JHOP March 2013

Journal oF

hematologyoncologyPharmacy™

The Peer-reviewed Forum For oncology Pharmacy PracTiceTm

March 2013Vol 3 I No 1

©2013 Green Hill Healthcare Communications, LLC

orIgInal reSearchPharmacist Assessment of Polypharmacy Risks in Patients with CancerRobert Mancini, PharmD, BCOP; Kathleen Clifford, MSN, FNP-BC, AOCNP, ACHPN

revIew artIcleIpilimumab: Unique Responses, Toxicities, and Recommendations for the Use of the First Anti–CTLA-4 Therapy in Patients with MelanomaMichael K. Wong, MD, PhD, FRCPC; Anthony Jarkowski III, PharmD, BCOP

From the LiteratureConcise Reviews of Studies Relevant to Hematology Oncology PharmacyBy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

WWW.JhoPoNlINE.coM

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages.

*A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1

AND HELPS HIS IMMUNE SYSTEMSUSTAIN* IT1

STARTS THE FIGHT

• Targets and attacks prostate cancer cells

• Statistically signifi cant overall survival advantage1,2

• Sustained* immune response

www.PROVENGEHCP.com

PROF34639_ProvengeAd_Jour_Hem_Onc_DR.indd 1 2/12/13 5:07 PM

PROVENGE® (sipuleucel-T)Suspension for Intravenous Infusion Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION •For Autologous Use Only. •TherecommendedcourseoftherapyforPROVENGEis3completedoses,givenat

approximately 2-week intervals. •Premedicatepatientswithoralacetaminophenandanantihistaminesuchas

diphenhydramine. •Beforeinfusion,confirmthatthepatient’sidentitymatchesthepatientidentifierson

the infusion bag. •Do Not Initiate Infusion of Expired Product. •InfusePROVENGEintravenouslyoveraperiodofapproximately60minutes.

Do Not Use a Cell Filter. •Interruptorslowinfusionasnecessaryforacuteinfusionreactions,dependingon

the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

•PROVENGE is intended solely for autologous use.

•Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the secondinfusion(2.1%vs0.8%followingthefirstinfusion),anddecreasedto1.3%following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

•Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

•Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent useofimmunosuppressiveagentsmayaltertheefficacyand/orsafetyofPROVENGE.Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE.

•Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determineabsenceofmicrobialgrowth.Thefinal(7-dayincubation)sterilitytestresults are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONSBecause 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 practice.

ThesafetyevaluationofPROVENGEisbasedon601prostatecancerpatientsinthePROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade3)andlife-threatening(Grade4)adverseeventswerereportedin23.6%and4.0%of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Seriousadverseeventswerereportedin24.0%ofpatientsinthePROVENGEgroupand25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oralparesthesia(12.6%),paresthesia(11.4%),andfatigue(8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. Thepopulationincluded485patientswithmetastaticcastrateresistantprostatecancerand 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The populationwasage40to91years(median70years),and90.6%ofpatients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Any Adverse EventChillsFatigueFeverBack painNauseaJoint acheHeadacheCitrate toxicityParesthesiaVomitingAnemiaConstipationPainParesthesia oralPain in extremityDizzinessMuscle acheAstheniaDiarrheaInfluenza-like illnessMusculoskeletal painDyspneaEdema peripheralHot flushHematuriaMuscle spasms

591 (98.3)319(53.1)247 (41.1)188(31.3)178(29.6)129(21.5)118(19.6)109(18.1)89(14.8)85(14.1)80(13.3)75 (12.5)74 (12.3)74 (12.3)74 (12.3)73 (12.1)71(11.8)71(11.8)65(10.8)60(10.0)58(9.7)54(9.0)52(8.7)50(8.3)49(8.2)46 (7.7)46 (7.7)

186 (30.9)13 (2.2)6(1.0)6(1.0)18(3.0)3(0.5)11(1.8)4(0.7)0(0.0)1(0.2)2(0.3)11(1.8)1(0.2)7 (1.2)0(0.0)5(0.8)2(0.3)3(0.5)6(1.0)1(0.2)0(0.0)3(0.5)11(1.8)1(0.2)2(0.3)6(1.0)2(0.3)

291 (96.0)33(10.9)105(34.7)29(9.6)87(28.7)45(14.9)62(20.5)20(6.6)

43 (14.2)43 (14.2)

23 (7.6)34 (11.2)40(13.2)20(6.6)

43 (14.2)40(13.2)34 (11.2)

17 (5.6)20(6.6)

34 (11.2)11 (3.6)31(10.2)

14 (4.6)31(10.2)29(9.6)18(5.9)17 (5.6)

97 (32.0)0(0.0)4 (1.3)3(1.0)9(3.0)0(0.0)5 (1.7)0(0.0)0(0.0)0(0.0)0(0.0)7 (2.3)3(1.0)3(1.0)0(0.0)1(0.3)0(0.0)0(0.0)2(0.7)3(1.0)0(0.0)3(1.0)3(1.0)1(0.3)1(0.3)3(1.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

(Table 1 continued on next page.)


In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages.

*A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1

AND HELPS HIS IMMUNE SYSTEMSUSTAIN* IT1

STARTS THE FIGHT

• Targets and attacks prostate cancer cells

• Statistically signifi cant overall survival advantage1,2

• Sustained* immune response

www.PROVENGEHCP.com


©2013DendreonCorporation. Allrightsreserved.January2013. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.P-A-01.13-002.00

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

HypertensionAnorexiaBone painUpper respiratory tract infectionInsomniaMusculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

45 (7.5)39(6.5)38(6.3)38(6.3)

37 (6.2)36(6.0)

35(5.8)34 (5.7)34 (5.7)33 (5.5)31 (5.2)30(5.0)30(5.0)

3(0.5)1(0.2)4(0.7)0(0.0)

0(0.0)2(0.3)

0(0.0)3(0.5)2(0.3)1(0.2)0(0.0)1(0.2)0(0.0)

14 (4.6)33(10.9)

22 (7.3)18(5.9)

22 (7.3)23 (7.6)

17 (5.6)14 (4.6)24(7.9)18(5.9)10(3.3)3(1.0)9(3.0)

0(0.0)3(1.0)3(1.0)0(0.0)

1(0.3)2(0.7)

0(0.0)2(0.7)1(0.3)2(0.7)0(0.0)0(0.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

*Control was non-activated autologous peripheral blood mononuclear cells.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE[packageinsert].DendreonCorporation;June2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med.2010;363:411-422.


The Journal of Hematology Oncology Pharmacy pro-vides a new avenue for the publication of peer-re-viewed, 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 re-search, clinical, and practice management issues in oncol-ogy pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

Call for PaPers

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

REVIEW ARTICLES• New drug classes• Disease states• Basic science• Pharmacology • Pathways and targeted drugs

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

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Practice-influencing issues• Logistics• Economics

Manuscripts should follow the Author Guidelines at www.JHOPonline.com.

For more information, call 732-992-1536.

5 www.JHOPonline.com l Journal of Hematology Oncology Pharmacy Vol 3, No 1 l March 2013

Editorial Board

CliniCal Controversies

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy ServicesIndiana University Simon Cancer CenterIndianapolis, IN

PraCtiCal issues in PharmaCy management Timothy G. Tyler, PharmD, FCSHP Director of PharmacyComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

original researCh R. Donald Harvey, PharmD, FCCP, BCPS, BCOPAssistant Professor, Hematology/Medical Oncology Department of Hematology/Medical OncologyDirector, Phase 1 UnitWinship Cancer InstituteEmory University, Atlanta, GA

review artiClesScott Soefje, PharmD, BCOPAssociate Director, Oncology PharmacySmilow Cancer Hospital at Yale-New HavenYale-New Haven HospitalNew Haven, CT

From the literatureRobert J. Ignoffo, PharmD, FASHP, FCSHPProfessor of Pharmacy, College of PharmacyTouro University–California Mare Island, Vallejo, CA

Patrick J. Medina, PharmD, BCOPAssociate ProfessorDepartment of PharmacyUniversity of Oklahoma College of PharmacyOklahoma City, OK

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

seCtion editors

Co-editors-in-ChieF

Joseph Bubalo, PharmD, BCPS, BCOPAssistant Professor of MedicineOncology Clinical Specialist and Oncology LeadOHSU Hospital and ClinicsPortland, OR

Sandra Cuellar, PharmD, BCOPDirector Oncology Specialty ResidencyUniversity of Illinois at Chicago Medical CenterChicago, IL

Sachin Shah, PharmD, BCOP Associate ProfessorTexas Tech University Health Sciences CenterDallas, TX

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy PracticeSamford University McWhorter School of PharmacyBirmingham, AL

John M. Valgus, PharmD, BCOP, CPPHematology/Oncology Senior Clinical Pharmacy SpecialistUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Daisy Yang, PharmD, BCOP Clinical Pharmacy SpecialistUniversity of Texas M. D. Anderson Cancer CenterHouston, TX

editors-at-large

This is the biologic medicine

That the patient counts on

That the nurse trusts

That the pharmacist has confi dence in

That the doctor relies on

Because it was manufactured knowing the patient’s

treatment depends on it.

Building confi dence in the quality and supply of biologic medicines

starts with a deeper understanding of how these medicines are made.

After all, there’s so much at stake.

That’s why manufacturing matters.

Learn more at buildingbiologics.com

©2012 Amgen Inc. All rights reserved. 71325-R1-V1 An educational initiative from

That the nurse trusts

That the pharmacist has confi dence in

That the doctor relies on

Because it was manufactured

After all, there’s so much at stake.

Building confi dence in the quality

©2012 Amgen Inc. All rights reserved. 71325-R1-V1 An educational initiative fromAn educational initiative from

Safety= .25” Trim= 10.875” x 13.875” Bleed= 11.125” x 14.125”

665399_M03DR_AMGEN_Journal Ads_KingTabloid_5.indd 1 1/23/13 10:39 AM

7 Vol 3, No 1 l March 2013 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com l

Senior Vice President, Sales & Marketing

Philip [email protected]

PublisherJohn W. Hennessy

[email protected] 732.992.1886

Editorial DirectorDalia Buffery

[email protected]

Associate EditorLara J. Lorton

Editorial AssistantJennifer Brandt

[email protected]

Associate PublishersJoe Chanley

[email protected] 732.992.1524

Cris [email protected]

732.992.1896

Production ManagerStephanie Laudien

Quality Control DirectorBarbara Marino

Business ManagerBlanche Marchitto

[email protected]

Editorial Contact:Telephone: 732.992.1536

Fax: 732.656.7938E-mail: [email protected]

Table of ConTenTs

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (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 Com munications, 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: [email protected]. 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 Commun i cations, 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 contraindi-cations. 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.

ORIGINAL RESEARCH 9 Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer Robert Mancini, PharmD, BCOP; Kathleen Clifford, MSN, FNP-BC, AOCNP, ACHPN

REvIEw ARtICLE16 Ipilimumab: Unique Responses, Toxicities, and

Recommendations for the Use of the First Anti–CTLA-4 Therapy in Patients with Melanoma

Michael K. Wong, MD, PhD, FRCPC; Anthony Jarkowski III, PharmD, BCOP

26 Letter to the Editor

From the Literature29 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

Publishing sTaff

Mission sTaTeMenTThe Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed jour-nal founded in 2011 to provide hematolo-gy 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

HEmAtOLOGyONCOLOGyPHARmACy™

The Peer-reviewed Forum For oncology Pharmacy PracTiceTm

March 2013 VoluMe 3, nuMber 1

Remember to vote for the 2013 T.O.P. Pharmacist Award,

sponsored by Teva Oncology. This annual award recognizes

an oncology pharmacist nominated by his/her peers for

outstanding contributions to oncology pharmacy practice,

research, or education in 2012.

The 6 leading nominees are profiled online and in the

February issue of The Oncology Pharmacist. Vote for the

winner at TheOncologyPharmacist.com/award. The winner

will be announced at the 2013 Hematology/Oncology

Pharmacy Association (HOPA) meeting and profiled

in the April issue of The Oncology Pharmacist.

Vote at TheOncologyPharmacist.com/award

Don’t Forget to Cast Your TOPPharmacist Vote

9 www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 3, No 1 l March 2013

ORIGINAL RESEARCH

Most patients with cancer have multiple co-morbidities and are at high risk of polyphar-macy. In addition, previous reviews have

shown that up to 33% of ambulatory patients with cancer are at risk for drug–drug interactions.1-3 A small percentage of patients (approximately 8%) have also been shown to be at risk for receiving du-plicate therapies.4 The published data show that risk of drug interactions increases with the number of medications a patient is taking and increased age.4,5

Pharmacists are uniquely trained in medication therapy management, and a thorough medication therapy review can assist other disciplines in their assessments and interventions.6 It may be especially useful to have an oncology-trained pharmacist (ie, specialty oncology residency training or several years

of practice in the field of oncology) in this setting, so that they could further integrate the patient’s cancer treatment with symptom management.7,8

Patients receiving multiple medications must be evaluated for both pharmacokinetic and pharmaco-dynamic interactions. In a retrospective study of 4 centers evaluating 160 patients, 91% of those patients were prescribed at least 1 drug that was a substrate for, inducer of, or inhibitor of 1 of the 5 cytochrome P450 isoforms leading to clinically significant drug–drug interactions in 21% of those patients.3 These patients are not only at risk of drug interactions between their routine noncancer medication and their antineoplas-tics, but also with their supportive care medications and with medications that they were already receiving before they started treatment.

