs.14 Short superficial peripheral cath-
understand situations where each would be preferred. eters are typically placed in the upper extremities. Midline

April 2024 pharmacytimes.org 57

 TABLE 1. PERIPHERAL VENOUS ACCESS DEVICE TYPES AND CHARACTERISTICS5,17-19

Type Placement Advantages Disadvantages

Short peripheral VAD Placed in a Ease of placement and removal, low Phlebitis, infiltration,
peripheral vein, cost. extravasation, contraindicated
usually 2 to 3 cm in for certain drugs with high
length. osmolality. Not for use with
continuous infusion vesicant
chemotherapy.
Midline peripheral VAD Placed in a Ease of placement and removal, low Phlebitis, thrombus, infiltration,
peripheral vein cost. Placement with ultrasound extravasation, contraindicated
usually with allows for deeper, larger veins, which for certain drugs with high
ultrasound can improve flow and reduce risk of osmolality. Not for use with
technology; typically phlebitis. Patients can be discharged continuous infusion vesicant
8-20 cm in length. with home parenteral therapy, if chemotherapy.
appropriate. Can be left in for up
to 30 days in most cases; refer to
manufacturer instructions for use.
Rapid infusion Peripheral VAD Allows for large-volume resuscitation. Short-term use only. Phlebitis,
peripheral catheter that is large in size Ease of placement. Low cost. infiltration, extravasation,
(8 french) used contraindicated for certain
in critical care or drugs with high osmolality. Not
trauma. for use with continuous infusion
vesicant chemotherapy.
VAD, venous access device.

catheters are longer peripheral VADs inserted into a periph- Considerations

eral vein, most commonly in the upper arm via the cephalic, The infusate/medication characteristics and planned dura-
basilic, or brachial vein.15 Midlines do not terminate in tion of infusion therapy must be carefully considered when
a central vein and are not to be confused with a central a peripheral VAD is in place to avoid pain, burning, and
VAD, as the tip of the catheter terminates at or below the possible infiltration or extravasation causing vein and tissue
level of the axilla in children and adults.5 Ultrasound guid- damage.5 Continuous infusion of medications with irritant
ance is often necessary for placement of midlines due or vesicant properties (vasopressors, anthracyclines, vinca
to vein depth and to ensure the appropriate amount of alkaloids, digoxin) and highly concentrated medications such
catheter is inserted into the vein.16 A rapid infusion cath- as potassium chloride greater than 20 mEq/100 mL should
eter is a peripheral VAD that is large in size (8 french) be avoided in peripheral VADs.4,20,21 Peripheral administra-
used in critical care or trauma for rapid resuscita- tion of parenteral nutrition requires a restricted dextrose and
tion. 17 TABLE 1 depicts the placement and comparison of protein concentration (≤10% and/or 5%) to reduce risk.5 The
peripheral VADs.5,17-19 site of insertion is chosen based on assessment of the vessels
including the health of the vessel and depth of vein consider-
Limitations ations. For short peripheral VADs, a forearm vein is preferred
Limitations of short superficial peripheral VADs include to reduce pain and device failure rates; care should be taken
inability to administer continuous infusion chemotherapy to avoid the antecubital fossa and other areas of flexion. If the
vesicant medications or medications with high osmolarity access is needed for less than 24 hours, a vein in the hand can
as these are associated with phlebitis, infiltration, and be used.5 Thrombosis can also occur in blood vessels accessed
extravasation; peripheral VADs must be monitored for patency by a peripheral VAD, especially if an empty IV fluid set is left
when in use.5 Phlebitis is an inflammation of the inner layer of attached to the cannula and the limb is constricted.7 For lifesaving,
the vein caused by the infusate.15 Infiltration is the passage or critical therapies where there is no other immediate access, the
escape of drug into the tissue while extravasation is the leakage peripheral VAD with confirmed patency (eg, positive blood
of drugs capable of causing tissue damage into subcutaneous or return and absence of signs and symptoms of infiltration) can
subdermal tissue.20 be used short term until a central VAD can be inserted.

