JHOP March 2014 by The Oncology Pharmacist

MARCH 2014 VOL 4 I NO 1

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

ORIGINAL RESEARCH

Recent Cancer Drugs Approved by the FDA CASE REPORT

uccessful Panitumumab Administration after Cetuximab-Induced Aseptic S Meningitis: A Case Report and Review Jane E. Rogers, PharmD, BCOP; Lindsey Law, MPAS, PA-C; Rachna Shroff, MD, MS FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

WWW.JHOPONLINE.COM

Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19:1008-1016. ÂŠ2013 Amgen Inc. All rights reserved. 11/13 74385-R2-V6

Fight it ONCOLYTIC IMMUNOTHERAPY

Cancer cell

is an innovative area of research that uses a modified virus designed to help T cells find and fight cancer cells as part of a hypothesized systemic, tumor-specific immune response.1

Learn more at: www.oncolyticimmunotherapy.com

Amgen. Leading the way in the study of Oncolytic Immunotherapy.

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

REVIEW ARTICLES

Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale-New Haven Yale-New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro Universityâ&#x20AC;&#x201C;California Mare Island, Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Division of Hematology and Medical Oncology Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

March 2014

Vol 4, No 1

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

MARCH 2014

VOLUME 4, NUMBER 1

PUBLISHING STAFF

Senior Vice President, Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY™

Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publishers Russell Hennessy rhennessy@the-lynx-group.com

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

Cristopher Pires cpires@the-lynx-group.com

TABLE OF CONTENTS

Editorial Director Dalia Buffery dbuffery@the-lynx-group.com

ORIGINAL RESEARCH

9 Evaluation of G-CSF Use in a Single Institution and Development

Associate Editor Lara J. Lorton

of Pocket Reference for Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia Taylor W. Butler, PharmD; J. Aubrey Waddell, PharmD; Brad J. Crane, PharmD; Amy M. Porter, PharmD

Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Lora LaRocca

THE LYNX GROUP President/CEO Brian Tyburski

FDA UPDATE 16 Recent Cancer Drugs Approved by the FDA

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly

CASE REPORT

Director, Human Resources Jennine Leale

18 Successful Panitumumab Administration after Cetuximab-Induced Aseptic

Associate Director, Content Strategy & Development John Welz

Meningitis: A Case Report and Review Jane E. Rogers, PharmD, BCOP; Lindsey Law, MPAS, PA-C; Rachna Shroff, MD, MS

Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

FROM THE LITERATURE

Quality Control Assistant Theresa Salerno

25 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Director, Production & Manufacturing Alaina Pede

With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca

MISSION STATEMENT

Director, Digital Media Anthony Romano

The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito

Journal of Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright © 2014 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

Vol 4, No 1

March 2014

Journal of Hematology Oncology Pharmacy

IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications 1249 South River Road – Ste 202A Cranbury, NJ 08512 Phone: 732-656-7935 • Fax: 732-656-7938

www.JHOPonline.com

Call for Papers The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

COMMENTARIES

LETTERS TO THE EDITOR

SUBMIT YOUR ARTICLE AT

www.JHOPonline.com Manuscripts should follow the Author Guidelines, available online.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

March 2014

Vol 4, No 1

ORIGINAL RESEARCH

ORIGINAL ARTICLE

Evaluation of G-CSF Use in a Single Institution and Development of Pocket Reference for Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia Taylor W. Butler, PharmD; J. Aubrey Waddell, PharmD; Brad J. Crane, PharmD; Amy M. Porter, PharmD Background: Granulocyte colony-stimulating factors (G-CSFs) are often prescribed as primary prophylaxis for patients with chemotherapy-induced febrile neutropenia (CIFN). Clinical controversy surrounds the appropriate use of G-CSFs. The American Society of Clinical Oncology (ASCO) recommends avoiding these medications in patients with a low risk for CIFN. Optimizing the use of G-CSFs was recently identified as a top method for reducing cost in patients with cancer. The extent of unnecessary use is unknown at many cancer institutions and is not well studied. Many difficulties present with identifying patients at a low risk for CIFN, and there are limited published studies available to help guide prescribing patterns. Objectives: To evaluate the use of G-CSFs for adherence to the ASCO guidelines at Blount Memorial Hospital, as well as to create a reference guide for the future assessment of the risk for CIFN. Methods: A retrospective chart review was conducted for each patient who had received chemotherapy at Blount Memorial Hospital between December 2010 and December 2012. A total of 256 patients were reviewed for the risk of CIFN, which included a review of the patient’s history and the chemotherapy regimen administered. The type of G-CSF and the number of doses used were collected and extrapolated using average wholesale price to determine potential cost-savings. PubMed and MEDLINE were searched for relevant clinical trials. Primary literature was reviewed to identify articles that reported a rate of febrile neutropenia for each regimen administered among the participating patients. These rates were compiled into a pocket reference to be distributed to prescribers at the conclusion of this review. Results: The results of this evaluation showed that prescribers were compliant with the ASCO guidelines in approximately 69% of the cases. Based on these findings, this institution could save more than $600,000 during the study period if G-CSFs were only administered in patients with a risk of ≥20% for developing CIFN. Furthermore, the rates of febrile neutropenia were discovered in the primary literature for 100 different chemotherapy regimens and were organized into a pocket reference. Conclusion: This analysis of a single community institution shows that patients with cancer undergoing chemotherapy are inconsistently evaluated for CIFN and are often prescribed these medications against ASCO guidelines. With the growing costs and the negative adverse events associated with these medications, prescribers need a readily available reference source to J Hematol Oncol Pharm. enhance their ability to evaluate patients for CIFN and manage it appropriately. Furthermore, 2014;4(1):9-14. the rates of febrile neutropenia in patients with cancer need to be compiled and provided to www.JHOPonline.com Disclosures are at end of text frequent prescribers to assist them with patient evaluation for CIFN risk until further research is available. More research is needed in this area to improve patient evaluation for this risk.

Dr Butler is PGY-2 Oncology Resident, Dana-Farber Cancer Institute, Brighton, MA; Dr Waddell is Associate Professor, University of Tennessee Health Science Center, Knoxville, TN; Dr Crane is Clinical Pharmacist, Antimicrobial Stewardship, Blount Memorial Hospital, Maryville, TN; Dr Porter is Clinical Pharmacist, Blount Memorial Hospital, Maryville, TN. Vol 4, No 1

March 2014

The original version of this research was presented as a poster at the American Society of Health-System Pharmacist’s mid-year meeting in Las Vegas, NV, in December 2012; at the Tennessee Pharmacists Association meeting in Nashville, TN, in February 2013; and at the Hematology/Oncology Pharmacy Association meeting in March 2013. It was also presented orally at the Southeastern Residency Conference in April 2013 in Athens, GA.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

ORIGINAL RESEARCH

hemotherapy-induced febrile neutropenia (CIFN) is a life-threatening, costly complication that may develop in patients with cancer after receiving myelosuppressive chemotherapy.1 In 1991, filgrastim (Neupogen) was approved for the treatment of patients with CIFN, because it stimulates the production of neutrophils, which potentially treats and prevents febrile neutropenia.2,3 Filgrastim, pegfilgrastim (Neulasta), and sargramostim (Leukine) are classified as granulocyte colony-stimulating factors (G-CSFs). A 2005 study of the use of pegfilgrastim showed that the G-CSFs were effective in the prevention of febrile neutropenia.4 Despite this finding, the determination of which chemotherapy regimens require primary prophylaxis for CIFN with G-CSFs is still controversial.5 In 2012, the American Society of Clinical Oncology (ASCO) identified the appropriate use of G-CSFs as 1 of the top 5 recommendations to reduce expenditures for patients with cancer.1 In addition to a potential financial detriment, inappropriate prescribing of these medications may also lead to unnecessary adverse reactions, most often injection-site reactions, flu-like symptoms, and bone pain.2 The ASCO guidelines define inappropriate use as administering these medications to patients with a low, <20% risk for developing CIFN.1,6

In 2012, the American Society of Clinical Oncology identified the appropriate use of G-CSFs as 1 of the top 5 recommendations to reduce expenditures for patients with cancer. In addition to a potential financial detriment, inappropriate prescribing of these medications may also lead to unnecessary adverse reactions. A ≥20% risk for developing this complication after chemotherapy would be considered having a high risk for CIFN and would indicate the need to administer one of the G-CSFs for primary prophylaxis.1,6 It is important to note that ASCO also advises to continue to use clinical judgment in evaluating patients at risk for CIFN, which usually involves considering patient-specific factors, such as comorbidities, age, and intent of chemotherapy.6-8 Applying the ASCO recommendations consistently is challenging in clinical practice, because the rates of CIFN are not always reported in clinical trials, and the cumulative effects of multidrug regimens are rarely re-

Journal of Hematology Oncology Pharmacy

ported in a drug’s package insert or product information. The decision to prescribe one of the G-CSFs can be based on a variety of factors, including comorbidities, dated G-CSF guidelines, and even the patient’s type of insurance coverage. A more thorough literature evaluation may lead to better prescribing patterns, but it may be tedious in the clinical practice setting. One trial by Fishman and colleagues demonstrated that prescribers were more likely to use G-CSFs appropriately when presented with the rates of febrile neutropenia and the updated National Comprehensive Cancer Network (NCCN) recommendations related to the use of G-CSFs.9 Of note, the NCCN Clinical Practice Guidelines differ from the ASCO guidelines by recommending that prescribers consider the use of G-CSFs for patients who have a 10% to 20% risk for CIFN.10 In this current study, we evaluated the use of G-CSFs and attempted to develop a reference guide to provide prescribers relevant CIFN rates associated with specific medications, in the hopes of optimizing the use of these medications at our institution.

