JHOP September 2013 by The Oncology Pharmacist

September 2013 Vol 3 I No 3

Journal OF

hematology Oncology ™ Pharmacy The Peer-Reviewed Forum for Oncology Pharmacy Practice

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Financial Savings from On-Site Dispensing of Oral Chemotherapies Robert S. Mancini, PharmD, BCOP; Adam Kramer, PharmD; Colleen Powell, CPhT

CASE REPORT FLAG-IDA Regimen-Induced Thrombotic Microangiopathy: A Case Report Juan Montoro, MD; Montserrat Gómez, MD; Mar Tormo, MD, PhD; Teresa Torrecillas, PhD; Marisa Calabuig, MD

ORIGINAL RESEARCH Quantification of Weight Changes Associated with New Diagnosis of Cancer in Pediatric Patients Misty M. Miller, PharmD, BCPS; Teresa V. Lewis, PharmD, BCPS; Ryan Webb, MPH; David A. Fields, PhD; Tracy M. Hagemann, PharmD, FCCP, FPPAG

FROM THE LITERATURE Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

WWW.JHOPONLINE.COM

Coming soon

GRANIX™ is a new option in short-acting G-CSF therapy 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.

Teva’s filgrastim, the same compound as GRANIX, is available in 39 countries*1

Approved through the rigorous US BLA† process

*As of August 2013.

Brought to you by Teva—a top-10 global pharmaceutical company‡2 » 1 out of every 6 prescriptions filled daily in the US is a Teva product » Teva offers supportive care, hematologic and oncolytic malignancy products; with a substantial portfolio of more than 50 oncology products in the US » Teva uses state-of-the-art manufacturing facilities and the most advanced testing equipment to produce quality biologics Excluding supportive care.

‡

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating 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 adjacent brief summary of full Prescribing Information. References: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. May 2013. 2. EvaluatePharma®, March 2013. Biologics License Application.

†

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 nonUS-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: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

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 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

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

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

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

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

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

September 2013

Vol 3, No 3

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.

September 2013 Publishing Staff

Senior Vice President, Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@greenhillhc.com Associate Editor Lara J. Lorton

Volume 3, number 3 Journal OF

hematology Oncology Pharmacy™ The Peer-Reviewed Forum for Oncology Pharmacy Practice

Table of Contents Practical Issues in Pharmacy Management

Editorial Assistant Jennifer Brandt Production Manager Stephanie Laudien

The LYNX Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

Financial Savings from On-Site Dispensing of Oral Chemotherapies Robert S. Mancini, PharmD, BCOP; Adam Kramer, PharmD; Colleen Powell, CPhT

Case Report

FLAG-IDA Regimen-Induced Thrombotic Microangiopathy: A Case Report

Juan Montoro, MD; Montserrat Gómez, MD; Mar Tormo, MD, PhD;

Teresa Torrecillas, PhD; Marisa Calabuig, MD

Original Research

uantification of Weight Changes Associated with New Diagnosis of Q Cancer in Pediatric Patients Misty M. Miller, PharmD, BCPS; Teresa V. Lewis, PharmD, BCPS; Ryan Webb, MPH; David A. Fields, PhD; Tracy M. Hagemann, PharmD, FCCP, FPPAG From the Literature

100 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma 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

MISSION STATEMENT

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. 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 ©2013 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. 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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

September 2013

Vol 3, No 3

2ND ANNUAL

se V Jh rie iew op s o th On nli e lin ne e. at co m

CONQUERING THE CANCER CARE CONTINUUM

™

FIRST ISSUE IN THE 2013 SERIES

CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE I E CONT IN

A 6-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:

NEXT ISSUE

SECOND ANNUAL

SECON

D ISSUE ™ IN THE 2013 SE RIES SE C O N D ANN UA L

Changing the Image of Palliative Care Lillie D. Shockney, RN, BS, MAS

vention and relief of suffering by means of early identiam enthusiastic about this 6-part series titled Confication and impeccable assessment and treatment of quering the Cancer Care Continuum. Each edition of pain and other problems, physical, psychosocial, and CCCC will address an important topic in oncology RIES spiritual.” (http://www.who.int/cancer/ management and offer expert E 2013 SE THstakeIN UE ISS palliative/en/). IRD commentaries. Topics will THholder For too long, however, the image of include: palliative care, pain manageNU AL AN ™ palliative care has been tied exclusively ment, hospice care, ND comprehensive SE CO to end-of-life care and focused solely on treatment planning, survivorship care, pain control. and the role of biosimilars in supportLillie D. Sho ckney, RN, BS, MAS The articles that follow provide a ive care. In this issue, we address paln part 2 of clear understanding of the intent of liative care. our Conque series, the ring the Can palliative care today, with the primary Palliation in cancer care is a topic focus is on mat pain man cer Care Continuum agemen goalt.ofDes ending its identification that commonly makes people (medical wel ic improvements inabilitysolely l as surgical in pite drato overco procedures pharmaceu cancer provideddie for wh theile dying. providers as well as patients) uncom- we still me it effe l agecare designed as tica nts, as have a ctively, fear in great pai monly resp ing con Instead, palliative be assofortable. I recently had the opportunity cessful on beh long way to go to be to help ™trol pain, care should ond that n. Family members, they will sucD.alf Shockney, of our patiRN, their grea nesscare I wasLillie too, theirforlov ent ciated with quality-of-life alled to speak with members of our palliative recently s. BS,wat MAS one in grea test fear is having comute chi to wit t pain care team at Johns Hopkins and learned ern s of an old, black-a ng a few min- cancer patients and survivors, no mat- ease the sufferin without a way nd-white movie. A to wes g. cow ter what their clinical outcome. tthat the word “palliative” comes from the word “palliare,” fear Fam boy by a gunslin these ily had been ger, and as Your shot patients may not tell you about the sidewitnes will be the final imamembers cancer tor atte which means to disguise or cloak. Centuries ago,mp this word s the befo ges the town doc re ted to rem Many org their loved one dies y ove effects of treatment they are experiencing or about their was used for the drapes that covered afrom casket. hisAlthough the chest, ano anizations . oped me ther cow bullet the wounde have dev asu boy discomfort due to their cancer diagnosis or its treatment. rem we continue to drape coffins—most memorably with the eld gav ent man a bot tice guidel tools and to drink tle of whi e ines for pracand a In many cases ske they may simply assume that the discomflag—the drape is no longer referred to this term. helping hisby teeth. I’m knife to bite betwee y providers the purpose of nwith the disease.” However, with the imeffectively age pain The World Health Organizationwas modified its sure orig-back infort how peo associat the “comes manday this ple coped it treatment. ed with cancer and inal definition of palliative care as quo follows: “Palliative witprovements in medicine and the power of science,its r to num b them and h pain – liprovide you The following d toquality arti doesn’t to anymore. Do not wait for your patients care is an approach that improveshar the of life somethhave call bite on. to wit cles h a wealth ing asking him This is far him back mation asso MAS of e initiate from ised he kney, RN, BS, to about their symptoms; be proacof patients and their families facingTod the ay problems asall pat ideal.a discussion t sank and guidel ciated with the inforhow surpr ien.tsI wrot hear Lillie D. Shoc My and said whthat se o ent l environ of hospita est thatat the time you are planer initiate tive and thisrequ discussion sociated withthe life-threatening through thesoon pre- t,after that thoughines. They also pro tools a to even men did next edition illness, an me. whe atieHe at all on he nd the nt metto r itand to bring to you inuum series. This the inp mati be of the infor sure that tful care be taken mote Lillie orrespo a clinic visi for uni D. Shoey ir was t is my privilege Cont doctor, all to ckney, I reiterated t witall Cancer Care options, RN, h t the long journ cancer pat of us address wit enaskede.to by phon talk are BS, MA abou we sure Conquering the es specifically on hospice Hopee-pain mea me com h our ien Green Hill Healthcare Communications, LLC her S told plete a ts the pai red toget focus experienci to read. of whethe ment toolhad n they are thaand issue, which wife had endu at age 30. t prohis ng ly important r and vital the vid he be y es to imp to relieve are presen ve gree. Pat e exposis al diagn will be initisom is one I belie tly in ressofion it. Pain stea lement ways herpain ien since addressed here tim n her cliniphysica , descr and toiptio what to circ ts have trou wha ble,dhow fully, concepts and better ways of it l endurancee, psychological ls away social on his t dele (a happy Base alertness,tua ever,and ed wel new limit pain as and l-be inte cer lly ted face ing can make was bad in rpreting ly ill. I absent for l can adop ition cond a ver calor grave and quality of , and terminally il y thatface the mornin som cause the she) ifwas life virntsad supporting our families. g but theirthe doctor adequate trea e patients. Accur y evide not their so I thou ate assessm tment for ment nee doctor. Fur took a pain pillwas ng an nowght patients and befohim thatbad effectiv ent self thatthehecan d to be prioriti al years ago getti He himbeviewed by thermore, is thistold re com essetod see I recall sever es for all e pain managestring Bill. his cer fiel o di the any as srma winfo of us wor tion actu a man named net and and sometim one during the to linger after I feel con d. king in difficult ally e-mail from it Som ir visi d t? next refident you es it is not thispro the Inter foun via ding me regar d etim g will Cer vok . tainly one ersationes it is, what he is ing and con find these had foun his youn of the grea brief conv articles tho stating that that tain will cer me And to ing pat . assi e can cant ien valu test wrot Mary a st you in ts is the fearfor s exp metastatic breas reassessing able information ught fear of painstep welbut ressher is not a drug oncan l(He ed by as dev ng wife, Mary, had gressed to her liver, your curren that andplaci now sufferin pro d- hospice. future pat eloping more effe calle g and cer that had . She was ctive way t patients as ei ients hav the special program before eis to hel and now brain d this term fectively manage e quality of life Lilliesleeping lungs, bone, had not hear n to explain some of by having p your d. hospital and D. Shockney, RN pain efI bega , BS, MAS currently in the awake, confused at © 201)3As ther. ice care, he Green Hill was hosp she RN, of , than still fits kney Healthcare“Lillie, my more “had the key bene and Lillie D. Shoc weight, but said, Communicat t until BS, MAS times, losing chemotherapy he fou got very upse 8 years old. I ions, LLC doctor rth issue of Conqu 2 sons, 6 and been receiving die. We have then told him that she wrote that the Colast erincann g theotCa wife the ntinuum ser yesterday.” He e.” I nce alonre s with thiadd care of her for nin I would work meet himies rescann ot raise themr Caice ses Tre e and staff and situ who had taken d him to com g Thro atio atm hosp said omeand He ir mTh that . ugh ent t but aske g steps n i die the s Pla o had d l Follow about next goa nn ren foor the hen. 4 years hileCancewoul r Ca preCpaont ds who l of the team re these child room to talk ing are 2 er for a wicle andy frien outcom is optimal him tore inuum.ly members rap morning in her onthe t would ling key art imes. role medical asized the im identify fami the cologis taking place,s to pro of the him vid were . I emph Th s help e boys ere ssion clin that usually ins ad these discu are igh – adica that t into l pha types him raise gistofas a me e considerati rmacolwoul doctor said in a row nowsomgh cals ly whenever these was very o d help obrief. 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Gone thebrain day, s, is for at or of life wil fective this drug LLC l oncology spe they should be, when s, trea be cation wh tme ile on nt as well cialists me n Hill Healthcare Communi as after trea rely passed – either on completed © 2013 Gree tment is on .

