February 2012 Vol5, No 1 by The Oncology Pharmacist

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FEBRUARY 2012

www.TheOncologyPharmacist.com

VOL 5, NO 1

BREAST CANCER

CANCER CENTER PROFILE

LSU Health Feist-Weiller Cancer Center Evolution of cancer treatments provides challenge

BOLERO-2: Practice-Changing Results With Exemestane Plus Everolimus in Advanced Breast Cancer By Alice Goodman

pdated results of the phase 3 BOLERO-2 trial demonstrated that adding everolimus to hormonal therapy extends progression-free survival (PFS) in hormone receptor– positive (HR+) metastatic breast cancer

that progressed on hormonal therapy with anastrozole or letrozole. The positive outcomes observed in this study suggest that everolimus plus exemestane will be a new option for postmenopausal metastatic HR+ breast cancer. Continued on page 17

LEUKEMIAS

Gary Jean, PharmD, BCOP, and Jill Comeau, PharmD, BCOP, clinical pharmacists at LSU Health Shreveport and the Feist-Weiller Cancer Center.

he Feist-Weiller Cancer Center, a department of Louisiana State University (LSU) Health Shreveport, provides comprehensive cancer care in a translational research environment. It was founded in 1993 as the Center for Excellence in Cancer Treatment, Research, Education and Prevention by an act of the Louisiana Board of Regents. In 1997, it was renamed the Feist-Weiller Cancer Center in acknowledgment of a philanthropic gift from the Feist and Weiller families. This gift led to the construction of a multidisciplinary outpatient cancer center that is also home to 1 of the 6 St. Jude Children’s Research Hospital Continued on page 19

Bruton’s Tyrosine Kinase Inhibitor: Potential Efficacy With No Myelosuppression in CLL By Alice Goodman

n investigational oral agent targeting the B-cell receptor achieved high rates of remission with little toxicity in patients with chronic lymphocytic leukemia (CLL) refractory to at least 2 previous treatments, according to results from a phase 2 study presented at the 53rd Annual

Meeting of the American Society of Hematology (ASH). The agent, called PCI-32765, is a firstin-class Bruton’s tyrosine kinase (Btk) inhibitor. Btk mediates B-cell receptor signaling, and this protein is essential for CLL cell survival and proliferation. PCI32765 is an irreversible inhibitor of Btk Continued on page 22

CONFERENCE NEWS: SABCS AND ASH

Gene Array Test for Predicting Recurrence Risk in DCIS By Alice Goodman

he Oncotype DX breast cancer assay for ductal carcinoma in situ (DCIS) is a strong and significant predictor of 10-year risk of recurrence in women with DCIS, according to a study presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) held in December 2011. It is the first clinically validated genomic assay to predict risk of local recurrence for women with

DCIS, and it is now available from Genomic Health. The assay utilizes a panel of 12 genes to predict the risk of local recurrence with DCIS and invasive breast cancer over the next 10 years. The score derived from the assay will be useful for guiding decision making in women with DCIS treated with local excision with or without adjuvant hormonal therapy.

INSIDE ConferenCe news

Survivors With BRCA Mutations Are at Increased Risk of Contralateral Breast Cancer . . . . . 9 Management of Lymphoma During Pregnancy Feasible . . . . . . 9 New Look at Discontinued Drug in Older Patients With Acute Myeloid Leukemia . . . . . . . . . . . . . . 10 PharmaCoeConomiCs

......

Should Everyone Be Required to Have Health Insurance?

Continued on page 8

multiPle myeloma

.........

The Health Burden of Multiple Myeloma

Koeller’s Corner Shooting from the Hip So You Want to Be an Oncology Pharmacist Specialist. What Are Your Options? Page 23

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Must be diluted before intravenous infusion Initial U.S. Approval: 1996

•

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1) CONTRAINDICATIONS • History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4) • Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS • Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) • Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) • Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) ADVERSE REACTIONS Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1) • The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Radiation toxicity. May cause severe and life-threatening toxicity. (5.8) ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Made in India

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Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Oklahoma University College of Pharmacy Tulsa, OK

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

ASSOCIATE EDITOR-IN-CHIEF

Beth Faiman, RN, MSN, APRN, BC, AOCN

Jim Koeller, MS

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

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Burt Zweigenhaft, BS

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

BioPharma Partners LLC New York, NY

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Marlo Blazer, RPh, PharmD

The University of Texas MD Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

February 2012 I VOL 5, NO 1

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

www.TheOncologyPharmacist.com

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Today I learned... handling hazardous medications safely doesn’t have to slow me down.

