Page 1

March 2013 Vol 3 I No 1

Journal OF

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

TM

ORIGINAL RESEARCH

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

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

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

WWW.JHOPONLINE.COM

©2013 Green Hill Healthcare Communications, LLC


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

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 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. www.PROVENGEHCP.com


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. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on 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 second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% 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 use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. 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 determine absence of microbial growth. The final (7-day incubation) sterility test results 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 REACTIONS 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 safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE 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 (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% 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. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% 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%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (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. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

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)

Grade 3-5 n (%) 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)

(Table 1 continued on next page.)


Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

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

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

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

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

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

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

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

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

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

Call for Papers The Journal of Hematology Oncology Pharmacy provides a new avenue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

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

Original Research 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.

Dendreon Corporation Seattle, Washington 98101

• 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” REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 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.

PRACTICAL ISSUES IN PHARMACY MANAGEMENT • Practice-influencing issues • Logistics • Economics

Manuscripts should follow the Author Guidelines at www.JHOPonline.com. ©2013 Dendreon Corporation. All rights reserved. January 2013. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation. P-A-01.13-002.00

For more information, call 732-992-1536.


Editorial Board

Co-Editors-In-Chief Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

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

Section Editors Clinical Controversies

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

Original Research

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

Review Articles

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

Practical Issues in Pharmacy Management

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

From the Literature

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island, Vallejo, CA

editors-At-Large Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

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

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

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

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

Vol 3, No 1

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Journal of Hematology Oncology Pharmacy

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This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it. Building confidence 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

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


March 2013

Volume 3, number 1

Journal OF

Publishing Staff

hematology Oncology Pharmacy™

Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889

The Peer-Reviewed Forum for Oncology Pharmacy Practice

TM

Associate Editor Lara J. Lorton

Table of Contents

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732.992.1536

ORIGINAL RESEARCH

9 Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer Robert Mancini, PharmD, BCOP;

Associate Publishers Joe Chanley joe@greenhillhc.com 732.992.1524

Kathleen Clifford, MSN, FNP-BC, AOCNP, ACHPN

Cris Pires cris@engagehc.com 732.992.1896

Review article

16

Production Manager Stephanie Laudien

Ipilimumab: Unique Responses, Toxicities, and Recommendations for the Use of the First Anti–CTLA-4 Therapy in Patients with Melanoma

Quality Control Director Barbara Marino

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

Business Manager Blanche Marchitto blanche@greenhillhc.com

26  Letter to the Editor From the Literature 29 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

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

Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

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

Journal of Hematology Oncology Pharmacy™, ISSN 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 Com­munications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Commun­i­cations, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Don’t Forget to Cast Your

TOP

Pharmacist Vote 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


ORIGINAL RESEARCH

Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer Robert 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 supportive care clinic from its initiation in June 2010 through May 2012 were assessed by a pharmacist. The risks for polypharmacy were assessed utilizing the AACME (Access, Adherence, Continuity of Care, Medication Reconciliation, and Education) method, which included evaluation 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 polypharmaJ Hematol Oncol Pharm. cy risks may be higher than the rates currently published in the literature. It is possible, however, 2013;3(1):9-14. that this is an overestimate resulting from the complexity of the patient population evaluated. It is www.JHOPonline.com Disclosures are at end of text therefore likely that the true value lies somewhere between the values already published and what was seen in this analysis.

M

ost patients with cancer have multiple comorbidities and are at high risk of polypharmacy. 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 duplicate 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

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.

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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 pharmacodynamic 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 antineoplastics, 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

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ORIGINAL RESEARCH

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

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 Total

Antidepressants, 4% Breakthrough pain medications, 27%

Sleep medications, 15%

Constipation medications (similar MOA), 7% Antianxiety, 10%

PPIs (or PPI + other), 7%

“Other” includes anticoagulants (1), antidiarrheals (2), antihistamines (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.

1

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

Journal of Hematology Oncology Pharmacy

Multiple acetaminophen products, 5%

Other, 12%

153

l

Diuretics, 4% BP medications, 5%

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 underlying chronic disease and its treatments along with the daunting task of treating the cancer and its accompanying symptoms. One of the best solutions today is improving communication and the involvement of multidisciplinary teams that include a pharmacist.

10

Antioxidants/supplements, 4%

l

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 assessment 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.

Methods All patients who were referred to and who attended 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

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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 findings that were discussed during a patient visit in the electronic 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-reported 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 causal relationships, and untreated conditions. Duplicate therapy was defined as any unintended duplication 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 interactions 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 LexiInteract online drug interaction analysis program. All major pharmacokinetic drug interactions were recorded, and pharmacodynamic interactions were recorded if they required intervention by the pharmacist.

Table 2 Most Frequent Drug Interactions Medication

Interactions, N (%)

Amlodipine

2 (1.4)

Chemotherapy

3 (2.1)

Citalopram

2 (1.4)

Clopidogrel

17 (12.1)

a

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)

Other

15 (10.7)

b

Proton pump inhibitors 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/supplements

a

Results Between 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) discussed with the pharmacist included constipation, depression, 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 insurance 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-

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March 2013

49 (35.0)

3 (5.1)

Warfarin

13 (22.0)

Zolpidem

3 (5.1)

Total DDIs, N

59

Patients, N

54

a

Represents interaction between chemotherapy and antioxidant-containing supplements. b “Other” includes aspirin/dipyridamole, aspirin, bupropion, clonazepam, cranberry, diphenhydramine, duloxetine, furosemide, hydroxyzine, levothyroxine, lorazepam, mirtazapine, morphine, posaconazole, potassium, solifenacin, sorafenib, and tamsulosin. NSAIDs indicates nonsteroidal anti-inflammatory drugs; DDIs, drug–drug interactions.