eriIng the u q n o C ancer Care C UM

• Palliation • Pain management • Hospice care • Treatment planning • Survivorship care • Biosimilars in supportive care

UUM

Introduc tion to O ncology Pain Ma nagem ent

CONTIN

FOURTH

ISSUE IN THE 2013 SERIES SE CPa Otie N nts D ANN to t Suppor UAL al itic Cr viding Pro : re Ca Hospice s and Familie

Conquering t Cancer Carehe CONTI

NUUM

™

Personaliz ed Treatm ent Plann ing

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PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Original Article

Financial Savings from On-Site Dispensing of Oral Chemotherapies Robert S. Mancini, PharmD, BCOP; Adam Kramer, PharmD; Colleen Powell, CPhT Background: The dispensing and management of oral chemotherapies involves many challenges, with access to and the finances of oral agents being the biggest barriers to treatment. The oncology literature is focused on the clinical benefits of on-site dispensing and management programs; however, little to no data are available regarding the financial benefits to third-party payers. Objective: To evaluate if on-site drug dispensing can reduce unnecessary dispensing of oral chemotherapies, which would help to reduce waste, lower drug costs, and ensure rapid start of therapy. Methods: The St Luke’s Mountain States Tumor Institute oral chemotherapy office conducted a 6-month prospective evaluation from March 2011 to September 2011 of all patients receiving active oral chemotherapy. During this time frame, any cancer-related drug prescription that was returned for credit was evaluated for its start date in relation to the date of the visit to the oncologist. Prescriptions were evaluated if they were permanently discontinued as a result of disease progression, or if a dose change resulted in a new dosing form that could not be made with the current dosage units. The costs of the unused agents were then computed based on the average wholesale price (AWP) of the specific drug. Results: During the 6-month period, a total of 39 prescriptions (for 37 patients) were returned for credit. The total amount saved based on the AWP for the 39 agents was $103,567.33. In addition, the amount saved in copayments was $13,850.34; of that, $9134.28 would have come from assistance funds and $2760.09 would have been covered by retroactive secondary insurance billing. After subtracting the patients with secondary insurance as well as the copay assistance funds, a total of 21 patients had out-of-pocket costs totaling $1955.97 worth of copayments, which averages $93 per patient. Conclusion: On-site dispensing of oral chemotherapy agents can reduce prescription medicaJ Hematol Oncol Pharm. 2013;3(3):80-83 tion waste and therefore reduce overall costs for health insurance plans, patients, and assistance www.JHOPonline.com foundation funds. Tighter control of dispensing, by keeping medications under the pharmacist’s Disclosures are at end of text control until patients see their oncologist, can eliminate waste and unnecessary dispensing of rather expensive medications, which further serves as a financial incentive for on-site dispensing.

here are many challenges associated with the dispensing and management of oral chemotherapy agents. Complications related to the rapid rate of drug development, financial concerns, medication adherence, monitoring of drug side effects, and drug–food and drug–drug interactions all combine to create a vast network of complexity that goes beyond the management techniques used to treat patients with intravenous oncolytics. Since 2007, 15 new oral oncolytics have been introduced to the US market, representing an average approval rate of 1 new drug every 4 months.1 This re-

flects an acceleration of new oral oncolytics hitting the market 12 times faster than in the past 50 years. As cancer centers in the United States look for ways to address these challenges, they need to find a way to pay for the resources that are allocated to managing patients with cancer. Despite the use of a mail-order pharmacy, many aspects of the care of these patients still have to be addressed by the patient’s treatment center. The oncology literature is focused on the clinical benefits of on-site dispensing and management programs,2-4 but little to no data are available on the financial benefits of on-site dispensing to third-party payers. There are

Dr Mancini is Oncology Pharmacist, St Luke’s Mountain States Tumor Institute; Dr Kramer is Oncology Pharmacist, St Luke’s Mountain States Tumor Institute; and Ms Powell is Pharmacy Technician and Billing Specialist, St Luke’s Health System Outpatient Pharmacy, Boise, ID.

Journal of Hematology Oncology Pharmacy

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September 2013

Vol 3, No 3

Financial Savings from On-Site Dispensing of Oral Chemotherapies

ways to ensure that resources can get paid for, provided that these clinics also have dispensing pharmacies. One of the most significant barriers to the optimal management of oral oncolytics is the financial component of costs to the patient and to the health insurance plan. One aspect of this is the requirement of certain health insurance companies to use a specific mail-order pharmacy because the specific center’s pharmacy is not “a contract provider.” In some cases, this can be overcome as easily as having a discussion with the insurance company and getting on contract. However, some insurance companies only allow prescriptions to be filled through a single mail-order pharmacy, in which case neither the patient nor the provider has any choice in how the patient obtains the medication. This is potentially problematic, because the direct lines of communication that exist between an internal pharmacy and the oncologist’s office do not exist with external pharmacies. In addition, patients will rarely have direct interactions with the healthcare team, specifically a pharmacist, if patients are required to use a mail-order pharmacy, and this may compromise optimal therapy for the patient.5 When patients are treated with oral chemotherapy agents, oncologists prefer to see their patients on the day of, or a few days before, the start of their next cycle. Patients are therefore responsible for ensuring that they have their medication with them that day. If they are required to use a mail-order pharmacy, often the patients have already called to request their refill to ensure that they have it on day 1 of their treatment cycle. Once a prescription has left a pharmacy’s control, the pharmacy cannot legally reuse the medication, because a pharmacy’s proper storage conditions cannot be guaranteed. Because a pharmacy cannot reuse the medication, it cannot credit the drug cost, leading to charges for a medication that will never be used. The goal of this article is to evaluate how on-site drug dispensing can provide a mechanism for reducing the unnecessary dispensing of oral oncolytics, which can lead to financial savings and ensure that there are no delays in the start of therapy.

Methods The St Luke’s Mountain States Tumor Institute oral chemotherapy office conducted a 6-month prospective evaluation from March 2011 to September 2011 of all patients receiving active oral chemotherapy to investigate the potential cost-savings by tracking any prescription that was returned for credit. Within this program, prescriptions for oral oncolytics are sent to the central oral chemotherapy office, which processes

Vol 3, No 3

September 2013

the prescription and fills it in conjunction with the outpatient dispensing pharmacy. Once prepared, the prescriptions are sent to 1 of 5 outpatient cancer centers, where the site pharmacist dispenses the medication to the patient after that patient has seen the oncologist. If a patient’s treatment is discontinued at that oncologist’s visit as a result of disease progression or drug toxicity, the prescription is returned to the central pharmacy for credit, because the medication remained under the pharmacist’s control. During the 6-month time frame of this study, any prescription that was returned for credit was evaluated for the start date in relation to the date of the oncologist’s visit. If the patient was due to start the medication on the day of, or the day after, the oncologist’s visit, that prescription was documented, including the medication name, the dosage, and the number of tablets supplied in that fill, before being returned to stock.

One of the most significant barriers to the optimal management of oral oncolytics is the financial component of costs to the patient and to the health insurance plan. The goal of this article is to evaluate how on-site drug dispensing can provide a mechanism for reducing the unnecessary dispensing of oral oncolytics, which can lead to financial savings and ensure that there are no delays in the start of therapy. In this analysis, prescriptions were evaluated if they were permanently discontinued as a result of disease progression or if a dose change resulted in a new dosage form that could not be made with the current dose. For example, a dose reduction for sunitinib from 50 mg to 37.5 mg would require replacing the prescription with new capsule sizes, and would therefore be included for analysis. An alternate example, such as reducing capecitabine from 1500 mg to 1000 mg twice daily, would not be included, because the patient could use the same tablet sizes in the prescription. These types of changes were not included in the analysis, because it would be assumed that the pharmacy would adjust the quantity of drugs to be dispensed for the subsequent cycle. Finally, the price of each of the prescriptions was then computed using the average wholesale price (AWP). The AWP was chosen as a benchmark because most third-party payers, dispensing pharmacies,

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Journal of Hematology Oncology Pharmacy

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Table A mount of Cost-Savings on Oral Chemotherapy in 6 Months, by Drug Prescriptions, N

Money saved, by AWP cost, $

40,595.52

Temozolomide

16,902.43

Erlotinib

13,946.94

Etoposide

3972.78

Lapatinib

5426.18

Everolimus

8984.15

Lenalidomide

5812.18

Sorafenib

4761.39

Sunitinib

3058.24

Cyclophosphamide

107.52

103,567.33

Drug Capecitabine

Total

AWP indicates average wholesale price.