Methods We performed a retrospective chart review for all patients who received chemotherapy at our community institution, which has 300 inpatient beds and a 20-chair outpatient infusion clinic. The data were collected from December 1, 2010, to December 31, 2012 (ie, 25 months). No exclusion criteria were included in this review. Data collection included the type of malignancy, the chemotherapy regimen used, and the administration of G-CSFs. Patients’ charts were also reviewed to identify patients with a documented episode of febrile neutropenia. The primary literature was extensively reviewed to determine the rates of CIFN in patients with cancer. PubMed and Ovid MEDLINE were the search engines used to locate the relevant clinical trials. The search was limited to phase 1, phase 2, or phase 3 clinical trials and included the chemotherapy drugs used in each of the regimens. Approximately 300 relevant articles and almost 200 regimens were found in our search of the literature. The trials found in this search were included in the analysis when documented rates of febrile neutropenia, neutropenic fever, or neutropenic sepsis were listed. The rates of primary prophylaxis of CIFN in each trial and the related regimens were compiled into a pocket guide for clinician reference. The highest rate of febrile neutropenia in each trial would determine a patient’s risk level. Each chemotherapy regimen, the rate of febrile neutropenia, and the reference for every clinical trial included in this evaluation were listed in the pocket guide. The data analysis was conducted in

www.JHOPonline.com

March 2014

Vol 4, No 1

G-CSF Use for Primary Prophylaxis of CIFN

the form of descriptive statistics using Microsoft Excel. Each chemotherapy regimen was evaluated using the ASCO guidelines,1 and the potential cost-savings were calculated based on average wholesale price and the elimination of unnecessary administrations of G-CSFs over the full study period.

Results This evaluation included 256 patients who received 322 different chemotherapy regimens at our institution. The evaluation of the use of G-CSFs in these patients is described in Table 1. G-CSFs were administered after 140 (43.5%) of the 322 chemotherapy regimens. Only 77 (23.9%) regimens prescribed at our institution had a risk of ≥20% for developing CIFN. Of note, 25.5% of regimens administered were for hematologic malignancies (primarily acute myeloid leukemia and non-Hodgkin lymphoma) compared with 74.5% for solid tumors (primarily breast cancer and lung cancer). A total of 223 of the 322 (69.3%) regimens used at our institution were compliant with the ASCO guidelines with G-CSFs, and the other regimens were not compliant with the guidelines. When G-CSFs were administered (N = 140), approximately 59 (42.1%) of the prescriptions were in compliance with the ASCO guidelines (Figure). In addition, 18 of the 77 (23.4%) high-risk regimens were not followed with prophylaxis for febrile neutropenia. Of note, 6 chemotherapy regimens did not have published articles that reported the data for the rate of CIFN. Table 2 shows how these 6 cases were evaluated in our analysis for the risk of CIFN. Two regimens were administered G-CSFs for secondary prophylaxis of CIFN. Based on these results, if all prescribers at our institution avoided the administration of G-CSFs in patients with a <20% risk for CIFN, more than $600,000 would have been saved during this study period. The completed reference guide based on our review of the literature contained CIFN rates for 100 different chemotherapy regimens. Only 24 regimens showed a risk of >20% for developing this complication. Discussion The use of G-CSFs in our institution suggests that the prescribing of these medications is not always in compliance with current ASCO guidelines. Furthermore, there is some disagreement regarding the definition of low risk for CIFN between the ASCO guidelines and the NCCN recommendations. Full compliance with the ASCO guidelines for G-CSFs use is not expected, because of a variety of factors, including treatment goals and patient comorbidities; however, it is concerning that in one representative (our) institution, 57.9% (81 of 140) of patients receiving these medications

Vol 4, No 1

March 2014

Table 1 E valuation of G-CSF Use for 322 Chemotherapy Regimens Used in 256 Patients Characteristics of 322 chemotherapy regimens used at a single institution

Regimens used, N (%)

Risk for CIFN ≥20% <20%

77 (23.9) 245 (76.1)

G-CSF administered Yes No

140 (43.5) 182 (56.5)

Compliant with ASCO guidelines G-CSF used in patients with ≥20% of CIFN risk G-CSF not used in patients with <20% of CIFN risk

223 (69.3) 59

Noncompliant with ASCO guidelines G-CSF used in patients with <20% of CIFN risk G-CSF not used in patients with ≥20% of CIFN risk

99 (30.7) 81

164

ASCO indicates American Society of Clinical Oncology; CIFN, chemotherapy-induced febrile neutropenia; G-CSF, granulocyte colony-stimulating factor.

Figure G-CSF Administered in 140 Patients with Cancer G-CSF administered ≥20% risk of CIFN <20% risk of CIFN

N = 81

N = 59

CIFN indicates chemotherapy-induced febrile neutropenia; G-CSF, granulocyte colony-stimulating factor.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

ORIGINAL RESEARCH

Table 2 T he Rationale for 6 Chemotherapy Regimens Administered without Supporting Data in the Literaturea Regimen

Graded

Rationale for suggesting CIFN risk

6-thioguanine + cytarabine + idarubicin

High

Idarubicin + cytarabine combination has shown up to a 92% risk for CIFN12

Cyclophosphamide

Low

Some cyclophosphamide combination regimens have shown a risk of <20% for CIFN13

Idarubicin + all-trans retinoic acid

High

Idarubicin is associated with significant myelosuppression12

Idarubicin + cytarabine + vincristine + methotrexate

High

Idarubicin + cytarabine combination has shown up to a 92% risk for CIFN12

Ifosfamide

Low

Combination regimen with cisplatin has an 11% risk for CIFN14-16

Cyclophosphamide + rituximab

Low

Certain cyclophosphamide regimens have shown a risk of <20% for CIFN, and rituximab is not bone marrow suppressive13,17

These regimens did not have published data for their CIFN risk; references cited explain the rationale for assessing a CIFN risk for each regimen. a

CIFN indicates chemotherapy-induced febrile neutropenia.

had a risk of <20% for CIFN. Furthermore, 39 of these 81 (48.1%) patients who received G-CSFs against the ASCO recommendations had a <10% risk for febrile neutropenia. By comparison, Fishman and colleagues reported that 52 of 245 (21%) total units of pegfilgrastim were administered for patients at low risk for febrile neutropenia.9 The most common regimens administered against the ASCO guidelines at Blount Memorial Hospital were azacitidine and eribulin.

The G-CSF medications were not available until the early 1990s, so many clinical trials before that time did not place the same emphasis on febrile neutropenia rates after chemotherapy. Noncompliance may also be explained by other factors. The rates of febrile neutropenia can be difficult to locate, including the challenges of gaining access to clinical trials or finding trials that actually studied or reported CIFN. Regimens included in this review required several hours to ascertain a clear clinical picture of whether G-CSFs were indicated for CIFN. The G-CSF medications were not available until the early 1990s, so many clinical trials before that time did not place the same emphasis on febrile neutropenia

Journal of Hematology Oncology Pharmacy

rates after chemotherapy. Rates of neutropenia or leukopenia are usually well documented in clinical trials today, but they can potentially lead to a detrimental clinical impact (ie, infection, death). Also, there is not always a correlation between neutropenia and neutropenic fever for every chemotherapy regimen. A more in-depth risk assessment tool is needed to ensure the optimal use of G-CSFs. The Multinational Association of Supportive Care in Cancer provides a risk assessment calculator for febrile neutropenia, but it is primarily used in practice to determine if a patient can be treated with outpatient antibiotics.11 It is unknown whether this tool can help clinicians with the prescribing of G-CSFs for primary prophylaxis. These medications are costly, and represent an additional injection, as well as the potential for adverse events for patients with cancer; it is therefore important to correctly evaluate the need before administering them. Table 3 provides the reference guide created for this study and lists the rates of CIFN associated with chemotherapy regimens at our institution based on clinical trial results. Providing prescribers with such a guide from institutional-specific chemotherapy regimens may aid in the evaluation of need, and can potentially eliminate the risk of not prescribing these medications when indicated, as well as decreasing the rate of unnecessary administrations of G-CSFs at institutions such as ours.

www.JHOPonline.com

March 2014

Vol 4, No 1

G-CSF Use for Primary Prophylaxis of CIFN

Table 3 E xample Pocket Reference Created Based on Chemotherapy Regimens Used in a Single Institution Regimen

Rate of febrile neutropenia, % Regimen

Rate of febrile neutropenia, %

ABVD every 3 wks

3-918,19

Cyclophosphamide 600 mg/m2 + doxorubicin 60 mg/m2 every 3 wks

213

Alemtuzumab 30 mg 3 times weekly

0-1420-22

Cyclophosphamide 187.5-400 mg/m2 daily + doxorubicin 12.5 mg/m2 daily + etoposide 60-90 mg/m2 daily continuous infusions (days 1-4)

Standard practice26,27

Azacitidine 75 mg/m2 (days 1-7) every 4 wks

823

Cyclophosphamide 600 mg/m2 + epirubicin 1-1028,29 60-90 mg/m2 + fluorouracil 600 mg/m2 every 3 wks

BCG live every wk

<124

Cyclophosphamide 600 mg/m2 + epirubicin 60-90 mg/m2 every 3 wks + trastuzumab

3-1030

Cyclophosphamide 600 mg/m2 + nab-paclitaxel 100 mg/m2 (days 1, 8, 15) + trastuzumab 6 mg/kg every 21 days

231

Bevacizumab 5-15 mg/kg <125 every 2 wks

ABVD indicates Adriamycin, bleomycin, vinblastine, dacarbazine; BCG, Bacillus Calmette-Guérin.