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

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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 Constipation

13 (9.7) 41 (30.6)

Seizure medications (2), narcotics (3), benzodiazepines (4), zolpidem, steroid, antihistamines (2) 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.

patients, 74 (48.4%) were found to have some form of unintentional therapeutic duplication within their medication list (Figure 1), 54 patients (35.3%) had documented clinically relevant drug窶電rug interactions (Table 2), and 127 patients (83%) reported side effects that the pharmacist attributed to 1 or more of their medications (Table 3). Despite this, most patients (88.9%) reported uncontrolled symptoms (Table 4), and a majority of patients

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

Discussion To 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-

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Pharmacist Assessment of Polypharmacy Risks in Patients with Cancer

Condition

Events, N (%)

Anxiety

3 (2.1)

Appetite (poor)

2 (1.4)

Blood pressure

2 (1.4)

Constipation

Fatigue, 20%

Depression

2 (1.4) 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

Other, 15%

3 (2.1)

Sleep

8 (5.7)

Thyroid

2 (1.4)

Total undertreated conditions, N

140a

Patients, N

136

Depression, 11% Constipation, 11%

Some patients had more than 1 undertreated condition.

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 medications 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, surgeons, 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 population 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-

March 2013

Mucositis, 8%

“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).

a

l

Pain, 5% Gastroparesis, 8%

10 (7.1)

Shortness of breath

% ,5 or) o (p

tite % pe p nia, 5 A Insom

17 (12.1)

Constitutional

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Figure 2 Most Frequent Untreated Conditions (N = 105) Anxiety, 4% Dry mou th, 4 % Re flu x, 4%

Table 4 Most Frequent Undertreated Conditions

teractions. Previous studies have not examined the impact of how certain medications may compound symptoms 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, cholesterol or blood pressure medications).12

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. In our evaluation, 83% of patients reported side effects that could be directly attributable to their medications, 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 reasons for them. For example, perhaps a patient is fatigued, but he or she is taking a thyroid medication with food, and

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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.

Conclusion We 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 medicine, 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 polypharmacy risks compared with those previously shown in the literature and provide more in-depth assessments. n Author Disclosure Statement Dr 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.

References

1. 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-provided 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 implications and management. Lancet Oncol. 2011;12:1249-1257. 10. Mancini R. Implementing a standardized pharmacist assessment and evaluating 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 Authors Manuscripts 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 accepted, authors will be notified of any recommended revisions. COPYRIGHT/DISCLOSURE Authors 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.