Figure Copayment Saved on Oral Oncolytics in 6 Months, by Responsible Party

$2760.09 Secondary insurance $9134.28 Assistance funds $1955.97 Patient copay

and clinics calculate what they pay or what they are reimbursed for in relation to the AWP and can calculate their own impact. In addition, the pharmacy records were reviewed to determine what the patientâ&#x20AC;&#x2122;s copayment responsibility would be if they had filled the medication. All patient charts were evaluated for documentation confirming the availability of secondary insurance or if the patients were receiving financial assistance to cover their copayments.

Journal of Hematology Oncology Pharmacy

Results Between March 2011 and September 2011, a total of 37 patients had 39 prescriptions returned for credit, which met the criteria for inclusion in this analysis. Of these, 2 patients were receiving combined-modality treatment (1 with lapatinib and capecitabine and 1 with cyclophosphamide and etoposide). In addition, 4 patients were receiving multiple-dose strengths of the same drug to make their total daily dosage (3 patients receiving capecitabine and 1 patient receiving temozolomide). The most frequently returned medication was capecitabine. As shown in the Table, the total amount that was saved based on the AWP for this 6-month period was $103,567.33. In addition, the amount saved by patients in copayments was $13,850.34, of which $9134.28 would have come from assistance funds and $2760.09 would have been covered by retroactive secondary insurance billing. After subtracting the patients with secondary insurance as well as copay assistance funds, 21 patients had outof-pocket costs totaling $1955.97 worth of copayments, which averages $93 per patient (Figure). Discussion The analysis by St Lukeâ&#x20AC;&#x2122;s Mountain States Tumor Institute oral chemotherapy program was able to show a potential extrapolated annual savings of more than $200,000 based on this prospective evaluation. By avoiding unnecessary dispensing, costs can be reduced for insurance plans that are paying a bulk of the cost, for patients paying out-of-pocket expenses (averaging approximately $100 per patient), and for copay assistance foundation funds, which can be used for other patients who are seeking financial assistance. By allowing more tightly controlled dispensing of chemotherapy prescriptions and ensuring that the prescription stays within the control of the pharmacy until the patient sees the oncologist, we are able to eliminate waste and the unnecessary dispensing of rather expensive medications. The issue that a mail-order pharmacy may face is getting the prescription to the patient on time versus dispensing medication that may get discontinued when the patient sees his or her oncologist. This issue can be overcome by allowing an on-site pharmacy to dispense for the patients, because the direct interaction between the pharmacy and the oncologist allows the medication to be ready in time while not dispensing medication that will not be utilized. One of the struggles that cancer centers face is putting the resources into processes that do not provide a revenue source to pay for those resources. This is essentially what happens when a cancer center is unable to fill medications for its patients.

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September 2013

Vol 3, No 3

Financial Savings from On-Site Dispensing of Oral Chemotherapies

By allowing on-site dispensing at centers that have proper management programs in place, these institutions can pay for the resources that are required to ensure that these patients are followed appropriately. Many centers face ongoing challenges with limited distribution models and insurance contracts that prevent them from dispensing drugs to their patients. In some cases, the health plan may force a patient to get his or her medication from a specific mail-order pharmacy, or may provide incentives to the patient for using that pharmacy by providing lower copayments. It can also be difficult to coordinate financial assistance for patients, because many pharmacies will not disclose copayment information with the clinic staff, such as social workers or financial advocates, leading to difficulty in ensuring that patients get their drugs at an affordable cost. As has already been discussed in the medical literature, direct access to laboratories, full medication lists, and oncologist visits have established the clinical benefit of on-site dispensing and pharmacist involvement, yet we still struggle without financial data.2-4 The data that are provided in this article can help to provide leverage for cancer centers that are seeking to be a “contract pharmacy” with various payers and to show that these types of programs may be able to save them money. Although the dollar amount shown in this analysis is spread over several health plans and may seem insignificant to a single payer, more cancer centers are seeking ways to incorporate the on-site dispensing of oral oncolytics. In the 12 months since this analysis, the workload of St Luke’s Mountain States Tumor Institute oral chemotherapy office has doubled. In addition, the field of oral oncolytics is constantly growing. In the past 9 years (since 2004), 22 new oral cancer agents have been approved by the US Food and Drug Administration (FDA), representing an approval rate of 1 new cancer medication approximately every 5 months, based on FDA approvals.1 If we look at just the past 5 years, 15 new drugs have been approved, further increasing the average approval rate to 1 new drug every 4 months.1 This represents an acceleration of new oral oncolytics hitting the market at a rate 12 times faster than in the past 50 years. In addition, up to 35% of the cancer drugs in clinical trials are oral, which suggests that this issue will only grow in the future.6

Limitations The main potential limitation to this evaluation was adequate documentation. Because it was the responsi-

Vol 3, No 3

September 2013

bility of the pharmacist working in the office that day to document the returns, it is possible that some of the tracking of returns may have been missed. It is possible that this dollar amount may be an understatement of the true potential savings. Another potential area of savings that was not tracked is the capecitabine example that was stated before, where a dose might have been reduced, thereby leading to leftover tablets from a previous cycle. Adjusting the quantity of the subsequent fill under protocol may also save additional costs that were not calculated in this evaluation.

By allowing on-site dispensing at centers that have proper management programs in place, these institutions can pay for the resources that are required to ensure that these patients are followed appropriately. Conclusion The unprecedented growth in oral chemotherapy agents means that as this field continues to grow, the potential for increases in cost-savings by allowing on-site dispensing is even bigger. Oral chemotherapy parity is a “hot topic,” and the present analysis can help provide leverage to those who are seeking it. Cancer centers are not asking to take over the market; they are simply asking for the chance to help their patients in the best way possible. One hopes that insurance companies will continue to recognize the clinical and financial benefits provided by these cancer centers. n Author Disclosure Statement Dr Mancini is on the Speaker’s Bureau of Millennium Pharmaceuticals and is a Consultant to GlaxoSmithKline. Dr Kramer and Ms Powell reported no conflicts of interest.

References

1. US Food and Drug Administration. Drug approval reports by month. Report produced November 28, 2012. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 2. Mancini R, Wilson D. A pharmacist-managed oral chemotherapy program: an economic and clinical opportunity. Oncol Issues. January/February 2012:28-31. 3. Drenker K, Sondag A, Mancini R. Impact of a pharmacist-managed oral chemotherapy program on nonfulfillment rates. J Hematol Oncol Pharm. 2012;2:42-45. 4. Mancini R, Kaster LM, Vu B, et al. Implementation of a pharmacist-managed interdisciplinary oral chemotherapy program in a community cancer center. J Hematol Oncol Pharm. 2011;1:23-30. 5. Jabbour EJ, Kantarjian H, Eliasson L, et al. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am J Hematol. 2012;87:687-691. 6. DeCardenas R, Helfrich JS. Oral therapies and safety issues for oncology practices. Oncol Issues. March/April 2010:40-42.

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Journal of Hematology Oncology Pharmacy

For appropriate patients receiving highly emetogenic chemotherapy,

Prevention of CINV With Triple Therapya Starts on Cycle 1, Day 1 EMEND® (fosaprepitant dimeglumine) for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information

• EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. • Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. • EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Selected Important Safety Information (continued)

• Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. • Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. • There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. • Coadministration of EMEND® (fosaprepitant dimeglumine) for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle. Triple Therapy=EMEND for Injection, a 5-HT 3 antagonist, and a corticosteroid. CINV=chemotherapy-induced nausea and vomiting.

emendforinjection.com

Please see the adjacent Brief Summary of the Prescribing Information.

Major oncology professional society guidelines recommend first-line use of a regimen including EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid1–3,b

Receive your complimentary copy of guidelines for antiemetic treatment.

Scan this QR code or visit emendforinjection.com. Selected Important Safety Information (continued)

• The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. • Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. • In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). • In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusionsite reactions included infusion-site erythema, infusionsite pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

Selected Important Safety Information (continued)

• In clinical trials, EMEND for Injection increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND for Injection should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND for Injection. EMEND® (aprepitant) increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND for Injection 115 mg. b

Based on the Category 2A level of evidence and consensus. Category 2A is based upon lower-level evidence, there is uniform National Comprehensive Cancer Network ® consensus that the intervention is appropriate.2

References: 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189–4198. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Version 1.2013. Antiemesis. www.nccn.org/professionals/physician_ gls/pdf/antiemesis.pdf. Published December 6, 2012. Accessed July 15, 2013. 3. Irwin MM, Lee J, Rodgers C, et al. Putting Evidence Into Practice: Improving Oncology Patient Outcomes. Chemotherapy-Induced Nausea and Vomiting Resource. Pittsburgh, PA: Oncology Nursing Society; 2012.

INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. Brief Summary of the Prescribing Information for

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction 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. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of ≥1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

EMEND® (fosaprepitant dimeglumine) for Injection Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0–24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as ↑, decrease as ↓, no change as ↔): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC ↑ 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8, and AUC ↓ 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC ↑ 1.5-fold A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant. CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it

produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant. Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For more detailed information, please read the Prescribing Information. Rx only

Original Article

Case Report

FLAG-IDA Regimen-Induced Thrombotic Microangiopathy: A Case Report Juan Montoro, MD; Montserrat Gómez, MD; Mar Tormo, MD, PhD; Teresa Torrecillas, PhD; Marisa Calabuig, MD Background: Acute myeloid leukemia (AML) is a malignant blood disorder that is characterized by blocked or impaired differentiation of hematopoietic stem cells. Drug-associated thrombotic microangiopathy (TMA) has been recognized for several years, but there is ambiguity regarding this diagnosis, and any relationship between drug exposure and the onset of TMA symptoms. Objective: To describe the case of a patient with AML with myelodysplasia-related changes who developed TMA after the first cycle of fludarabine plus high-dose cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-IDA). Discussion: A 65-year-old woman with secondary AML received chemotherapy with a regimen of FLAG-IDA. On day 4 of the cycle, the patient developed oliguria and generalized edema. Laboratory findings revealed renal dysfunction, hemolysis, and low platelet count. The peripheral blood smear showed 30% schistocytes. The development of renal failure, microangiopathic hemolytic anemia, and neurologic deterioration during the treatment with the FLAG-IDA regimen led to the diagnosis of drug-induced TMA. Despite the prompt implementation of supportive treatment and the immediate discontinuation of the drug, the prognosis was fatal. Conclusion: Chemotherapy-induced TMA is of considerable clinical importance, because of the J Hematol Oncol Pharm. 2013;3(3):88-92 abrupt onset, fulminant clinical course, and high morbidity and mortality. To our knowledge, this is the first case to describe the association of TMA with the first cycle of FLAG-IDA. Healthcare www.JHOPonline.com Disclosures are at end of text professionals should be more aware of the possibility of a patient developing chemotherapyinduced TMA to ensure rapid initiation of appropriate treatment.

cute myeloid leukemia (AML) is a malignant blood disorder that is characterized by blocked or impaired differentiation of hematopoietic stem cells, resulting in the abnormal accumulation of immature precursors, the suppression of growth, and the maturation of normal hematopoiesis. The use of a regimen that combines fludarabine plus high-dose cytarabine (arabinofuranosyl Cytidine), idarubicin, and granulocyte colony-stimulating factor (G-CSF) and is known as “FLAG-IDA” is an effective treatment for patients with refractory or with relapsed AML. The FLAG-IDA regimen shows evidence of antileukemic activity in patients with high-risk myeloid malignancies and has an acceptable toxicity. Myelosuppression and infections resulting from neutropenia are the most frequent adverse effects associated with this regimen of drugs.1 Thrombotic thrombocytopenic purpura and hemolyticuremic syndrome (TTP-HUS) is a concept that involves

a group of common disorders, such as thrombocytopenia, microangiopathic hemolytic anemia, and the functional impairment of various organs, resulting from platelet agglutination in the arterial microvasculature.2 Because of a considerable overlap between the clinical presentation and the morphologic findings of both disorders—TTP and HUS—these 2 syndromes are now increasingly referred to as thrombotic microangiopathy (TMA). Many factors are associated with the development of TMA, including infections, autoimmune disorders, malignancy, and a variety of drugs.3 Drug-associated TMA has been recognized for several years, but many cases are difficult to interpret, because of the uncertainty regarding its diagnosis and the relationship between the drug exposure and the onset of the clinical manifestations. The mechanism of drug-induced TMA is primarily immune-mediated or is a result of direct toxicity.4 Although uncommon, TMA is of

Dr Montoro is a Hematologist, Department of Hematology and Medical Oncology, Hospital Clínico Universitario; Dr Gómez is a Hematologist, Department of Hematology and Medical Oncology, Hospital Clínico Universitario; Dr Tormo is a Hematologist, Department of Hematology and Medical Oncology, Hospital Clínico Universitario; Dr Torrecillas is a Pharmacologist, Department of Pharmacy, Hospital Clínico Universitario; and Dr Calabuig is a Hematologist, Department of Hematology and Medical Oncology, Hospital Clínico Universitario, Valencia, Spain.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

September 2013

Vol 3, No 3

FLAG-IDA Regimen-Induced Thrombotic Microangiopathy

considerable clinical importance, because of its abrupt onset, fulminant clinical course, and the associated high morbidity and mortality in the absence of early recognition and treatment.4 Cases related to direct toxicity of a drug usually have a poor prognosis. We report the case of a 65-year-old woman who was diagnosed with AML associated with myelodysplasia-related changes and who developed TMA after the first cycle of the FLAG-IDA regimen. To our knowledge, this association has not been described in the literature to date.

Case Description A 65-year-old woman was diagnosed with myelodysplastic syndrome (MDS) with refractory anemia subtype and an excess of blasts (RAEB)-2. Her medical history was unremarkable, except for an allergy to penicillin. At diagnosis, a bone marrow aspirate revealed dyserythropoiesis, including megaloblastoid changes of erythroid precursors; multinuclearity; nuclear fragmentation and unstained area in the cytoplasm (dyshemoglobinization); dysgranulocytopoiesis, including hypogranular neutrophils and pseudo-Pelger-Huët anomaly of neutrophils and dysmegakaryocytopoiesis with micromegakaryocytes; large mononuclear forms; and multiple separate nuclei. The bone marrow blast percentage was 12%. Based on the World Health Organization (WHO) 2008 classification of MDS, a diagnosis of RAEB-2 was made. The cytogenetic abnormalities showed a complex karyotype with deletion of chromosome 5, del(5) (q13q31). Fluorescence in situ hybridization detected amplification of the MLL and 5q deletion in 70% of the nucleus. The patient was treated with a hypomethylating agent, 5-azacytidine, administered subcutaneously at 75 mg/m2 daily for 7 days of every 28-day cycle for 6 cycles, without complications. The bone marrow aspirate after treatment showed a transformation to an AML, with 43% of blasts. The patient’s initial physical examination was unremarkable (performance status 0), and her complete blood count included a white blood cell (WBC) count of 9.67 × 10³/µL, hemoglobin 88 g/L, and platelets 155 × 10³/µL. The baseline creatinine level was 0.62 mg/dL and the liver enzymes and coagulation parameters were normal (Table 1). The patient had a good performance status, without infection or bleeding complications. Cytogenetic abnormalities were the same as at diagnosis, and molecular studies revealed no mutations in the nucleophosmin and the FLT3-ITD gene. The patient was diagnosed with an AML associated with myelodysplasia-related features, as defined by the 2008 WHO classification system, with poor prognosis.

Vol 3, No 3

September 2013

She was then started with the FLAG-IDA regimen chemotherapy. Two days after the beginning of chemotherapy, the patient developed fever. Laboratory evaluation revealed a WBC count of 5.2 × 10³/µL, without microbiologic documentation or changes in chest radiography. Renal function, coagulation parameters, and liver enzymes were normal. No symptoms or signs of clinical infection were evident. Antibiotic therapy was started empirically, with tigecycline and amikacin. On day 4 of the first chemotherapy cycle, the patient presented with oliguria and generalized edema. Laboratory findings revealed renal function impairment, a decrease in the platelet count, and hemolysis that was suggested by elevated lactate dehydrogenase, decreased haptoglobin concentration, and elevated indirect bilirubin. A urinary tract ultrasound showed no signs of obstruction. The peripheral blood smear revealed 30% schistocytes per high-power field (Figure). Partial thromboplastin and prothrombin time were within normal limits. This led to the suspicion of chemotherapy-induced TMA, and we initiated supportive treatment. Chemotherapy was stopped, and the patient received hemodialysis and transfusion support. In the next 24 hours, laboratory tests revealed progressive hemoglobin and a decrease in platelet count, with urea and creatinine elevation. The patient received hemodialysis daily between days 4 and 7, without any clinical or analytical improvement (Table 1). On day 8, the patient developed uremic encephalopathy and respiratory insufficiency, with a suspected alveolar hemorrhage, and she died hours later. Because of the abrupt onset, the fatal prognosis of the symptoms, and the suspected diagnosis of drug-induced TMA, we did not carry out a determination of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motives). Table 2 shows a complete list of all the medications that the patient started and stopped using during this period. The development of a microangiopathic hemolytic anemia, renal failure, and neurologic deterioration during the treatment with the FLAG-IDA regimen led us to a diagnosis of drug-induced TMA. Despite the prompt implementation of the supportive treatment and the immediate discontinuation of the chemotherapy, the disease had unfavorable development and no response to hemodialysis, which resulted in a fatal outcome.

Discussion Compared with the general population, patients with cancer show an increased susceptibility to thromboembolic disease.5 The risk factors for cancer-associated thrombosis include the type of malignancy, the presence

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Journal of Hematology Oncology Pharmacy

Original Article

Table 1 Laboratory Findings Days after the start of chemotherapy

White blood cell, 4.0-10.8 × 109/L

9.67

9.5

5.2

4.46

4.8

0.11

0.03

0.04

Hemoglobin, 11.2-15.5 g/dL

8.8

8.9

8.0

7.3

7.2

5.7

7.1

8.1

Platelets, 130-400 × 109/L

155

153

Creatinine, 0.51-0.95 mg/dL

0.62

–

0.67

4.7

4.5

4.0

3.61

AST/ALT, 1-31 U/L

26/15

–

27/20

21/75

–

70/35

66/32

Bilirubin, 0.1-1 mg/dL

0.53

–

0.50

2.29

3.5

3.2

3.1

–

Haptoglobin, 60-270 mg/dL

–

LDH, 240-480 U/L

806

–

2200

–

2100

–

2308

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase.