It is important to assess for polypharmacy in patients who are prescribed several drugs concurrently for the treatment of 1 or more coexisting diseases. A good example is a patient who may have been prescribed a benzodiazepine for an underlying anxiety disorder and

Dr Mancini is Oncology Pharmacist, Oral Chemotherapy, Infusion and Supportive Care, and Ms Clifford is Oncology Nurse Practitioner, at St Luke’s Mountain States Tumor Institute, Boise, ID.

Pharmacist Assessment of Polypharmacy Risks in Patients with CancerRobert Mancini, PharmD, BCOP; Kathleen Clifford, MSN, FNP-BC, AOCNP, ACHPN

Background: Most patients with cancer have multiple comorbidities and are at high risk of polypharmacy. In addition, reviews have shown that up to 33% of ambulatory patients with cancer are at risk of drug–drug interactions.Objectives: To evaluate the polypharmacy risks and the impact that pharmacist assessments can play in a multidisciplinary supportive oncology clinic. Methods: In this retrospective review, all patients who were referred to and attended the sup-portive care clinic from its initiation in June 2010 through May 2012 were assessed by a phar-macist. The risks for polypharmacy were assessed utilizing the AACME (Access, Adherence, Continuity of Care, Medication Reconciliation, and Education) method, which included evalua-tion for duplicate therapy, drug interactions, lack of efficacy and undertreated conditions, side effect causal relationships, and untreated conditions.Results: Of 153 patients evaluated during the first year of the clinic, 69 patients (45.1%) were found to have some form of therapeutic duplication within their medication list, 54 patients (35.3%) had documented drug interactions, and 127 patients (83%) reported side effects that were attributable to 1 or more of their medications. Despite this, most patients (88.9%) reported uncontrolled symptoms, and a majority of patients (68.6%) reported symptoms that had not been previously treated.Conclusion: These data suggest that, when evaluated by a pharmacist, the rates of polypharma-cy risks may be higher than the rates currently published in the literature. It is possible, however, that this is an overestimate resulting from the complexity of the patient population evaluated. It is therefore likely that the true value lies somewhere between the values already published and what was seen in this analysis.

J Hematol Oncol Pharm. 2013;3(1):9-14.www.JHOPonline.comDisclosures are at end of text

10 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com March 2013 l Vol 3, No 1

ORIGINAL RESEARCH

is then given another benzodiazepine for anticipatory nausea. Polypharmacy occurs when patients are treated by multiple providers.9

It is often difficult for oncologists to manage an un-derlying chronic disease and its treatments along with the daunting task of treating the cancer and its accom-panying symptoms. One of the best solutions today is improving communication and the involvement of multidisciplinary teams that include a pharmacist.

At St Luke’s Mountain States Tumor Institute, patients with complex physical and/or psychosocial issues are referred by providers to a multidisciplinary

symptom management clinic. Patients are requested to bring in their medications so that the pharmacist can review them in full detail with the patient and confirm actual medications and their doses. Recommendations based on the medication reconciliation are provided to the supervising nurse practitioner, who determines the ultimate plan based on input from the entire supportive care team, which includes a dietitian, a social worker, a registered nurse, and a chaplain on a consultant basis.10

The findings of a supportive care clinic pharmacist as-sessment are outlined here. The objectives of this article are to evaluate polypharmacy risks in oncology patients and to evaluate the impact that pharmacist assessments can have on a multidisciplinary supportive oncology clinic.

MethodsAll patients who were referred to and who at-

tended the supportive care clinic from its initiation in June 2010 through May 2012 were assessed by a pharmacist. Patient demographics were collected on all patients, including visit date, referring physician, cancer type, and the number of medications taken at the time of the clinic visit (divided into scheduled and as needed). Medication therapy management visits

Table 1 Patients by Diagnosis

Cancer type Patients, N

Bladder 1

Brain 1

Breast 17

Colorectal 9

Gastric/esophageal 8

Gynecologic 14

Head and neck 14

Kidney 2

Leukemia 4

Liver 1

Lung 29

Lymphoma 8

Melanoma 3

Myeloma 6

Pancreatic 27

Prostate 5

Sarcoma 3

Thyroid 1

Total 153

At St Luke’s Mountain States Tumor Institute, patients with complex physical and/or psychosocial issues are referred by providers to a multidisciplinary symptom management clinic. Patients are requested to bring in their medications so that the pharmacist can review them in full detail with the patient.

Breakthrough pain medications,

27%

Sleep medications, 15%

Other, 12%

Antianxiety, 10% PPIs (or PPI + other), 7%

Constipation medications (similar MOA), 7%

Multiple acetaminophen products, 5%

BP medications, 5%

Diuretics, 4%

Antioxidants/supplements, 4%

Antidepressants, 4%

“Other” includes anticoagulants (1), antidiarrheals (2), antihista-mines (1), mucositis solutions (1), neuropathic pain medications (1), NSAIDs (1), nausea medications with the same MOA (1), potassium supplements (1).

BP indicates blood pressure; MOA, mechanism of action;NSAIDs, nonsteroidal anti-inflammatory drugs; PPIs, proton pump inhibitors.

Therapeutic Duplications, by Class (N = 74)Figure 1

Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer


conducted by the pharmacist followed the AACME (Access, Adherence, Continuity of Care, Medication Reconciliation, and Education) method.10,11 Using this model, the pharmacist documented all assessment find-ings that were discussed during a patient visit in the elec-tronic medical record. Data documented in the medical record were collected and summarized, and assessment notes helped to isolate the main issues discussed with the pharmacist in these visits. In addition, the total time that the pharmacist spent with the patient was recorded.

Within the assessment, some parameters were based on patient report, the pharmacist’s clinical judgment, or both. Parameters based on patient report included insurance or cost issues, transportation issues, self-re-ported missed doses, and adverse effects. Parameters based on the pharmacist’s clinical assessment included the presence of duplicate therapy, clinically relevant drug–drug interactions, lack of efficacy, side effect caus-al relationships, and untreated conditions.

Duplicate therapy was defined as any unintended du-plication in therapy for a single symptom or disease state and/or 2 medications in the same class (for example, 2 benzodiazepines or 2 short-acting narcotics). Drug inter-actions were assessed by inputting the patient’s complete medication list into the Micromedex 2.0 Drug Interactions checker, and were cross-checked with the Lexicomp Lexi-Interact online drug interaction analysis program. All major pharmacokinetic drug interactions were recorded, and pharmacodynamic interactions were recorded if they required intervention by the pharmacist.

ResultsBetween June 2010 and May 2012, 153 patients were

seen in supportive care clinics conducted on different days across 4 clinic sites. All patients were seen by the same pharmacist to maintain consistency in clinical evaluation. Most patients were referred by a medical oncologist or medical oncology nurse practitioner (94%), although some referrals were received from radiation oncologists.

The most frequent diagnoses were lung, pancreatic, breast, gynecologic, and head and neck cancers (Table 1). The most frequent issues (found in >20% of patients) dis-cussed with the pharmacist included constipation, depres-sion, fatigue, medication-related questions, nausea, pain, and sleep. The average time spent with the pharmacist was 44 minutes (range, 15-90 minutes).

With regard to access, 60 patients (39.2%) reported cost issues mostly related to high copays and lack of in-surance coverage for certain medications. A total of 37 patients (24.2%) reported transportation issues, and 61 (39.9%) reported issues with healthcare access. A total of 94 patients (61.4%) reported adherence issues and noted missing at least 1 dose of their routine medica-

tions in the past 2 to 3 months, with the most frequent reason being forgetfulness; however, confusion about medications and a lack of desire to take medications also played a role.

The medication reconciliation demonstrated the incidence of polypharmacy in these patients. Of the total

Table 2 Most Frequent Drug Interactions

Medication Interactions, N (%)

Amlodipine 2 (1.4)

Chemotherapya 3 (2.1)

Citalopram 2 (1.4)

Clopidogrel 17 (12.1)

Corticosteroids 2 (1.4)

Cyclobenzaprine 12 (8.6)

Erlotinib 8 (5.7)

Fluoxetine 2 (1.4)

Levofloxacin 1 (0.7)

Metoclopramide 2 (1.4)

NSAIDs 2 (1.4)

Otherb 15 (10.7)

Proton pump inhibitors 49 (35.0)

Quetiapine 10 (7.1)

Ropinirole 8 (5.7)

Simvastatin 3 (2.1)

Spironolactone 2 (1.4)

Tramadol 3 (5.1)

Trazodone 2 (3.4)

Venlafaxine 5 (8.5)

Vitamins/supplementsa 3 (5.1)

Warfarin 13 (22.0)

Zolpidem 3 (5.1)

Total DDIs, N 59

Patients, N 54aRepresents interaction between chemotherapy and antioxidant-containing supplements.b “Other” includes aspirin/dipyridamole, aspirin, bupro-pion, clonazepam, cranberry, diphenhydramine, duloxe-tine, furosemide, hydroxyzine, levothyroxine, lorazepam, mirtazapine, morphine, posaconazole, potassium, solifenacin, sorafenib, and tamsulosin.NSAIDs indicates nonsteroidal anti-inflammatory drugs;DDIs, drug–drug interactions.

ORIGINAL RESEARCH


patients, 74 (48.4%) were found to have some form of un-intentional therapeutic duplication within their medica-tion list (Figure 1), 54 patients (35.3%) had documented clinically relevant drug–drug interactions (Table 2), and 127 patients (83%) reported side effects that the pharma-cist attributed to 1 or more of their medications (Table 3).

Despite this, most patients (88.9%) reported uncon-trolled symptoms (Table 4), and a majority of patients

(68.6%) reported symptoms that had not been previously treated (Figure 2).

DiscussionTo date, the literature has shown that polypharmacy

is a real risk to patients with cancer. A large part of this is a result of the fact that oncology is a specialty service, and thus patients, especially older patients, have mul-

Table 3 Most Common Side Effects and Associated Medications

Side effect type Patients, N (%) Associated medications

Anxiety 1 (0.7) Venlafaxine

Bleeding 1 (0.7) Ibuprofen

Bruising 1 (0.7) Everolimus

CNS alterations 13 (9.7) Seizure medications (2), narcotics (3), benzodiazepines (4), zolpidem, steroid, antihistamines (2)

Constipation 41 (30.6) Narcotics (30), 5-HT3 antagonists (9), iron, loperamide

Cough 1 (0.7) Paclitaxel

Dehydration 1 (0.7) Furosemide

Diarrhea 7 (5.2) Imatinib, capecitabine (2), docusate (2), lactulose, venlafaxine

Dry mouth 13 (9.7) Hydrochlorothiazide, zolpidem (5), amitriptyline (2), benzodiazepines, tolterodine, diphenhydramine (3)

Fatigue 6 (4.5) Various chemotherapies

GI pain 1 (0.7) Methylnaltrexone

Increased INR 1 (0.7) Warfarin

Insomnia 5 (3.7) Venlafaxine, DHEA, steroids (3)

Lack of appetite 1 (0.7) Modafanil

Low BP 5 (3.7) Various BP medications

Mucositis 3 (2.2) Various chemotherapies

Nausea 12 (9.0) Narcotics (3), supplements (2), tube feeds, capecitabine (2), sumatriptan, citalopram, venlafaxine, megestrol

Neuropathy 1 (0.7) Paclitaxel

Pain 1 (0.7) Imatinib

Rash 6 (4.5) Sorafenib, citalopram, risperidone, pemetrexed, levofloxacin, oxycodone

Sedation 10 (7.5) Narcotics (6), diphenhydramine (2), gabapentin, nortriptyline

Sexual dysfunction 2 (1.5) Fluoxetine, DHEA

Thrush 1 (0.7) Fluticasone/salmeterol

Tremor 1 (0.7) Promethazine

Urinary incontinence 1 (0.7) Cevimeline

Total ADRs, N 134

Patients, N 127

ADRs indicates adverse drug reactions; BP, blood pressure; CNS, central nervous system; DHEA, dehydroepiandrosterone; GI, gastrointestinal; INR, international normalized ratio.

Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer


tiple providers that they have seen for months to years before ever seeing their oncologist. As a result, patients enter the realm of cancer care with multiple medi-cations well before their oncologist starts prescribing treatment-related medications.

Before this intervention, many patients have never had their medication list evaluated in full because of the use of multiple providers (eg, family medicine, sur-geons, oncologists, other specialists).5,9

These data have shown that when evaluated by a pharmacist, the rates of polypharmacy risks may be higher than those currently published in the literature. It is possible, however, that based on the patient popu-lation evaluated, this may be an overestimate resulting from the fact that these patients were often getting treated for cancer which was complicated by or in turn complicated their other chronic disease states. It is likely that the true value lies somewhere between the values already published and what was seen here.

The unique aspect of our study is the evaluation and correlation of clinically relevant side effects related to medications, or, in other words, pharmacodynamic in-

teractions. Previous studies have not examined the im-pact of how certain medications may compound symp-toms in patients receiving active treatment for cancer.

Problems often arise from medications started for primary preventive measures that, because of shifting treatment goals, may no longer be needed (eg, choles-terol or blood pressure medications).12

In our evaluation, 83% of patients reported side effects that could be directly attributable to their medica-tions, many of which were not their cancer treatments. In addition, extended time with a pharmacist has allowed discussions of each medication in detail with the patient. This helps to isolate undertreated conditions and the rea-sons for them. For example, perhaps a patient is fatigued, but he or she is taking a thyroid medication with food, and

Table 4 Most Frequent Undertreated Conditions

Condition Events, N (%)

Anxiety 3 (2.1)

Appetite (poor) 2 (1.4)

Blood pressure 2 (1.4)

Constipation 17 (12.1)

Constitutional 2 (1.4)

Depression 12 (8.6)

Diarrhea 8 (5.7)

Fatigue 2 (1.4)

Hot flashes 1 (0.7)

Incontinence 2 (1.4)

Mucositis 2 (1.4)

Nausea 15 (10.7)

Pain 49 (35.0)

Reflux 10 (7.1)

Shortness of breath 3 (2.1)

Sleep 8 (5.7)

Thyroid 2 (1.4)

Total undertreated conditions, N

140a

Patients, N 136aSome patients had more than 1 undertreated condition.

Fatigue, 20%

Other, 15%

Depression, 11% Constipation,

11%

Mucositis, 8%

Gastroparesis, 8%

Pain, 5%

Insomnia, 5%Appe

tite (p

oor), 5

%

Reflu

x, 4%

Dry m

outh

, 4%

“Other” includes cough (2), dizziness (2), electrolyte abnormalities (1), gas/bloating (2), infection (2), inflammation (2), nausea (1), neuropathy (1), rash (1), secretions (1), sedation (1), sexual dysfunction (1), smoking cessation (1).

Most Frequent Untreated Conditions (N = 105)Figure 2

Anxi

ety,

4%

Before this intervention, many patients have never had their medication list evaluated in full because of the use of multiple providers. These data have shown that when evaluated by a pharmacist, the rates of polypharmacy risks may be higher than those currently published in the literature.

ORIGINAL RESEARCH


therefore a thyroid-stimulating hormone level is taken and found to be subtherapeutic. Or perhaps a patient’s pain is out of control, but he or she is only taking a long-acting pain medication as needed. Hence, some undertreated conditions or side effects can be resolved with education on proper use rather than increasing doses or changing medications. These issues may not be able to be evaluated fully in the limited time that oncologists have with their patients, and, therefore, referrals to pharmacists can help the oncologists focus on treatment-related issues.

ConclusionWe agree that pharmacists who have completed

general and oncology specialty residencies or who have equivalent practice experience would be best equipped to fill this type of role.7,8,13 A background in general med-icine, coupled with the specialty training or extensive practice in oncology, gives a pharmacist a unique ability to integrate all aspects of the patients’ care into this type of assessment. This background may also be why our study has been able to realize an increase in polyphar-macy risks compared with those previously shown in the literature and provide more in-depth assessments. n

Author Disclosure StatementDr Mancini is on the Speaker’s Bureau for Millenium

Pharmaceuticals and has received consultant fees from GlaxoSmithKline. Ms Clifford has no conflicts of interest to report.

References1. Riechelmann RP, Del Giglio A. Drug interactions in oncology: how common are they? Ann Oncol. 2009;20:1907-1912.2. Riechelmann RP, Zimmermann C, Chin SN, et al. Potential drug interactions in cancer patients receiving supportive care exclusively. J Pain Symptom Manage. 2008;35:535-543.3. Wilcock A, Thomas J, Frisby J, et al. Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centers: a multicentre audit. Br J Clin Pharmacol. 2005;60:326-329.4. Riechelmann RP, Tannock IF, Wang L, et al. Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst. 2007;99:592-600.5. Edwards BK, Howe HL, Ries LA, et al. Annual report to the nation on the status for cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer. 2002;94:2766-2792.6. van Leeuwen RW, Swart EL, Booms FA, et al. Potential drug interactions and duplicate prescriptions among ambulatory cancer patients: a prevalence study using an advanced screening method. BMC Cancer. 2010;10:679.7. Watkins JL, Landraf A, Barnett CM, Michaud L. Evaluation of pharmacist-pro-vided medication therapy management services in an oncology ambulatory setting. J Am Pharm Assoc (2003). 2012;52:170-174.8. Clinical pharmacists in oncology practice. J Oncol Pract. 2008;4:172-174.9. Lees J, Chan A. Polypharmacy in elderly patients with cancer: clinical implica-tions and management. Lancet Oncol. 2011;12:1249-1257.10. Mancini R. Implementing a standardized pharmacist assessment and evalu-ating the role of a pharmacist in a multidisciplinary supportive oncology clinic. J Support Oncol. 2012;10:99-106.11. Kliethermes MA, Schullo-Feulner AM, Tilton J, et al. Model for medication therapy management in a university clinic. Am J Health Syst Pharm. 2008;65:844-856.12. Lord S, Hall PS, Seymour MT. Concomitant medications in cancer patients: should we be more active in their management? Ann Oncol. 2010;21:430.13. Mancini R. The role of oncology pharmacists in the care team: chemotherapy management and supportive care at St. Luke’s Mountain States Tumor Institute. Oncol Pract Manag. 2012;2:16-19.

Information for AuthorsManuscripts submitted to Journal of Hematology Oncology Pharmacy (JHOP) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP, and must adhere to the format described in the full Guidelines for Authors available at www.JHOPonline.com. All manuscripts undergo peer review, and acceptance is based on that review. If accept-ed, authors will be notified of any recommended revisions.

COPYRIGHT/DISCLOSUREAuthors must sign a Copyright Transfer Form, assigning all copyrights to Green Hill Healthcare Communicatioins, LLC, publisher of JHOP, as well as a Financial Disclosure Form, disclosing any potential conflict of interest.

MANUSCRIPT FORMAT• Title page: provide a proper title for the article; list names, degrees, titles, and affiliations for all authors, as well

as contact information for the corresponding author • Abstract: 200-300 words • Tables and figures: cite these in the text, but place graphic elements after the references; type all tables in a Word format • References: 35-45 current, post-1990 references, cited in the text but listed at the end of the manuscript; avoid

automatic numbering, footnotes, endnotes• Length of article: 3000-4000 words, plus tables and figures • Provide all Figures as PDF, jpg, or PowerPoint files, saved at 300 dpi

PERMISSIONS Authors must secure a written permission from the original publisher for any previously published (online or in print) Table or Figure. Provide the source with each element.

Submit the manuscript online at www.JHOPonline.com. For assistance call 732-992-1536.

CONQUERING THECANCER CARE

C O N T I N U U M™

A 6-part series

www.TheOncologyPharmacist.com

��Green Hill Healthcare Communications, LLC

Cancer is an illness associated with substantialphysical, emotional, social, and financial ram-ifications for affected individuals and their

families. In a significant number of cases, the diagnosisof cancer is either preceded by a periodof gradual, nonspecific symptoms ordiscovered by routine screening, andindividuals are then thrust into awhirlwind of diagnostic testing, in-vasive procedures, and complicatedtreatments with very little warning oropportunity to assimilate their circum-stances. Frequently, a multidisciplinaryapproach to treatment is necessary, re-quiring patients to engage with numer-ous medical teams comprising severaldifferent specialties, often in differentlocations. Many patients have beenrelatively healthy prior to the cancer event and there-fore are not sophisticated consumers of medical ser-vices. Consequently, it is incumbent on healthcareprofessionals to be able to facilitate patients’ transitioninto care in order to minimize their distress and maxi-mize their clinical outcomes.

Challenges exist beyond the initial diagnosis andtreatment period as well. According to the NationalCancer Institute (NCI), more than 12 million individ-uals in the United States are living with a history of

cancer.1 More than half are living well beyond 5 yearsafter diagnosis. Women comprise a majority of long-term survivors due to the favorable outcomes withbreast, cervical, and uterine cancers.2 The number of

people living with a history of canceris projected to grow considerably overthe next 20 years for 2 major reasons.First, the number of Americans overage 65 is predicted to double betweenthe years 2000 and 2030.3 Conse-quently, as a disease primarily of olderadults, cancer will also increase. Sec-ond, as the effectiveness of cancertreatments improves, the number ofpatients cured of the disease will in-crease, and an even larger percentagewill be living longer with the diseasewhile receiving multiple “lines” of

therapy (first-line, second-line, etc) over time. Theoverall demand for oncology services is expected to in-crease by 48% by 2020, while the supply of oncologistswill increase by only 14% based on current patterns.4

These statistics underscore the need for a wide varietyof health professionals and other support personnel toplay a part in enabling each and every patient to re-ceive quality care that addresses all of their needsthroughout the continuum of the illness. Patients de-fine quality of care based on their ability to5:

Challenges Patients Face in Cancer Care:Implications for the Healthcare TeamLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen,PharmD, BCOP

CONQUERING THECANCER CARE


��


T he past decade has seen a dramatic upsurge inthe utilization of specialty pharmacies for alltypes of therapeutic modalities, including

those for cancer. The cost of cancer care may rise from

about $125 billion in 2010 to $207 bil-lion by the end of the decade. By thattime, specialty drugs are predicted toaccount for 2 of every 5 pharmacy dol-lars spent.1 The purpose of this articleis to explain the evolution of the spe-cialty pharmacy and the functions itcan serve in the treatment of cancerand to discuss the potential benefitsand challenges of the system from thepoint of view of the patient.

The Evolution of SpecialtyDrugs and SpecialtyPharmacyThere is a lack of consensus on the definition of a

specialty drug. The Food and Drug Administration has

not defined the term. Initially, the label was virtually

synonymous with biotechnology products, either pro-

teins produced by recombinant DNA techniques or

monoclonal antibodies produced with cellular hy-

bridomas, but this is no longer the case. The 2007

Medicare Modernization Act defined a specialty drug

as “a part D drug with plan-negotiated prices that ex-

ceed $400 per month.”2 Other health plans may de-

fine specialty drugs differently. In general, they arehigh cost, administered by injectionor infusion, require special handling,or are used for complex diseases thatrequire special monitoring. In on-cology, however, the most commonagents dispensed by a specialty phar-macy provider (SPP) are the newertargeted agents that are adminis-tered orally. After a systematic re-view of the literature, one academicgroup of authors proposed the mostcritical descriptors of a specialtydrug to be3:• High cost (prescriptions cost more than $600 per month)

• Difficult medication delivery, such as— Special handling requiring strict temperature

control— Restricted location for medication preparation

or distribution site— Restricted location for medication adminis-tration

Convenience, Challenges, and Cost Containment:

The Impact of Specialty Pharmacies on

Patient CareLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University


CONQUERING THECANCER CAREC O N T I N U U M™

��


The predominant scenario for systemic treatment

of cancer has traditionally involved administra-

tion of intravenous chemotherapy by highly

trained personnel who closely monitored the patient.

When these procedures took place in an

oncologist’s office or in a hospital infu-

sion center, extensive education of the

patient and family was possible. More

recently, however, an increasingly com-

mon situation involves the use of one or

more oral medications and self-admin-

istered subcutaneous therapies in the

home environment. The direct respon-

sibility for drug acquisition and admin-

istration is shifting to the patients and

their social support network, if avail-

able. At the present time, more than 20

oral medications are FDA approved for

the first-line treatment of cancer (Table 1). In addition,

a number of other oral agents are used for tumors that

have relapsed or are refractory to initial treatment. Ac-

cording to the National Comprehensive Cancer Net-

work, approximately 25% of all compounds in the

oncology research and development pipeline are admin-

istered orally, so the trend is likely to continue.1

With this shift in responsibility comes the increased

possibility that anticancer medications may not be ad-

ministered correctly, especially for regimens that require

repeated dosing. Overall estimates of adherence to long-

term oral medication regimens range from 17% to 80%,

with an average around 50%.2-4 A common assumption

that adherence to oral anticancer agents would be

higher, due to the severity of the disease, has been

proven untrue. Studies indicate the

adherence rates for cancer therapy are

15% to 97%.5 Nonadherence has

been associated with worse outcomes

in a number of disease states and with

increased physician visits, higher hos-

pitalization rates, longer hospital stays,

disease worsening, and increased mor-

tality.6 Approximately one-third to

two-thirds of all medication-related

hospitalizations are due to medication

nonadherence—at a cost of $100 bil-

lion annually.7 The purpose of this ar-

ticle is to describe general concepts

regarding patient adherence and the research related to

adherence to cancer treatment. The incidence, risk fac-

tors, and consequences of this problem will be reviewed.