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TOP_February 2012_FINAL_TOP 2/16/12 9:56 AM Page 6

From the Editor PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

elcome to the first issue of The Oncology Pharmacist (TOP) for 2012. We’re looking forward to a new year of keeping you up-to-date about what is happening in the field of oncology and bringing you information you can use in your daily practice. In this issue, we tell you some of the news coming out of the San Antonio Breast Cancer Symposium and the American Society of Hematology annual meeting—news about therapies and tests on the horizon, and the results of a study that takes a new look at a discontinued drug. In addition, we report on the specifics of the FDA approval of a supplemental new drug application that updates the label for Velcade (bortezomib). Jim Koeller tells us how he entered

the field of oncology pharmacy and discusses the various pathways to the profession today. Gary Jean, from LSU Health Feist-Weiller Cancer Center, this month’s featured cancer center, is a relatively new practitioner who tells us how he was inspired to become an oncology pharmacist. Both Jim and Gary acknowledge the importance of loving the job. As always, I encourage you to visit our Web site, www.TheOncologyPharmacist.com. Please answer this month’s Reader Poll about the health insurance mandate issue and let us know how you feel. Be sure to tell us what topics you want to see covered in TOP. We want to hear from you, and we appreciate your feedback. ●

Quality Control Director Barbara Marino Directors, Client Services Joe Chanley joe@greenhillhc.com

Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

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Recent FDA Approvals

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered 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.

Vismodegib Capsule Approved for Metastatic Basal Cell Carcinoma The FDA approved Erivedge (vismodegib; Genentech) capsule for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred after surgery or who are not candidates for surgery, and who are not candidates for radiation. Basal cell carcinoma is the most common type of skin cancer, and vismodegib is the first drug approved by the FDA for metastatic basal cell carcinoma. Vismodegib inhibits the hedgehog pathway, a channel used by cells to communicate. Malfunctions in the hedgehog pathway are thought to play a role in several types of cancer, and this pathway is a focus of research. The hedgehog pathway is crucial to embryonic development. The most common adverse reactions (≥10%) for vismodegib were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. Three of 10 premenopausal women developed amenorrhea in clinical trials. Vismodegib approval carries a black box warning for the risk of fetal death or severe birth defects.

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EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@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 The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® 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. BPA Worldwide membership applied for April 2011.

February 2012 I VOL 5, NO 1

Ingenol Mebutate Gel Approved for Actinic Keratosis Picato (ingenol mebutate; LEO Pharma) gel was approved in January by the FDA for the topical treatment of actinic keratosis (AK) on the face, scalp, trunk, and extremities. AK is a precancerous condition caused by cumulative sun exposure that has the potential to progress to squamous cell carcinoma, which is the second most common type of skin cancer. AK is a dry, scaly, rough-textured patch or lesion that forms on the outermost layer of the skin after cumulative exposure

to ultraviolet light, including sunlight. Ingenol mebutate 0.015% gel is used once daily on the face and scalp for 3 consecutive days, and ingenol mebutate 0.05% gel is used once daily on the trunk and extremities for 2 consecutive days. In four phase 3 clinical studies of more than 1000 patients with AK, a higher proportion of those treated with ingenol mebutate gel (n=503) saw complete clearance of AKs in the field of treatment compared with placebo (n=502). The most common adverse events were local skin reactions, including erythema, flaking/scaling, crusting, and swelling. Pain, pruritus, and infection at the application site, as well as periorbital edema and headache, were other adverse events that occurred in ≥2% of individuals treated with ingenol mebutate gel.

Bevacizumab Approval for Breast Cancer Revoked The FDA revoked approval of the breast cancer indication for Avastin (bevacizumab; Genentech), ruling that the drug has not been proved to be safe and effective for that use. Bevacizumab remains on the market as approved for use for certain types of other cancers, including colon, kidney, lung, and brain (glioblastoma multiforme) cancer. Bevacizumab had received accelerated approval for the breast cancer indication in 2008; however, the FDA’s Oncologic Drugs Advisory Committee later recommended this approval be withdrawn. Bevacizumab’s manufacturer filed an appeal, and the FDA held a 2-day public hearing on the issue in June 2011. The FDA issued the decision to revoke the breast cancer indication for bevacizumab on November 18, 2011. The Oncology Nurse-APN/PA will address the implications of the FDA’s decision in an upcoming issue. ●

www.TheOncologyPharmacist.com

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NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

RUX-1004C

11/11

TOP_February 2012_v6_TOP 2/15/12 3:44 PM Page 8

Conference News: SABCS and ASH The following articles are based on presentations at the CTRC-AACR SABCS held December 6-10, 2011, in San Antonio, Texas, and the 53rd Annual ASH Meeting held December 10-13, 2011, in San Diego, California.

Gene Array Test for Predicting... Continued from cover The score can identify low-risk forgo further treat who can ment, as well as high-risk patients who require more aggressive therapy; it can

patients

also identify intermediate-risk patients, who comprise a small but challenging group for treatment decisions. Some insurance plans cover the DCIS

assay, and Genomic Health has an assistance program to help patients gain reimbursement from plans that may not cover the test.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its Reactions Gradesa metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d Urinary Tract Infections 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

February 2012 I VOL 5, NO 1

“The DCIS score [derived from the multigene RT-PCR assay] can be used to quantify an individual patient’s 10-year risk of developing a recurrence. The score provides independent information on recurrence risk beyond clinical and pathological variables. We are not just reinventing the wheel here,” said lead author Lawrence J. Solin, MD, chair of radiation oncology at Einstein Medical Center in Philadelphia, Pennsylvania. The increased incidence of DCIS is attributed to increased use of screening mammography finding cancers at very early stages. The majority of patients diagnosed with DCIS will not have a recurrence. However, until now there has been no validated method to predict recurrence, so all patients with DCIS typically receive radiation and/or hormonal therapy if they are estrogen receptor positive.