Limitations A confounding factor in the current analysis is that previously documented cases of febrile neutropenia were not well recorded at our institution. We found 2 documented cases of previous febrile neutropenia in our review, and we hypothesize that more than 2 patients developed febrile neutropenia and required secondary prophylaxis with G-CSFs. Patients could also possibly have received G-CSFs at another site. In addition, a weakness in the evaluations of risk for CIFN is that there are few available data on how to evaluate additional factors that may potentially affect the patient’s risk for CIFN. This leaves room for interpretation that may vary between prescribers. Conclusion Improving the optimal use of G-CSFs will require future research, including the evaluation of confounding factors associated with the evaluation of CIFN. A risk assessment tool needs to be developed and evaluated in a clinical trial to determine the exact impact of the many variables associated with febrile neutropenia, including the patient’s age and potential for bone marrow compromise. Until this research is completed, the first step is to increase awareness of the risk for CIFN with each regimen. Providing institution-specific reference guides may immediately help improve compliance rates, with the primary focus not only on limiting the inappropriate administrations, but also on making sure patients get these medications when indicated. Our institution will be reevaluated in the future to deter-

Vol 4, No 1

March 2014

mine if the pocket reference improves compliance with ASCO guidelines and reduces the expenditure associated with the inappropriate use of G-CSFs. n Author Disclosure Statement Dr Crane is Principal Investigator and Study Site Coordinator for the CAPTURE study for Cerexa, a subsidiary of Forest Pharmaceuticals. Dr Butler, Dr Waddell, and Dr Porter have reported no conflicts of interest.

References

1. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30:1715-1724. 2. Neupogen (filgrastim) [prescribing information]. Thousand Oaks, CA: Amgen Inc; revised September 2013. 3. Glaspy JA, Bleecker G, Crawford J, et al. The impact of therapy with filgrastim (recombinant granulocyte colony-stimulating factor) on the health care costs associated with cancer chemotherapy. Eur J Cancer. 1993;29A(suppl 7):S23-S30. 4. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23:1178-1184. 5. Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol. 2004; 50:129-146. 6. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187-3205. 7. Lyman GH, Lyman CH, Agboola O. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10:427-437. 8. Lyman GH, Kuderer NM, Crawford J, et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer. 2011;117:1917-1927. 9. Fishman ML, Kumar A, Davis S, et al. Guideline-based peer-to-peer consultation optimizes pegfilgrastim use with no adverse clinical consequences. Am J Manag Care. 2012;18(5 special issue 2):e168-e172. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines (NCCN Guidelines®): myeloid growth factors. Version 2.2013. www.nccn.org/pro fessionals/physician_gls/pdf/myeloid_growth.pdf. Accessed February 15, 2014. 11. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038-3051.

www.JHOPonline.com

Continued

Journal of Hematology Oncology Pharmacy

ORIGINAL RESEARCH

12. Chen YC, Lin SF, Yao M, et al. Induction therapy of newly diagnosed acute nonlymphocytic leukemia with idarubicin and cytosine arabinoside—the Taiwan experience. Semin Hematol. 1996;33(4 suppl 3):30-34. 13. Muss HB, Berry DA, Cirrincione C, et al; for the Cancer and Leukemia Group B Experience. Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol. 2007;25:3699-3704. 14. Mountzios G, Dimopoulos MA, Bamias A, et al. Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study. Ann Oncol. 2009;20:1362-1368. 15. van den Bent MJ, Schellens JH, Vecht CJ, et al. Phase II study on cisplatin and ifosfamide in recurrent high grade gliomas. Eur J Cancer. 1998;34:1570-1574. 16. Vallejos C, Solidoro A, Gómez H, et al. Ifosfamide plus cisplatin as primary chemotherapy of advanced ovarian cancer. Gynecol Oncol. 1997;67:168-171. 17. Coiffier B, Osmanov EA, Hong X, et al; for the LYM-3001 Study Investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12:773-784. 18. Harker WG, Kushlan P, Rosenberg SA. Combination chemotherapy for advanced Hodgkin’s disease after failure of MOPP: ABVD and B-CAVe. Ann Intern Med. 1984;101:440-446. 19. Rueda A, Alba E, Ribelles N, et al. Six cycles of ABVD in the treatment of stage I and II Hodgkin’s lymphoma: a pilot study. J Clin Oncol. 1997;15:1118-1122. 20. Lundin J, Kimby E, Björkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2002;100:768-773. 21. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:56165623. 22. Wierda WG, Kipps TJ, Keating MJ, et al; for the CLL Research Consortium. Self-administered, subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia. Cancer. 2011;117:116-124. 23. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alter-

native dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27:1850-1856. 24. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus CalmetteGuerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163:1124-1129. 25. Nagane M, Nishikawa R, Narita Y, et al. Phase II study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. Jpn J Clin Oncol. 2012; 42:887-895. 26. Sparano JA, Negassa A, Lansigan E, et al. Phase I trial of infusional cyclophosphamide, doxorubicin, and etoposide plus granulocyte-macrophage colony stimulating factor (GM-CSF) in non-Hodgkin’s lymphoma. Med Oncol. 2005;22:257-267. 27. Sparano JA, Wiernik PH, Strack M, et al. Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin’s lymphoma: a highly active regimen. Blood. 1993;81:2810-2815. 28. Edlund P, Ahlgren J, Bjerre K, et al. Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1. Acta Oncol. 2011;50:329-337. 29. Martín M, Rodríguez-Lescure A, Ruiz A, et al; for the GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer. J Natl Cancer Inst. 2008;100:805-814. 30. Untch M, Muscholl M, Tjulandin S, et al. First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial. J Clin Oncol. 2010;28:1473-1480. 31. Yardley D, Burris H III, Peacock N, et al. A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2positive patients, in the treatment of early-stage breast cancer. Breast Cancer Res Treat. 2010;123:471-475.

Request your SUBSCRIPTION to THE JOURNAL OF HEMATOLOGY ONCOLOGY PHARMACY™ q YES! I would like to receive the Journal of Hematology Oncology Pharmacy q NO. Please discontinue my subscription.

™

as well as related educational supplements.

Signature (Required)

Specialty

Date (Required)

Address

Name

City/State/Zip

Company

E-mail

Title

Phone Please provide all information indicated, including date and signature. INCOMPLETE CARDS WILL NOT BE PROCESSED.

Fax to: 732.992.1881

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

March 2014

Vol 4, No 1

NEW FOR 2014

Principles in Value and Market Access

An educational session for product managers, reimbursement specialists, account managers, and marketers focusing on access, reimbursement, proving product value, and international markets. CO-CHAIRS

MAY 6, 2014 Loews Hollywood Hotel Los Angeles, CA

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Gary M. Owens, MD

President Gary Owens Associates

AGENDA 10:45am – 11:00am

Introductions and Opening Remarks Grant Lawless, RPh, MD, FACP; Gary M. Owens, MD

11:00am – 11:40am

Changing Access and Payer Challenges in Oncology - Medicare and Commercial Speaker TBD

11:40am – 12:20pm

Proving the Value for Oncology Therapy Using Comparative Effectiveness Research Dan Malone, PhD, Professor, University of Arizona College of Pharmacy

12:20pm – 1:30pm

Lunch

1:30pm – 2:10pm

Methods and Tools for Optimal Reimbursement Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead

2:10pm – 2:50pm

Impact of Healthcare Reform, Affordable Care Act, and Accountable Care Organizations on the Coverage of Cancer Treatments Speaker TBD

2:50pm – 3:30pm

Impact of New Risk Models on Traditional Pharmaceutical Relationships Ken Schaecher, MD, FACP, CPC, Medical Director, SelectHealth

3:30pm – 4:00pm

Break

4:00pm – 4:40pm

Using Competitive Intelligence to Maintain Coverage and Access Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting

4:40pm – 5:20pm

Panel Discussion - Will improvements in clinical outcomes and efficacy come from new products or a more thoughtful use of existing products using new adaptations? Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE) AVBCC2014May6agenda Asize_20714

FDA UPDATE

Recent Cancer Drugs Approved by the FDA

n the first quarter of 2014, several drugs have already received approval by the US Food and Drug Administration (FDA) as new therapies, new combinations, or new indications for patients with different types of cancer, including solid tumors and hematologic malignancies. The following briefs provide updates on new

First Drug Combination Approved for Unresectable or Metastatic Melanoma On January 8, 2014, the FDA approved the use of dabrafenib (Tafinlar; GlaxoSmithKline) plus trametinib (Mekinist; GlaxoSmithKline) as a new combination therapy for the treatment of patients with advanced melanoma that is unresectable or metastatic. The 2 drugs were individually approved by the FDA in 2013 for melanoma. Each of the 2 drugs blocks molecular signaling in different sites of the same pathway that promotes cancer-cell growth. Dabrafenib was initially approved for patients with melanoma whose tumors express the BRAF V600E mutation. The dabrafenib-trametinib combination is indicated for patients with melanoma who also have the BRAF V600E or BRAF V600K mutation. Approximately 50% of skin melanomas have a BRAF mutation. “Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Their development for combination use is based on the strong understanding of the biological pathways of the disease. This approval illustrates the value of continuing to study drugs in combination for clinical development.” The FDA approval was based on results of a clinical trial of 162 patients with unresectable or metastatic melanoma with the BRAF V600E or BRAF V600K mutation; the majority of the patients were treatment-naïve. They received dabrafenib as a single agent until their disease progressed or their side effects became intolerable, at which point they began using the combination. Overall, 76% of patients receiving the combination had an objective response for an average of 10.5 months compared with 54% of patients receiving dabrafenib alone who had an objective response lasting 5.6 months. Clinical trials are ongoing to determine whether this combination will also result in improved survival. The side effects reported with the combination are similar to those reported with each individual drug. Specifically, the combination was associated with an increase in the incidence and severity of fever.

Journal of Hematology Oncology Pharmacy

FDA approvals and indications to help hematology and oncology pharmacists keep up with new information regarding drugs that are coming to market for the management of patients with cancer. This section also provides brief updates on the FDA’s decisions for drugs in the pipeline before the final approval.