The last article in this series will subsequently examine

the best practices for maximizing adherence and clinical

outcomes.

��

��

Adherence was defined by the World Health Organ-

ization in 2003 as the “extent to which a person’s be-

havior, taking medication, following a diet, and/or

Impact of Nonadherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOP

Associate Professor, Virginia Commonwealth University

Lea Ann Hansen,

PharmD, BCOP

CONQUERING THE

CANCER CARE


��


The previous installment in this cancer care se-ries examined the growing importance of oraltherapies for the treatment of cancer and the

implications of patient adherence on its success. At thepresent time, more than 20 oral med-ications are approved by the Food andDrug Administration (FDA) for first-line treatment of cancer. A number ofother oral agents are used for tumorsthat have relapsed or are refractory toinitial treatment, and about 25% of theoncology research pipeline consists oforal compounds.1 This is in addition toself-administered subcutaneous thera-pies for the home environment thatare under FDA review. When cancer medications are ad-ministered orally in the home envi-ronment rather than in the clinic or hospital, the rates

of adherence range from 15% to 97%.2 For example,at the end of the first year of treatment with adjuvanthormonal treatment (AHT) for early-stage breast can-cer, only 79% of patients remained on therapy withouta gap exceeding 60 days and 85% without a gap ex-ceeding 180 days. By year 5, only 27% and 29% re-mained without 60- and 180-day gaps, respectively.3

In another study of AHT, patients with a medica-tion possession ratio (MPR) >80% had a statisticallysignificantly higher 10-year survival rate than those

with a lesser MPR (82% vs 78%).4 (MPR is a metricderived from electronic prescription records based onrefill patterns over time, and 80% is an arbitrary cutpoint for adherence used by many investigators.) Thesame study found survival at 10 yearsto be 81% for those who continuedtherapy versus 74% for those whohad discontinued it. Nonadherencehas also been shown to produce sub-stantial detriment in clinical out-comes in chronic myeloid leukemiaand childhood acute lymphoblasticleukemia.5-8 For each of these disor-ders, prolonged oral therapy hasbeen the standard of care for adecade or more. It is likely that neg-ative consequences of nonadherencewith other oral cancer medications

will be documented in the future as their role in ther-apy matures. The purpose of this article is to discussthe results of available research on maximizing adherence and suggest best practices to improve clin-ical outcomes.

�� Direct communication with all patients about their

personal barriers to taking daily therapy for a prolongedperiod is an important aspect to maximizing adher-

Best Practices in Maximizing Adherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University


CONQUERING THECANCER CAREC O N T I N U U M™

��

The publishers of The OncologyNurse-APN/PA, The OncologyPharmacist, and PersonalizedMedicine in Oncology are proud to present our 2nd annualConquering the Cancer CareContinuum series. Upcoming topics include:

TO VIEW THE SERIES ONLINEPLEASE LOG ON TO:

2ND ANNUAL View the

series online at

TheOncologyPharmacist.com

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

IN THISISSUE

CCC Asize_revised_030413_TON0210 3/6/13 10:37 AM Page 1

REVIEW ARTICLE


REVIEW ARTICLE

The outlook for patients with advanced or meta-static melanoma is poor; historical benchmark data from a recent meta-analysis encompassing

more than 2000 patients with advanced or metastatic melanoma indicate that only 25% of patients are still alive at 1 year.1 There has been little change in the stan-dard of care for metastatic melanoma for several decades. Dacarbazine, which was approved by the US Food and Drug Administration (FDA) in 1975, remains the only chemotherapy approved for use in this setting. However, single-agent dacarbazine achieved overall response rates of between 5% and 10% in recent phase 3 trials of pa-tients with melanoma, with very few complete responses and no impact on overall survival (OS).2,3 Although not approved by the FDA for this indication, other chemotherapies, including temozolomide, taxanes, and

platinum agents, are in clinical use in this setting, with response rates of up to 26%.4-11

Interleukin (IL)-2 was approved by the FDA in 1998 for the treatment of patients with metastatic melanoma. Although durable complete and partial responses are possible, its routine clinical use has been limited for this patient population by low response rates (approximately 16% with high-dose IL-2), lack of consistent improvement on OS, and risk of significant toxicity,12 necessitating that patients receive therapy in the intensive care unit of facilities specializing in the administration of IL-2.

In 2011, 2 new medications were approved by the FDA for patients with advanced melanoma. The first of these, ipilimumab, is a recombinant, human mono-clonal antibody (immunoglobulin G1 subtype) that augments antitumor T-cell responses by binding to and neutralizing the cytotoxic T-lymphocyte antigen (CTLA)-4 immune repressor cell-surface receptor on T-cells. Ipilimumab has demonstrated improved OS in 2 phase 3 studies: as a single agent in previously treated patients and in combination with dacarbazine

Dr Wong is Professor of Medicine, Norris Comprehensive Cancer Center Keck School of Medicine, Los Angeles, CA, and Dr Jarkowski is Clinical Pharmacy Specialist, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY.

Ipilimumab: Unique Responses, Toxicities, and Recommendations for the Use of the First Anti–CTLA-4 Therapy in Patients with MelanomaMichael K. Wong, MD, PhD, FRCPC; Anthony Jarkowski III, PharmD, BCOP

Background: In 2011, the first anticytotoxic T-lymphocyte antigen (CTLA)-4 therapy ipilimumab was approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma based on a demonstrated overall survival benefit with this agent in phase 3 clinical trials. Objectives: To review ipilimumab’s novel mechanism of action, efficacy, and toxicities, and to provide a practical overview of the use of this drug for the management of patients with melanoma. Discussion: Ipilimumab is unique in its response patterns, toxicities, and activity in subgroups of patients with melanoma. This drug produces responses that differ from the conventional responses that are observed with cytotoxic agents. Therefore, new immune-related response criteria have been proposed to prevent immature withdrawal of therapy with ipilimumab. Across ipilimumab studies, the most frequently affected organs were the gastrointestinal tract and skin; less frequently seen were hepatic, endocrine, and neurologic events. Ipilimumab’s immune- related adverse events may be severe and long-lasting, but these are reversible with prompt recognition and early treatment.Conclusion: The first-in-class anti–CTLA-4 therapy to be approved, ipilimumab has demonstrat-ed efficacy and overall survival benefit in patients with unresectable or metastatic melanoma, but toxicity is a concern. Ipilimumab is currently available as a monotherapy, but current research is expected to help shape the melanoma treatment landscape by establishing the most effective combination regimens, without compromising tolerability.

J Hematol Oncol Pharm. 2013;3(1):16-26.www.JHOPonline.comDisclosures are at end of text

Ipilimumab Overview


in treatment-naïve patients with unresectable stage III or stage IV melanoma.2,13 In previously treated patients, ipilimumab alone or in combination with the glycopro-tein (gp)100 peptide vaccine reduced the risk of death by 34% and 32%, respectively, compared with the gp100 vaccine alone.13 In treatment-naïve patients, the combi-nation of ipilimumab with dacarbazine reduced the risk of death by 28% compared with dacarbazine alone.2

The second therapy approved in 2011 is vemu-rafenib, a BRAF inhibitor that has antitumor activity in melanoma tumors with a BRAF V600E mutation. Approximately 40% to 60% of melanomas carry this mutation.3 In treatment-naïve patients with metastatic melanoma harboring the BRAF mutation, vemurafenib demonstrated improved 6-month OS compared with dacarbazine (84% vs 64%, respectively) and dramati-cally higher response rates (48% vs 5%, respectively).3 Although interim 6-month survival data for vemu-rafenib are encouraging, resistance already has been documented14-20; longer follow-up times will confirm the durability of the initial responses. In contrast, ipilimumab data have a longer follow-up time and show that for some patients, long-term survival can be achieved—on the order of 2 to 3 years for phase 3 studies and up to 4 years for phase 2 studies reported thus far.21,22

Although little information is available regarding whether vemurafenib and ipilimumab use is exclusive to each other, these are 2 very distinct therapies, with different mechanisms of action and nonoverlapping tox-icity profiles. As such, the combination of these 2 agents is being evaluated in a phase 1/2 trial in patients with BRAF V600 mutation metastatic melanoma.23 Started in November 2011, the study aims to recruit 50 patients with the primary end point of the phase 1 and phase 2 portions being safety and OS, respectively. This review will focus on ipilimumab, its unique toxicities, and the management of these toxicities.

CTLA-4 as a Therapeutic TargetThe recognition of CTLA-4’s critical role in im-

mune downregulation led to drug development aimed at targeting this pathway.24 Two signals are required for the activation of a T-cell response. The first occurs when the T-cell binds the antigen presented by the antigen-presenting cell (APC) that is bound to the major histocompatibility complex. At the same time, CD28 interacts with the B7 molecule on the same APC, resulting in CTLA-4 upregulation. CTLA-4 competitively inhibits the binding of B7 to CD28 and therefore acts as a “brake” on the nascent immune

Figure 1 Ipilimumab’s Mechanism of Action

NOTE: T-cells require 2 signals to activate. In response, CTLA-4 is upregulated to suppress the T-cell by competing for B7 against CD28. Ipilimumab blocks CTLA-4, thereby removing its opposition to CD28-mediated activation; thus, this potentiates T-cell activity against tumors.APC indicates antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.

T-cell activation

ActivationTCR

MHC

CD28

B7

CTLA-4

Activation

APC

TCR

MHC

B7

CTLA-4CD28

T-cell inhibition

Inhibition

APC

TCR

MHC

CD28

B7

CTLA-4

IpilimumabblocksCTLA-4

T cell remains activated

Activation Activation

APC

T-cell activation T-cell inhibition T-cell remains activated

ActivationActivation Inhibition ActivationActivation

Ipilimumab blocks CTLA-4

REVIEW ARTICLE


response. The importance of this system is dramatically demonstrated in mice devoid of functional CTLA-4, who develop massive CD28-dependent expansion of autoreactive T-cells and die within 3 to 4 weeks as a result of rampant lymphoproliferation and lymph-adenopathy. Ipilimumab blocks the CTLA-4 and, therefore, potentiates antitumor T-cell responses (Figure 1). Early studies in mice and primates, and later in humans, demon-strate that ipilimumab competitively binds to CTLA-4 more efficiently (an approximate 100-fold greater affinity) than native B7 while preserving CD28 signaling.25-30

Ipilimumab has demonstrated efficacy and safety in 2 randomized, multicenter, phase 3 trials. In the first study (MDX010-20), 676 previously treated patients with unresectable stage III or IV melanoma were randomized to receive ipilimumab alone (N = 137), ipilimumab in combination with the experimental vaccine gp100 (N = 403), or gp100 alone (N = 136).13 Patients were also required to be human leukocyte an-tigen (HLA)-A*0201–positive, a require-ment based on the mechanism of action of the gp100 vaccine.13

Ipilimumab 3 mg/kg, alone or in combina-tion with gp100, significantly improved me-dian OS versus gp100 alone (10.1 months, 10.0 months, and 6.4 months, respective-ly).13 No difference in OS was detected between the ipilimumab groups (Figure 2, Table).2,13,27-29 Of note, patients in this study had poor prognosis: more than 70% of pa-tients had visceral metastases and more than 36% had elevated lactate dehydrogenase (LDH) levels, both of which are associated with reduced survival.13 These findings led to the FDA approval of 4 doses of ipilimumab, given at 3 mg/kg on an induction schedule of every 3 weeks for patients with unresectable or metastatic melanoma.

The second study—CA184-024—differed in ipilimumab dose, schedule, and subse-quent toxicity profile.2 In this study, 502 treatment-naïve patients with unresect-able stage III or stage IV melanoma re-ceived either ipilimumab in combination with dacarbazine (N = 250) or dacarbazine alone (N = 252). Ipilimumab was adminis-tered at a dose of 10 mg/kg on an induction of every 3 weeks for 4 cycles and included

Ipilimumab Demonstrates Increase in Overall Survival in Patients with Advanced or Metastatic Melanoma

Survival curves from 2 separate phase 3 trials are shown. In each study, overall survival is increased compared with nonipilimumab control arms in patients treated with ipilimumab alone (A) or ipilimumab in combination with dacarba-zine (B). Long-term survival up to 3 years was observed in some patients treated with ipilimumab. Reprinted with permission from Hodi FS, et al. Improved survival with ipili-mumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723. Copyright © 2010 Massachusetts Medical Society; and Robert C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526. Copyright © 2011 Massachusetts Medical Society.