The majority of patients diagnosed with DCIS will not experience a recurrence.

The validation study presented at SABCS was based on paraffin-embedded tumor samples from 327 patients enrolled in ECOG 5194, a multi-institutional study of patients with low-, intermediate-, or high-grade DCIS who underwent breast conservation surgery with wide negative margins but did not receive radiation; treatment with tamoxifen was optional. The Oncotype DX DCIS multigene assay was used to classify patients as low, intermediate, or high risk according to prespecified characteristics. Solin noted that about 75% were low risk. The DCIS score was a significant and strong predictor of local recurrence (P = .02) and invasive local recurrence (P = .01) over a 10-year period. The cost of the DCIS test will be similar to that of the Oncotype DX 21-gene assay. Solin said the cost should be offset by the ability to avoid radiation and further treatment in low-risk DCIS. “Treatment selection is not clear for intermediate-risk patients, but this test allows us to provide information on their individual risk level. The numbers of patients in the intermediate-risk group are actually very small. Most patients with DCIS are low risk,” Solin said. ●

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Conference News: SABCS and ASH

Survivors With BRCA Mutations Are at Increased Risk of Contralateral Breast Cancer By Alice Goodman

RCA mutation carriers who have had breast cancer are at increased risk of developing contralateral breast cancer, according to a study presented at the 2011 CTRCAACR San Antonio Breast Cancer Symposium. In fact, women with a BRCA1 or BRCA2 mutation had a greater than 10% risk of developing contralateral breast cancer, and the risk was strongly associated with younger age at diagnosis and a diagnosis of triple-negative (estrogen receptor–negative, progesterone receptor–negative, and HER2negative) breast cancer. “As far as we know, this is the first study to show that subgroups of BRCA1 or BRCA2 carriers have an increased or decreased risk of contralateral breast cancer,” said Alexandra J. van den Broek, MSc, a doctoral candidate at the Netherlands Cancer Institute in Amsterdam.

Women with a BRCA1 or BRCA2 mutation had a greater than 10% risk of developing contralateral breast cancer, and the risk was strongly associated with younger age at diagnosis and a diagnosis of triple-negative breast cancer.

The study included 5061 women who were diagnosed with unilateral, invasive breast cancer at 10 different institutions in the Netherlands. Of these, 211 (4.2%) were carriers of the BRCA1 or BRCA2 mutation. At a median follow-up of 8.4 years, 8.6% of the women developed contralateral breast cancer. The overall 10-year risk for developing contralateral breast cancer was 6%

in noncarriers versus 17.9% in carriers. Among carriers who were diagnosed with their first breast cancer before age 40, the 10-year risk of developing contralateral breast cancer rose to 26%; carriers between the ages of 40 and 50 years at first diagnosis had a 10-year risk of 11.6%. Mutation carriers diagnosed at first with triple-negative breast cancer had a 10-year risk of

developing contralateral breast cancer that reached 18.9%, compared with 11.2% among carriers whose first cancer was not triple-negative. When asked whether knowing their risk of developing contralateral breast cancer might be overwhelming to carriers, who are already anxious over their mutational status, van den Broek said it is crucial to know who is at risk and by how much. In her view, these findings point to the importance of revisiting current guidelines for mutation carriers and incorporating risk factors such as younger age at first diagnosis of breast cancer and a diagnosis of triple-negative breast cancer when considering prophylactic measures and screening. “If these findings are confirmed, it will be possible to personalize the guidelines for these specific subgroups,” she stated. ●

Management of Lymphoma During Pregnancy Feasible

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©iStockphoto.com/JoKMedia

lthough management of lymphoma during pregnancy is not well studied, a retrospective review at 10 academic centers in the United States suggests that in selected cases, lymphoma can be treated with minimal maternal and fetal complications, and that treatment can be deferred until after giving birth in patients with low-risk lymphomas. The study was presented at the 53rd Annual Meeting of the American Society of Hematology held December 2011 in San Diego, California. “To our knowledge, this represents one of the largest experiences reported of lymphoma during pregnancy. There is not much published data in the literature to guide us. Therefore, 10 different centers came together to collect our experiences for guidance for not only ourselves, but treating oncologists across the world,” said lead author of this study, Andrew M. Evens, DO, MSc, University of Massachusetts Medical School, Worcester, Massachusetts. “The main point of our study is that the outcomes we found were consistent with non– pregnancy-associated lymphoma outcomes.” In the United States, approximately 3500 new cases of cancer are diagnosed each year in pregnant women. Breast cancer is the most common type, and hematologic malignancies (about 20% of all cases) are the second most common.