Figure Peripheral Blood Smear Showing 30% Schistocytes

of metastatic disease, and the use of chemotherapy. In most patients with cancer, a procoagulant state can be identified, ranging from subclinical laboratory abnormalities to full-blown disseminated intravascular coagulation. The presence of TMA that is specifically related to chemotherapy or to radiotherapy is a unique entity. TMA is a severe and rare condition that could be fatal. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ involvement, including renal failure, neurologic abnormalities, and gastrointestinal symptoms. The pathogenesis of TMA is complicated and multifactorial. Adverse reactions to drug therapy are increasingly reported as potential causes of TMA. Mitomycin is the most common antineoplastic drug known to be associated with TMA.6 Many other chemotherapeutic agents have been implicated in the etiology of TMA,

Journal of Hematology Oncology Pharmacy

such as 5-fluorouracil, bleomycin, cisplatin, gemcitabine, sunitinib, fludarabine, and docetaxel.5,7 It has been reported that fludarabine induces apoptosis, activation, and alloreactivity of human endothelial cells, as well as causes damage to the dermal and alveolar epithelial cells.8 The effect of fludarabine on endothelial cells may contribute to the pathogenesis of TMA after a patient receives the FLAG-IDA regimen.8 Furthermore, G-CSF has been associated with this effect as well.9,10 Besides the direct injury to the endothelium, the activation of an underlying autoimmune disease has also been proposed as a possible mechanism for TMA that is associated with G-CSF.9,10 Classic idiopathic TMA is associated with severe deficiency or inhibition of the plasma metalloprotease ADAMTS13. This protease specifically cleaves von Willebrand factor, thereby reducing its multimeric size. Inherited or acquired deficiencies of ADAMTS13 impair von Willebrand factor cleavage, leading to the disseminated formation of platelet-rich thrombi in the microcirculation and to symptoms of organ ischemia.11 Idiopathic TMA is characterized by inhibition of ADAMTS13 by an autoantibody, thus causing accumulation of unusually large von Willebrand factor multimers, which are implicated in the formation of platelet aggregates.11 Basic science discoveries in the late 1990s now suggest that the most likely mechanisms by which chemotherapeutic agents lead to a thrombotic microangiopathy include an immune-mediated phenomenon involving the ADAMTS13 metalloprotease or a direct endothelial toxicity.12 However, many aspects of the complex biologic relationship between von Willebrand factor–cleaving metalloproteinase and acquired TMA are still unclear. In chemotherapy-induced TMA, the pathogenic mechanism appears to be associated with direct endothelial

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FLAG-IDA Regimen-Induced Thrombotic Microangiopathy

Table 2 Medications Started and Stopped Days after the start of chemotherapy

Fludarabine

Ara-C

Idarubicin

Granulocyte colony-stimulating factor

Ranitidine

Ciprofloxacin

Tigecycline

Amikacin

X X

Posaconazole

Furosemide

Ara-C indicates arabinofuranosyl Cytidine.

damage, not with the ADAMTS13 deficiency described in idiopathic TMA.13 In this sense, fludarabine has been associated with postâ&#x20AC;&#x201C;stem-cell transplantation TMA.13 Although the diagnosis of TMA is based on recognizing microvascular thrombosis, red blood cell destruction, and platelet consumption, no guidelines are available to completely define TMA or its severity. The Common Terminology Criteria for Adverse Events (CTCAE) provides similar definitions to TTP-HUS.14 Based on the CTCAE, the grade of the case discussed here would be 5 (ie, death). The role of therapeutic plasma exchange is clearly stated in idiopathic TMA, but its role is discussed in chemotherapy-induced TMA as a result of pathophysiologic differences between TTP-HUS and TMA. Although plasma exchange has improved survival rates and recent advances in understanding the pathogenesis of this syndrome are remarkable, clinical decisions remain empirical. Therefore, the management decisions for patients with suspected TMA rely on individual experience and opinion, resulting in different practice patterns. Multipractice clinical trials are required to define optimal management.15 Experience has shown that rituximab, for example, can be used for the early treatment of chemotherapy-induced TMA, particularly when plasma exchange is not rapidly effective.16 Patients with postâ&#x20AC;&#x201C;stem-cell transplant TMA refractory to at least 1 week of plasma exchange and prednisolone have been treated with rituximab (375 mg/m2 weekly) and have achieved remission.16 In these patients, levels of ADAMTS13 and anti-ADAMTS13 antibody did not change significantly

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September 2013

with rituximab-induced remission. Because the course of TMA is unpredictable, the role of rituximab in such cases requires rigorous investigation.17 The Naranjo Adverse Drug Reaction probability scale is a simple and widely used nonspecific questionnaire-based scale developed for the assessment of adverse drug reactions.18 In the case of our patient, it suggests a probable relationship between TMA and the FLAG-IDA regimen (Table 3).

Although the diagnosis of TMA is based on recognizing microvascular thrombosis, red blood cell destruction, and platelet consumption, no guidelines are available to completely define TMA or its severity. Chemotherapy-induced TMA is difficult to diagnose, because of the uncertainty regarding the diagnosis of TMA, and its presentation overlaps with other side effects that are associated with chemotherapy (ie, cytopenias, renal failure, neurologic disorders). Therefore, the diagnosis of chemotherapy-induced TMA requires a high level of clinical suspicion. We have not found in the literature any case report implicating the FLAG-IDA regimen with thrombotic microangiopathy.

Conclusion TMA is a severe and rare complication after chemotherapy. The presence of thrombocytopenia and micro-

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Journal of Hematology Oncology Pharmacy

Original Article

Table 3 Naranjo Adverse Drug Reaction Probability Scale: Items and Score Question

Yes

Do not know

Our score

Are there previous conclusive reports on this reaction?

Did the adverse event appear after the suspect drug was administered?

–1

Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?

Did the adverse reaction reappear when the drug was readministered?

–1

Are there alternate causes (other than the drug) that could solely have caused the reaction?

–1

Did the reaction reappear when a placebo was given?

–1

Was the drug detected in the blood (or other fluids) in a concentration known to be toxic?

Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

Was the adverse reaction confirmed by objective evidence?

Total

NOTE: Adverse drug scoring for Naranjo algorithm: >9 = definite; 5-8 = probable; 1-4 = possible; 0 = doubtful.

angiopathy, markedly increased lactate dehydrogenase, and fragmented red blood cells in peripheral blood film, in the absence of alternative apparent etiologies, requires a high level of clinical suspicion. Our case shows that it can be provoked by various agents, and that it can be fatal despite early treatment. Fludarabine and G-CSF have been reported as causative agents of the TMA by several mechanisms. Because it is difficult to diagnose chemotherapy-induced TMA as a result of its presentation that is overlapping with other complications, hematologists must be aware of this syndrome to ensure the rapid initiation of treatment. Further research into the optimal management of the patients with TMA is required. n Author Disclosure Statement Dr Montoro, Dr Gómez, Dr Tormo, Dr Torrecillas, and Dr Calabuig had no conflicts of interest to report.

References

1. de la Rubia J, Regadera A, Martín G, et al. FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res. 2002;26:725-730. 2. Hollenbeck M, Kutkuhn B, Aul C, et al. Haemolytic-uraemic syndrome and thrombotic-thrombocytopenic purpura in adults: clinical findings and prognostic factors for death and end-stage renal disease. Nephrol Dial Transplant. 1998;13:76-81. 3. Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol. 2001;8:286-293. 4. Elliott MA, Nichols WL. Thrombotic thrombocytopenic purpura and hemolytic

Journal of Hematology Oncology Pharmacy

uremic syndrome. Mayo Clin Proc. 2001;76:1154-1162. 5. Moya-Horno I, Querol Niñerola R, Bonfill Abella T, et al. Haemolytic uraemic syndrome associated with gemcitabine. Clin Transl Oncol. 2010;12:381-383. 6. D’Elia JA, Aslani M, Schermer S, et al. Hemolytic-uremic syndrome and acute renal failure in metastatic adenocarcinoma treated with mitomycin: case report and literature review. Ren Fail. 1987;10:107-113. 7. Zakarija A, Bennett C. Drug-induced thrombotic microangiopathy. Semin Thromb Hemost. 2005;31:681-690. 8. Eissner G, Multhoff G, Gerbitz A, et al. Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood. 2002;100:334-340. 9. Naina HV, Gertz MA, Elliott MA. Thrombotic microangiopathy during peripheral blood stem cell mobilization. J Clin Apher. 2009;24:259-261. 10. Kovacic JC, Macdonald P, Freund J, et al. Profound thrombocytopenia related to G-CSF. Am J Hematol. 2007;82:229-230. 11. Mannucci PM, Peyvandi F. TTP and ADAMTS13: when is testing appropriate? Hematology Am Soc Hematol Educ Program. 2007:121-126. 12. Plaimauer B, Zimmermann K, Völkel D, et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood. 2002;100:3626-3632. 13. Shimoni A, Yeshurun M, Hardan I, et al. Thrombotic microangiopathy after allogeneic stem cell transplantation in the era of reduced-intensity conditioning: the incidence is not reduced. Biol Blood Marrow Transplant. 2004;10:484-493. 14. National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE): Version 4.0. May 28, 2009. Version 4.03, revised June 14, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference _8.5x11.pdf. Accessed August 21, 2013. 15. George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood. 2000;96:1223-1229. 16. Au WY, Ma ES, Lee TL, et al. Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab. Br J Haematol. 2007;137:475-478. 17. Gourley BL, Mesa H, Gupta P. Rapid and complete resolution of chemotherapy-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) with rituximab. Cancer Chemother Pharmacol. 2010;65:1001-1004. 18. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.