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Th

2ND ANNUAL

eO

nc seri Vie olo es w gy on the Ph lin ar e a m t ac ist .co

CONQUERING THE CANCER CARE

m

CONTINUUM

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

A 6-part series



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

IN THIS ISSUE

• Palliation

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer  of gradual, nonspecific symptoms or is projected to grow considerably over  discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Pha Associate opportunity to assimilate their circumProfessor, rmD, BCOP adults, cancer will also increase. SecVirginia Commond, stances. Frequently, a multidisciplinary as the effectiveness of cancer onweal versity ™ th Uni approach to treatment is necessary, retreatments improves, the number of he past dec ade has seen quiring patients to engage with numerthe utilizat a drapatients matic upscured of the disease will in     ion of spe urgan e in   several ous medical teams comprising crease, and even larger percentage cialty pha types of Medic rmacies for are Moder the Lea Ann Hansen, rap eutic mo will be living all different specialties, often in different those for cancer. longer with disease nization Ac dalities, as “athe PharmD, BCOP t defined part D dru The inc cos lud t of cancer while receiving a specialty ing multiple “linesâ€? locations. Many patients have beenabout $125 bill of g with plan-n care may cee drug ion in 201 egotiated 0 rise from etc) overd $40 0 to (first-line, prices tha relatively healthy prior to the cancer lion eventbyand second-line, time. per Themonth.â€? 2 Oth thethere7 bilend of the therapy$20 fine spe t exer health cial dru dec tim ade. demand plans ma gs differe fore are not sophisticated consumers ofe,medical overall specialtyserBy that for oncology services is expected totyiny dently. In gen drugs are acc predic ounhealthcare eral, they vices. Consequently, it is incumbent on crease byted 48% t for 2 of toby 2020, while the supply of oncologists high cost, adminis are every 5 pha tere lars 4 d by injectio spent. 1 professionals to be able to facilitate patients’ transition increase cy dolby The purpos willrma - only 14% based on current patterns. or infusion, require n e of this arti special han to expand ersity intoBCO carePin order to minimize theirisdistress the need for a wide varietyor are used lain maxicle underscore dling, the evoluti These statistics en, PharmD, Commonwealth Univ for comple 80%, cialty pha on nia their clinical outcomes. Lea Ann Hans ssor, Virgimize from 17% toand other support personnel torequire x diseases of range the of ens health professionals spe rmacycatio Profe regim that special mo ption andnthe Associate on assumeach oral mediand can nitoring. functio term serv cology, how Anscomm Challenges exist beyond the diagnosis play a part and every patient to re.2-4 t initial e in the around 50% In onitin enabling d be ever, the mic treatmen getreatment woul syste avera ts for an and rio agen mo r with of can to the agents disp st commo ance nt scena period as well. According to ceive quality all of their needs discNational aantic cer care that addresses uss nistr thee pot to oral ensed by n he predomina treatment been renc involved admi entthroughout adheindividandthat a specialty disease, has of the illness. Patients deial ofefit macy pro the traditionally (NCI), more million llen pharges oftothe highlythan 12cha s the continuum severityben vider (SP of cancer has Cancer Institute thesyst ate the otherapy by due P) are the poi high er, ies indic em targeted from of view e. Stud venous chem United States fine quality of care based on are their ability to5: are a history untru nt.livingntwith the newer of theofpatproven agents tha the patie tion of intra uals in the py ient. t are adm ly monitored for cancer thera tered ora inisnnel who close lly. After adherence rates5 rence has trained perso in an The a adhe place syst Non vie Evo . took ematic rew dures lution of 15% to 97% Hill outc Healthcare omes Communications, LLC of the literature, Specialt Green e When these proce infuDrugs an one academ group of y iated with wors or in a hospital d assoc authors pro ic s and with oncologist’s office of the Pharmac Specialtbeen y posed the critical des disease state Lea Ann sive education most y in a number of Hansen criptors er hossion center, exten , high More of a spe There is drug to be 3 ician visitsPha rmD, BCO , ly was possible. cialty a lack of , : increased phys consen patient and fami hospital stays P specialty r ly comsus asing longe • , Hig on incre rates drug. The n defi h cost (pre the ver, an nition incre Food andpitalizatio ased morscriptions recently, howe not defined one or of of and use a Dru g, the tha cos enin g n $600 per t more wors the term. involves seAd ministratio • month) Initialldisea mon situation one-third toDifficult medicatio synonymo dminn has ately y, the6 Approxim us with bio n delivery, cations and self-a l was virt tality. labe ated— Special technology the such as more oral medi teins pro uallcatio handling y n-rel Leain of all medi producs ts, duced by eous therapies Ann requiring n eitherdue recombin two-third istered subcutan strict tem pro-to medicatio control respon-Hansen,mo nocrmD Asstoci ant DNA ations are lonal, ant perature ate Profes Pha ent. The direc BCibo italiztechnique — OPdies pro hosp sor,om home environm brid adminsa or Virg cost of $100 bil- Restricted location and duc n inia —at as, ed isitio ence Co but acqu dher h cellula for medicat thismm nonawit aris noonw sibility for drug r hynts and lonea ion prepar 7 purpose of this or distribution site ger lth theUni ation ng to the patie sityThe casver annu — e.ally. en, lion epts Th e ibe istration is shifti 200gene if avail 7 ral conc Restricted locatio he -previous Lea Ann Hans ort network, BCOP n for medic ticle is to descr insPhar tallmD, their social supp rch related totration ment in thi than 20 ation adm e and the resea nt time, more ries examin inis renc cannt  adhe cer car ed the gro regardingspatie able. At the prese en Hill ence, risk faceGre oved for seincid appr Hea The t. FDA win lthc are men ion, wit g import ns therap1). In addit treat h are Com wed. canceerof mun revie oral medicatio er icatR rence to anc willabeless MP ions adhe lem cancer (Table ies for the ora of t , prob LLC trea (82 l imp men this that of % vs 78% 4 tment of can rs treat licationused derquen equences ivedtlyfrom examine the first-line ). (MPR pattumo ts are s of for tors, and conscer and the ient adh electronic is a metric series will subse other oral preagen sent to initia prescriptio clinical l treatment. Ac-erenceThe refirence on its article in this a number of lastsuc ll patand e, mo adhe n records bas terns over cess. for refractory tim re tha Netor are ica Atmaxi themizing poi time, and ed on ensive Cancern 20 oral me have relapsed tions are prehapp best practices thednt for adh 80% is an the National Com roved sbyinthe erence use arbitrary cut cording to the all compound Dru25% omes. ofmin Food outc d g by Ad and ma nately ny admi investigat inenare atio pipel work, approxim linedevelopmentistr (FD same study ors.) The  rch and treatment continue.1 A) for firstfound surviv  Organoncology resea al at 10 yea is likely toof cancer. Aased  World Health to the trend by be oth the num ed so 81% y, er incre rs ber ofAdherence was defin oral age n’s befor those wh istered orall lity comes the to which a perso the o continued in responsibi nts are use adtha as the “extent t have relacations may notdbefor tumors With this shift a diet, and/orrapy versus 74% ization in 2003 n, following for those anticancer medi psed or thatrefr require had discont possibility that initial treaially for regimensare who actory tohavior, taking medicatio inued it. No ctly, espec tment, and abo longnadherenc has also bee ministered corre utto25% of onc ates of adherence estim oloall e gy the n Over rese g. sho dosin arch pipelin wn to produc repeated stantial det e consists hcare Communications, LLC oral compou e subriment in of nds.1  reen Hill Healt ThisG clinical is in com self

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Conveni ence, C The Imp halleng es a Patient ct of Specialty , and Cost Con Care Pharma cies on tainment:

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addition to es in chroni out-administe c myeloid red subcut and childh leukemia aneous the pies for the ood acute rahome env lymphobla leukemia. 5-8 ironment are under stic that For each of FDA review these diso . ders, prolon When can rged oral cer medic therapy has been the ations are ministered standard adLea Ann orally in the of care for Hansen, decade or home env ronment rath a PharmD more. It is ier than in , BCOP likely that ative conseq the clinic of adherence neg or hospital, uences of non range from the rates adherence with other 15% to 97% 2 at the end will be doc oral cancer of the first . For examp umented in medicatio year of trea le, hormonal the future ns tment wit apy matur treatment as their role h adjuvant es. The pur (AHT) for in thercer, only 79% pose of thi ear the ly-s res tag s article is to ults of ava of patients e breast can remained on discuss ilable res a gap exceed adherence earch on therapy wit ing 60 day and sugges maximizin hout s and 85% ceeding 180 t best practic g ical outcom without a days. By yea es to improv es. gap exr 5, only 27% e clinmained wit hout 60- and and 29% re180-day gap In anothe    s, respective 3 r study of     ly. AHT, pat tion possess ients with  

  ion ratio (M    a medicaPR) >80% significant Direct com had a statisti ly higher municatio 10-year sur cally n with all vival rate personal bar patients abo than those riers to tak ut their ing daily the period is an rapy for a pro important longed aspect to Gr maximizin een Hill Hea g adherlthcare Com munication s, LLC

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REVIEW ARTICLE REVIEW ARTICLE

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

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 immunerelated 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 demonstratJ Hematol Oncol Pharm. 2013;3(1):16-26. 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 www.JHOPonline.com Disclosures are at end of text expected to help shape the melanoma treatment landscape by establishing the most effective combination regimens, without compromising tolerability.

T

he outlook for patients with advanced or metastatic 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 standard 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 patients 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

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.

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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 monoclonal 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

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Ipilimumab Overview

Figure 1 Ipilimumab’s Mechanism of Action T-cell T-cell activation activation

T-cell T-cellinhibition inhibition

T-cell activated T cell remains remains activated

CTLA-4

TCR

Activation Activation

CD28

Activation Activation

TCR

CD28

CTLA-4

Activation Inhibition Inhibition Activation

Activation Activation

B7

MHC

APC

CTLA-4 CD28

B7

B7 MHC

TCR

Ipilimumab Ipilimumab blocks blocks CTLA-4 CTLA-4

MHC

APC

APC

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.

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 glycoprotein (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 combination of ipilimumab with dacarbazine reduced the risk of death by 28% compared with dacarbazine alone.2 The second therapy approved in 2011 is vemurafenib, 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 dramatically higher response rates (48% vs 5%, respectively).3 Although interim 6-month survival data for vemurafenib 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

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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 toxicity 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 Target The recognition of CTLA-4’s critical role in immune 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

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A.