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk

Ipilimumab-dacarbazine

Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.

Ipi plus gp100Censored

gp100CensoredCensored

Ipi

Placebo–dacarbazine

Ipilimumab–dacarbazine

Censored

Censored

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk


Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.



Ipi



Censored

Censored

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk


Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.



Ipi



Censored

Censored

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk


Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.



Ipi



Censored

Censored

Figure 2

Months

Months

Months

Patie

nts

surv

ivin

g, %

Ipilimumab plus gp100

Censored

Gp100

Censored

Ipilimumab

Censored

Censored

Censored

Placebo plus dacarbazine

Ipilimumab plus dacarbazine

Patients at risk, N

Ipilimumab plus dacarbazine

Placebo plus dacarbazine

Patients at risk, N

Ipilimumab plus gp100

Ipilimumab

Gp100

A

B

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk


Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.



Ipi



Censored

Censored

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Over

all s

urvi

val,

%

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

250 230 199 181 157 131 114 104 91 85 79 74 68 61 59 56 56 52 41 31 17 10 4 2 0

252 229 190 160 136 116 89 78 72 64 56 47 44 42 42 37 34 31 26 19 11 7 5 3 0

Ove

rall

Su

rviv

al (

%)

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

MonthsNo. at Risk

Ipi plus gp100

Ipi

gp100

403 297 223 163 115 81 54 42 33 24 17 7 6 4 0

137 106 79 56 38 30 24 18 13 13 8 5 2 1 0

136 93 58 32 23 17 16 7 5 5 3 1 0 0 0

Pat

ien

ts S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 108 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

MonthsNo. at Risk


Placebo-dacarbazine

250 230 199 181 131157 114 104 91 7985 6874 61 59 56 5256 173141 10 4 2 0

252 229 190 160 116136 89 78 72 5664 4447 42 42 37 3134 111926 7 5 3 0

A.

B.



Ipi



Censored

Censored

Ipilimumab Overview


a maintenance phase. Patients with a response or stable disease to ipilimumab were randomized to ipilimumab or to placebo every 12 weeks as maintenance therapy.

Adding ipilimumab to dacarbazine significantly im-proved OS versus dacarbazine alone (11.2 months vs 9.1 months, respectively; Figure 2, Table).

Table Ipilimumab’s Efficacy and Immune-Related Adverse Event Profile in Phase 2 and 3 Clinical Trials

Study

Trialphase

Population

Treatmenta

ORR,

%

PFS

Median OS, months

(95% CI)

Toxicity/irAEs

CA184-008(N = 155) O’Day SJ, et al, 201028

2 Heavily pretreated, progressed on previous therapy

Ipilimumab 10 mg/kg

5.8 NR 10.2 (7.6-16.3) Most common irAEs GI and skin: Any-grade irAEs: 70.3%Grade 3-4 irAEs: 22%Grade 5 AEs: 3.2%

CA184-022(N = 217) Wolchok JD, et al, 201029

2 Intolerant of previous therapy

Ipilimumab 10 mg/kgIpilimumab 3 mg/kgIpilimumab 0.3 mg/kg

11.14.20.0

18.9%b

12.9%b

2.7%b

11.4 (6.9-16.1)8.7 (6.9-12.1)8.6 (7.7-12.7)

Most common irAEs GI and skin:Any-grade irAEs: 19%-50%Grade 3-4 irAEs: 0%-18%Grade 5 AEs: 0.46%

CA184-007(N = 115)Weber J, et al, 200927

2 Treatment naïve and previously treated

Ipilimumab 10 mg/kgIpilimumab 10 mg/kg + budesonide

15.812.1

NR 19.3 (12.0-34.5)17.7 (6.8-45.0)

Most common irAEs GI and skin:Any-grade irAEs: 81%-84%Grade 3-4 irAEs: 12%-21%Grade 5 AEs: 0%

MDX010-20(N = 676)Hodi FS, et al, 201013

3 Pretreated, progressed on previous therapy

Ipilimumab 3 mg/kg + gp100Ipilimumab 3 mg/kggp100 alone

5.710.9

1.5

2.76 months2.86 months2.76 months

10.0 (8.5-11.5)10.1 (8.0-13.8)6.4 (5.5-8.7)

Most common irAEs GI and skin:Any-grade irAEs: 58%-61% ipilimumab groupsAny grade irAEs: 32% gp100 aloneGrade 3-4 irAEs: 10%-15% ipilimumab groupsGrade 3-4 irAEs: 3% gp100 aloneGrade 5 AEs: 1.8% ipilim-umab groupsGrade 5 AEs: 0.3% gp100 alone

CA184-024(N = 502)Robert C, et al, 20112

3 Treatment naïve

Ipilimumab 10 mg/kg + dacarbazineDacarbazine alone

15.210.3

Median PFS similar in both arms, but overall 24% reduction in risk of pro-gression for ipilimumab + dacarbazine vs dacarbazine alone (HR, 0.76; P = .006)

11.2 (9.4-13.6)9.1 (7.8-10.5)

Most common irAEs liver and:Any-grade irAEs: 78% ipilimumab + dacarbazineAny-grade irAEs: 38% dacarbazine aloneGrade 3-4 irAEs: 38% ipilimumab + dacarbazineGrade 3-4 irAEs: 4% dacarbazine aloneGrade 5 AEs: 0% ipilimumab + dacarbazineGrade 5 AEs: 0.2% dacarbazine alone

aEvery 3 weeks × 4 doses (induction).bPFS at 24 weeks.AE indicates adverse event; CI, confidence interval; GI gastrointestinal; HR, hazard ratio; irAE, immune-related adverse event; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

REVIEW ARTICLE


This trial reported some differences in grade 3 or grade 4 adverse events (AEs) compared with other ip-ilimumab studies. Gastrointestinal (GI) complications (including GI perforations) and endocrinopathies, which are consistently part of ipilimumab’s toxicity profile, were lower in this trial, and no GI perforations were seen. Although not previously seen, hepatic toxic-ity was increased, possibly as a result of the higher dose of ipilimumab that was utilized (10 mg/kg) or because of the combination with dacarbazine and its associated hepatotoxicity.2,31 With the exception of hepatic toxici-ty, no new safety concerns were observed.2

The current scope of ipilimumab use is not restricted to specific patient populations within those with ad-vanced melanoma. There is no HLA requirement,32 and ipilimumab has demonstrated safety and efficacy in both treatment-naïve and previously treated patients (Table).

Ipilimumab is showing interesting activity in pa-tients with melanoma who have brain metastases, distinguishing it from other immunotherapies. This is one of the most difficult-to-treat patient subsets, because the median OS is only approximately 4 months after the diagnosis of brain metastases.33 The MDX010-20 study allowed the inclusion of patients with stable brain metastasis, and subsequent analysis of this subgroup demonstrates disease control in these patients, including responses and stable disease.13 The immune-related AE (irAE) profile in these patients did not differ from those treated patients without brain metastases.34 In addition, patients with advanced melanoma and stable asymptom-atic brain metastases who entered the ipilimumab ex-panded-access program showed prolonged survival and durable responses without an increase in central nervous system (CNS)-related toxicities or unique toxicities.35

Furthermore, recent results from a prospective phase 2 study of patients with melanoma and symptomatic brain metastases showed that prolonged survival and durable responses can occur in some patients with brain metasta-ses. The 1- and 2-year OS rates for patients with asymptomatic metastases were 31% and 26%, respectively, whereas respective rates for symptomatic patients were 19% and 10%, respectively. No new safety concerns or increases in CNS-related events were reported.36 A retrospective analysis of a phase 2 trial, which included patients with stable brain metastases, revealed a me-dian OS of 14 months.37 In contrast, previous reports of this patient population who had undergone surgery, radiation, chemotherapy, or a combination resulted in a median OS of 9 months.38 Together, the data are en-couraging and are the first to demonstrate the potential for immunotherapy to be effective in patients with mel-anoma who have brain metastases.

Although the underlying basis of ipilimumab activity

in brain metastases is unknown, it is possible that this agent is able to cross the blood-brain barrier, which may be leaky as a result of the tumor, or that ipilimumab-ac-tivated T-cells are able to breach the barrier to exert antitumor effects against brain metastases. Steroid treatment is an additional and unknown confounding factor in the decision to administer ipilimumab to pa-tients with brain metastases, because systemic steroids may theoretically blunt an immune response.

Ipilimumab also has similar activity regardless of patient characteristics, such as BRAF mutation status, and is independent of negative prognostic factors, such as advanced-stage disease (M1c), advanced age (>60 years), male sex, or elevated baseline LDH levels.39,40 In at least 1 reported case, a patient with melanoma and brain metastases experienced complete remission after being treated with ipilimumab.41 So far, ipilimumab appears active in a wide cross section of patients with melanoma, albeit with few complete responses.

Patterns of ResponseThe pattern of clinical responses observed across ipilim-

umab studies can resemble both that of conventional cy-totoxic agents and immunotherapies (Figure 3).2,13,42 An example of the former includes rapid decline of baseline lesions without evidence of new lesions after treatment. Stable disease, which in some cases may be followed by a slow and steady decline in tumor burden, is also ob-served in response to ipilimumab.42 In a more typical immune-like antitumor response, patients who receive ipilimumab have a slow evolution to long, durable, stable disease with responses lasting months or even years.21,29

Two novel “mixed-response” patterns have been ob-served during the clinical development of ipilimumab.42 In one, response to ipilimumab therapy is seen after an initial increase in tumor burden. This flare-like type of response is thought to be associated with the inflam-matory infiltration of T-cells into the tumor, thereby expanding its size and mimicking progressive disease. In another pattern, the reduction in total tumor burden oc-curs during or after the appearance of new lesions. This could be because after ipilimumab-mediated activation of the immune system, an effective antitumor immune response takes time to develop, whereas tumor growth proceeds unabated. Both the traditional and the new re-sponse patterns are associated with favorable survival.42

It has become increasingly evident that standard response criteria developed for conventional cytotoxic therapy do not adequately capture the full range of anti-tumor immune responses. New response criteria for the evaluation of immune therapy have been proposed, the so-called immune-related response criteria (irRC).42 The use of irRC to capture additional responses to immuno-

Ipilimumab Overview


therapeutic agents has been recommended to prevent premature withdrawal of therapy.43,44

Based on irRC, progressive disease is defined by at least a 25% increase in tumor burden compared with the nadir at 2 consecutive time points separated by at least 4 weeks. Complete response is a disappearance of all lesions, a partial response is at least a 50% decrease in tumor burden compared with baseline, and stable disease is all responses not meeting the criteria for a complete or partial response in the absence of progressive disease.

Adverse Events Associated with IpilimumabThe most frequent AEs associated with ipilimumab

are irAEs, which is most likely a result of the agent’s mechanism of action. A recent pooled analysis of 14 phase 1 to 3 studies at various doses of ipilimumab

found that 64.2% of patients enrolled in ipilimumab clinical trials experienced an irAE of any grade, the majority of which were low grade (grade 1 or 2).45

Although irAEs can be potentially life-threatening, death occurred in <1% of patients.45 Of note, in the most recent phase 3 study, there were no deaths reported related to the study drug.2 The confounder in this trial was that the addition of dacarbazine may alter lymphocyte subsets during ipilimumab therapy, thereby modulating the toxicity profile.2 The lack of fatalities in this study2 also may reflect a growing familiarity of the irAEs and earlier recognition of tox-icities, which are leading to earlier corrective therapy.

Across studies of ipilimumab, the most frequently affected organs were the GI tract and the skin (any grade, 31%-46% and 47%-68%, respectively; grade

Figure 3 Patterns of Response in Patients Treated with Ipilimumab

In patients treated with ipilimumab, 4 types of responses have been observed and have been associated with positive patient outcomes. (A) Patients have an immediate response to treatment and tumor burden decreases. (B) Patients experience sta-ble disease. (C) Patients have a response after an initial increase in tumor burden. (D) Reduction in total tumor burden is observed while there is an initial appearance of new (shown as “N”) lesions. Triangles are ipilimumab dosing time points. SPD indicates sum of the product of the perpendicular diameters. Reprinted with permission from Wolchok JD, et al. Guidelines for the evaluation of immune therapy in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.