58 pharmacytimes.org April 2024

 www.pharmacytimes.org

FIGURE 2. CENTRAL VEIN INSERTION SITES30 be avoided as a site of entry into the femoral vein due to the
increased risk of infection.25 Central VADs have lower rates
of complications when placed by trained personnel with
ultrasound technology.26,27

Benefits
Central access offers several benefits beyond direct access
to central circulation. Central VADs can be placed for longer
durations, making them ideal for patients requiring weeks of
parenteral nutrition, chemotherapy, or antibiotics.6,28 Patients
may also be more comfortable with a central VAD if they
require frequent blood draws, treatment, or have limited
peripheral venous access, as repeated venous puncture is not
required with a central VAD with the exception of implanted
ports that require a special needle to be used for each access.6
Republished from Castro D, Martin Lee LAM, Bhutta BS. Femoral vein cen- Today many vascular catheters are power rated, which
tral venous access. In: StatPearls [internet]. Treasure Island, FL: StatPearls
Publishing. Updated August 17, 2023. Accessed March 5, 2024. https:// allows for accurate CVP monitoring, rapid infusion of fluids,
www.ncbi.nlm.nih.gov/books/NBK459255/figure/article-21684.image.f1/
under the terms of the Creative Commons Attribution-NonCommercial-
and power injection of contrast media during radiographic
NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (http://creativecom- testing.15 Central VADs that are power rated can be used for
mons.org/licenses/by-nc-nd/4.0/)
hemodynamic monitoring by way of measuring the CVP and
mixed venous oxygen saturation.6
Midline peripheral VADs may dwell longer than other short
peripheral lines (up to 30 days).5 They can be a safe alternative Limitations
to a central line for patients who require short-term therapies, Central VADs require more equipment, time, and personnel
including antibiotics.22 Phlebitis may be reduced with midlines for insertion and are associated with higher risks than periph-
as they are generally placed in a deeper vein.15 Safe admin- eral VADs.28 Risks to the patient include catheter-related
istration of medications, including vancomycin, has been bloodstream infection, occlusion, thrombus, and malposition.
demonstrated using midline VADs and this catheter should be Central VADs are a major cause of health care-associated
considered as an alternative to a central VAD when possible.23 bloodstream infections in the United States and are associated
It is important for pharmacy staff to work collaboratively with significant morbidity, mortality, and cost.29 Central lines
with the multidisciplinary team to assess the appropriateness that are not implanted, such as peripherally inserted central
and risk of administration of various medications and infusate catheter (PICC) or non-tunneled central VADs (FIGURE 1,14
peripherally. The team should consider the diluent, rate, FIGURE 2 30), can provide a pathway for bacteria directly into
method of administration, anticipated duration of therapy, the bloodstream14,30; patients with these VADs must consis-
vein type and size, catheter patency, and number of infusions tently maintain a clean environment at the site and avoid
when choosing to use a peripheral vascular device. getting the insertion site wet.6 If central VADs are required
for therapy, the type chosen should be based on the predicted
Central VADs length of therapy, the patient’s preference, and their ability to
Central VADs provide access to the central circulation with safely care for the catheter. Central VADs should be removed
the tip ideally located in the superior vena cava (SVC)/ when no longer necessary for treatment.
right atrial juncture to prevent complications.5 Bass and
colleagues found that there were fewer complications when Considerations
central VAD tips were placed at the SVC/right atrial junc- Central VADs are differentiated by their size, number of
ture.24 For lower body sites, the catheter is typically placed lumens, and whether they are tunneled or percutaneous
via a femoral vein with the tip of the central VAD advanced (TABLE 25,15,19,31). Central line types include short-term percu-
to the inferior vena cava above the diaphragm.5 When a taneous, non-tunneled (eg, single, double, or triple lumen),
central VAD is placed in the femoral vein, the groin should tunneled central VADs, PICCs, implanted central venous