response. The importance of this system is dramatically demonstrated in mice devoid of functional CTLA-4, who develop massive 80 . A. A. A. CD28-dependent expansion of autoreactive A 100 Ipi plus gp100 Ipi 100 Gp100 plus gp100 IpiIpilimumab IpiIpilimumab plus gp100 gp100 Ipiplus plus gp100 Ipi gp100 IpiIpi gp100 gp100 gp100 100 100 100 70 Censored Censored T-cells and die within 3 to 4 weeks as a result Censored Censored Censored Censored Censored Censored CensoredCensored Censored Censored Censored Censored Censored 90 90 of rampant lymphoproliferation and lymph9090 90 60 80 80 adenopathy. Ipilimumab blocks the CTLA-4 50 8080 80 and, therefore, potentiates antitumor T-cell 70 70 40 12 16 0 20 24 28 32 36 40 44 48 52 56 responses (Figure 1). Early studies in mice 4 8 7070 70 60 60 and primates, and later in humans, demon30 50 6060 Months 50 60 strate that ipilimumab competitively binds 20 40 to CTLA-4 more efficiently (an approximate 40 5050 50 10 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0 100-fold greater affinity) than native B7 30 30 0 4040 40 while preserving CD28 signaling.25-30 137 106 79 20 56 30 2 12 2416 18 20 0 38 20 2413 28 13 32 368 40 5 44 48 521 56 0 4 8 Ipilimumab has demonstrated efficacy 30 136 93 58 3030 32 23 17 16 7 5 5 3 1 0 0 0 and safety in 2 randomized, multicenter, 10 10 Months No. at Risk 2020 phase 3 trials. In the first study (MDX01000 20 Ipi plus gp100 403 115 33 24 17 7 6 4 0 0 4 8 163 12 16 20 24 28 32 36 40 44 48 52 56 12 24 42 0 297 16 81 20 54 28 32 36 40 44 48 52 56 4 223 8 20), 676 previously treated patients with 1010 10137 106 79 56 38 30 Months Ipi 24 18 13 13 8 5 2 1 0 unresectable stage III or IV melanoma were Months Months gp100 Patients at risk, N 136 93 58 32 23 17 16 7 5 5 3 1 0 0 0 randomized to receive ipilimumab alone (N No. at Risk 0 0 0 Ipilimumab plus gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0 = 137), ipilimumab in combination with IpiIpilimumab plus gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0 38 1616 30 16 20 24 20 18 24 13 3232 8 3636 5 36 40 2 40 1 44 12 2413 2828 0 1037 0 106 20 24 28 32 40 44 440 4848 48 5252 52 5656 56 4 44 79 8 8856 1212 the experimental vaccine gp100 (N = 403), IpiGp100 137 106 79 56 38 30 24 187 135 5 13 83 51 20 0 0 1 0 136 93 58 32 23 17 16 or gp100 alone (N = 136).13 Patients were 136 93 58 32 23 17 16 7 Months 5 5 3 1 0 0 0 B. gp100 Months Months B also required to be human leukocyte anNo. atat Risk No. atRisk Risk 100 No. 100 Censored Censored tigen (HLA)-A*0201–positive, a requireIpiIpi plus gp100 223 Ipiplus plus gp100 403 gp100 403297 297 223163 163115 1158181 81 5454 54 4242 42 3333 33 2424 24 1717 17 7 77 6 66 4 44 0 00 297 223 163 115 90403 90 Censored Censored ment based on the mechanism of action of Censored B. IpiIpi 137 Ipi 137106 1067979 79 5656 56 3838 383030 30 2424 24 1818 18 1313 13 1313 13 8 88 5 55 2 22 1 11 0 00 106 80 80137 the gp100 vaccine.13 Censored 100 gp100 136 gp100 gp100 136 9393 935858 58 3232 32 2323 231717 17 1616 16 7 77 5 55 5 55 3 33 1 11 0 00 0Ipilimumab 136 00 0 00 3 mg/kg, alone or in combina70 70 90 tion with gp100, significantly improved me60 60 Censored dian OS versus gp100 alone (10.1 months, 80 Censored 50 50 10.0 months, and 6.4 months, respective70 . B. B. 40 Ipilimumab plus dacarbazine ly).13 No difference in OS was detected 40 Ipilimumab–dacarbazine Ipilimumab–dacarbazine 60 between the ipilimumab groups (Figure 2, 30 30 100 100 100 50 Table).2,13,27-29 Of note, patients in this study Placebo Placebo–dacarbazine plus dacarbazine 20 20 had poor prognosis: more than 70% of pa9090 90 40 Ipilimumab–dacarbazine Placebo–dacarbazine 10 10 Censored Censored Censored tients had visceral metastases and more than 30 8080 80 Censored 00 36% had elevated lactate dehydrogenase Censored Censored Placebo–dacarbazine 20 0 4 6 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 0 22 4 6 8 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 (LDH) levels, both of which are associated 7070 70 Months with reduced survival.13 These findings led to 10 Months 0 Patients at risk, N No. at Risk 6060 60 the FDA approval of 4 doses of ipilimumab, Ipilimumab plus 250 230 199 131 114 68 61 59 56 56 52 41 4 22 199 181 181 15718 131 20 114 104 91 85 79 74 104 79 74 59 56 52 38 41 31 314017 10 17 42 10 4 0 Ipilimumab-dacarbazine 2 dacarbazine 4 6 8 100 250 12230 14 16 157 22 912485 26 28 68 3061 32 3456 36 44 4600 48 given at 3 mg/kg on an induction schedule of 0 229 2 190 4 160 6 136 8 116 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 427 44 46 48 252 89 78 72 64 56 47 44 42 42 37 34 31 26 19 11 5 3 0 Placebo-dacarbazine 50 Placebo plus 5050 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 dacarbazine every 3 weeks for patients with unresectable MonthsMonths No. at Risk 4040 40 or metastatic melanoma. Ipilimumab–dacarbazine Ipilimumab–dacarbazine Ipilimumab–dacarbazine Ipilimumab-dacarbazine Survival curves 3 trials In52each study, 250 from 230 199 2 181separate 157 131 114 phase 104 91 85 79 74 are 68 61shown. 59 56 56 41 31 17 10 overall 4 2 0 The second study—CA184-024—differed 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 30increased 30252 229 190compared 30 160 136 116 89 78 72nonipilimumab 64 56 47 44 42 42control 37 34 31arms 26 19in11patients 7 5 3 0 survival is with Placebo-dacarbazine in ipilimumab dose, schedule, and subse252 229 190 160 136 116 89 78 72 64 56 47 44 42 42 37 34 31 26 19 11 7 5 3 0 treated with ipilimumab alone (A) or ipilimumab in combination with dacarbaPlacebo–dacarbazine Placebo–dacarbazine Placebo–dacarbazine quent toxicity profile.2 In this study, 502 20 20 zine (B).20 Long-term survival up to 3 years was observed in some patients treated treatment-naïve patients with unresectwith ipilimumab. 1010 10 able stage III or stage IV melanoma reReprinted with permission from Hodi FS, et al. Improved survival with ipiliceived either ipilimumab in combination mumab in0 patients with metastatic melanoma. N Engl J Med. 2010;363:71100 723. Copyright 2010 Society; and Robert al.3838 with (N = 250) or dacarbazine 0 0 02©2 2 4 4 46 6Massachusetts 1212 1414 16Medical 1818 20 22 2424 2626 28 30 3232 34C, 36et 38 4040 4242 4444 46dacarbazine 4848 68 810 8 10 10 12 14 16 1820 20 22 24 2628 28 30 32 34 36 40 42 44 46 48 16 22 30 34 36 46 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. alone (N = 252). Ipilimumab was adminisN Engl J Med. 2011;364:2517-2526. CopyrightMonths ©Months 2011 Massachusetts Medical Months tered at a dose of 10 mg/kg on an induction o.No. at at Risk No. atRisk Risk Society. of every 3 weeks for 4 cycles and included 100 Ipilimumab

Ipi plus gp100 gp100 Demonstrates IncreaseIpiin Overall Survival in Censored Censored Censored Patients with Advanced or Metastatic Melanoma 90

Patients surviving, %

Patients Surviving (%) Patients (%) Patients Surviving SurvivingPatients (%) Surviving Patients Surviving (%) (%)

Overall survival, %

Overall Survival (%) Overall Survival (%) Overall Survival (%)(%) Overall Survival (%) Overall Survival