Ibrutinib Receives New Indication for Use in Patients with Chronic Lymphocytic Leukemia On January 12, 2014, the FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least 1 previous therapy. The approval was granted under the FDA’s accelerated approval process to expedite access to patients with CLL to this promising new medication. Ibrutinib also received an orphan drug designation by the FDA. On November 13, 2013, the FDA granted accelerated approval to ibrutinib for the treatment of patients with mantle-cell lymphoma, a rare and aggressive type of hematologic cancer; this approval, too, was for patients who had received at least 1 previous therapy. “Today’s approval provides an important new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most,” Dr Pazdur said. The new FDA indication for ibrutinib for CLL is based on the results of a clinical trial with 48 previously treated patients with CLL. Patients were diagnosed with CLL, on average, 6.7 years before enrolling in the study and had received 4 previous therapies. Patients received oral ibrutinib until disease progression or unacceptable toxicity. Overall response was seen in nearly 58% of the patients, with a response duration of 5.6 months to 24.2 months during the study. Improvements in survival or disease-related symptoms have not been established. The most common side effects reported with ibrutinib include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, mouth sores, sinusitis, and dizziness. n

www.JHOPonline.com

March 2014

Vol 4, No 1

NeW foR 2014

Government and Employers An educational session for policymakers and employers focusing on healthcare reform, benefit design, insurance, and coverage trends. Co-Chairs

May 7, 2014 Loews Hollywood Hotel Los angeles, Ca

aGEnda

Jayson Slotnik, JD, MPH

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

F. Randy Vogenberg, PhD, RPh

Principal Institute for Integrated Healthcare

8:30am – 8:40am

Introductions and Opening Remarks Jayson Slotnik, JD, MPH; F. Randy Vogenberg, PhD, RPh

8:40am – 9:25am

Session 1: Investor Community Views on Healthcare Market Winners and Losers Michael E. Meyers, MPH, Managing Director, Head of Investment Banking, T.R. Winston & Company

9:25am – 10:10am

Session 2: Insurance Innovation on Reinsurance and Benefit Design Trends Matthew Palmgren, PharmD, President, Healthcare Solutions in Int’Ovation Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC

10:10am – 10:15am

Break

10:15am – 11:00am

Session 3: Private Exchanges: Why Different from Public Exchange Trends for Oncology Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions

11:00am – 11:40am

Session 4: Diagnostics: Recent FDA and CMS Policies Impacting Access to Diagnostic and Oncology Drugs John Ridge, Senior Director, Managed Care and Reimbursement, Exact Sciences Timothy J. Thompson, Chief Executive Officer, Intervention Insights

11:40am – 12:00pm

Session 5: What’s Next with Healthcare Reform – Fixes or More Related to Oncology? Denise Pierce, President and CEO, DK Pierce & Associates Jayson Slotnik, JD, MPH, Vice President of Reimbursement Strategy & Innovation, United BioSource Corporation F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare

12:00pm – 12:15pm

Break

12:15pm – 1:15pm

Lunch/Product Theater

1:15pm – 1:30pm

Break

1:30pm – 2:15pm

Session 6: Employer Onsite Clinic Trends from Wellness into Infusion and Emergent Care Larry Boress, President & CEO, Midwest Business Group on Health; Executive Director, National Association of Worksite Health Centers

2:15pm – 3:45pm

Meet the Experts Roundtables Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE)

3:45pm – 4:15pm

Poster Presentations

4:15pm – 5:00pm

Poster and Session Discussant

5:00pm – 7:00pm

Cocktail Reception in the Exhibit Hall

AVBCC2014May7agenda Asize_20714

ORIGINAL RESEARCH

CASE REPORT

Successful Panitumumab Administration after Cetuximab-Induced Aseptic Meningitis: A Case Report and Review Jane E. Rogers, PharmD, BCOP; Lindsey Law, MPAS, PA-C; Rachna Shroff, MD, MS Background: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptors and are used in the treatment of patients with KRAS wildtype metastatic colorectal cancer (mCRC). In addition, cetuximab is used for the treatment of patients with non–small-cell lung cancer and head and neck cancers. Cetuximab and panitumumab have similar and common adverse effects, but they also have subtle differences. Recent reports of cetuximab-induced aseptic meningitis have been reported in the literature. Objective: This case report delineates an example of cetuximab-related aseptic meningitis in the population of patients with mCRC and provides guidance for continuing therapy after such an adverse reaction. Discussion: We report a case of cetuximab-induced aseptic meningitis in a female patient with KRAS wild-type mCRC. The patient was then rechallenged with panitumumab and had no subsequent adverse reaction. Of the recent reported cases of cetuximab-induced meningitis, common symptoms reported included fever, headache, and neck stiffness. The cerebrospinal fluid evaluation showed an elevated white blood cell count and elevated protein levels, with negative cytology and cultures. Our patient presented with symptoms similar to these cases, as well as the cerebrospinal fluid evaluation that was negative for cytology and cultures, had an elevated white blood cell count, slightly elevated protein level, and a normal glucose level. After the patient’s reaction to cetuximab, our patient was rechallenged with panitumumab, with diphenhydramine and acetaminophen given before the panitumumab infusion. She received a J Hematol Oncol Pharm. total of 12 cycles of panitumumab therapy and had no adverse reactions. 2014;4(1):18-21. Conclusion: The exact mechanism of cetuximab-induced aseptic meningitis is not yet www.JHOPonline.com Disclosures are at end of text known. The symptoms can be severe and can last for several days, even with supportive care measures.

etuximab and panitumumab, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), are an integral component in the management of patients with metastatic colorectal cancer (mCRC), specifically those with KRAS wild-type tumors.1 Cetuximab is also used in the treatment of non–small-cell lung cancer (NSCLC) and head and neck cancers.2,3 Most patients with KRAS wild-type mCRC will receive cetuximab or panitumumab during the course of the systemic treatment of their disease. Therefore, with colorectal cancer (CRC) remaining the third most common cancer diagnosed annually in the United States, clinicians using these agents need to familiarize themselves with the common adverse effects that accompany their use.4 Cetuximab and panitumumab have similar common adverse effects, including acneiform rash, skin dryness,

hypomagnesemia, and paronychia.3,5 Although differences lie in the severity and incidence of adverse effects between cetuximab or panitumumab, their adverse effects are managed similarly through supportive measures. A key difference between these 2 targeted therapies lies in their monoclonal antibody structure. Cetuximab is a chimeric (mouse/human) monoclonal antibody, whereas panitumumab is a fully humanized monoclonal antibody; therefore, the greatest risk for hypersensitivity reactions is associated with the use of cetuximab.6 The reported incidence of severe hypersensitivity infusion reactions with cetuximab ranges from 3% to as high as 22%, depending on factors such as geographic distribution.6 The incidence of severe hypersensitivity reactions associated with panitumumab is less than 1%.6

Dr Rogers is Clinical Pharmacy Specialist, Pharmacy Clinical Programs; Ms Law is Physician Assistant, Department of Gastrointestinal Medical Oncology; and Dr Shroff is Assistant Professor, Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

March 2014

Vol 4, No 1

Panitumumab after Cetuximab-Induced Aseptic Meningitis

Although rare, there have been recent reports of cetuximab-induced aseptic meningitis in patients with NSCLC and in patients with head and neck cancers.7-11 The mechanism of this adverse reaction remains unknown; however, it may be related to a hypersensitivity reaction.12 With such rarity in incidence, there is limited information to aid in the decision for rechallenge or discontinuation of the drug. Furthermore, to date, only 1 report of rechallenging such a patient with panitumumab exists.11 We report a case of the successful administration of panitumumab after cetuximab-induced aseptic meningitis in a patient with mCRC.

Case Report A Hispanic woman aged 42 years with KRAS wildtype CRC that had metastasized to the liver reported to our institution after primary tumor resection. At the time, she had isolated liver metastases and sigmoid mesocolon lymphadenopathy. After 3 months of systemic chemotherapy with bevacizumab, fluorouracil, leucovorin, and oxaliplatin, she was considered a candidate for hepatic resection. The patient was found to be inoperable on exploratory laparotomy because of extensive steatosis. Therefore, she was initiated with a maintenance chemotherapy regimen with bevacizumab, fluorouracil, and leucovorin, reserving the use of oxaliplatin or irinotecan to prevent further liver damage. Nevertheless, after 6 months of maintenance chemotherapy, her disease was found to have progressed. It was then recommended that she begin therapy with single-agent cetuximab, given at a dose of 500 mg/m2 intravenously (IV) every 2 weeks. Of note, the US Food and Drug Administration (FDA)-approved dosing of cetuximab is a loading dose of 400 mg/m2 IV weekly for the first dose, then subsequent weekly doses of 250 mg/m2 IV. The use of cetuximab 500 mg/m2 IV every 2 weeks is an option for the treatment of patients with mCRC for added convenience for the patient.13 The patient began her first dose of cetuximab 500 mg/m2 IV administered over 2 hours after diphenhydramine premedication. Within a few hours after her first dose, she became febrile with a severe intractable headache, nausea and vomiting, and increasing pain and neck stiffness. The patient was admitted to the emergency department, and because of her systemic complaints, she was evaluated for possible meningitis. Her cerebrospinal fluid showed no infection, an elevated white blood cell count (2865 uL), elevated neutrophil percentage (100% segs), normal glucose level (43 mg/ dL), and a slightly elevated protein level (93 mg/dL). She was admitted for 5 days and was given empiric antibiotics, with supportive measures. Her neurologic symptoms resolved.

Vol 4, No 1

March 2014

After a review of the literature, the decision was made to continue with EGFR-directed therapy but to replace cetuximab with panitumumab. The patient received 12 cycles of panitumumab, 6 mg/kg IV every 2 weeks, with diphenhydramine and acetaminophen given before the infusion until disease progression, and was then switched to a regimen with fluorouracil, leucovorin, and irinotecan. She did not have a recurrence of her symptoms of aseptic meningitis during any of the 12 cycles of panitumumab.