April 2024 pharmacytimes.org 59

 TABLE 2. CENTRAL VENOUS ACCESS DEVICE TYPES AND CHARACTERISTICS5,15,19,31

Catheter type Characteristics Advantages Disadvantages

Peripherally Typically placed in upper Ease of placement. Bedside Risk of thrombus, care and
inserted central extremities. Tip in superior placement and removal by trained maintenance issues related
catheter vena cava/right atrial juncture. registered nurses or provider. Lower to location. Caregiver needed
cost compared to other central for dressing changes and
VADs. Single, double, and triple flushing.
lumen options available.
Implanted port Placed in a subcutaneous Can be de-accessed when not in Placed with sedation usually
pocket in chest or upper arm. use to eliminate maintenance (eg, in interventional radiology
Tip in superior vena cava/ dressing changes and flushing). or the operating room.
right atrial juncture. Accessed Single and double ports are available. Higher cost, risk of thrombus,
with a non-coring needle for Can be left in for months or years. infection, discomfort with
infusion. Patients may be discharged to a needle sticks for access.
home setting with this catheter in Removal requires opening port
place. pocket and closing wound.
Short-term, Placed at bedside or in Multi-lumen access for emergency Risk of pneumothorax
non-tunneled, interventional radiology or and acute care needs. Bedside during placement, thrombus,
percutaneous the operating room in the removal. infection especially if placed
central VAD subclavian or jugular vein. Can in femoral vein via the
be placed in a femoral vein. groin. Internal jugular sites
Tip in superior vena cava/right can be difficult to maintain
atrial juncture. dressing over. Restricted
patient activity depending
Available in larger sizes for on catheter exit site. Not for
emergent pheresis or dialysis use outside of an acute care
procedures. environment.
Tunneled central Typically placed in the Tunnel for catheter that sits between Placed with sedation in
VAD subclavian or jugular veins. the skin and muscle in combination interventional radiology or
Tip in superior vena cava/ with or without an antimicrobial the operating room. Higher
right atrial juncture. Single cuff on the catheter to anchor and cost, risk of thrombus,
or double lumen with an provide a barrier for infection. Can infection. Increased cost for
antimicrobial cuff on the be in place for months to years. placement and removal. More
catheter. Patients may be discharged to a difficult removal compared to
home setting with this catheter in non-tunneled central VADs.
Available in larger sizes for place. Requires maintenance for
chronic pheresis or dialysis dressing and flushing.
procedures.
VAD, venous access device.

port or ports, and tunneled and non-tunneled large bore a common cause of medication error.32 Pharmacists can assist
(FIGURE 1,14 FIGURE 230).10 in the safe care of patients with multiple IV administration
Tunneled and non-tunneled large bore catheters are used requirements, such as those in an intensive care unit or
for pheresis or dialysis. Larger central VADs, 10 french or receiving chemotherapy, by reviewing updated compatibility
greater, can be used for transfusion exchange, apheresis, references and providing evidence-based recommendations.5
plasma exchange, continuous renal replacement therapy, and
hemodialysis. Placement of the tip of a central VAD in the
STA R *
SVC/right atrial juncture, where the blood flow is rapidly
Considering the limitations of peripheral VADs for
circulating, allows for the infusion of non-compatible fluids/ infusion therapy, what are some scenarios where a
medications through separate lumens of the catheter and central VAD would be most appropriate?
reduces the risk of phlebitis.15
IV medication incompatibility, defined as an unwanted *S = Stop; T = Think; A = Assess; R = Review
physical or chemical reaction between different infusates, is