50

–21 21 63

Relative Day from Randomization Date Relative Day from Date of First Dose

Relative Day from Date of First DoseRelative Day from Date of First Dose

Ch

ang

e fr

om

Bas

elin

e S

PD

(%

)

SP

D (

mm

2 )

105 147 189 231 273 315 357 399 441 483 525–63

–26

–8

10

28

46

64

82

99

117

135

153

25

0

–25

–50

–75

–100

–125

A

C

B

D

Ch

ang

e fr

om

Bas

elin

e S

PD

(%

)

SP

D (

mm

2 )

50

–21 21 63 105 147 189 231 273 315 357 –63

–468

–140

187

515

843

1171

1498

1826

2154

2482

2810

25

0

–25

–50

–75

–100

–125

Ch

ang

e fr

om

Bas

elin

e S

PD

(%

)

SP

D (

mm

2 )150

–21 21 63 105 147 189 231 273 315 357 –63

–1937

194

2325

4456

6587

8718

10849

12980

15111

17242

19373

125

100

75

50

0

25

–25

–50

–75

–100

–125

Ch

ang

e fr

om

Bas

elin

e S

PD

(%

)

SP

D (

mm

2 )

50

–21 21 63 105 147 189 231 273 315 357 –63

–468

–64

85

233

382

530

678

827

975

1124

1272

25

0

–25

–50

–75

–100

–125

N

N

N NN N N

Chan

ge fr

om b

asel

ine

SPD,

%Ch

ange

from

bas

elin

e SP

D, %

Chan

ge fr

om b

asel

ine

SPD,

%Ch

ange

from

bas

elin

e SP

D, %

SPD,

mm

2

SPD,

mm

2

SPD,

mm

2SP

D, m

m2

Relative day from date of first dose

Relative day from randomization date




REVIEW ARTICLE

3 or 4, 8%-23% and 0%-4%, respectively); less fre-quent were hepatic (any grade, 3%-9%; grade 3 or 4, 3%-7%), endocrine (any grade, 4%-6%; grade 3 or 4, 1%-5%), and neurologic events (any grade, <1%).45,46

Of note, increased liver function test values were observed more frequently than expected when ipilim-umab was combined with dacarbazine.2

In addition, irAEs can have a rapid onset and are usually observed during the first 12 weeks of therapy, although a minority of events has occurred weeks or months after receiving the last dose of ipilimumab. In a pooled analysis of data from phase 2 and 3 studies with the approved dose of ipilimumab (3 mg/kg), median time to onset of grade 2 to 5 irAEs was 6 to 7 weeks.47,48 Overall, the times to onset and to resolution of irAEs are similar for the 3-mg/kg approved dose of ipilimumab and the investigational higher dose of 10 mg/kg (Figure 4).47 The onset is approximately 5 to 6 weeks, with resolution of between 4 and 8 weeks.47

However, depending on the organ system affected, these rates can vary (based on the 10-mg/kg dose; Figure 5).48 Dermatologic irAEs are typically the earliest to occur, sometimes after only 1 or 2 doses of ipilimumab, whereas endocrine events appear within a median of 11 to 19 weeks after initiation of ipilimumab. The time to resolution also varies by organ system: skin, GI, and liver events resolve within a few weeks, whereas endocrine events take approximately 20 weeks to resolve and, in some cases, are irreversible (Figure 5).48 During the course of the clinical development of ipilimumab, a stan-dard set of guidelines was developed to provide advice on the management of irAEs.

In the MDX001-20 study, 14 deaths (2.1%) were at-tributed to the study drug and 7 were related to irAEs.13

This demonstrates that irAEs can be life-threatening, and it highlights that vigilance is needed in monitor-ing patients and in educating them on the signs and symptoms and the need for timely reporting of possible irAEs. Reinforcement of the importance of early de-tection and prompt reporting may reduce serious and sometimes fatal events. Unless an alternative etiology can be identified, any sign or symptom of immune-me-diated events should be considered drug-related and the appropriate treatment should be initiated.

Management of irAEsAt baseline and at each follow-up visit, patients

should be assessed for the signs and symptoms of irAEs. Most low-grade (grade 1-2) events can be man-aged symptomatically.45,46 Patients exhibiting possible GI events should be assessed for changes in bowel habits and for the following signs and symptoms: diar-rhea, abdominal pain, blood or mucus in stool with or without fever, peritoneal signs consistent with bowel perforation, and ileus.49 Low-grade events can be man-aged symptomatically (eg, dietary modifications and loperamide) while the etiology is being investigated.

Should symptomatic management not be effective after 1 week, prednisone (or an equivalent) should be initiated at 0.5 mg/kg daily or oral budesonide should be administered.49,50 The administration of prednisone 1-2 mg/kg or an equivalent is appropriate in patients with ≥7 stools daily over baseline, peritoneal signs consistent with bowel perforation, ileus, or patients

Figure 4 Time to Onset and Time to Resolution of Immune-Related Adverse Events

NOTE: Data from ipilimumab phase 3 (MDX010-20) or from pooled phase 2 studies (CA184-004, CA184-007, CA184-008, CA184-022) were analyzed for times to onset and to resolution of irAEs. Data presented were collected only during the initial induction phase of dosing.irAEs indicates immune-related adverse events.Adapted with permission from Dummer R, et al. Time to onset and resolution of immune-related adverse events associated with ipilimumab therapy in patients with advanced melanoma. Presented at Perspectives in Melanoma XIV; September 17-18, 2010; Amsterdam, the Netherlands. Abstract P-0004.

Grade 2-5

Grade 3-5

Grade 2-4

Grade 3-4

Phase 2 (10 mg/kg)

Phase 2 (3 mg/kg)

Phase 3 (3 mg/kg)

Time to onset

Time to resolution

Weeks 0 5 10

4.93

5.07

6.57

4.57

6.93

5.71

8.57

4.29

6.07

6.29

8.21

7.71

Ipilimumab Overview


with a fever. Early endoscopy should be considered if the diagnosis is uncertain. Of note, prophylactic steroid use has not proved effective in reducing the rate of grade ≥2 diarrhea.27,51 Beware that the use of

opioids to manage abdominal pain may mask the signs of bowel perforation.45 Ipilimumab should be withheld for moderate GI adverse reactions until improvement to mild severity or complete resolution.

Figure 5 Onset and Resolution of Gastrointestinal, Liver, Endocrine, and Skin Events

Adapted with permission from Lebbé C, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at Perspectives in Melanoma XII; October 3, 2008; New York, NY. Abstract O-015.

Patients treated with ipilimumab (10 mg/kg) had varying times to onset (A) and resolution (B) based on the organ system affected.

Median time to onset, weeks(n, 95% CI)

Type

Skin

GI

Liver

Endocrine

Grade 2–5 Grade 3–5

3.6(61, 3.1–4.1)

6.6(76, 5.1–8.0)

6.7(23, 6.1–9.3)

9.2(16, 6.7–11.1)

4.4(9, 3.1–4.4)

6.9(40, 5.7–8.9)

6.7(23, 6.1–9.7)

10.1(8, 7.0–11.4)

A

B

Pro

po

rtio

n n

ot

reso

lved

Pro

po

rtio

n n

ot

reso

lved

GI

Endocrine

Liver

Skin

Median: 2.29 weeks

Median: 20.1 weeks

Week

Week

Week

Week

Median: 4.00 weeks

Median: 6.14 weeks

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Patients at riskTx 10 mg/kg 76 28 16 22 118 5 5 4 4 2 2 2 2 1 1 7 5 1 1 0

Patients at riskTx 10 mg/kg 16 13 9 61 398 7 6 4 3 3 1 1 1 1 1 25 16 12 9 7 6 3 2 1 1 1 1 0

Monotherapy 10 mg/kg treated patientsCensored

Time to resolution

Median time to onset, wks (N, 95% confidence interval)

Type Grades 2-5 Grades 3-5

Skin 3.6 (61, 3.1-4.1) 4.4 (9, 3.1-4.4)

Gastrointestinal 6.6 (76, 5.1-8.0) 6.9 (40, 5.7-8.9)

Liver 6.7 (23, 6.1-9.3) 6.7 (23, 6.1-9.7)

Endocrine 9.2 (16, 6.7-11.1) 10.1 (8, 7.0-11.4)

B Time to resolution

A

Monotherapy 10-mg/kg treated patients

Censored

Gastrointestinal

Median, 2.29 wks

Liver

Median, 4.00 wks

Week

Week

Week

Week

Skin

Median, 6.14 wks

Endocrine

Median, 20.1 wks

Prop

ortio

n no

t res

olve

dPr

opor

tion

not r

esol

ved

Patients at risk Tx 10mg/kg

Patients at risk Tx 10mg/kg

REVIEW ARTICLE


Ipilimumab should be permanently discontinued in patients with severe GI adverse reactions. In patients with persistent GI symptoms that do not resolve with sys-temic steroid treatment, administration of an alternative immunosuppressive therapy (ie, infliximab) should be considered. Of note, rapid tapering of steroids (<1 month) in severe cases can result in enterocolitis. Recognizing the importance of early detection, prompt reporting, and the appropriate management of diarrhea is important. Ipilimumab can result in severe inflammation of the GI tract,49 and routine oncologic diarrhea management may not include ruling out inflammatory etiology or the use of systemic corticosteroids as a treatment modality.

With regard to skin irAEs, patients should be evaluated for the signs and symptoms of pruritus, vitiligo, or rash. Mild-to-moderate events can be treated symptomatical-ly, and topical moisturizers and oatmeal baths may help relieve such cases. Topical and/or systemic corticosteroids may be required to manage symptoms in moderate-to-se-vere cases. Ipilimumab should be withheld in patients with moderate-to-severe signs and symptoms, and it should be permanently discontinued in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash that is complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations.49

Liver function tests should be conducted on patients who are receiving ipilimumab at baseline and before each infusion or more frequently if warranted, especially because elevations of liver function test results may occur in the absence of clinical symptoms. Patients should also be monitored for any signs of autoimmune hepatitis. Ipilimumab should be withheld in patients with moder-ate aspartate aminotransferase (AST) or alanine amino-transferase (ALT) elevations of >2.5 times but ≤5 times upper limit of normal (ULN), or moderate total bilirubin elevation of >1.5 times but ≤3 times ULN. Because the rate of rise is not predictable, short interval testing or even daily monitoring may be helpful. Ipilimumab should be permanently discontinued for severe AST or ALT eleva-tions of >5 times ULN, or total bilirubin elevations of >3 times ULN. Corticosteroid therapy may be appropriate for ≥grade 3 hepatotoxicity.49 Mycophenolate treatment has been administered in patients who have persistent, severe hepatitis, despite treatment with high-dose cortico-steroids.46,52 Tacrolimus (target trough, 5-20 ng/mL) could also be considered for severe cases.53

Endocrinopathies are probably the most difficult irAEs to diagnose, because many of the signs and symp-toms are protean and nonspecific. These symptoms include fatigue, headache, changes in mental status, abdominal pain, unusual bowel habits, and hypotension. The prescribing guidelines recommend that appropriate blood analysis be carried out to evaluate the function

of the thyroid, adrenal, and pituitary glands before each ipilimumab dose52; however, the rate of functional change is such that our practice is to formally assess less frequently or when prompted by symptoms. Adrenal insufficiency is rare but may occur quietly and may manifest as adrenal crisis.54 Hypopituitarism and hypothyroidism have also been observed.13 Hypophysitis can give rise to bitemporal visual field loss, which is confirmed by magnetic resonance imaging of the brain with pituitary.49,54 Patients with ip-ilimumab-associated hypophysitis have been successfully treated with high-dose dexamethasone, but they may also require long-term physiologic doses of hydrocortisone.55 Ipilimumab should be withheld when moderate reactions or any symptomatic endocrinopathy occur, until complete resolution or until stability with hormone replacement therapy is reached. Long-term hormone replacement ther-apy may be necessary in some patients.

Other irAEs that can occur include neurologic events, such as sensory and motor neuropathy, and patients should be encouraged to report any signs of muscle weakness or sensory alternations. New-onset or worsen-ing symptoms may require permanent discontinuation of ipilimumab. Rarely, Guillain-Barré syndrome, myasthe-nia gravis, and severe sensory alterations have occurred. Ocular events are also rare, and corticosteroid eyedrops should be administered to patients who develop uveitis, iritis, or episcleritis.49 Immune-related thrombocytope-nia (grade 4) has recently been reported in a 57-year-old man who was receiving ipilimumab,56 highlighting the value of monitoring full blood counts during therapy.

General Safety InformationA high level of suspicion and recognition of the clin-

ical presentation, coupled with judicious interpretation of the diagnostic blood panels, are important in the management of irAEs. Although irAEs can be severe in some patients, overall studies indicate that they are manageable, and most resolve in a reasonable amount of time if identified early and appropriate treatment is administered.47,48 The guidelines advise that on improvement to ≤grade 1 for all irAEs, corticosteroid tapering should be initiated and continue to be tapered over at least 1 month.45,46 It is also recommended that ipilimumab be discontinued in patients who have failed to complete the full treatment course within 16 weeks from the administration of the first dose. In addition, ipilimumab should be permanently discontinued in pa-tients who are unable to have their corticosteroid dose reduced to prednisone 7.5 mg or an equivalent daily.