With such rarity in incidence, there is limited information to aid in the decision for rechallenge or discontinuation of the drug. Furthermore, to date, only 1 report of rechallenging such a patient with panitumumab exists. Discussion Currently, 7 reports of cetuximab-induced aseptic meningitis exist (Table).7-11 The typical symptoms associated with this reaction include fever, frontal headache, nausea and vomiting, neck stiffness, and photophobia. Symptoms occurred within 24 hours of the first dose of cetuximab in these patients, ranging from a few hours to 16 hours after the infusion. Cerebrospinal fluid tends to show elevated white blood cell count with a high neutrophil percentage, elevated protein, normal glucose, and negative cytology and cultures. The symptoms can be severe, and their duration can range from 2 to 12 days. All 7 patients received empiric antibiotics and recovered from their adverse reaction. Of the 7 patients, 4 were rechallenged with an EGFR inhibitor. Of these 4 patients, 2 were rechallenged with cetuximab at a lower dose, with antihypersensitivity premedications (ie, diphenhydramine, dexamethasone, and famotidine added in 1 of these 4 cases). One of these 4 cases received cetuximab at a slower infusion rate on rechallenge. Of the 4 rechallenged patients, 1 was rechallenged with panitumumab dosed at 3 mg/kg weekly with hydrocortisone, ranitidine, and diphenhydramine antihypersensitivity premedications. The other 3 rechallenged patients did not have a subsequent recurrence of aseptic meningitis. One of the 4 rechallenged patients developed signs and symptoms similar to the patientâ&#x20AC;&#x2122;s first reaction (febrile, headache with cerebrospinal fluid showing elevated white blood cell count, elevated neutrophil percentage, slightly elevated protein, normal glucose,

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

ORIGINAL RESEARCH

Table S ummary of Reported Cases of Cetuximab-Induced Meningitis Cases reported: patient receiving cetuximab 400 mg/m2

Symptoms

Outcomes

Female with NSCLC

• • • •

• Duration of symptoms not specified • Resumption of therapy not discussed

Male with NSCLC8

• Onset: a few hrs after first dose • Encephalopathy

• Symptom duration of several days • Resumption of therapy not discussed

Male with locally recurrent laryngeal squamous-cell carcinoma9

• O nset: a few hrs after first infusion • F ebrile • F rontal headache

• S ymptom duration of 4 days • Rechallenged with cetuximab 250 mg/m2, dexamethasone, and diphenhydramine • N o subsequent reactions

Male with locally advanced squamouscell carcinoma of the right tonsil9

• • • • •

nset: 8 hrs after first dose O F ebrile F rontal headache N eck stiffness S evere photophobia

• S ymptom duration of 12 days • Rechallenged with cetuximab 250 mg/m2 infused at slower rate, dexamethasone, diphenhydramine, and famotidine • N o subsequent reactions

Stage IVB squamous maxillary cancer7

• • • •

nset: a few hrs after first dose O F ebrile F rontal headache N eck discomfort

• S ymptom duration not specified • Repeat symptoms occurred on subsequent cetuximab 250-mg/m2 dose; recovered with supportive therapy • No subsequent reactions with further cetuximab (premedication not discussed)

Recurrent/metastatic squamous-cell carcinoma of the hypopharynx10

• • • • • •

nset: a few hrs after first dose O F ebrile H eadache N eck stiffness Rigidity of arms and legs Admitted to ICU for respiratory failure

• S ymptom duration of 5 days • Not rechallenged with cetuximab

Squamous-cell carcinoma of left base of tongue11

• • • • • •

O nset: 16 hrs after first dose H eadache N ausea F ever P hotophobia B lurred vision

• S ymptom duration of 2 days • R echallenged with panitumumab, hydrocortisone, ranitidine, and diphenhydramine • N o subsequent reactions

Onset: a few hrs after first dose Occipital and frontal headache Nausea/vomiting Neck stiffness

ICU indicates intensive care unit; NSCLC, non–small-cell lung cancer.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

March 2014

Vol 4, No 1

Panitumumab after Cetuximab-Induced Aseptic Meningitis

and negative cultures) with a second dose of cetuximab (250 mg/m2). That patient made a full recovery on both occasions and thereafter had no complications with further cetuximab infusions at the same dose.7 Information regarding cetuximab infusion time or premedications used on rechallenge for additional doses of cetuximab in this patient are not specified in the report.7 Aseptic meningitis, a noninfective inflammation of the meninges, is a self-limiting disorder. Drug-induced aseptic meningitis is rare and involves a diagnosis of exclusion.12 Infectious causes must be ruled out before a diagnosis of drug-induced meningitis can be considered. Many medications, including nonsteroidal anti-inflammatory drugs, antimicrobials, intrathecal agents, and intravenous immunoglobulin, have been reported to cause such a reaction. Aseptic meningitis cases have also been reported with other monoclonal antibodies, such as infliximab, adalimumab, and efalizumab.14-16 The main management strategies for drug-induced aseptic meningitis include discontinuing the offending agent and managing the patient with supportive care.12 Two mechanisms of this adverse reaction have been proposed with other agents.12 One mechanism proposed suggests that the meninges are directly affected by the drug as a result of its administration into the cerebrospinal fluid, such as with intrathecal drug administration. The second proposed mechanism is thought to be an immunologic hypersensitivity type of reaction, which may be the mechanism responsible for cetuximab-induced aseptic meningitis. Whether the development of aseptic meningitis is more of a concern with the first dose of cetuximab or with higher doses of cetuximab remains to be determined.

Conclusion Cetuximab-induced aseptic meningitis represents a rare adverse effect. The true incidence of this reaction and the mechanism behind it remain unknown and warrant further investigation. However, clinicians should be aware that this reaction can occur with cetuximab, and a workup and supportive care should be initiated at the first sign of symptoms of cetuximab-induced aseptic meningitis. Fortunately, panitumumab is an FDA-approved available option for the management of mCRC KRAS wild-type, and can be considered an alternative for patients who manifest this reaction to cetuximab. Based on our case report, it appears that rechallenging a patient with panitumumab is safe and should be

Vol 4, No 1

March 2014

considered before discontinuing anti-EGFR therapy. In malignancies for which panitumumab may not be a suitable alternative to cetuximab, one may consider

The main management strategies for drug-induced aseptic meningitis include discontinuing the offending agent and managing the patient with supportive care. rechallenging the patient with a lower dose of cetuximab, a slower infusion rate, and heavy premedications consisting of dexamethasone and histamine-1 and histamine-2 antagonists. n Author Disclosure Statement Dr Rogers, Ms Law, and Dr Shroff reported no conflicts of interest.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): colon cancer. Version 3.2014. January 27, 2014. www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed February 20, 2014. 2. Pirker R, Periera JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531. 3. Erbitux (cetuximab) injection, for intravenous infusion [prescribing information]. Branchburg, NJ: Eli Lilly and Company; August 2013. 4. American Cancer Society. Cancer Facts and Figures 2012. 2012. www.cancer. org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc031941.pdf. Accessed February 20, 2014. 5. Vectibix (panitumumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; February 2013. 6. George TJ Jr, Laplant KD, Walden EO, et al. Managing cetuximab hypersensitivity-infusion reactions: incidence, risk factors, prevention, and retreatment. J Support Oncol. 2010;8:72-77. 7. Emani MK, Zaiden RA Jr. Aseptic meningitis: a rare side effect of cetuximab therapy. J Oncol Pharm Pract. 2013;19:178-180. 8. Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol. 2010;5:751. 9. Feinstein TM, Gibson MK, Argiris A. Cetuximab-induced aseptic meningitis. Ann Oncol. 2009;20:1609-1610. 10. Vulsteke CA, Joosens E, De Klippel N, Mebis J. Aseptic meningitis as a rare but serious side effect of cetuximab therapy. Belg J Med Oncol. 2010;4:257-259. 11. Riggs CE. Panitumumab treatment of head and neck cancer after cetuximab-induced aseptic meningitis: case report. J Clin Oncol. 2011;29(15 suppl). Abstract e16033. 12. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22:215-226. 13. Martín-Martorell P, Roselló S, Rodríguez-Braun E, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008;99:455-458. 14. Manthey C, Lohse AW, Pace A. Case report of aseptic meningitis in a patient with Crohn’s disease under infliximab therapy. Inflamm Bowel Dis. 2011;17:E10. 15. Jazeron A, Lallier JC, Rihn B, Thiercelin MC. Aseptic meningitis possibly induced by adalimumab. Joint Bone Spine. 2010;77:618-619. 16. Kluger N, Girard C, Gonzalez V, et al. Efalizumab-induced aseptic meningitis. Br J Dermatol. 2007;156:189-191.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

Author Guidelines MISSION STATEMENT—The Journal of Hematology Oncology Pharmacy (JHOP) is an independent, peerreviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals in these fields with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

EDITING—Routine editorial changes are made on all articles to conform to house style, following the AMA Manual of Style, 10th ed.1 The edited manuscript is sent to the corresponding author for a final review and for any outstanding editorial queries. Time from submission to publication is generally 3 to 6 months, but could be longer, depending on the peer-review and revision processes.

GENERAL INFORMATION—Manuscripts submitted to JHOP must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP.

AUTHORSHIP/COPYRIGHT—Authors listed on the manuscript should only include those who have made a direct contribution to the content of the article, in accordance with the authorship criteria provided by the International Committee of Medical Journal Editors (ICMJE).2 Credit for authorship is based on a substantial contribution to (1) conception and design, or data analysis/interpretation, (2) drafting or revising the article critically for intellectual content, and (3) approval of the final version to be published. These 3 criteria must all be met.2 Those who have contributed to the article but do not meet these authorship criteria should be acknowledged at the end of the article.