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FLAG-IDA Regimen-Induced Thrombotic Microangiopathy

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www.ValueBasedMyeloma.com Value-Based in Myeloma 2013 is a publication of Engage Healthcare Communications, a member The Lynx Group. © 2012 All rights reserved. 93 Vol 3, No 3 Care www.JHOPonline.com of of Hematology Oncology Pharmacy l Journal l September VBCC0112_VBMAsizeGH

Original Research

Quantification of Weight Changes Associated with New Diagnosis of Cancer in Pediatric Patients Misty M. Miller, PharmD, BCPS; Teresa V. Lewis, PharmD, BCPS; Ryan Webb, MPH; David A. Fields, PhD; Tracy M. Hagemann, PharmD, FCCP, FPPAG Background: Children diagnosed with cancer undergo changes in body weight secondary to illness and treatment. With progression to malnutrition come a number of significant complications. A better understanding of these changes allows for earlier nutritional intervention, which could improve clinical outcomes and quality of life. Objectives: The main purpose of this exploratory study was to track weight changes in children diagnosed with cancer. Secondary objectives were to identify factors that may influence body weight. Methods: This study enrolled children aged 18 years or younger who were diagnosed with cancer for at least 6 months. Patients were divided into 4 age-groups to account for similar expected growth rates: 0 to <2 years, 2 to <6 years, 6 to <12 years, and 12 to 18 years. Linear mixed models were performed to predict changes in body mass index, height, weight, and percentiles of each of these elements over time. A manual reverse-stepwise model selection procedure was used with 2-sided alpha set at 0.05 for inclusion in the final model. Results: A total of 42 children were diagnosed with cancer during the study between January 1, 2010, and June 30, 2010, resulting in 121 weight measurements. Patients diagnosed with solid tumors lost 13.2 weight percentiles over the study period whereas those with hematologic malignancies had an increase of 3.0 weight percentiles (P = .013). A significant (P = .041) gender difference was found, with female patients exhibiting a greater drop in weight percentiles (20.3) compared with males (0.51), and no other differences were observed. Conclusion: A significant decrease in weight percentile was noted in patients diagnosed with J Hematol Oncol Pharm. 2013;3(3):94-98 solid tumors whereas patients with hematologic malignancies had an increase in weight. Female patients were more likely than male patients to have a decline in weight percentile. Providers www.JHOPonline.com Disclosures are at end of text should consider close monitoring and early nutritional intervention in children with cancer to prevent significant weight loss, which may improve long-term prognosis as well as quality of life.

pproximately 16 per 100,000 children are diagnosed with cancer each year in the United States.1 Patients diagnosed with cancer typically present with different symptoms depending on their type of cancer, most often including fatigue, infection, and weight loss. Changes in weight have not been described in children with cancer outside of anecdotal evidence, although the medical literature in adults indicates that as many as 50% of patients diagnosed with cancer lose up to 25% of their body weight.2 Weight loss and resulting malnutrition in patients with

cancer are detrimental in several ways. Malnutrition in children has been associated with increased intolerance to chemotherapy, a decrease in immune status, leading to increased risk of infection, and increased mortality.3,4 Cachexia, a complex process including anorexia, wasting, and metabolic abnormalities also develops in up to 40% of children with advanced or progressing cancer.2,4 A change in weight status can also alter normal growth velocity, lead to detrimental psychological consequences, and decrease the quality of life for many patients with cancer and their family members.4

Dr Miller is Clinical Assistant Professor, Department of Pharmacy, Clinical and Administrative Sciences; Dr Lewis is Assistant Professor, Department of Pharmacy, Clinical and Administrative Sciences; Mr Webb is Research Biostatistician; Dr Fields is Assistant Professor, Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma College of Medicine; and Dr Hagemann is Professor, Department of Pharmacy, Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City.

Journal of Hematology Oncology Pharmacy

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September 2013

Vol 3, No 3

Weight Changes in Pediatric Patients with Cancer

Weight loss may be of greater concern in children than in adults, because they have greater nutritional needs related to ongoing growth but fewer caloric stores than their adult counterparts.2,5 Although weight changes in children diagnosed with cancer are expected, these changes have not been described or quantified in the literature. Therefore, the purpose of this retrospective study was to identify weight changes seen in children diagnosed with cancer, examine possible contributing factors, and provide clinicians with an awareness for timing of supplemental nutrition initiation.

Methods This study was an Institutional Review Board–approved retrospective chart review conducted at a pediatric academic hospital. All children aged 18 years and younger who were diagnosed with cancer and presented to the Children’s Hospital at the University of Oklahoma Medical Center (OUMC) between January 1, 2010, and June 30, 2010, were chosen for this study. The only exclusion criteria were incomplete records (eg, lack of recorded weight) and age greater than 18 years at diagnosis. After identification, patients were followed at baseline, 1 month, and 6 months after diagnosis. Patient information collected included age, gender, height, weight, and type of cancer. Based on this information, height percentile for age, weight percentile for age, body mass index (BMI) for age, and BMI percentile for age were calculated. To assess the possibility of confounding measures, information on the patient’s nutritional status and interventions was also collected. The interventions reviewed included use of total parenteral nutrition (TPN), enteral tube feedings, and appetite stimulants. When available, albumin and prealbumin levels were also documented as markers of nutritional status. Cancer types were stratified into hematologic malignancies and solid tumors. Patients were also sorted into 4 groups based on their age, including 0 to <2 years, 2 to <6, 6 to <12, and 12 to 18. Groupings were based on similar predicted growth velocities. Linear mixed effects models were used to test changes in height, weight percentile, BMI, or BMI percentile over time, using a manual reverse-stepwise selection procedure for each type of change. The independent variables of interest were cancer type (hematologic or solid tumor), time (in months), and the cancer type by time interaction. Other independent variables tested included age-group (in weight and BMI models) and gender. To account for nonindependence among repeated measurements, patient-specific intercepts and slopes for time were used as random components of the models, and restricted maximum likelihood estimation was used. All analyses were performed using SAS v9.2. A 2-sided alpha level of 0.05 was considered significant for all analyses.

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Table 1 Baseline Demographics Patient characteristics (N = 41) Gender, male

N (%) 26 (63.4)

Age-group

0 to <2 yrs

4 (9.7)

2 to <6 yrs

15 (36.6)

6 to <12 yrs

9 (22.0)

12 to 18 yrs

13 (31.7)

Cancer type Hematologic cancer

19 (46.3)

Leukemias

10 (52.6)

Lymphomas

9 (47.4)

Solid tumor

22 (53.7)

Brain

8 (36.4)

Sarcomas

7 (31.8)

Wilms’ tumor

4 (18.2)

Germ cell

2 (9.1)

Langerhans cell histiocytosis

1 (4.5)

Results A total of 42 children diagnosed with cancer were seen at the Children’s Hospital at OUMC in the 6 months of the study period, yielding 126 possible time points for data collection. One child moved shortly after diagnosis (and was not included in the study) and 2 children moved before their 6-month appointment but were included in the study. This resulted in a total of 121 weight measurements for study inclusion, representing 41 patients.

The purpose of this retrospective study was to identify weight changes seen in children diagnosed with cancer, examine possible contributing factors, and provide clinicians with an awareness for timing of supplemental nutrition initiation. Baseline demographics are represented in Table 1. The most common age-groups at diagnosis were 2 to <6 years and 12 to 18 years. Overall, the mean age at diagnosis was 8.4 (± 0.9) years. Diagnosis with solid tumor was more common than hematologic cancer, occurring

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Original Research

Figure 1 P redicted Weight Percentile Change Over Time: Repeated Measures Regression Estimates Hematologic cancers Solid tumors (N = 121)

Predicted weight change, %

90 80 70 60 50 40 30 20 10 0 0

Time, month

Figure 2 P redicted BMI Percentile Change Over Time: Repeated Measures Regressions Estimates Males Females (N = 109)

Predicted BMI change, %

90 80 70 60 50 40 30 20 10 0 0

Time, month BMI indicates body mass index.

in 53.7% of patients. Within this group, brain tumors and sarcomas exceeded other forms of solid tumors while leukemias and lymphomas were nearly evenly split among the hematologic malignancies. Of note, acute lymphoblastic leukemia (ALL) was the most common form of leukemia, occurring in 8 of 10 cases (50% in females). Mean weight percentile at baseline for all ages was 60.6 (Âą 4.9); BMI percentile was similar at 60.8 (Âą 5.3). As seen in Figure 1, children diagnosed with solid

Journal of Hematology Oncology Pharmacy

tumors had a decrease in weight percentile, with a loss of 13.2 percentile points over the 6-month period, whereas children diagnosed with hematologic malignancies had an increase in weight of 3.0 percentile points (P = .013). Change in BMI percentile over 6 months was compared among genders (Figure 2), also with significant results. Male patients demonstrated a decrease in BMI percentile of 0.51 and female patients had a loss of 20.3 in BMI percentile (P = .041). Because BMI is not a viable measurement until children reach age 2 years or older, 4 patients were excluded from this analysis, leaving 109 measurements. Differences in height and height percentile were not statistically significant among the genders or the type of cancer diagnosis. Information on nutritional support was collected for each patient; however, the use of appetite stimulants, TPN, and enteral feedings occurred too infrequently to compare between the groups. Overall, 7 patients received appetite stimulants alone, 1 patient received TPN only, 1 patient received TPN and an appetite stimulant, and 3 patients received TPN, appetite stimulants, and enteral feeds. The most common appetite stimulants used were megestrol and cyproheptadine, each used in 5 patients; 2 patients received dronabinol. Assessment of nutritional status was done through collection of albumin and prealbumin for each patient. A trend was found toward a more frequent decrease in albumin levels in children diagnosed with hematologic malignancies; however, this difference was not statistically significant. In addition, 3 of 4 prealbumin measurements were below normal; however, no baseline information was available to identify a trend over time.