Prior to this study, knowledge about lymphoma during pregnancy came primarily from case reports, Evens explained. The retrospective review included 82 evaluable cases of lymphoma in pregnant women over a 13-year period. Treatment of selected cases of localized disease during the second and third trimester was associated with minimal maternal and fetal risk of complications. The data suggest that treatment for lymphoma can be safely deferred until after giving birth in patients with low-risk lymphomas, such as indolent non-Hodgkin lymphoma (NHL), and/or diagnosis late in gestation. Evens said that this approach can achieve survival similar to that of nonpregnant patients with lymphoma.

Almost all of the cases of lymphoma during pregnancy were comanaged with high-risk maternal fetal medicine, with the goal of carrying the fetus to term (beyond 36 weeks’ gestation). In the 82 evaluable patients, median age was 31 years, about 38% were nulliparous, and lymphoma was diagnosed at a median of 24 weeks’ gestation (range, 5-40): 15% during the first trimester, 46% during the second trimester, 35% during the third trimester, and 4% was preexisting. Of the 82 evaluable cases, 43 were NHL and 39 were Hodgkin lymphoma (HL). Median weight gain was 3.1%, which is considered low. Since lymphoma is associated with weight loss, this low weight gain makes sense, Evens noted. Almost two-thirds (63%) of NHL patients had advanced-stage disease (most of them diffuse large Bcell lymphoma), and 46% of those with HL were in advanced stage; 25% of HL patients had stage IIB. Six patients (4 NHL, 2 HL) terminated pregnancy to initiate chemotherapy (5 in the first trimester and 1 in the early second trimester). Chemotherapy was based mainly on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP) for NHL and doxorubicin, bleomycin, vinblastine, and dacarbazine for HL patients. Therapy was deferred in 34% of patients (n=28).

Seventy-two percent of patients had a vaginal delivery. Among 48 patients who received chemotherapy during pregnancy, full-term gestation occurred in 73% (85% delivered at 35 weeks’ gestation or longer). Among 28 patients who deferred chemotherapy, delivery was at a median of 38 weeks, and 86% of pregnancies were carried to full term. Most common preterm complications were induction of labor (45%), pre-eclampsia (8%), spontaneous rupture of membranes (5%), and diabetes mellitus (4%). No difference in events was observed between patients treated during pregnancy and those who deferred treatment. One stillbirth occurred in an NHL patient treated with 1 cycle of R-CHOP. Fetal outcomes were evaluable in 76 live births. No difference was seen in median birth weight between infants of chemotherapy-treated patients and those who deferred therapy. Only 1 fetal malformation was found: microcephaly in an NHL patient treated with 4 cycles of CHOP. For all patients, 3-year progression-free survival (PFS) and overall survival (OS) were 79% and 89%, respectively: for Bcell NHL, 73% and 82%; for T-cell NHL, 50% and 90%; and for HL, 90% and 95%, respectively. Among the 6 patients who terminated pregnancy, 3year PFS and OS were 100%. ● —AG

February 2012 I VOL 5, NO 1

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Conference News: SABCS and ASH

New Look at Discontinued Drug in Older Patients With Acute Myeloid Leukemia

dministering gemtuzumab ozogamicin (GO) on a new schedule achieved impressive progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in older patients

with acute myeloid leukemia (AML) with favorable cytogenetics, according to a phase 3 study presented at the Plenary Session of the 53rd Annual Meeting of the American Society of Hematology (ASH). GO was taken off the market in

2010 due to toxicity concerns and is no longer available in the US. â&#x20AC;&#x153;Research has demonstrated that GO has very potent anti-cancer properties, and with this study, we have identified a dosing regimen that gives

â&#x20AC;&#x153;Managing patients with myeloma means staying current.â&#x20AC;?

Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

Value-Based Care in Myeloma !&%0!,- !2 &/-%0! %(.!,0%!1 ( *!,-*! .%0!- ,!& .! .) )-. +/ &%.3 ( !-- %--/!- *! % & -! .%)(- "), -! &%(% % (- 0 ( ! *, .% ! (/,-!- ( *$ ,' %-.- 1%&& &-) ") /- )( .$! /(%+/! $ &&!(#!%( .$! ' ( #!'!(. )" '/&.%*&! '3!&)'

www.ValueBasedMyeloma.com Value-Based Care in Myeloma %- */ &% .%)( )" (# #! ! &.$ ,! )''/(% .%)(- '!' !, )" $! 3(2 ,)/* 5 && ,%#$.- ,!-!,0! -%4! (# #!