The editors invite readers to submit articles on a variety of points of view and approaches to meet the mission of the journal. Articles will be divided into 4 main categories, including (1) original research, to provide an outlet for translational and practice-based research, including case reports and case series; (2) review articles that focus on drug and disease state as well as on basic science regarding the complex molecular biology of cancer with a pharmacy focus; (3) clinical controversies that discuss common clinical issues for which treatment is unclear, or “point, counterpoint” and “how I treat” type of articles; (4) practical issues in pharmacy management that will focus on real-world issues involving logistics, economics, and other practice-related topics. PEER REVIEW—All articles undergo an initial internal review for topic appropriateness and manuscript format. Manuscripts that are not submitted according to the guidelines in this document will be returned to the author. All manuscripts are subject to a strict, blinded peer review (by 2-3 reviewers), and acceptance is determined by the section editor based on that review. Reviewers look for accuracy of the information and data presented, as well as relevance to the objectives of JHOP. All authors’ identifying information is removed from the article for the purpose of the peer review, but any study funding information is provided to reviewers. Authors are notified as soon as possible regarding the initial decision of acceptance or rejection of the article. The majority of articles that are accepted for publication, however, will require revisions and resubmission.

Journal of Hematology Oncology Pharmacy

Provide authors’ highest academic degree and professional affiliations. Also provide the name, address, telephone number, e-mail, and fax number of the corresponding author. The corresponding author is responsible for securing signatures for all forms from all authors. All authors are required to sign an Authorship/Copyright Transfer Form, assigning all copyrights for the manuscript to Green Hill Healthcare Communications, LLC, publisher of JHOP. For an article to be considered for publication, authors must adhere to the manuscript format described in this document and follow the general ICMJE guidelines.2 DISCLOSURE STATEMENTS—All authors must disclose any relationship that could be viewed as a potential conflict of interest, based on ICMJE guidelines,2 including any financial interests, direct or indirect, and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript. Each author must sign the Financial Disclosure Form in accordance with the ICMJE guidelines.2 JHOP discloses all information regarding employment, consultancies, stock ownership, honoraria, grants, or other financial sources with potential conflict of interest

www.JHOPonline.com

March 2014

Vol 4, No 1

in relation to a manuscript, or if authors discuss any products or services with such commercial interest. Any information regarding funding, grants, or other financial compensation must be listed on the title page of the manuscript. All published articles will include disclosure statements listing any relationships with real or potential conflict of interest for all authors and for the manuscript/research. PERMISSIONS—Authors must secure written permission to reuse or adapt any graphic elements (table, figure) from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. Authors are responsible for acknowledging all information that has been published previously. MANUSCRIPT FORMAT—Manuscripts that do not adhere to the format described in this document will be returned to the author. Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author. List all funding sources for the study/article. Abstract: Articles must include an abstract (200-250 words) that describes the main objectives of the article, why this article is important, and what it adds to the literature. The abstract must be divided into these categories: Background, Objective, Methods (and Study Design, if relevant), Results, and Conclusion. An abstract for an article that does not represent research findings should include the following categories to suggest why the article is important and what its main objective is: Background, Objective, Discussion, Conclusion. Text: The entire text must be provided as a double-spaced Word file and all pages numbered consecutively. Cite any graphic elements (tables, figures, algorithms, appendix) consecutively in the text, but place actual tables/figures at the end of the article, after the references. Limit the length of the text to 3500 words (excluding references, tables, and figures). Conclusion: The conclusion is not a summary of the article. Rather, it should add something new to the

Vol 4, No 1

March 2014

article, a point of view or comments related to the rationale for the article and what the article adds to the literature. Tables and figures: Cite all figures, tables, algorithms, and other graphics in the text, but place the graphic elements at the end of the article, after the references. Type all tables and all figure heads and captions in the Word document. Figures and other images (excluding tables) must also be provided as individual graphic files, saved at high resolution (300 dpi), as jpg or pdf file. Attach an individual file for each image. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact JHOP@greenhillhc.com. References: Use most up-to-date, post-1990, primary sources only, cited consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Avoid automatic numbering or footnote/endnote features. Try to limit the number of references to 35. Use citation format according to the AMA Manual of Style.1 Examples:

1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news? pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

HOW TO SUBMIT MANUSCRIPTS—Articles that do not follow the guidelines described in this document will not be considered for publication. Save the manuscript as a Word file and attach individual files for each image or figure. Save images (figures) individually as an image file (jpg or pdf). Submit the entire manuscript and a cover letter stating the objectives of the article at www.JHOPonline.com. For assistance call 732-992-1536. REPRINTS—Reprints may be ordered for a nominal fee by contacting JHOP@greenhillhc.com. 1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007. 2. International Committee of Medical Journal Editors. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Updated December 2013. http://www.icmje.org/icmje-recommendations.pdf. Accessed February 29, 2014.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

NeW foR 2014

Personalized Medicine and Payers An educational session for payers focusing on cost efficiency, value, outcomes, and impacts on treatment of personalized medicine. Co-ChAirs

May 8, 2014 Loews Hollywood Hotel Los angeles, Ca

AgendA 7:00am – 8:30am 8:30am – 8:40am 8:40am – 9:20am

9:20am – 10:00am

10:00am – 10:40am

10:40am – 11:20am

11:20am – 12:00pm

12:00pm – 12:15pm 12:15pm – 1:15pm 1:15pm – 2:45pm

2:45pm – 3:00pm 3:00pm – 4:00pm 4:00pm – 5:00pm 5:00pm – 7:00pm

Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Special Session: Value-Based Strategies for Patients with Multiple Myeloma Supported by funding from Millennium: The Takeda Oncology Company Introductions and Opening Remarks Michael A. Kolodziej, MD; Grant Lawless, RPh, MD, FACP Session 1: Personalized Medicine and Value Peter Bach, MD, MAPP, Memorial Sloan-Kettering Cancer Center Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna Session 2: Measuring the Value of Prognostic and Predictive Outcomes Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine Macey Johnson, Vice President of Managed Care and Reimbursement, BioTheranostics Session 3: Utilizing Big Data to ID Phenotypes and Predictive Outcomes Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint George W. Sledge, MD, FASCO, Chief of Oncology, Stanford University Department of Medicine Session 4: Value Paradigm in Drug Development Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Kevin Knopf, MD, MPH, California Pacific Medical Center Christiane Langer, MD, Lead Medical Director for CRC, GU, and GBM, Genentech Panel Discussion - How will personalized medicine impact future treatment and use existing therapy? Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint Break Lunch/Product Theater Meet the Experts Roundtables Al Benson, MD, Professor of Medicine and Oncology, Northwestern University Medical School Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Break Poster Presentations Poster and Session Discussant Cocktail Reception in the Exhibit Hall AVBCC2014May8agenda Asize_20714

FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro Universityâ&#x20AC;&#x201C;California, Mare Island, Vallejo, CA

nO binutuzumab

versus Rituximab for the Treatment of Older Patients with Chronic Lymphocytic Leukemia

BACKGROUND: The anti-CD20 antibody rituximab, combined with chemotherapy agents, has been shown to prolong overall survival (OS) in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL), but not in patients with comorbidities. In a recent head-to-head, randomized, phase 3 trial of older patients, researchers investigated the benefit of the antiCD20 antibody obinutuzumab plus chlorambucil compared with rituximab plus chlorambucil in patients with previously untreated CLL and coexisting conditions. METHODS: In this open-label study, 781 patients were randomized in a 1:2:2 ratio to receive six 28-day cycles of obinutuzumab plus chlorambucil (N = 333), chlorambucil alone (N = 118), or to rituximab plus chlorambucil (N = 330). Patients were required to have a Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of 30 mL/min to 69 mL/min. The groups receiving obinutuzumab and rituximab were well-balanced. The patients had a median age of 73 years, a CrCl of 62 mL/min, and a CIRS score of 8 at baseline. Most of the patients (82%) had more than 3 coexisting conditions, such as hypertension, coronary artery disease, and diabetes. Chlorambucil was administered orally at 0.5 mg/kg of body weight on days 1 and 15 of each cycle. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 through 6. Rituximab was administered intravenously at doses of 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 through 6. RESULTS: Patients in the obinutuzumab plus chlorambucil group had a significant increase in median prolonged progression-free survival (PFS) and a higher response rate than the rituximab plus chlorambucil group. The median PFS was 26.7 months in the obinutuzumab group and 15.2 months in the rituximab group (hazard ratio [HR], 0.39; 95% confidence interval, 0.31-0.49; P <.001). The complete response rates were 20.7% and 7%, respectively. The median PFS in patients receiving chlorambucil monotherapy was 11.1 months, which was

Vol 4, No 1

March 2014

shorter than the obinutuzumab plus chlorambucil group (HR, 0.18) or the rituximab plus chlorambucil group (HR, 0.44). Grades 3 to 5 adverse events ranged from 11% to 14% and did not differ significantly among treatment groups. The main difference was in infusion-related reactions. In the obinutuzumab plus chlorambucil group, 20% of the patients experienced infusion-related reactions compared with 4% of patients in the group receiving rituximab plus chlorambucil. In the group receiving obinutuzumab plus chlorambucil, the researchers noted that the reaction occurred during the first infusion, and no deaths were associated with infusion-related reactions. The researchers concluded that the combination of obinutuzumab or rituximab with chlorambucil improves outcomes in patients with previously untreated CLL and coexisting conditions. In this patient population, obinutuzumab plus chlorambucil showed an OS advantage over chlorambucil monotherapy. Furthermore, obinutuzumab plus chlorambucil induced prolonged PFS and a higher complete response rate than rituximab plus chlorambucil. Source: Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Jan 8 [Epub ahead of print]. COMMENTARY BY ROBERT J. IGNOFFO

Although obinutuzumab is an anti-CD20 monoclonal antibody similar to rituximab, its mechanism differs in that it binds to a different epitope on CD20 that enhances immune effector functions, especially antibody-dependent cell-mediated cytotoxicity. It also has been shown to produce greater B-cell depletion compared with rituximab.1 Phase 2 studies were very promising in highly refractory non-Hodgkin lymphoma. This phase 3 study by Goede and colleagues provides high-level evidence that obinutuzumab is a very active drug in CLL. Although OS with the combination of obinutuzumab plus chlorambucil was not significantly better than rituximab plus chlorambucil, PFS was better by approximately 75%. The 20% incidence of infusion-related reactions is greater than that reported

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

FROM THE LITERATURE

for rituximab and may be somewhat more problematic for oncology nurses to handle. Fortunately, most of the reactions occurred during the first cycle. The average wholesale cost for 1000 mg is $6192. A monthly cycle consists of three 1000-mg doses, making the cost of a typical treatment $18,576, which varies as a result of differences in purchasing methods. The FDA has approved obinutuzumab as a breakthrough therapy and as an orphan drug. It is likely that this drug will be added to standard algorithms for both the initial and refractory treatments of symptomatic CLL. 1 . Mossner E, BrĂźnker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393-4402.