Figure 2

limumab-dacarbazine Ipilimumab-dacarbazine 250250 Ipilimumab-dacarbazine 230230 199199 181181 157157 131131 114114 104104 91 9191 85 8585 79 7979 74 7474 68 6868 61 6161 59 5959 56 5656 56 5656 52 5252 41 4141 31 3131 17 1717 10 1010 4 250 230 199 181 157 131 114 104

acebo-dacarbazine Placebo-dacarbazine Placebo-dacarbazine

18

l

4 42 2 20 0 0

252252 229229 190190 160160 136136 116116 89 8989 78 78 72 64 6464 56 5656 47 4747 44 4444 42 4242 42 4242 37 3737 34 3434 31 3131 26 2626 19 1919 11 11117 7 57 5 53 3 30 0 0 252 229 190 160 136 116 78 7272

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Ipilimumab Overview

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

Study

Population

Treatmenta

ORR, %

PFS

5.8

NR

Median OS, months (95% CI)

Toxicity/irAEs

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

2

Heavily Ipilimumab pretreated, 10 mg/kg progressed on previous therapy

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/kg Ipilimumab 3 mg/kg Ipilimumab 0.3 mg/kg

11.1 4.2 0.0

18.9%b 12.9%b 2.7%b

11.4 (6.9-16.1) Most common irAEs GI 8.7 (6.9-12.1) and skin: 8.6 (7.7-12.7) 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/kg Ipilimumab 10 mg/kg + budesonide

15.8 12.1

NR

19.3 (12.0-34.5) Most common irAEs GI 17.7 (6.8-45.0) 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 + gp100 Ipilimumab 3 mg/kg gp100 alone

5.7 10.9 1.5

2.76 months 2.86 months 2.76 months

10.0 (8.5-11.5) Most common irAEs GI 10.1 (8.0-13.8) and skin: 6.4 (5.5-8.7) Any-grade irAEs: 58%-61% ipilimumab groups Any grade irAEs: 32% gp100 alone Grade 3-4 irAEs: 10%-15% ipilimumab groups Grade 3-4 irAEs: 3% gp100 alone Grade 5 AEs: 1.8% ipilimumab groups Grade 5 AEs: 0.3% gp100 alone

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

3

Treatment naïve

Ipilimumab 10 mg/kg + dacarbazine Dacarbazine alone

15.2 10.3

Median PFS 11.2 (9.4-13.6) Most common irAEs liver similar in both 9.1 (7.8-10.5) and: arms, but overall Any-grade irAEs: 78% 24% reduction ipilimumab + dacarbazine in risk of proAny-grade irAEs: 38% gression for dacarbazine alone ipilimumab + Grade 3-4 irAEs: 38% dacarbazine vs ipilimumab + dacarbazine dacarbazine Grade 3-4 irAEs: 4% alone (HR, dacarbazine alone 0.76; P = .006) Grade 5 AEs: 0% ipilimumab + dacarbazine Grade 5 AEs: 0.2% dacarbazine alone

Every 3 weeks × 4 doses (induction). PFS 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. a

b

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.

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

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This trial reported some differences in grade 3 or grade 4 adverse events (AEs) compared with other ipilimumab 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 toxicity 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 toxicity, no new safety concerns were observed.2 The current scope of ipilimumab use is not restricted to specific patient populations within those with advanced 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 patients 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 asymptomatic brain metastases who entered the ipilimumab expanded-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 metastases. 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 median 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 encouraging and are the first to demonstrate the potential for immunotherapy to be effective in patients with melanoma who have brain metastases. Although the underlying basis of ipilimumab activity

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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-activated 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 patients 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 Response The pattern of clinical responses observed across ipilimumab studies can resemble both that of conventional cytotoxic 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 observed in response to ipilimu- mab.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 observed 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 inflammatory infiltration of T-cells into the tumor, thereby expanding its size and mimicking progressive disease. In another pattern, the reduction in total tumor burden occurs 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 response 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 antitumor 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-

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Ipilimumab Overview

Figure 3 Patterns of Response in Patients Treated with Ipilimumab B

82 64

–50

46

–75

28 10

–100

–8

Change Changefrom fromBaseline baseline SPD SPD, (%) %

–25

2

99

SPD,(mm mm2) SPD

–26

–125

2154

0

1826

–25

1498 1171

–50

843

–75

515 187

–100

–140 –468

–125

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

–63

–21

RelativeDay dayfrom fromRandomization randomization date Relative Date 19373

125

17242

100

15111

75

12980

50

10849

25

8718

0

6587

–25

4456

–50

2325

–75

N

194 –1937

–125 –63

–21

21

63

105

147

189

231

273

105

147

189

231

273

315

357

315

D

1272

50

Change from from Baseline baseline SPD, % Change SPD (%)

150

–100

63

RelativeDay dayfrom fromDate date of of First first dose Relative Dose

SPD SPD,(mm mm2)2

Change Changefrom from Baseline baseline SPD SPD, (%) %

C

21

1124

25

975

0

827 678

–25

530

N

–50 –75

382 233

N N

N

–100

N

85

N

–64 –468

–125

357

–63

Relative RelativeDay dayfrom fromDate dateofofFirst first Dose dose

2

–63 –21 21

2482

25

SPD,(mm mm2) SPD

Changefrom fromBaseline baseline SPD SPD, (%) % Change

117

0

2810

50

135

25

2

153

50

SPD,(mm mm2) SPD

A

–21

21

63

105

147

189

231

273

315

357

Relative Dose RelativeDay dayfrom fromDate date of of First first dose

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 stable 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.