ConclusionIpilimumab, the first-in-class anti–CTLA-4 therapy

to be approved by the FDA, has demonstrated efficacy

Ipilimumab Overview


and OS benefit in patients with unresectable or meta-static melanoma. The majority of patients experience an irAE, but these are usually low grade and manageable; the focus is on early recognition and vigilance with appropriate monitoring and the use of established irAE management guidelines. Low-grade AEs are typically managed symptomatically, although higher-grade AEs can be severe and life-threatening. The times to onset and to the resolution of irAEs are relatively consistent across the approved 3-mg/kg dose and the higher 10-mg/kg dose, but they vary for each organ system. Ipilimumab 3 mg/kg is currently available as a monotherapy, but ongoing research will help to shape the melanoma treat-ment landscape by establishing the most effective com-bination regimens, without compromising tolerability. n

AcknowledgmentThe authors take full responsibility for the content of this

publication and confirm that it reflects their viewpoints and medical expertise. The authors also wish to acknowl-edge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.

Author Disclosure Statement

Dr Wong is on the Physician Advisory Board of Bristol-Myers Squibb and Genentech. Dr Jarkowski reported no conflicts of interest.

References1. Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26:527-534.2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previ-ously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.4. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic mela-noma. J Clin Oncol. 1999;17:2745-2751.5. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004;22:1118-1125.6. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temo-zolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-166.7. Legha SS, Ring S, Papadopoulos N, et al. A phase II trial of taxol in metastatic melanoma. Cancer. 1990;65:2478-2481.8. Einzig AI, Hochster H, Wiernik PH, et al. A phase II study of taxol in patients with malignant melanoma. Invest New Drugs. 1991;9:59-64.9. Hodi FS, Soiffer RJ, Clark J, Finkelstein DM, Haluska FG. Phase II study of paclitaxel and carboplatin for malignant melanoma. Am J Clin Oncol. 2002;25:283-286.10. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106:375-382.11. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melano-ma. J Clin Oncol. 2009;27:2823-2830.12. Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunother-apy for melanoma. J Clin Oncol. 2008;26:3445-3455.13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

14. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29:3085-3096.15. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-435.16. Paraiso KH, Xiang Y, Rebecca VW, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750-2760.17. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF–targeted melanoma cells. Cancer Res. 2010;70:6670-6681.18. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.19. Seghers AC, Wilgenhof S, Lebbé C, Neyns B. Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor. Melanoma Res. 2012;22:466-472.20. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500-504. 21. Haanen JB, Hodi FS, O’Day SJ, et al. Ipilimumab improves overall survival in patients with previously treated, advanced melanoma: long-term survival results from phase III trial. Ann Oncol. 2010;21(suppl 8):viii402. Abstract 1327P.22. Wolchok JD, Weber JS, Maio M, et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II trials. Presented at: Perspectives in Melanoma XV; September 16, 2011; New York, NY. Abstract P-20.23. ClinicalTrials.gov. Ph I/II Ipilimumab Vemurafenib Combo. ClinicalTrials.gov Identifier NCT01400451. http://clinicaltrials.gov/ct2/show/NCT01400451. Accessed October 27, 2011.24. Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37:533-546.25. Keler T, Halk E, Vitale L, et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol. 2003;171:6251-6259.26. Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950-5956.27. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, place-bo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-5598.28. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter sin-gle-arm phase II study. Ann Oncol. 2010;21:1712-1717.29. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.30. Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimu-mab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29:489-498.31. Marsh JC. Hepatic vascular toxicity of dacarbazine (DTIC): not a rare compli-cation. Hepatology. 1989;9:790-792.32. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010;10:9.33. Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117:1687-1696.34. Lebbé C, McDermott DF, Robert C, et al. Ipilimumab improves survival in pre-viously treated, advanced melanoma patients with poor prognostic factors: subgroup analyses from a phase III trial. Ann Oncol. 2010;21(suppl 8):viii401. Abstract 13240.35. Heller K, Pavlick AC, Hodi FS, et al. Safety and survival analysis of ipilimu-mab therapy in patients with stable asymptomatic brain metastases. J Clin Oncol. 2011;29(suppl 15):Abstract 8581.36. Margolin K, Hodi FS, McDermott DF, et al. Safety and efficacy of ipilimumab-treated patients with melanoma and brain metastases. Eur J Cancer. 2011;47(suppl 1):S654. Abstract 9306.37. Weber JS, Amin A, Minor D, et al. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res. 2011;21:530-534.38. Eigentler TK, Figl A, Krex D, et al. Number of metastases, serum lactate dehy-drogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer. 2011;117:1697-1703.39. Wolchok JD, de Pril V, Linette G, et al. Efficacy of ipilimumab 10 mg/kg in advanced melanoma patients (pts) with good and poor prognostic factors. J Clin Oncol. 2009;27(15 suppl):Abstract 9036.40. Shahabi V, Whitney G, Hamid O, et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:733-737.41. Schartz NEC, Farges C, Madelaine I, et al. Complete regression of a previously untreated melanoma brain metastasis with melanoma. Melanoma Res. 2010;20:247-250.42. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.43. Pennock GK, Waterfield W, Wolchok JD. Patient responses to ipilimumab, a


REVIEW ARTICLE

novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses? Am J Clin Oncol. 2012;35:606-611.44. O’Regan KN, Jagannathan JP, Ramaiya N, et al. Radiologic aspects of immune- related tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy. AJR Am J Roentgenol. 2011;197:W241-W246.45. Ibrahim R, Berman D, de Pril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29(suppl): Abstract 8583.46. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697.47. Dummer R, Maio M, Hamid O, et al. Time to onset and resolution of immune-related adverse events associated with ipilimumab therapy in patients with advanced melanoma. Presented at Perspectives in Melanoma XIV; September 17-18, 2010; Amsterdam, the Netherlands. Abstract P-0004.48. Lebbé C, O’Day SJ, Sileni VC, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at Perspectives in Melanoma XII; October 3, 2008; New York, NY. Abstract O-015.49. Ipilimumab US prescribing information: risk evaluation and mitigation strategy (REMS). www.hcp.yervoy.com/pdf/rems-management-guide.pdf. Accessed

September 12, 2011.50. O’Day S, Weber JS, Wolchok JD, et al. Effectiveness of treatment guidance on diarrhea and colitis across ipilimumab studies. J Clin Oncol. 2011;29(suppl):Abstract 8554.51. Grob JJ, Hamid O, Wolchok J, et al. Antitumor responses to ipilimumab in advanced melanoma are not affected by systemic corticosteroids used to manage immune-related adverse events (irAEs). Presented at Joint ECCO 15-34th ESMO Multidisciplinary Congress; September 22, 2009; Berlin, Germany. Abstract P-9312.52. Ipilimumab package insert. Princeton, NJ: Bristol-Myers Squibb; March 2011. http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed September 12, 2011.53. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864-872.54. Dillard T, Yedinak CG, Alumkal J, et al. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13:29-38.55. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.56. Ahmad S, Lewis M, Corrie P, et al. Ipilimumab-induced thrombocytopenia in a patient with metastatic melanoma. J Oncol Pharm Pract. 2012;18:287-292.

LETTER To ThE EdIToR

My student and I have read the above article with much interest. It has led to much research this afternoon and reading of the American College

of Chest Physicians (ACCP) 2012 guidelines for confir-mation of some of the statements within the article. We would like to point out 2 items.

The first point is a typo: on page 134, in discussing the exclusion criteria, we believe the authors meant to say less than (<)18 years, but the symbol used was the greater than sign (>18), inferring that the study was conducted on pediatric patients only.

Second, I challenge the authors that the 2012 guidelines do not suggest as far as I can find, that low-molecular-weight heparin (LMWH) should be used as monotherapy for 6 months. Their suggestion is for 3 months.

Mallory Johnson, PharmD candidate Pamela C. Evans, PharmD

Residency DirectorSt. Dominic-Jackson Memorial Hospital

Jackson, MS

Authors’ response Thank you for your interest in this study. Your first

point is correct. This was a typo. This study was not con-ducted with pediatric patients. The results of the study illustrate that the study population was aged 22 to 89

years (mean age, 66 years). The study was not intended to cover only patients under age 18.

Second, we did not intend to imply that the 2012 ACCP guidelines suggest LMWH monotherapy for 6 months. These guidelines recommend extended anticoag-ulant therapy over 3 months (Grade 1B). The 2012 ACCP guidelines were referenced in the “background” section of the article, because they are the most current guidelines for venous thromboembolism (VTE) therapy. In the back-ground, we did not discuss a specific duration of therapy, but simply stated that the use of LMWH as an extended anticoagulant therapy is preferred over vitamin K antago-nist therapy for the treatment of VTE in patients with can-cer. At the time our study was conducted, the 2008 ACCP guidelines were the most recent guidelines published by the ACCP, and they are referenced in the “methods” section of the article. The 2008 ACCP guidelines recom-mend LMWH for the first 3 to 6 months of long-term anti-coagulant therapy (Grade 1A). The duration of 6 months is specifically preferred in the 2007 American Society of Clinical Oncology and the 2010 National Comprehensive Cancer Network guidelines, which are also referenced in the article and were the most recent guidelines published by these organizations at the time the study was conduct-ed. In addition, the CLOT trial, which demonstrated the superiority of LMWH over warfarin, used the 6-month duration of LMWH monotherapy within its study design. We regret any confusion. n

Evaluation of Pharmacists’ Intervention in Altering Prescribing Patterns for the Treatment of VTE in Patients with Cancer

Steward VM, Hamid H, Hooker K. J Hematol Oncol Pharm. 2012;2(4):132-139.

AVBCCAsize20413

CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsMarcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and QualityKip Piper

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher; Lillie Shockney, RN, BS, MAS

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm Cocktail Reception in the Exhibit Hall

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and ChallengesThomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm Summary and Conclusion of Conference*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by the Florida Society of Clinical Oncology, MedicalLearning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excel-lence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATIONMedical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs)

of continuing pharmacy education credit. The Universal Activity Number for this activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing value

in cancer care delivery.• Define the barriers associated with cost, quality, and access as they relate to health-

care reform and what solutions are currently being considered.• Compare and contrast the different approaches/tools providers and payers are

utilizing to manage and deliver care collaboratively.• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

$375.00 until March 15, 2013$425.00 after March 15, 2013

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based

Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

This activity is jointly sponsored by the Florida Society of Clinical Oncology,

Medical Learning Institute Inc, Association forValue-Based Cancer Care, Inc.,

Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

CONFERENCE REGISTRATION

AVBCC2013Asize13013_AVBCC 2/4/13 2:10 PM Page 1

AGENDA*

FRIDAY, JULY 26, 20133:00 pm – 7:00 pm Registration5:30 pm – 7:30 pm Welcome Reception/Exhibits

SATURDAY, JULY 27, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Welcome to the Second Annual World Cutaneous Malignancies

Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies• Keynote Lecture Understanding the Basic Biology and Clinical

Implications of the Hedgehog Pathway• Keynote Lecture Pathogenesis of Merkel Cell Carcinoma:

An Infectious Etiology? - Paul Nghiem, MD, PhD

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 4:30 pm General Session II: Current Treatment Guidelines in Cutaneous

Malignancies• Case Studies Optimal, Value-Based Therapy of Cutaneous

Malignancies: The Expert’s Perspective on How I Treat My Patients• Panel Discussion Management Controversies and Accepted

Guidelines for the Personalized Management of Cutaneous Malignancies

• Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm Meet the Experts/Networking/Exhibits

SUNDAY, JULY 28, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Review of Saturday’s Presentations and Preview of Today’s Sessions8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for

Cutaneous MalignanciesGeneral Session IV: Challenges for the Cutaneous Malignancies Clinician• Panel Discussion How Can the Healthcare Team Work Best

Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 2:45 pm General Session V: “Hot Data” — What I Learned at Recent Meetings:

Focus on Cutaneous Malignancies2:45 pm – 3:00 pm Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

A 2-day congress dedicated to informing, educating, and fostering the exchangeof clinically relevant information in the field of cutaneous malignancies on topics inmelanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carci-noma, and Merkel cell carcinoma, including:

• Epidemiology and genetic/environmental factors

• Molecular biology and cytogenetics related to the pathogenesis of cutaneousmalignancies

• Risk stratification based on patient and tumor characteristics

• Principles of cancer prevention of melanoma and basal cell carcinoma

• Current treatment guidelines

• Emerging treatment options for personalized therapy

• Future strategies in management based on translational data from current clinicaltrials and basic research

PROGRAM OVERVIEW

This activity was developed for medical and surgical oncologists, dermatologists,radiation oncologists, and pathologists actively involved in the treatment of cu-taneous malignancies. Advanced practice oncology or dermatololgy nurses,oncology pharmacists, and researchers interested in the molecular biology andmanagement of cutaneous malignancies are also encouraged to participate.