February 2012 I VOL 5, NO 1

patients the therapeutic benefit of the drug without some of the toxicities reported at higher doses,â&#x20AC;? stated lead author Sylvie Castaigne, MD, professor, department of hematology at HĂ´pital de Versailles, Versailles, France. â&#x20AC;&#x153;The standard of care has been daunorubicin plus cytarabine for many years. There hasnâ&#x20AC;&#x2122;t been a new therapeutic option for several decades, and with this research we are encouraged that GO may be able to improve overall outcomes for these AML patients with limited alternatives.â&#x20AC;? GO is an anti-CD33 antibody conjugated with a toxin; the antibody binds to the surface of CD33-positive leukemia cells and releases the toxin (ie, calicheamicin) into the leukemia cells. The antibody is specifically targeted to the leukemia cells and theoretically spares toxicity to other cells that do not express CD33. The phase 3, prospective, openlabel, randomized trial enrolled newly diagnosed de novo AML patients aged 50 to 70 years. The new 3,3,3 regimen (ie, 3 mg/m2 GO IV on days 1, 4, 7) was designed to give lower but repeated doses that might enhance the efficacy of GO and minimize hepatic and hematologic toxicities reported earlier with this antibody. Patients (N = 280) were randomized to arm A (standard daunorubicin plus cytarabine) or arm B (the same chemotherapy plus the GO 3,3,3 regimen). Those who achieved remission on 2 cycles of treatment were further randomized to 2 courses of consolidation therapy with the same treatments. The experimental arm extended event-free survival (EFS) by just under 8 months. At 2 years, median EFS was 11.9 months with standard therapy versus 19.6 months with the addition of GO, a result that was highly significant (P = .0018). The addition of GO also extended OS: median OS was 19.2 months with standard chemotherapy versus 34 months with chemotherapy plus GO (P = .046). Improvement in EFS and OS was observed in patients with favorable cytogenetics, but not in those with unfavorable cytogenetics, Castaigne emphasized. Fatal events occurred in 6.7% in the standard therapy arm versus 8.7% in GO arm. Adverse events of note in the GO arm included prolonged grade 3 thrombocytopenia in 19 patients and sinusoidal obstructive syndrome in 3 patients (2 fatal). No differences were observed between the treatment arms in the rate of severe sepsis or intensive care admission during therapy. This study, and 2 other positive studies of GO reported at ASH will put pressure on Pfizer to reconsider applying for approval for GO. A Pfizer spokesperson said that the company plans to review results of the positive studies presented at ASH. â&#x2014;? â&#x20AC;&#x201D;AG

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Multiple Myeloma

The Health Burden of Multiple Myeloma: Subcutaneous Bortezomib a New, Convenient Route of Administration Option By Rhonda Williams

n 2011, the American Cancer Society projected there would be 20,520 cases of newly diagnosed multiple myeloma (MM) and 10,610 deaths from the disease that year.1 MM is an incurable hematologic cancer marked by great heterogeneity in terms of its biology and clinical course. Morbidity and survival rates vary widely, even in the age of novel, molecularly based targeted therapies. Many factors account for the differences in prognoses among patients with MM, including genomic aberrations in the plasma cells of the myeloma neoplasm. Survival outcomes range from <1 year in patients with aggressive disease to >10 years in those with indolent disease.2 A variety of patient-, disease-, and therapy-related characteristics have been identified to predict the disease course and outcome among patients with MM. Evaluation of prognostic factors and risk stratification is important to define appropriate treatment strategies, compare therapeutic outcomes, and predict survival among patients.2 The Approach to Therapy in Multiple Myeloma Use of the proteasome inhibitor bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and bisphosphonates such as zoledronic acid (Zometa) and pamidronate (Aredia) has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects, which can negatively affect a patientâ&#x20AC;&#x2122;s quality of life. The majority of preferred regimens for initial therapy are 3-drug combinations, although some 2-drug combinations are also recommended in the current guidelines from the National Comprehensive Cancer Network, because these multidrug regimens are associated with the best response rates.3

New Treatment Option The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, bortezomib disrupts biologic pathways related to the growth and survival of cancer cells.4 Bortezomib was approved by the FDA in 2003 for IV injection for the treatment of patients with MM who had

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the chymotrypsin-like activity of the 26S proteasome in mammalian cells; the 26S proteasome degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of this pathway can therefore affect multiple signaling cascades within the cell and can lead to cell death.5

Pharmacokinetics After IV administration of bortezomib 1 mg/m2 and 1.3 mg/m2 in 24 patients with MM, the maximum plasma concentrations (Cmax) of bortezomib were 57 ng/mL and 112 ng/mL, respectively. The mean elimination half-life of bortezomib with multiple dosing ranged from 40 to 193 hours after administration of the 1 mg/m2 dose and 76 to 108 hours after administration of the 1.3 mg/m2 dose. After an IV or a bolus SC injection of a 1.3 mg/m2 dose in patients with MM, the total systemic exposure with a repeat dose administration was equivalent for the SC and the IV routes of administration. The Cmax after SC administration (20.4 ng/mL) was lower than that after IV administration (223 ng/mL).5 In vitro studies suggest that bortez omib is primarily oxidatively metabolized via the cytochrome P450 enzymes 3A4, 2C19, and 1A2.5