A dverse Events Reporting Suboptimal in Oncology Publications

BACKGROUND: Transparent and comprehensive reporting of adverse events (AEs) in published results of oncology-related clinical trials is crucial for the treatment of patients with cancer. In efforts to improve reporting clinical trials results, the Consolidated Standards of Reporting Trials (CONSORT) extension group developed 10 recommendations in 2003 for reporting AEs. METHODS: A new study of 175 publications assessed the degree to which the publication of phase 3 trials in oncology adhered with CONSORT recommendations. The researchers also evaluated characteristics associated with AE reporting completeness score using regression analysis. RESULTS: The findings from this analysis showed that the reporting of AEs is suboptimal in published studies and is characterized by significant selectivity of the data. The researchers reviewed PubMed, MEDLINE, and EMBASE citations to identify randomized, phase 3 trials in metastatic solid malignancies published between January 2009 and December 2011. Publications were assessed for 14 AE reporting elements taken from the CONSORT harms extension statement, with a completeness score of 0 to 14 being calculated. Data on 96,125 patients were included in the analysis. The median completeness score was 8 (range, 3-12). The majority of publications (96%) only reported AEs occurring above a particular threshold rate or severity. Another 37% of publications did not specify the criteria for determining which AEs were reported, and 88% grouped AEs of varying severity. The findings showed that 91% of the articles analyzed had a title or an abstract stating whether AEs were addressed, and 58% had introductions stating whether AEs

Journal of Hematology Oncology Pharmacy

were addressed in the study. For methods, 93% specified an instrument or scale used to categorize AEs, 65% specified whether the reported AEs encompassed all recorded events or a select sample, and 62% specified a surveillance time frame. For the results, 77% of articles reported absolute numbers of AEs, 75% reported if there were deaths related to AEs, 71% reported whether patients were evaluable for toxicity, and 65% reported reasons for treatment discontinuation. The regression analysis used to assess characteristics associated with the AE reporting completeness score revealed that trials without a specified funding source and with an earlier year of publication were associated with significantly lower completeness scores. This analysis shows substantial selectivity and heterogeneity in the reporting of AEs in oncology publications, which may affect the results used to guide clinical practice. The researchers cited potential factors for the observed variability in AE reporting and poor adherence with the recommendations, including the authorsâ&#x20AC;&#x2122; awareness of these recommendations and a lack of compliance with guidelines imposed by journals as a prerequisite. This study further illustrates the importance of developing oncology-specific standards for AE reporting to ensure consistency in the reporting of AEs to provide oncologists with the information required to determine treatment recommendations and to facilitate shared decision-making. Source: Sivendran S, Latif A, McBride RB, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol. 2014;32: 83-89. COMMENTARY BY ROBERT J. IGNOFFO

The article by Sivendran and colleagues illustrates the variability in reporting the results of AEs in phase 3 clinical trials of anticancer drugs. The journals included for review were those considered to be important to obtaining clinical information about new treatment strategies. The journals include Annals of Oncology, Breast Cancer Research and Treatment, British Journal of Cancer, Cancer, European Journal of Cancer, Journal of Clinical Oncology, Lancet, Lancet Oncology, New England Journal of Medicine, and others. Of the 175 journals, most articles appeared in the Journal of Clinical Oncology. It is apparent from the article by Sivendran and colleagues that more stringent criteria should be used by editorial boards requiring that an article about a phase 3 clinical therapeutics trial reach a particular level of completeness before being published. Certain reporting elements should probably always be included, such as a statement in the abstract about whether AEs

www.JHOPonline.com

March 2014

Vol 4, No 1

FROM THE LITERATURE

occurred, the percentage of patients who discontinued therapy as a result of toxicities, and whether any grade 4 or 5 toxicities occurred. n

C ombination of Bortezomib and Thalidomide Used as Maintenance Improves Overall Survival in TransplantIneligible Patients with Newly Diagnosed Multiple Myeloma

BACKGROUND: Patients with multiple myeloma (MM) who are not fit to undergo stem-cell transplantation typically receive melphalan plus prednisone in combination with either thalidomide or bortezomib. Recent studies are exploring the clinical benefit of the 4-drug induction regimen of bortezomib, melphalan, prednisone, and thalidomide, followed by maintenance with bortezomib plus thalidomide (VMPT-VT). METHODS: In this recent phase 3 trial, a total of 511 patients with newly diagnosed MM who were not candidates for stem-cell transplantation were randomized to receive VMPT-VT (N = 254) or bortezomib, melphalan, and prednisone (VMP; N = 257). The patientsâ&#x20AC;&#x2122; median age was 71 years, and 27% of the patients were aged >75 years. RESULTS: After a median follow-up of 54 months, the progression-free survival (PFS) was 35.3 months for patients receiving VMPT-VT and 24.8 months for patients receiving bortezomib, melphalan, and prednisone VMP (hazard ratio [HR], 0.58; P <.001). Of note, the overall survival (OS) was significantly prolonged with VMPTVT compared with VMP; the 5-year OS rates were 61% with VMPT-VT and 51% with VMP (HR, 0.70; P = .01). A multivariable analysis revealed that treatment with VMPT-VT, age <75 years, female sex, and disease stages I and II were associated with the significantly longer OS. In addition, the difference between median PFS and time to next therapy was approximately 1 year with VMPT-VT, but only 3 months with VMP. Researchers suggested that the significant tumor reduction and ongoing treatment with maintenance therapy delayed disease progression in patients treated with VMPT-VT. The most common adverse events (AEs) were hematologic and included grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia; neutropenia was reported in 38% of patients in the VMPT-VT arm and in 28% of patients in the VMP arm, whereas thrombocytopenia was reported in 22% of patients in the VMPT-VT arm and in 20% of patients in the VMP arm. The most common nonhematologic AEs in both treatment arms included infections, cardiologic events, and peripheral neuropathy. Of the patients in the VMPT-VT arm, 28% discontinued treatment and required dose reduction be-

Vol 4, No 1

March 2014

cause of AEs; the same was true for 16% of patients in the VMP arm. The researchers concluded that the VMPT-VT regimen was superior to the VMP regimen in terms of PFS, OS, and time to next therapy in patients with newly diagnosed MM who are not eligible for stem-cell transplantation. Although these follow-up results are encouraging, an important question remains to be answered: is the clinical benefit observed with the VMPT-VT attributed to the 4-drug induction combination or to the maintenance treatment with bortezomib and thalidomide? Overall, researchers believe these results provide the foundation for newer, less toxic combinations of immunomodulatory agents and proteasome inhibitors. Source: Palumbo A, Bringhen S, Larocca A, et al. Bortezomibmelphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32: 634-640. COMMENTARY BY ROBERT J. IGNOFFO

The phase 3 study by Palumbo and colleagues combines all of the first-line chemotherapy drugs for the treatment of advanced MM for patients who are unable to undergo stem-cell transplant. The 4-drug combination of bortezomib, melphalan, prednisone, and thalidomide with maintenance significantly prolongs PFS and OS, as well as delays the time to next therapy. This regimen was very effective in the 65- to 75-year-old agegroup. The overall complete response rate to the 4-drug combination with maintenance was an impressive 14%. Unfortunately, the study did not include a third arm to assess if the benefit was a result of the 4-drug induction therapy or the maintenance therapy. The 4-drug regimen produced more toxicity than the 3-drug combination of bortezomib, melphalan, and prednisone, in particular neutropenia and thrombocytopenia. Expectantly, patients aged >75 years were more susceptible to toxicity and required greater dose reduction and discontinued therapy more often than younger patients. The thalidomide plus bortezomib maintenance therapy utilized once-weekly bortezomib rather than the usual twice-weekly schedule, and decreased the incidence of peripheral neuropathy substantially. The authors noted that the study was limited by not having a predefined salvage regimen and a second randomization in the maintenance arm versus the control arm. The 4-drug combination is a reasonably effective and low-toxicity regimen for the treatment of advanced MM in patients who are ineligible for stemcell transplant.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

FROM THE LITERATURE

N intedanib plus Docetaxel an Effective Combination in Patients with Advanced Lung Cancer

BACKGROUND: The current US Food and Drug Administration (FDA)-approved second-line treatments for nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC) include monotherapy with docetaxel, erlotinib, or pemetrexed. A recent trial explored the safety and efficacy of nintedanibâ&#x20AC;&#x201D;a potent oral angiokinase inhibitorâ&#x20AC;&#x201D;in combination with docetaxel, as a second-line treatment in patients with NSCLC. METHODS: In this phase 3 LUME-Lung 1 trial, 1314 patients were randomized to receive nintedanib and docetaxel (ie, the treatment group; N = 655) or docetaxel and placebo (ie, the placebo group; N = 659). The primary end point was progression-free survival (PFS) as assessed by the central independent review. The key secondary end point was overall survival (OS). The OS was assessed in the following order: first in patients with adenocarcinoma who progressed within 9 months of starting first-line therapy, next in all patients with adenocarcinoma, and, finally, in all patients, regardless of histology. RESULTS: After a median follow-up of 7.1 months, the median PFS was 3.4 months in the treatment group compared with 2.7 months in the placebo group (P = .001). After a median follow-up of 31.7 months, the OS of patients with adenocarcinoma who progressed within 9 months of starting first-line therapy was 10.9 months in the treatment group versus 7.9 months in the placebo group (P = .007). Furthermore, in all patients with adenocarcinoma, the OS was 12.6 months in the treatment group and 10.3 months in the placebo group (P = .035). Although treatment with nintedanib plus docetaxel had a significant effect on OS in patients with adenocarcinoma who progressed within 9 months of first-line treatment and in all patients with adenocarcinoma, there was no difference in OS between the 2 groups when all patients, independent of histology, were assessed. Adverse events (AEs) that were more common in the treatment group than in the placebo group included diarrhea, increases in alanine aminotransferase, nausea, increases in aspartate aminotransferase, decreased appetite, and vomiting. Most of these AEs were managed with supportive care or with dose reduction. The investigators suggest that nintedanib plus docetaxel may be an appropriate second-line treatment option for all patients with NSCLC and is particularly effective in patients with an adenocarcinoma histology. Source: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155.