Discussion This is the first study to quantify and assess associated factors of weight loss in children with different types of malignancies. Weight changes in children diagnosed with cancer are expected at the initial stage, considering the many factors affecting their metabolism, intake, and treatments. Tumors induce a hypermetabolic state associated with the release of inflammatory cytokines, including tumor necrosis factor alpha and interleukins 1 and 6.6 In addition to causing an increase in energy expenditure, these mediators also lead to glycogenolysis, lipolysis, proteolysis, and gluconeogenesis.6 Malnutrition can quickly develop in patients with cancer, particularly if their premorbid weight is below or within the normal range. In this study, childrenâ&#x20AC;&#x2122;s baseline measurements were at a normal weight and BMI percentile and exhibited significant weight changes. Females and patients diagnosed with solid tumors

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Weight Changes in Pediatric Patients with Cancer

Table 2 Baseline Weight, Height, and BMI Measurements Patient characteristic (N = 41)

Mean ± standard deviation

Baseline weight, kg

0 to <2 yrs

9.1 ± 1.5

2 to <6 yrs

16.1 ± 0.8

6 to <12 yrs

37.3 ± 4.1

12 to 18 yrs Baseline height, cm

71.8 ± 5.5 a

0 to <2 yrs

76.5 ± 3.9

2 to <6 yrs

100.5 ± 2.5

6 to <12 yrs

141 ± 5.4

12 to 18 yrs

172.5 ± 2.5

Baseline BMI

0 to <2 yrs

2 to <6 yrs

15.9 ± 0.4

6 to <12 yrs

18.1 ± 0.9

12 to 18 yrs

24 ± 1.4

Baseline weight percentile

0 to <2 yrs

54.9 ± 18.8

2 to <6 yrs

49.2 ± 8.1

6 to <12 yrs

69.2 ± 10.2

12 to 18 yrs

69.5 ± 4.9

Baseline BMI percentileb

0 to <2 yrs

2 to <6 yrs

57.2 ± 8.9

6 to <12 yrs

60.3 ± 11.5

12 to 18 yrs

64.9 ± 8.5

A total of 39 patients were included for height measurements. A total of 36 patients were included for measurements involving BMI. BMI indicates body mass index; NA, not applicable. a

were at greater risk for the most significant decreases; these findings indicate that these populations should be followed more closely and possibly receive earlier interventions than their counterparts. Children diagnosed with hematologic malignancies were more likely to have a positive change in weight than any other population studied. As noted, 80% of these children were diagnosed with ALL, for which chemotherapy typically includes a corticosteroid for induction and main-

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September 2013

tenance therapy. Because corticosteroids can cause appetite stimulation and weight gain, the results of this study are not entirely unexpected. However, the alterations in metabolism secondary to corticosteroid therapy lead to an increase in lipolysis, protein catabolism, hyperglycemia, and often obesity.7-9 Quantitatively, these changes are positive, but qualitatively they are not; these children should still be closely monitored and encouraged to maintain adequate nutrition.

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Original Research

Reduced intake is also a component of weight loss in children with cancer. Gastrointestinal adverse events, including nausea, vomiting, diarrhea, and constipation associated with chemotherapy, radiation, and the cancer itself, are well-described in the literature.6,10 Other aspects affecting patientsâ&#x20AC;&#x2122; intake include early satiety, food aversions, and taste changes.10 Mucositis, which can last for several days, can also negatively impact a childâ&#x20AC;&#x2122;s willingness to eat or drink. Only 9% of children in this study received forms of nutritional support, including appetite stimulants, TPN, nasogastric feeding, and orogastric feeding. Healthcare professionals have a limited number of available therapeutic options to attempt to mitigate the weight loss associated with cancer diagnosis and treatment. Patients may receive nutrition via enteral or parenteral administration. These alternative measures are often initiated once the patient has already lost a significant amount of body mass, potentially limiting their full benefits. Providing clinicians with a greater guidance in populations with increased likelihood of having significant weight loss should improve the appropriate use of this type of support and reduce the development of negative consequences such as cachexia, delayed treatment, and infection.

Providing clinicians with a greater guidance in populations with increased likelihood of having significant weight loss should improve the appropriate use of this type of support. Limitations This study had limitations. First, the size of the patient population is relatively small. Including patients diagnosed over a longer time period or across several centers could allow for greater scrutiny on each cancer type rather than a generalization of solid and hematologic malignancies. In addition, information on chemotherapy regimens was not collected in this study. Although many chemotherapeutic agents cause some degree of nausea and vomiting, certain agents have a greater emetogenicity than others. Furthermore, corticosteroids can lead to an increase in weight, potentially preventing the provider from noticing the loss of lean body weight. Neither BMI nor weight loss accurately indicates the changes in lean body weight or the presence of malnutrition.

Journal of Hematology Oncology Pharmacy

Finally, weight measurements were taken without consideration of timing of chemotherapy, hydration status, or nutrition, each of which can impact potential changes. Despite these limitations, we believe that this exploratory study provides preliminary data to help clinicians identify at-risk populations, as well as providing background information for further research in appropriate nutritional support.

Conclusion This exploratory study quantified the changes in weight percentile in pediatric patients diagnosed with cancer, demonstrating a significant decrease in patients with solid tumors and an increase in weight in patients with hematologic malignancies. Female patients endured a greater decrease in weight percentile than their male counterparts. This information provides a background for clinicians to better identify patients at risk for malnutrition and the development of cachexia. It can also be an impetus for further research in nutritional status and supplementation in pediatric patients diagnosed with cancer. n Author Disclosure Statement Dr Lewis has received research funding from Cubist Pharmaceutical. Dr Hagemann is a Consultant to Lexicomp. Dr Miller, Mr Webb, and Dr Fields reported no conflicts of interest.

References

1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2010. Updated June 14, 2013. http://seer.cancer.gov/csr/1975_2008/. Accessed August 9, 2013. 2. Lai JS, Cella D, Peterman A, et al. Anorexia/cachexia-related quality of life for children with cancer. Cancer. 2005;104:1531-1539. 3. Mosby TT, Barr RD, Pencharz PB. Nutritional assessment of children with cancer. J Pediatr Oncol Nurs. 2009;26:186-197. 4. Couluris M, Mayer JL, Freyer DR, et al. The effect of cyproheptadine hydrochloride (periactin) and megestrol acetate (megace) on weight in children with cancer/treatment-related cachexia. J Pediatr Hematol Oncol. 2008;30:791-797. 5. ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr. 2002;26(1suppl):1SAâ&#x20AC;&#x201C;138SA. Erratum in: JPEN J Parenter Enteral Nutr. 2002;26:144. 6. Andrassy RJ, Chwals WJ. Nutritional support of the pediatric oncology patient. Nutrition. 1998;14:124-129. 7. Lexi-Comp Online. Pediatric and Neonatal Lexi-Drugs Online. Hudson, OH: LexiComp, Inc; August 5, 2011. 8. Mok CC, To CH, Ma KM. Changes in body composition after glucocorticoid therapy in patients with systemic lupus erythematosus. Lupus. 2008;17:1018-1022. 9. Reilly JJ, Brougham M, Montgomery C, et al. Effect of glucocorticoid therapy on energy intake in children treated for acute lymphoblastic leukemia. J Clin Endocrinol Metab. 2001;86:3742-3745. 10. Yavuzsen T, Walsh D, Davis MP, et al. Components of the anorexia-cachexia syndrome: gastrointestinal symptom correlates of cancer anorexia. Support Care Cancer. 2009;17:1531-1541.

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Vol 3, No 3

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

Manuscripts should follow the Author Guidelines at www.JHOPonline.com. For more information, call 732-992-1536.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

nC oncurrent

Nivolumab plus Ipilimumab Superior to Monotherapy in Advanced Melanoma

Background: Immune blockade is one approach that has been found to induce tumor regression in several types of cancer. Ipilimumab, a fully human, immunoglobulin (Ig) G1 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), has demonstrated overall survival in patients with advanced melanoma. Nivolumab, a fully human, IgG4 antibody that blocks the programmed death 1 (PD-1) receptor, produced durable objective responses in patients with melanoma, renal-cell cancer, and non–small-cell lung cancer. In preclinical models, the combination of CTLA-4 plus PD-1 blockade was shown to be complementary in regulating immune activity, and was hypothesized to increase antitumor activity compared with blockade with either pathway alone. Method: This phase 1 clinical trial was designed to evaluate the safety and efficacy of combined nivolumab and ipilimumab in patients with advanced melanoma. All patients were aged >18 years; had a diagnosis of measurable, unresectable, stage III or IV melanoma; and had a life expectancy of at least 4 months. A total of 86 patients were treated from December 2009 through February 2013; 53 patients received concurrent therapy with intravenous nivolumab and ipilimumab every 3 weeks for 4 weeks, followed by nivolumab alone every 3 weeks for 4 doses. This combined treatment was subsequently administered every 12 weeks for up to 8 doses. In the sequenced therapy arm, 33 patients who were previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. Results: The objective response rate (according to the modified World Health Organization criteria) for all patients in the concurrent regimen group was 40% (95% confidence interval [CI], 27-55). Clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was seen in 65% of patients (95% CI, 51-78). At the maximum allowed dose, 53% of patients (95% CI, 28-77) demonstrated objective response with concurrent nivolumab plus ipilimumab compared with only 20% of patients in the sequenced monotherapy group (95% CI, 8-39). Overall, 16 patients in the

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combined regimen had tumor reductions of ≥80% at 12 weeks. Adverse events of any grade, regardless of whether they were attributed to the therapy, were seen in 98% of patients in the concurrent regimen group. The most common treatment-related adverse events in this patient poulation were rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Grade 3 or 4 adverse events related to therapy were reported in 53% of the patients in the concurrent regimen group, but these were similar to events seen with monotherapy and were reversible. The most common events were related to elevated levels of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). In the sequenced therapy group, the rate of grade 3 or 4 adverse events was 18% with elevated lipase level as the most common event (6%). Takeaway: Over the past few years, the treatment of malignant melanoma has advanced substantially with the approval of 4 new drugs. Ipilimumab was approved in March 2011 for the treatment of unresectable or metastatic melanoma on the basis of improved overall survival. It appears that the immune response to some tumors, including melanoma, is inversely proportional to the level of expression of PD-1 and PD-1 ligand, which promotes immunosuppression (Topalian SL, et al. N Engl J Med. 2012;366:2443-2454). Inhibitors of PD-1 ligand improve the immune response to melanoma. Nivolumab is one of several PD-1 inhibitors being developed for the treatment of cancers that have a high expression of PD-1 or its ligand. This was a phase 1 study evaluating 2 dose strategies in patients with stage III or IV melanoma. Previous treatment had been given to 38% of patients assigned to the concurrent strategy and to 100% of those assigned to sequential therapy. Eighty-six patients (53 in the concurrent arm and 33 in the sequential arm) were entered into the study, with 82 patients eligible for efficacy assessment. Treatmentrelated toxicities were frequent (93% in the concurrent arm and 73% in the sequential arm), which were managed with immunosuppressive therapy (primarily corticosteroids). However, serious side effects occurred in 11 (49%) of those patients treated with the concurrent therapy, resulting in a 21% discontinuation rate, compared with 7 patients (21%) in the sequential arm, and with 3 patients discontinuing therapy. Efficacy was demonstrated in both arms, with 40% of patients responding in the concurrent