60 pharmacytimes.org April 2024

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Administration Devices as multiple keystrokes (aka “key bounce”) and can lead to
Infusion Pumps inaccurate infusion rates. For example, a user programs an
The choice of administration device used for infusion into a infusion rate of 10 mL/hour but the pump registers an infu-
VAD depends on factors such as patient condition, age, rate sion rate of 100 mL/hour. Human factors are an additional
of infusion, drug stability, dosing, and the health care setting. concern: health care workers may have alert fatigue, difficulty
Nonelectronic flow devices may be used for low-risk infu- interpreting units or device warnings, or the design of device
sions where a slight variation in flow rate is insignificant, such results in pushing an unintended button.35 It is essential that
as with antibiotic administration in the home (eg, elastomeric users of these devices are well trained and understand that
balloon pumps, spring-based pumps).5 Gravity infusion, errors are still possible despite safeguards.
without the use of an electric pump, allows for a gentle infu-
sion of the medication while the patient is closely monitored Tubing
for signs and symptoms of extravasation or infiltration; gravity Infusion tubing delivers the solution or medication from the
infusions are often used for administration of chemotherapy bag to the patient. FIGURE 3 shows an example of a typical
vesicants that require frequent monitoring of site and vein infusion line set-up.10 The infusion tubing/administration set
patency (eg, anthracyclines and vinca alkaloids). Electronic may include a drip chamber, roller clamp to regulate flow, and
infusion pumps are the standard of care for most IV infusions Luer-lock or needleless connector to attach to the IV catheter
in the hospital setting, allowing for the administration of or needle.10 Common tubing types include primary (long line)
continuous, intermittent, bolus, or secondary infusions. These and secondary tubing. Primary tubing is most often used for
pumps have more precise flow control, can be programmed delivery of continuous medications or fluids and is inserted or
at a set rate, and should have anti-free flow protection, air- spiked directly into the fluid container. Primary tubing often
in-line detection, and occlusion/pressure alarms. The use of contains a side port under the bag spike for secondary infu-
dose-error reduction solutions (eg, drug libraries) integrated sions and a side port at the patient side for IV push medica-
into electronic infusion pumps is recommended as a best tions or flushing. Secondary tubing, also known as the Y-site
practice to reduce programming errors.33 When possible, or piggyback tubing, is attached to the top of the primary
“smart” pumps should be used with dose error reduction tubing and is used to deliver intermittent medications through
software for error prevention during IV therapy.33 This is an the primary tubing (FIGURE 310). Before attaching tubing to a
opportunity for pharmacy and nursing staffs to collaborate to patient, it must be primed with fluid to the end to remove any
build pump libraries to ensure the highest level of safety and air from the line. Priming volumes differ based on tubing size
usability/compliance. and length and are determined by the manufacturer.
Compared with manual delivery, advantages of electronic Some electronic pumps have a risk of concurrent flow, also
infusion devices include the ability to deliver very small called sympathetic flow, which occurs when the primary line
volumes at precise rates or automated intervals. A variety and the secondary line are flowing at the same time, causing a
of specific electronic pumps have been developed: Patient- delay in the administration of the secondary line. It is impor-
controlled analgesia (PCA) and insulin pumps are probably tant that the primary bag is hung lower than the secondary bag
two of the most well-known.34 PCA pumps enable the patient for the pump to pull the drug from the secondary tubing and
to control administration of medication, within limits set by bag. Once the dose is administered, the secondary tubing can
providers, allowing the patient to receive timely pain relief on be lowered below the primary bag and backfilled with flush
demand, thus also alleviating some of the burden on nursing. solution, also called backpriming. After a medication has been
Studies have demonstrated that PCA pumps are a more effec- delivered on an infusion pump (eg, the bag has been fully
tive pain control method than non-patient‒controlled opioid administered), medication remains in the tubing and needs
injections and result in higher patient satisfaction.3 to be flushed through for full delivery. After backpriming the
While these infusion devices offer several advantages, secondary tubing, the pump is then programmed to administer
issues occur if used incorrectly. Software problems have a flush solution through the tubing, ensuring all of the medica-
been reported, such as error messages in the absence of an tion reaches the patient.
identifiable problem, making the pumps inoperable; pumps The type of tubing also affects the rate at which the medica-
may also malfunction due to physical damage to device and tion or solution can be administered. Macrodrip tubing is used
battery failures. The pump may interpret a single keystroke for drip rates of 10, 15, or 20 drops per milliliter compared

April 2024 pharmacytimes.org 61

 FIGURE 3. PRIMARY IV LINE WITH A SECONDARY IV a short set tubing allows for the full dose to reach the patient
INFUSION10 as the primary short set can be run dry and the primary line
can be used to flush the remaining drug into the patient. The
use of short primary tubing eliminates the risk of sympathetic
flow and errors related to unopened roller clamps, head-height
differentials, and limitation in concurrent flow rates.20
If tubing is primed with solution during pharmacy prepara-
tion, staff need to be properly trained according to the specific
manufacturers’ step-by-step guidelines. Aseptic technique
should be used when connecting, changing, and accessing
administration tubing sets and injection ports to prevent infec-
tion. Proper technique when priming tubing reduces infection
risk and air-in-line alarms. Air-in-line alarms can cause signif-
icant delays in medication administration, increase risk of HD
exposure to staff, and be a nuisance to staff and patients.37
Some manufacturers provide antisiphon valves that minimize
air in line and can be added to the tubing set up at the initia-
tion of the infusion.37