Journal of Hematology Oncology Pharmacy

COMMENTARY BY ROBERT J. IGNOFFO

Nintedanib is not yet approved by the FDA for clinical use in patients with NSCLC. The LUMELung 1 study evaluated this drug in combination with the standard second-line agent, docetaxel. The benefit appears to be minimal, with only a 3-month improvement in PFS and a 2-month improvement in OS in patients with adenocarcinoma. However, the authors noted that this is the first study combining a targeted agent with chemotherapy in the second-line setting that has produced a median OS greater than 1 year. OS was not improved in patients with squamous-cell histology. Other antiangiogenic agents that have been combined with chemotherapy include vandetanib, sunitinib, and aflibercept, and none have improved OS in patients with NSCLC. The efficacy of nintedanib is apparent in both squamous-cell carcinoma and adenocarcinoma histologies. Although AEs were substantially higher with the combination, these were primarily diarrhea and elevations in hepatic enzymes. This is notably different from other antiangiogenic drugs, which generally cause hypertension, bleeding, perforation, and thromboembolism. Reck and colleagues noted that further studies should be performed to determine if biomarker analyses correlate with response to nintedanib in patients with refractory adenocarcinoma. This study did not analyze tissue samples for potentially useful biomarkers. n

S tatin Therapy Lowers Mortality in Patients with Prostate Cancer

BACKGROUND: Statin use has been shown to improve lipid profiles and to reduce cardiovascular morbidity and mortality. A 2012 study found that statins may have antitumor effects in various cancer types, including prostate cancer. Observational studies have investigated the association between statin use and different prostate cancer outcomes, but the findings were inconsistent. Also, these studies did not specifically assess whether the use of statins before the diagnosis of prostate cancer modified the association regarding the use of statins after diagnosis. In a new study, researchers examined the correlation between the use of statins after a prostate cancer diagnosis and the risk of cancer-related and all-cause mortality. METHODS: The data come from a large, populationbased electronic database of 11,772 men in the United Kingdom. The cohort focused on patients newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, who were followed until October 1, 2012. The mean age at study entry was 71.3 years.

www.JHOPonline.com

March 2014

Vol 4, No 1

FROM THE LITERATURE

RESULTS: During a mean follow-up of 4.4 years, the researchers identified 3499 deaths, and 1791 (approximately 52%) of those deaths were specific to prostate cancer. The postdiagnostic use of statin therapy was associated with a 24% risk reduction in prostate cancer mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.88). The results also showed a 14% decreased risk of all-cause mortality (HR, 0.86; 95% CI, 0.78-0.95), with the HRs gradually decreasing with longer cumulative durations of use and higher cumulative doses. For patients who used statins before their diagnosis, these decreased risks were more pronounced (HR, 0.55; 95% CI, 0.410.74, and HR, 0.66; 95% CI, 0.53-0.81, respectively). However, weaker effects were observed in patients who started statins after diagnosis (HR, 0.82; 95% CI, 0.710.96, and HR, 0.91; 95% CI, 0.82-1.01, respectively). RESULTS: Overall, these findings indicate that statin use after a diagnosis of prostate cancer is correlated with a reduced risk of cancer-related mortality and all-cause mortality. This effect, however, was stronger in patients who also used statins before their diagnosis of prostate cancer, suggesting a possible effect of longer cumulative duration of use and higher cumulative doses. Although the study results provide evidence that statin use may be associated with a decreased risk of prostate cancer mortality, the researchers cautioned that additional well-conducted, observational studies are needed to validate these findings before initiating randomized controlled trials to evaluate the effects of statins in the adjuvant setting. Source: Yu O, Eberg M, Benayoun S, et al. Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol. 2014; 32:5-11.

COMMENTARY BY ROBERT J. IGNOFFO

The basis for the large number of studies evaluating statins and prostate cancer stems from research demonstrating that they have antitumor properties through their effects on lipid metabolism.1,2 This large cohort study suggests that statins may reduce the risk of prostate cancer death and all-cause mortality. In an accompanying editorial, Mucci and Stampfer state, â&#x20AC;&#x153;From the perspective of etiology and prevention, we propose that lethal prostate cancer is the optimal disease end point for epidemiologic investigations. Given the long natural history of prostate cancer, such studies require long-term and complete follow-up of large cohorts of men.â&#x20AC;?3 Mucci and Stampfer mention that the Yu study provides important new information on the use of statins. The benefit was seen primarily in men who were taking statins before their diagnosis of prostate cancer. This result suggests that statins need to be given over a specific time or exposure period to have a chemopreventive effect. Considerations include what the optimal exposure time is and when a statin should be started. An extremely large and unfeasible study would be required to answer these questions. This study may, however, convince some clinicians to institute statin therapy in a high-risk family member with borderline cardiovascular disease. 1 . Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367:1792-1802. 2. Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol. 2012;12:751-759. 3. Mucci LA, Stampfer MJ. Mounting evidence for prediagnostic use of statins in reducing risk of lethal prostate cancer. J Clin Oncol. 2014;32:1-2.

AVBCC LEADERSHIP Burt Zweigenhaft, BS President and CEO OncoMed

FOURTH ANNUAL CONFERENCE

Craig K. Deligdish, MD

Hematologist/Oncologist Oncology Resource Networks

MAY 6-9, 2014

Loews Hollywood Hotel Los Angeles, California

HELD IN PARTNERSHIP WITH

Gary M. Owens, MD President Gary Owens Associates

www.regonline.com/avbcc2014 Vol 4, No 1

March 2014

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

NEW FOR 2014

Oncology Practice Management, Advocacy, and Navigation An educational session for practice managers and other care providers focusing on cancer care and innovative delivery techniques. CO-CHAIRS

MAY 9, 2014 Loews Hollywood Hotel Los Angeles, CA

Linda Bosserman, MD, FACP President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AGENDA 8:30am – 8:45am

Introductions and Opening Remarks Linda Bosserman, MD, FACP; Vicki Kennedy, LCSW

8:45am – 9:15am

Session 1: Cancer Care in Crisis: An Imperative for Change Douglas Blayney, MD, Ann & John Doerr Medical Director, Cancer Center, Stanford University Medical Center; Professor of Medicine, Stanford University School of Medicine

9:15am – 10:30am

Session 2: Innovation in Practice Management and Care Delivery: A Progress Report on Value-Based Innovation Linda Bosserman, MD, FACP, President, Wilshire Oncology Medical Group John Fox, MD, Associate Vice President of Medical Affairs, Priority Health John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

10:30am – 10:45am

Break

10:45am – 11:45am

Session 3: Uniting the Patient, Provider, and Community Voice in Value-Based Cancer Care Terry Langbaum, Chief Administrative Officer, Kimmel Center, Johns Hopkins School of Medicine Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center Kim Thiboldeaux, President & CEO, Cancer Support Community

11:45am – 1:00pm

Lunch/Meet the Experts Roundtables John Fox, MD, Associate Vice President of Medical Affairs, Priority Health Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

1:00pm – 1:45pm

Keynote Address Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna

1:45pm – 2:00pm

Closing Remarks

AVBCC2014May9agenda Asize_20714

PEER REVIEW

Thank You JHOP Peer Reviewers The Editors of the Journal of Hematology Oncology Pharmacy wish to extend a heartfelt Thank You to all those who participated in the peer-review process during 2013. Your diligence and careful comments go a long way to ensure the continued high quality of articles published in the journal.

Vol 4, No 1

Val Adams, PharmD, FCCP, BCOP

Trevor McKibbin, PharmD, MS, BCPS

David Baribeault, RPh, BCOP

Katherine Mandock, PharmD, BCPS

Chad Barnett, PharmD, BCOP

Patrick Medina, PharmD, BCOP

Marlo Blazer, PharmD, BCOP

Betsy Poon, PharmD, FCCP

Joseph S. Bubalo, PharmD, BCPS, BCOP

Lindsey B. Poppe, PharmD, MS, BCPS

Larry W. Buie, PharmD, BCPS, BCOP

Michelle L. Rockey, PharmD, BCOP

Rebecca Greene, PharmD

Jane Rogers, PharmD, BCOP

Donald Harvey, PharmD, FCCP, BCOP

Rowena Schwartz, PharmD, BCOP

David Henry, MS, BCOP, FASHP

Sachin Shah, PharmD, BCOP, FCCP

Lisa Holle, PharmD, BCOP

Julian Slade, PharmD, BCOP

Andrea Iannucci, PharmD, BCOP

Scott Soefje, PharmD, MBA, BCOP

LeAnne Kennedy, PharmD, BCOP

John Valgus, PharmD, BCOP, CPP

Susannah E. Koontz, PharmD, BCOP

Sarah Wenger, PharmD

Edward Li, PharmD, BCOP

Siu Fun Wong, PharmD, FASHP

March 2014

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

To learn more about this study, please visit www.ClinicalTrials.gov.