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September 2013

Vol 3, No 3

FROM THE LITERATURE

group and 20% of patients responding in the sequential group. Of the 21 patients who responded, 16 had a >80% tumor shrinkage at 12 weeks, with 5 patients experiencing a complete response. These are impressive results in a phase 1 study and will obviously lead to phase 2 and probably to phase 3 randomized trials. It appears that nivolumab has complementary effects when combined with ipilimumab, which should be compared with other standard therapies for advanced melanoma. Although toxicity is frequent, it is manageable. The results of this study should lead to a fast-track research strategy for nivolumab. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.

nL ong-Term Effect of Chemotherapy-Induced

Neuropathy Seen in Colorectal Cancer Survivors

Background: Colorectal cancer is the third most common cause of cancer among men and women in the Western world. In 2007, 12,000 patients were diagnosed with colorectal cancer in the Netherlands, and this number is expected to increase to 17,000 in 2020. Because of the increasing prevalence, more patients are living with the long-term adverse effects of this cancer and its treatment. Neuropathy, a common adverse effect of treatment with oxaliplatin, is a major concern. Chemotherapy-induced peripheral neuropathy can be severe, may result in serious limitations of daily functioning, and might therefore have a negative impact on patients’ health-related quality of life (HRQOL). Studies on the association between neuropathy and HRQOL are limited, and most studies have focused on acute instead of chronic neuropathy. Methods: In a population-based sample, researchers assessed the prevalence and severity of chemotherapy-induced neuropathy and its effect on HRQOL in 1643 colorectal cancer survivors at 2 to 11 years after diagnosis. All patients diagnosed with colorectal cancer between 2000 and 2009 who were registered in the Dutch population–based Eindhoven Cancer Registry and included in the PROFILES (Patient Reported Outcomes Following Initial Treatment and Long Term Evaluation of Survivorship) registry were enrolled. Of all of the eligible participants, 83% completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy (CIPN) 20. Of the total groups of respondents, 500 patients (31%) had been treated with chemotherapy. These patients were significantly younger, diagnosed more recently, and were more often diagnosed with colon instead of rectal cancer

Vol 3, No 3

September 2013

compared with patients not treated with chemotherapy. They also had a higher disease stage and a higher disease grade at diagnosis, reported a higher body mass index, and were more often employed at the time of the survey. Results: Among all respondents, the 5 neuropathy subscale–related symptoms that patients reported bothering them the most during the past week were erectile problems (42% of men), trouble hearing (11%), trouble opening jars or bottles (11%), tingling in toes or feet (10%), and trouble walking stairs or standing up (9%). Logistic regression analyses among patients diagnosed from 2007 and onward (eg, after the induction of oxaliplatin) showed that those treated with oxaliplatin more frequently reported tingling (29% vs 8%; P = .001), numbness (17% vs 5%; P = .0047), and aching or burning pain (13% vs 6%; P = .0293) in toes or feet compared with patients who did not receive chemotherapy. Furthermore, those treated with oxaliplatin more frequently reported tingling in toes or feet (29% vs 14%; P = .0127) compared with those treated with chemotherapy other than oxaliplatin. Analyses among patients with colon cancer diagnosed since 2007 showed that both patients treated with oxaliplatin and those receiving chemotherapy without oxaliplatin reported significantly higher scores on EORTC QLQ-CIPN20 sensory scale problems compared with patients not receiving chemotherapy, with these differences being clinically relevant. As for HRQOL, no significant differences were found on EORTC QLQ-C30 subscale scores between colorectal cancer survivors diagnosed since 2007 who were treated with chemotherapy and those treated with chemotherapy with or without oxaliplatin. However, among the total group of patients with colorectal cancer, those with many neuropathy symptoms (eg, upper 10%) reported statistically significant and clinically relevant HRQOL scores on all EORTC QLQ-C30 subscales (P <.01) compared with patients with fewer symptoms. Takeaway: Oxaliplatin-based chemotherapy is the standard of care for the treatment of stages III and IV colorectal cancer. With an ever-growing aging population and the increase in the overall survival of patients with colorectal cancer, the prevalence of oxaliplatin-induced neuropathy is likely to increase, along with having a major impact on quality of life. This population-based retrospective study evaluated the prevalence of oxaliplatin-induced neuropathy, with emphasis on the duration. The study method included a self-reporting system with 1643 patients responding to the survey (83% response rate). Approximately 30% of patients treated with chemotherapy experienced peripheral neuropathy, which was primarily manifested as sensory neuropathy (tingling, numbness, or burning of the hands and feet). The complication could last 2 to 11 years after completion of therapy. HRQOL scores were worse

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Journal of Hematology Oncology Pharmacy

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FROM THE LITERATURE

for patients who developed chronic oxaliplatin-induced neuropathy. Chemotherapy-induced neuropathy is difficult to prevent and treat. In patients who are at risk for oxaliplatin-induced neuropathy (approximately 30% incidence), a prevention therapy is very welcome. Hopefully, this study will lead to further research for an effective therapy for this condition. Mols F, Beijers T, Lemmens V, et al. Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry. J Clin Oncol. 2013;31:2699-2707.

TK Targeting with Ibrutinib Shows Good B Results in Patients with Relapsed Chronic Lymphocytic Leukemia

Background: Treatment for chronic lymphocytic leukemia (CLL), the most common leukemia in adults, has resulted in few durable remissions. Unlike chronic myeloid leukemia, CLL lacks a common genetic target. However, B-cell receptor signaling has emerged as a driving factor for CLL tumor-cell survival. Brutonâ&#x20AC;&#x2122;s tyrosine kinase (BTK) is a critical signaling molecule for the activation of several constitutively active pathways of CLL-cell survival. In addition, BTK is essential to chemokine-mediated homing and adhesion of B-cells. Given the importance of B-cell receptor signaling in CLL and the central role of BTK in this pathway, one strategy is to target inhibition of this kinase. Ibrutinib is an orally, bioavailable, potent inhibitor that covalently binds to the cysteine-481 amino acid of the BTK enzyme. Previous clinical studies with ibrutinib have shown that treatment inhibits numerous processes, including extracellular signal-regulated kinase. The drug also has little effect on healthy T-cells, distinguishing it from most regimens that are used for the treatment of CLL. Methods: In this phase 1b-2, open-label, multicenter study, 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma were randomized to receive 420 mg of ibrutinib (N = 51) or 840 mg of ibrutinib (N = 34). Both doses were administered orally on a continuous schedule until the onset of disease progression or unacceptable toxicity. A majority of these patients had high-risk disease and had received a median of 4 previous therapies. A total of 65% of the patients had advanced-stage disease, 33% had 17p13.1 deletions, and 36% had 11q22.3 deletions. At a median follow-up of 20.9 months, 54 patients (64%) were still receiving treatment and 31 (36%) had discontinued treatment. The primary end point was the safety of the 2 regimens. The secondary end points were the overall response rate (ORR), progression-free survival (PFS), pharmacodynamics, and pharmacokinetics.

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Results: The ORRs were 71% in each of the treatment arms with ibrutinib, and an additional 20% of patients in the 420-mg cohort and 15% of patients in the 840-mg cohort experienced a partial response with lymphocytosis. Blood lymphocytosis was generally noted by day 7 in 79% of the patients; it peaked at a median of 4 weeks and then slowly declined. After a follow-up of 26 months, the estimated rate of PFS was 75%, and the rate of overall survival was 83% for all patients, irrespective of the dose. At both doses of ibrutinib, pharmacokinetic data showed rapid absorption and elimination. Furthermore, pharmacodynamic data showed that once-daily ibrutinib provided effective and complete occupancy of BTK. Long-term therapy with ibrutinib was associated with modest toxicity. Most of the adverse events were grade 1 or 2 and included transient diarrhea (47%), upper respiratory tract infection (33%), and fatigue (28%). A majority of the adverse events resolved without the need for suspension of treatment. Takeaway: Ibrutinib appears to be both relatively safe and efficacious in the treatment of refractory or relapsed CLL or small lymphocytic lymphoma. It is noteworthy that this study, which was initially designed with 2 arms, was expanded to include a third arm of patients with high-risk disease. Most patients had received a previous nucleoside analog, rituximab, or an alkylator. Despite patients receiving an average of 4 previous therapies, the incidence of infectious complications was not observed during the extended period of therapy (unlike with other salvage therapies). Improvement in cytopenias was seen in 71% of patients who were treated at both dose levels. Complete or partial responses increased over time and peaked at 18 months of therapy. The drug was rapidly absorbed and blocked the BTK enzyme almost completely (a reflection of surrogate kinase inhibition). Ibrutinib was well tolerated, with most adverse events rated as grade 1 or 2 regardless of cause. In the 85 patients who were treated, 7 serious adverse events were observed. In the accompanying editorial in the same issue, FoĂ and Guarini posed several questions about the role of this drug in patients with relapsed or high-risk CLL (FoĂ R, Guarini A. N Engl J Med. 2013;369:85-87). They suggest that ibrutinib may play a role when used earlier in the treatment plan. It may also provide an option for patients with CLL who often have multiple comorbidities that would preclude the use of more toxic salvage drugs. Ibrutinib is currently not available commercially, but this study may provide enough data to allow for its approval as an orphan drug. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.

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September 2013

Vol 3, No 3

ANNUAL CONFERENCE

"! ! !

! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

* 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

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*Agenda is subject to change.

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