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 Ipilimumab The 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

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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 toxicities, 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

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

Time to onset

4.93

Grade 2-5 Grade 3-5

5.07

Grade 2-4

Time to resolution

6.93 6.07 6.57

Weeks 0

Phase 2 (3 mg/kg)

5.71 6.29

4.57 4.29

Grade 3-4

Phase 2 (10 mg/kg)

8.57 8.21

5

Phase 3 (3 mg/kg) 7.71

10

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.

3 or 4, 8%-23% and 0%-4%, respectively); less frequent 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 ipilimumab 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 standard set of guidelines was developed to provide advice on the management of irAEs.

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In the MDX001-20 study, 14 deaths (2.1%) were attributed 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 monitoring 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 detection and prompt reporting may reduce serious and sometimes fatal events. Unless an alternative etiology can be identified, any sign or symptom of immune-mediated events should be considered drug-related and the appropriate treatment should be initiated.

Management of irAEs At 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 managed symptomatically.45,46 Patients exhibiting possible GI events should be assessed for changes in bowel habits and for the following signs and symptoms: diarrhea, 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 managed 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 â&#x2030;Ľ7 stools daily over baseline, peritoneal signs consistent with bowel perforation, ileus, or patients

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A

Ipilimumab Overview

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

Grade 2–5

Grade 3–5

3.6Events Figure 5 Onset and Resolution of Gastrointestinal, Liver, Endocrine, and Skin

4.4 (9, 3.1–4.4)

Type Skin

(61, 3.1–4.1)

Patients treated with ipilimumab (10 mg/kg) had varying times to onset (A) and resolution (B) based on the organ system affected. 6.9 6.6 GI A (40, 5.7–8.9) (76, 5.1–8.0) Median time to onset, wks (N, 95% confidence interval)

Liver Type

Grades 2-5

Skin

3.6 (61, 3.1-4.1)

6.7

Grades (23,3-5 6.1–9.7)

4.4 (9, 3.1-4.4)

9.2 6.6 (76, 5.1-8.0) (16, 6.7–11.1)

Endocrine Gastrointestinal

B

6.7 (23, 6.1–9.3)

10.1 (8, 7.0–11.4)

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

Proportion not not resolved Proportion resolved

Time resolution Time totoresolution 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Gastrointestinal GI

Median: 2.29 Median, 2.29weeks wks

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 50 52 54

Patients at risk Patients at risk Tx 10 mg/kg 76 Tx 10mg/kg

Proportion resolved Proportion not not resolved

Monotherapy 10-mg/kg treatedtreated patientspatients Monotherapy 10 mg/kg Censored Censored

28

16

8

5

5

4

4

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 50 52 54

Week Week 2

2

2

2

1

1

22

11

7

5

1

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Endocrine Endocrine Median, 20.1 wks Median: 20.1 weeks

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 atrisk risk Patients at Tx 10 mg/kg 16 Tx 10mg/kg

Median: Median,4.00 4.00weeks wks

Week Week

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

Liver Liver

1

0

Skin

Skin Median: 6.14 weeks Median, 6.14 wks

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 50 52 54

Week Week 13

9

8

7

6

4

3

Week Week 3

1

1

1

1

1

61 39

25 16

12

9

7

6

3

2

1

1

1

1

0

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.

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

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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.

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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 systemic 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 symptomatically, 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-severe cases. Ipilimumab should be withheld in patients with moderate-to-severe signs and symptoms, and it should be permanently discontinued in patients with StevensJohnson 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 moderate aspartate aminotransferase (AST) or alanine aminotransferase (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 elevations 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 corticosteroids.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 symptoms 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

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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 ipilimumab-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 therapy 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 worsening symptoms may require permanent discontinuation of ipilimumab. Rarely, Guillain-Barré syndrome, myasthenia 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 thrombocytopenia (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 Information A high level of suspicion and recognition of the clinical 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 patients who are unable to have their corticosteroid dose reduced to prednisone 7.5 mg or an equivalent daily. Conclusion Ipilimumab, the first-in-class anti–CTLA-4 therapy to be approved by the FDA, has demonstrated efficacy

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Ipilimumab Overview

and OS benefit in patients with unresectable or metastatic 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 treatment landscape by establishing the most effective combination regimens, without compromising tolerability. n

Acknowledgment The 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 acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither BristolMyers 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 BristolMyers Squibb and Genentech. Dr Jarkowski reported no conflicts of interest.

References

1. 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 previously 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 melanoma. 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 temozolomide 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 melanoma. J Clin Oncol. 2009;27:2823-2830. 12. Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy 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.

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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, placebo-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 single-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 ipilimumab 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 complication. 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 previously 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 ipilimumab 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 dehydrogenase 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

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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 immunerelated 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

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.