Pharmacodynamics After twice-weekly administration of bortezomib 1 mg/m2 and 1.3 mg/m2, the maximum inhibition of 20S proteasome activity, relative to baseline, occurred 5 minutes after drug administration.5

Phase 3 Clinical Trials: SC Versus IV Bortezomib The FDA approval of SC bortezomib was based on a randomized, open-label, phase 3, noninferiority trial that compared the efficacy and safety of SC ver-

SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.

received at least 2 previous therapies and had demonstrated disease progression on their last therapy.4 In 2008, the FDA approved an expanded indication for bortezomib for the first-line treatment of patients with previously untreated MM. The approval was based on data from the VISTA trial, which compared the addition of bortez omib to melphalan plus prednisone (MP) versus MP without bortezomib (ie, control group) in 682 patients with newly diagnosed MM. At a median follow-up of 16.3 months, the addition of bortezomib to the MP regimen resulted in significantly improved outcomes, including improved response rates, increased time to disease progression, overall survival (OS), and progressionfree survival.5 The trial was stopped early and patients in the control group were permitted to cross over to the bortezomib regimen. In December 2011, results of 5-year median follow-up of the VISTA trial confirmed a >13-month OS advantage of the bortezomib plus MP regimen for patients with previously untreated MM. Bortezomib is also indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 previous therapy.5 In January 2012, the FDA approved a new route of administration for bortezomib. The new subcutaneous (SC) form of bortezomib for injection offers patients an easier mode of administration, with a safety profile comparable to the IV form but with significantly reduced peripheral neuropathy (6% vs 16%, respectively),5 providing patients with MM a new option for route of administration. Clinical Pharmacology of Bortezomib

Mechanism of Action Bortezomib is a reversible inhibitor of

Table 1 Summary of Efficacy Analyses in the Relapsed MM Study of Bortezomib SC Versus IV5 Intent-to-Treat Population

Bortezomib SC (n = 148)

Bortezomib IV (n = 74)

63 (43)

31 (42)

Primary end point Response rate at 4 cycles ORR (CR + PR), n (%) Ratio of response rates (95% CI) CR, n (%) PR, n (%) nCR, n (%)

1.01 (0.73, 1.40) 11 (7) 52 (35) 9 (6)

6 (8) 25 (34) 4 (5)

ORR (CR + PR), n (%) CR, n (%) PR, n (%)

78 (53) 17 (11) 61 (41)

38 (51) 9 (12) 29 (39)

nCR, n (%)

14 (9)

7 (9)

Median time to progression, months

10.4

9.4

Median progression-free survival, months

10.2

8.0

1-year overall survival, %*

72.6

76.7

Secondary end points Response rate at 8 cycles

*Median duration of follow-up is 11.8 months. CI, confidence interval; CR, complete response; MM, multiple myeloma; nCR, near-complete response; ORR, overall response rate; PR, partial response; SC, subcutaneous.

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Multiple Myeloma sus IV administration of bortezomib in patients with relapsed MM. A total of 222 bortezomib-naive patients were randomly assigned, in a 2:1 ratio, to receive bortezomib 1.3 mg/m2 by either SC injection (n = 148) or IV infusion (n = 74) for 8 cycles. Patients were stratified according to the number of lines of previous therapy they had received (1 previous line vs >1 previous line of therapy) and stage of disease, using International Staging System (ISS) stage I, II, or III.5

The primary study end point was to demonstrate noninferiority of singleagent SC bortezomib with respect to overall response rate (ORR)—complete response (CR) plus partial response (PR). In this study, noninferiority was defined as retaining at least 60% of the ORR relative to single-agent IV bor tezomib after 4 cycles of therapy.5 Patients who did not obtain an optimal response (less than CR) to treatment with bortezomib alone after 4 cycles were allowed to receive oral dex-

amethasone 20 mg daily on the day of and day after bortezomib administration (n = 82 in the SC treatment group; n = 39 in the IV treatment group). Patients with baseline grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/μL, were excluded from trial participation. A total of 218 patients were evaluable for response.5 The baseline demographic and other characteristics of the 2 treatment groups were similar. The median patient age was approximately 64 years

Table 2 Most Common Adverse Events (≥10%) in the Relapsed MM Study of Bortezomib SC Versus IV5 Bortezomib SC (n = 147)* toxicity MedDRA System Organ Class MedDRA preferred term

Total n (%)

grade 3

grade ≥4

n (%)

Bortezomib IV (n = 74)* toxicity grade 3

grade ≥4

n (%)

Total n (%)

n (%)

Blood and lymphatic system disorders Anemia

53 (36)

14 (10)

4 (3)

26 (35)

6 (8)

Leukopenia

29 (20)

9 (6)

16 (22)

4 (5)

1 (1)

Neutropenia

42 (29)

22 (15)

4 (3)

20 (27)

10 (14)

3 (4)

Thrombocytopenia 52 (35) Gastrointestinal disorders

12 (8)

7 (5)

27 (36)

8 (11)

6 (8)

Abdominal pain

5 (3)

1 (1)