Filtration
Filters may be used in product preparation and/or within IV
tubing to filter particulate matter, such as bacteria, contami-
IV, intravenous.
Republished from Anderson R, Doyle GR, McCutcheon JA. Intravenous nation, in-line chemical precipitates, or entrapped air.4 Filtra-
Therapy. Clinical Procedures for Safer Patient Care- Thompson Rivers
University Edition. Kamloops: Thompson Rivers University. August 31,
tion is required for administering parenteral nutrition, blood
2018. Accessed September 22, 2023. https://pressbooks.bccampus.ca/ products, and many medications, including but not limited
clinicalproceduresforsaferpatientcaretrubscn, under the terms of a
Creative Commons Attribution 4.0 International License. to amiodarone, mannitol, and phenytoin.38 Filters are also
required when withdrawing medications from glass ampules.5
to microdrip tubing which can have a drip rate of 60 drops Priming and positioning of filters should be performed
per milliliter. Microdrip tubing is used in neonatal or pediatric according to the manufacturers’ guidelines. The specific filter
care and sometimes in clinical trials in adults and pediatrics needed may be provided by the manufacturer in the product
for small volume drugs.36 packaging.39 The pore size required for filtration is based on
Other tubing types include multi-port primary tubing, used the medication-specific information such as molecular size
with a multi-channel infusion pump, in conjunction with short and/or the concentration of the infusion.5 Often a 0.22-micron
sets to administer multiple compatible drugs simultaneously filter is recommended to filter bacteria, while 5-micron filters
or in sequence using the primary to flush in between drugs. may be used to filter particulates introduced during prepara-
The use of short primary tubing with a primary infusion tion, such as glass particles.39 While all parenteral nutrition
tubing (carrier fluid) is a novel strategy for administration requires filtration, the filter size needed depends on the pres-
of medications, especially antineoplastic therapies that have ence of lipids.40,41 Other considerations include the need for
hazardous drug (HD) potential as it allows for a closed system low protein-binding filters (eg, polyether sulfone, polyvinyli-
and reduced risk of HD exposure. Most importantly, the use of dene fluoride, and cellulose acetate) for some protein-based

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American College of Physicians

https://www.facs.org/media/2tcnbb4f/understanding_your_central_line.pdf
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American Cancer Society
https://www.cancer.org/cancer/managing-cancer/making-treatment-
Intravenous Lines, Catheters, and Ports
decisions/tubes-lines-ports-catheters.html
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9. American Society of Clinical Oncology. Catheters and ports in cancer treatment. Cancer.Net. 24. Bass J, Halton J, Drouet Y, Ni A, Barrowman N. Central venous catheter database: an

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org/guidelines/safe-implementation-and-use-smart-pumps doi:10.1002/ncp.10587

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POSTTEST QUESTIONS
1. Which vascular access device (VAD) is inserted into 4. When determining type of vascular access, which
the central vein via a subcutaneous pocket in the factors are most important to avoid vein or tissue
chest or arm? damage?
A. Peripherally inserted central catheter A. Medication characteristics and planned duration of
B. Implanted port therapy
C. Midline peripheral VAD B. Patient preference for VAD type
D. Tunneled central VAD C. Planned duration of therapy and patient
comorbidities
2. Which statement describes a disadvantage of central D. Dose-error probability and medication
catheters? characteristics
A. Major cause of health care-associated bloodstream
infections 5. Which peripheral VAD has a longer dwell time and
B. Need for multiple venipuncture attempts may reduce the incidence of phlebitis?
C. Inability to administer continuous infusion vesicants A. Peripherally inserted central catheter
D. Contraindicated for certain high osmolality B. Implanted port
medications C. Midline peripheral VAD
D. Short peripheral VAD
3. Which administration device can be programmed at
a set flow rate and integrate dose-error reduction
solutions such as drug libraries?
A. Elastomeric balloon pump
B. Electronic infusion pump
C. Gravity infusion *Pharmacy technician posttest questions can be found at
D. Spring-based pump www.advancepharmacist.com/iv-lines-techs

April 2024 pharmacytimes.org 65