M

y 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 confirmation 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 Director St. 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 conducted with pediatric patients. The results of the study illustrate that the study population was aged 22 to 89

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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 anticoagulant 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 background, 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 antagonist therapy for the treatment of VTE in patients with cancer. 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 recommend LMWH for the first 3 to 6 months of long-term anticoagulant 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 conducted. 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

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference 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 Collaborations Marcus 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

Upon 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 healthcare 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.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015? Ted Okon; John D. Sprandio, MD

TARGET AUDIENCE

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

LEARNING OBJECTIVES

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

DESIGNATION OF CREDIT STATEMENTS SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

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

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. 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, 2013 7:00 am - 8:00 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

PHYSICIAN CREDIT DESIGNATION

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

REGISTERED NURSE DESIGNATION

Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am

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 Proposition Mark 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

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

SUNDAY, MAY 5, 2013

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

*Agenda is subject to change. AVBCCAsize20413


        

â&#x20AC;˘ Melanoma â&#x20AC;˘ Basal Cell Carcinoma â&#x20AC;˘ Cutaneous T-Cell Lymphoma â&#x20AC;˘ Squamous Cell Carcinoma â&#x20AC;˘ Merkel Cell Carcinoma



July 26-28, 2013

Hyatt Regency La Jolla â&#x20AC;˘ San Diego, California

PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: â&#x20AC;˘ Epidemiology and genetic/environmental factors â&#x20AC;˘ Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies â&#x20AC;˘ Risk stratification based on patient and tumor characteristics â&#x20AC;˘ Principles of cancer prevention of melanoma and basal cell carcinoma â&#x20AC;˘ Current treatment guidelines â&#x20AC;˘ Emerging treatment options for personalized therapy â&#x20AC;˘ Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma â&#x20AC;˘ Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics â&#x20AC;˘ Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

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

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

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

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Lukeâ&#x20AC;&#x2122;s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

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

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm â&#x20AC;&#x201C; 7:00 pm

Registration

5:30 pm â&#x20AC;&#x201C; 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am â&#x20AC;&#x201C; 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am â&#x20AC;&#x201C; 8:15 am

BREAK

8:15 am â&#x20AC;&#x201C; 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress â&#x20AC;&#x201D; Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am â&#x20AC;&#x201C; 11:45 am General Session I: A Clinicianâ&#x20AC;&#x2122;s Primer on the Molecular Biology of Cutaneous Malignancies â&#x20AC;˘ Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway â&#x20AC;˘ Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm â&#x20AC;&#x201C; 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â&#x20AC;&#x201C; 1:15 pm

BREAK

1:15 pm â&#x20AC;&#x201C; 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies â&#x20AC;˘ Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients â&#x20AC;˘ Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies â&#x20AC;˘ Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Antiâ&#x20AC;&#x201C;PD-1

4:30 pm â&#x20AC;&#x201C; 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits â&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. Oâ&#x20AC;&#x2122;Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am â&#x20AC;&#x201C; 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am â&#x20AC;&#x201C; 8:15 am

BREAK

8:15 am â&#x20AC;&#x201C; 8:30 am

Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Todayâ&#x20AC;&#x2122;s Sessions

8:30 am â&#x20AC;&#x201C; 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician â&#x20AC;˘ Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm â&#x20AC;&#x201C; 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â&#x20AC;&#x201C; 1:15 pm

BREAK

1:15 pm â&#x20AC;&#x201C; 2:45 pm

General Session V: â&#x20AC;&#x153;Hot Dataâ&#x20AC;? â&#x20AC;&#x201D; What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm â&#x20AC;&#x201C; 3:00 pm

Closing Remarks - Steven J. Oâ&#x20AC;&#x2122;Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com


FROM THE LITERATURE

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

nA  biraterone 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 options available for patients who have not received chemotherapy have been proved to produce response in these patients, 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 progression-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

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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 therapy, effects that clearly improved patientsâ&#x20AC;&#x2122; quality of life. Furthermore, abiraterone plus prednisone was well tolerated 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.

nA  dding Rituximab to Chlorambucil Improves EventFree Survival in Patients with MALT Lymphoma Background: Approximately 8% of patients with nonHodgkin 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 patients 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)

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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 receiving 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 combined had not been reached. At 5 years, the EFS in the patients receiving rituximab plus chlorambucil was significantly better than the patients receiving chlorambucil alone (68% vs 50%, respectively; 95% confidence interval [CI], 59%-76% vs 41%-60%, respectively; P = .002). Adding rituximab to chlorambucil led to a significant 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 tolerated, 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, bendamustine 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 chlorambucil 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 chlorambucil plus rituximab is better than single-agent rituximab. Zucca E, Conconi A, Laszlo D, et al. Addition of rituximab to chlorambucil 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.

nT  -DM1 Significantly Prolongs Survival in Patients with HER2 Advanced Breast Cancer Background: Approximately 20% of patients with advanced breast cancer exhibit amplification of the epidermal growth factor, HER2, which is associated with shortened survival. The combination of cytotoxic chemotherapy and HER2-targeted agents is an effective therapy for these cases. The antibody drug conjugate trastuzumab

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emtansine (T-DM1) includes antiâ&#x20AC;&#x201C;HER2-targeted antitumor 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 HER2positive 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 adjustments, including reductions and delays, as well as discontinuation because of adverse events, were done per protocol. 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 symptom progression. Results: The median PFS (as assessed by an independent review) was 9.6 months with T-DM1 compared with 6.4 months with the combination of lapatinib and capecitabine, 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 allcause death, 0.68; 95% CI, 0.55-0.85; P <.001). The objective 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 combination. 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 compound 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 HER2positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.

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Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION 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 patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In 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 LD 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. 50

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.


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

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

1

8.3 months (95% CI: 6.3, 10.8)

Patients who achieved a PR

1

0

2

4

6

Months

8

10

12

The efficacy 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%).

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. • 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

Learn more at www.TREANDAHCP.com

Please see accompanying brief summary of full Prescribing Information. Reference: 1. Data on file. Teva Pharmaceuticals.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2577b January 2013

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