8 (11)

Abdominal pain upper

3 (2)

8 (11)

Constipation

21 (14)

1 (1)

11 (15)

1 (1)

Diarrhea

35 (24)

2 (1)

1 (1)

27 (36)

3 (4)

1 (1)

Nausea

27 (18)

14 (19)

Vomiting

17 (12)

3 (2)

12 (16)

1 (1)

21 (14)

1 (1)

8 (11)

1 (1)

8 (5)

1 (1)

8 (11)

2 (3)

0 5 (3)

0 0

8 (11) 17 (23)

0 7 (9)

0 0

56 (38)

8 (5)

1 (1)

39 (53)

11 (15)

1 (1)

18 (12)

8 (11)

Safety Profile: Reduced Peripheral Neuropathy With SC Administration The safety data reported herein are from the randomized, open-label study that compared the SC administration of bortezomib with IV administration of bortezomib at the recommended dose of 1.3 mg/m2 in 222 patients with relapsed MM. Overall, the safety data were similar between the SC and IV treatment groups (Table 2), but with significant differences in some adverse events (AEs) favoring the SC form of bortez omib. Differences of ≥5% between the 2 groups favoring the SC administration were reported for neuralgia (3% SC vs 9% IV), peripheral neuropathy grade ≥3 (6% SC vs 16% IV) and all grades (38% vs 53%), and thrombocytopenia (13% SC vs 19% IV).5 In the SC treatment group, local reactions, primarily redness, were reported in 6% of patients; 2 patients (1%) experienced local reactions that were considered severe (1 case of pruritus and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in 1 patient and reduction in dose concentration in 1 patient.5 Dose reductions associated with drug-related AEs were reported in 31% of patients in the SC group compared with 43% of patients in the IV group. The most common AEs leading to dose reduction included sensory peripheral neuropathy (17% SC vs 31% IV) and neuralgia (11% SC vs 19% IV).5

9 (12)

2 (3)

Warnings and Precautions Associated With Bortezomib

General disorders and administration site conditions Asthenia Fatigue

23 (16) 17 (12)

3 (2) 3 (2)

0 0

14 (19) 15 (20)

4 (5) 3 (4)

0 0

Pyrexia

28 (19)

12 (16)

16 (11)

2 (1)

7 (9)

1 (1)

22 (15)

2 (3)

1 (1)

7 (9)

Infections and infestations Herpes zoster Investigations Weight decreased

Metabolism and nutrition disorders Decreased appetite

14 (10)

Musculoskeletal and connective tissue disorders Back pain Pain in extremity

Nervous system disorders Headache 5 (3) Neuralgia 35 (24) Peripheral neuropathies NEC† Psychiatric disorders Insomnia

Respiratory, thoracic, and mediastinal disorders Dyspnea

11 (7)

2 (1)

Vascular disorders Hypertension

14 (10)

3 (2)

3 (4)

*Safety population: 147 patients in the SC treatment and 74 patients in the IV treatment who received at least 1 dose of study medication. † Represents MedDRA high-level term. MedDRA, Medical Dictionary for Regulatory Affairs; NEC, not elsewhere classified; SC, subcutaneous.

(range, 38-88 years), and the majority of patients were male (SC, 50%; IV, 64%). The primary type of myeloma was immunoglobulin G. ISS stage I/II/III was 27%, 41%, and 32%, respectively, with both SC and IV routes of administration. The Karnofsky performance status score was ≤70 in 22% of SC-treated patients and 16% of IV-treated patients. Creatinine clearance was 67.5 mL/min in the SC group and 73 mL/min in the IV group. The median years from diagnosis were 2.68 years and 2.93 years in the SC and IV groups, respectively. The proportion of patients with >1 prior line of therapy was 38% with SC treatment versus 35% with IV treatment.5 This study met its primary objective (noninferiority) that treatment with single-agent SC bortezomib retains at least 60% of the ORR after 4 cycles versus IV bortezomib (Table 1).5

February 2012 I VOL 5, NO 1

Peripheral Neuropathy Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. The peripheral neuropathy associated with bortezomib use

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Multiple Myeloma is primarily sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported with use of the agent. Patients with preexisting symptoms such as numbness, pain, or a burning sensation in the feet or hands, and/or signs of peripheral neuropathy, may experience worsening of peripheral neuropathy, including grade ≥3, during treatment with bortezomib.5 A paradigm shift regarding bortezomib use currently exists, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. The results of a phase 3 study by Moreau and colleagues that included patients with relapsed MM who had received 1 to 3 previous lines of therapy showed that SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.6 The protocol of this study provided for a robust comparison of the 2 routes of administration, since it specified 4 cycles of single-agent bortezomib with the addition of oral dexamethasone 20 mg to enhance response at the end of cycle 4 in patients who achieved a suboptimal response.6 In this trial, the incidence of grade ≥2 peripheral neuropathy was 24% in patients who received SC bortezomib and 41% in those who received IV bortezomib.5,6 Also in this trial, grade ≥3 peripheral neuropathy occurred in 6% of patients in the SC treatment group and 16% of those in the IV treatment group.5,6 When initiating bortezomib therapy, SC administration may be considered for patients with preexisting peripheral neuropathy or those who are at high risk for developing peripheral neuropathy. In patients with preexisting, severe peripheral neuropathy, the risk-benefit should be carefully assessed prior to beginning bortezomib therapy.5 Prevention rather than treatment is the best approach to use when addressing bortezomib-related neuropathy. One advantage of bortezomib is that most episodes of grade 3/4 neuropathy can be prevented by closely adhering to the algorithm for dose modification and interruption provided in the prescribing information (Table 3). By following these recommendations, the severity of peripheral neuropathy can usually be decreased to grade 1 or 2, and in many cases, patients may resume bortezomib therapy.5