TARGET AUDIENCE

Upon completion of this activity, the participant will be able to:

• Review the molecular biology and pathogenesis of cutaneous malignancies asthey relate to the treatment of cutaneous T-cell lymphoma, basal cell carci-noma, Merkel cell tumors, and malignant melanoma

• Compare risk stratification of patients with cutaneous malignancies, and how totailor treatment based on patient and tumor characteristics

• Summarize a personalized treatment strategy that incorporates current stan-dards of care and emerging treatment options for therapy of patients with cu-taneous malignancies

LEARNING OBJECTIVES

DESIGNATION OF CREDIT STATEMENTS

PHYSICIAN CREDIT DESIGNATION

SPONSORS

REGISTERED NURSE DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 12.0AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

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

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

Medical Learning Institute IncProvider approved by the California Board of Registered Nursing, Provider Number15106, for 12.0 contact hours.

Sanjiv S. Agarwala, MDProfessor of Medicine Temple University School ofMedicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

Steven J. O’Day, MDHematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer CenterClinical Associate Professor of MedicineUSC Keck School of MedicineLos Angeles, California

Professor Dr. Med. AxelHauschildProfessor, Department of DermatologyUniversity of KielKiel, Germany

CONFERENCE CO-CHAIRS

July 26-28, 2013Hyatt Regency La Jolla • San Diego, California

• Melanoma

• Basal Cell Carcinoma

• Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma

• Merkel Cell Carcinoma

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN!$175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharmacyeducation. Completion of this knowledge-based activity provides for 12.0contact hours (1.2 CEUs) of continuing pharmacy education credit. The

Universal Activity Number for this activity is (To be determined).

For complete agenda please visit www.CutaneousMalignancies.com

WCMC HouseAd_A-size_11512_Layout 1 11/12/12 5:02 PM Page 1

FROM THE LITERATURE


n Abiraterone plus Low-Dose Prednisone before Chemotherapy Improves Outcomes of Patients with Metastatic Prostate Cancer Background: Metastatic castration-resistant prostate

cancer (CRPC) is associated with rapid deterioration and leads to mortality within 2 to 4 years. The treatment op-tions available for patients who have not received chemo-therapy have been proved to produce response in these pa-tients, but new options are needed that could lead to tumor regression or prolong life. Previous studies have shown that the use of abiraterone plus low-dose prednisone in patients with CRPC who have received chemotherapy improves survival; this combination was subsequently approved by the US Food and Drug Administration for this patient population. Early-phase clinical trials in patients with CRPC who have not received chemotherapy have shown increased response rates with this combination.

Design: This phase 3 clinical trial was designed to evaluate the effects of the combination of abiraterone plus low-dose prednisone on radiographic progres-sion-free survival (PFS) and overall survival (OS) and other measures of disease progression in patients with advanced or metastatic disease before chemotherapy. Between April 2009 and June 2012, a total of 1088 patients were randomized in a 1:1 ratio to receive 1000 mg of abiraterone plus prednisone 5 mg twice daily (ie, low dose) or placebo plus prednisone. The primary end points were radiographic PFS and OS.

Discussion: By the time of the first interim analysis on December 20, 2010, the combination of abiraterone plus low-dose prednisone resulted in a 57% reduction in the risk of radiographic progression or death. The study was unblinded after this analysis, when 43% of the expected deaths occurred. The median radiographic PFS was 16.5 months with the active combination versus 8.3 months with placebo (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.45-0.62; P <.001). At a median follow-up of 22 months, OS was improved with abiraterone plus low-dose prednisone versus 27.2 months with placebo plus prednisone. In addition, a 25% reduction in mortality risk was seen with the active combination (HR, 0.75; 95% CI, 0.61-0.93; P = .01), showing a strong trend of improved survival. The PFS was favorable across all subgroups with the active combination. The addition of abiraterone to low-dose prednisone was associated with favorable PFS

across all subgroups compared with prednisone and with placebo. Furthermore, the abiraterone plus prednisone combination was superior to prednisone plus placebo in terms of time to initiation of cytotoxic chemotherapy, pain medication use, prostate-specific antigen progression, and performance status. As can be expected, grade 3 or grade 4 adverse events and abnormalities on liver function were more frequent with the abiraterone plus prednisone combination.

Takeaway: Having a noncytotoxic pharmacotherapy is an important advance in the treatment of metastatic prostate cancer. Not only did combination abiraterone and prednisone improve PFS, but it also led to a delay in the use of subsequent chemotherapy or analgesic thera-py, effects that clearly improved patients’ quality of life. Furthermore, abiraterone plus prednisone was well tol-erated and safe for long-term use, in contrast to systemic chemotherapy which can cause life-threatening adverse effects and poor quality of life. Of note is that abiraterone acetate is hydrolyzed to the active metabolite abiraterone and is then further metabolized to inactive metabolites abiraterone sulphate and N-oxide abiraterone sulphate by CYP3A4 and SULT2A1. Therefore, there are many potential drug interactions with abiraterone, including CYP2D6 and CYP2D8 substrates and CYP3A4 substrates.Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148.

n Adding Rituximab to Chlorambucil Improves Event-Free Survival in Patients with MALT LymphomaBackground: Approximately 8% of patients with non-

Hodgkin lymphoma have extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The condition can occur in any extranodal location, although the stomach is the most frequent site. Although eradication of Helicobacter pylori has been shown to be successful in treating localized gastric involvement, no consensus exists about the optimal treatment for pa-tients with extensive MALT lymphoma.

Design: The first phase of the IELSG-19 (Randomized Trial of Chlorambucil Versus Chlorambucil plus Rituximab Versus Rituximab in MALT Lymphoma), international, multicenter, phase 3 clinical trial, from January 2003 to October 2005, randomized 252 patients with MALT lymphoma in a 1:1 ratio to chlorambucil alone (arm A)

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

FROM THE LITERATURE


or to chlorambucil plus rituximab (arm B). All patients were aged >18 years and had a diagnosis of CD20-positive MALT lymphoma at any extranodal site. Patients did not receive any previous therapy other than for the purpose of H pylori eradication. After October 2005, a third arm re-ceiving rituximab therapy alone (arm C) was added. This report is based on the results of the first phase only, which included only 2 arms.

Results: After a median follow-up of 62 months, the median event-free survival (EFS) in the 2 arms com-bined had not been reached. At 5 years, the EFS in the patients receiving rituximab plus chlorambucil was significantly better than the patients receiving chlo-rambucil alone (68% vs 50%, respectively; 95% confi-dence interval [CI], 59%-76% vs 41%-60%, respectively; P = .002). Adding rituximab to chlorambucil led to a sig-nificant improvement in EFS (hazard ratio, 0.52; 95% CI, 0.34-0.79). A total of 22 patients had an event that was not related to progression or to death. Although the overall response rate was similar in the 2 arms, the combination of rituximab plus chlorambucil resulted in a greater rate of complete remission compared with chlorambucil alone (78% vs 65%, respectively). The 5-year overall survival rate was 89% in the 2 arms. Both treatments were also well toler-ated, and no unexpected toxicities were reported in any arm.

Takeaway: There is no standardized treatment for advanced cases of extranodal MALT lymphomas. The National Comprehensive Cancer Network guidelines recommend chemotherapy regimens that are effective for follicular lymphoma, including R-CHOP/R-CVP, ben-damustine plus rituximab, single-agent alkylating agents (cyclophosphamide or chlorambucil), or rituximab alone. This study shows that rituximab added to chlorambucil improves EFS and the response rate compared with chlo-rambucil alone. It is likely that the addition of rituximab to other alkylators, such as cyclophosphamide, would be equivalent in efficacy to chlorambucil plus rituximab. These regimens are particularly useful for elderly patients. It will be interesting to see the results of the third arm of this trial and whether combination therapy with chloram-bucil plus rituximab is better than single-agent rituximab. Zucca E, Conconi A, Laszlo D, et al. Addition of rituximab to chlorambu-cil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 randomized study. J Clin Oncol. 2013;31:565-572.

n T-DM1 Significantly Prolongs Survival in Patients with HER2 Advanced Breast Cancer Background: Approximately 20% of patients with

advanced breast cancer exhibit amplification of the epi-dermal growth factor, HER2, which is associated with shortened survival. The combination of cytotoxic chemo-therapy and HER2-targeted agents is an effective therapy for these cases. The antibody drug conjugate trastuzumab

emtansine (T-DM1) includes anti–HER2-targeted anti-tumor properties with the cytotoxic activity of DM1, a microtubule-inhibitor agent.

Design: In this international phase 3 clinical trial known as EMILIA, 991 patients with advanced HER2-positive breast cancer were randomized in a 1:1 ratio to T-DM1 3.6 mg/kg intravenously every 21 days or to 1250 mg of oral lapatinib plus oral capecitabine. Dose adjust-ments, including reductions and delays, as well as discon-tinuation because of adverse events, were done per proto-col. All patients had previously received trastuzumab and a taxane. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate and time to symp-tom progression.

Results: The median PFS (as assessed by an indepen-dent review) was 9.6 months with T-DM1 compared with 6.4 months with the combination of lapatinib and capecit-abine, with a hazard ratio (HR) for disease progression or death of 0.65 (95% confidence interval [CI], 0.55-0.77; P <.001). At the second interim analysis, the median OS was 30.9 months with T-DM1 versus 25.1 months for the combination of lapatinib plus capecitabine (HR for all-cause death, 0.68; 95% CI, 0.55-0.85; P <.001). The objec-tive response rate was also higher with T-DM1 than with the combination (43.6% vs 30.8%, respectively; P <.001). All of the results for the other secondary end points also favored T-DM1. Overall, the new agent was less toxic than the combination of lapatinib and capecitabine in this setting. Grade 3 or 4 events were more frequent with the combination than with T-DM1.

Takeaway: T-DM1 is the first immunoconjugate drug approved by the US Food and Drug Administration for the treatment of any cancer. A very potent cytotoxic drug, a maytansine-like agent, emtansine is linked to the targeted drug trastuzumab. This immunoconjugate is approved for HER2-positive, metastatic breast cancer in patients who were previously treated with trastuzumab or a taxane alone or in combination. This pivotal randomized trial of T-DM1 versus the second-line combination of lapatinib plus capecitabine in patients with locally advanced or metastatic breast cancer produced a very impressive 50% prolongation of PFS, a 5-month improvement in OS, and a 32% reduction in mortality. The toxicity profile of T-DM1 was significantly better than the cytotoxic combi-nation. This new drug may now be considered a first-line treatment for recurrent advanced HER2-positive breast cancer. As an aside, this study provides evidence for the proof of concept by linking a very toxic cytotoxic com-pound to a targeted linking agent. It is expected that more immunoconjugates will be forthcoming in the treatment of patients with cancer.Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has ProgressedINDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. 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 practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176).

System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0.General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0.Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0.Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2).Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5).Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0.Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0.Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0.Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0.Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0.Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1).*Patients may have reported more than 1 adverse reaction.NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA

in the NHL Studies

Percent of patientsHematology Variable All Grades Grade 3/4Lymphocytes Decreased 99 94Leukocytes Decreased 94 56Hemoglobin Decreased 88 11Neutrophils Decreased 86 60Platelets Decreased 86 25In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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 drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]OVERDOSAGE: The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed by:Cephalon, Inc.Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved.

©2008-2012 Cephalon, Inc., or its affiliates. TRE-2486c November 2012(Label Code: 00016287.06)This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

KJob Number: 16090Revision No: 0Date: 1/29/13

727-34290 Digital

Months0 2 4 6 8 10 12

9.2 months(95% CI: 7.1, 10.8)

10.4 months1

(95% CI: 9.3, 13.6)

8.3 months1

(95% CI: 6.3, 10.8)

All responders(n=74)

Patients whoachieved a

CR/CRu

Patients whoachieved a PR

Median DRMedian DR

0 2 4 6 8 10 12

All responders(n=74)

Patients whoachieved a

CR/CRu

Patients whoachieved a PR

• TREANDA is administered with a convenient dosing schedule

– The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles

Important Safety Information• Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions

including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur

• Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment

• TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

• The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia

Please see accompanying brief summary of full Prescribing Information.

Reference: 1. Data on � le. Teva Pharmaceuticals.

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Learn more at www.TREANDAHCP.com©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2577b January 2013

The ef� cacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen

Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses

that lasted a median of 9 months

Established treatment, demonstrated results

KJob Number: 16090Revision No: 0Date: 1/31/13

YMC727-34290 Digital

Documents

JHOP March 2013