Hypotension The incidence of hypotension, which included postural hypotension, orthostatic hypotension, and hypotension not otherwise specified, reported with the use

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Table 3 Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy5 Severity of Peripheral Neuropathy Modification of Dose and Regimen Signs and Symptoms* Grade 1 (asymptomatic; loss of deep No action tendon reflexes or paresthesia) without pain or loss of function Grade 1 with pain or grade 2 (moderate Reduce bortezomib to 1 mg/m2 symptoms; limiting instrumental activities of daily living [ADL])† Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL)‡

Grade 4 (life-threatening consequences; urgent intervention indicated)

Withhold bortezomib therapy until toxicity resolves; when toxicity resolves reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once weekly Discontinue bortezomib

*Grading is based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. † Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money. ‡ Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

of bortezomib was 13%. These events occurred throughout treatment. Caution should be used when administering bortezomib to patients with a history of syncope, those receiving medications known to be associated with hypotension (eg, antihypertensive agents), and persons who are dehydrated.5

Cardiac Disorders Exacerbation or acute development of congestive heart failure and new onset of decreased left ventricular ejection fraction (LVEF) have been reported in patients receiving treatment with bortezomib, including those with no known risk factors for decreased LVEF. Thus, patients at risk for the development of heart disease or those with a history of existing heart disease should be monitored closely.5

lopathy syndrome (RPLS), a rare, reversible neurologic disorder that can present with seizure, hypertension, lethargy, headache, blindness, confusion, and other visual and neurologic disturbances, has been reported in patients receiving bortezomib therapy. Bortezomib should be discontinued in patients who develop RPLS that has been confirmed by brain imaging, preferably MRI.5

Gastrointestinal Events Nausea, diarrhea, constipation, and vomiting, at times requiring the use of antiemetic therapy and antidiarrheal agents, have been reported in patients receiving bortezomib. In order to prevent dehydration, fluid and electrolyte replacement should be administered to these patients.5

The primary study end point was to demonstrate noninferiority of single-agent SC bortezomib with respect to overall response rate.

Pulmonary Disorders Reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, acute respiratory distress syndrome, and lung infiltration, have been noted among patients receiving treatment with bortezomib.5 Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencepha-

Thrombocytopenia and Neutropenia Bortezomib is associated with the development of thrombocytopenia and neutropenia that follows a cyclical pattern, with nadirs that generally occur following the last dose of each cycle and typically recover prior to initiation of the next cycle of therapy. This cyclical pattern remained consistent over 8 cycles of twice-weekly therapy, with no evidence of cumulative thrombocy-

topenia or neutropenia observed. In patients experiencing thrombocytopenia, platelet counts should be monitored prior to the administration of each dose; an adjustment in dose and/or schedule may be required. There have been reports of gastrointestinal and intracerebral hemorrhage associated with the use of bortezomib.5

Tumor Lysis Syndrome Tumor lysis syndrome may occur with the use of bortezomib because the agent is cytotoxic and can rapidly kill malignant cells. Patients with a high tumor burden prior to therapy may be at a higher risk for the development of tumor lysis syndrome.5 Hepatic Events Acute liver failure has occurred in bortezomib-treated patients receiving multiple concomitant medications and in those with serious underlying medical conditions. Other hepatic events reported with the use of bortezomib include elevations in liver enzymes, hyperbilirubinemia, and hepatitis.5 Hepatic Impairment Because bortezomib is metabolized by the liver, exposure is increased in patients with moderate or severe hepatic impairment. Therefore, such patients should be started on reduced doses of bortezomib and closely monitored for the development of toxicities.5 Use in Pregnancy Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.5 Dosing Bortezomib is for IV or SC administration only and should not be administered by any other route. The recommended starting dose of bortezomib is 1.3 mg/m2 for both SC and IV forms of administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume of drug to be administered. With IV administration, the recommended concentration of bortezomib is 1 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL.5

Dosage in Patients With Previously Untreated MM In patients with previously untreated MM, bortezomib is administered in combination with oral melphalan and oral prednisone for a total of nine 6week treatment cycles. In cycles 1 through 4, bortezomib is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (on days 1, 8, 22, and 29). At least

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Multiple Myeloma 72 hours should elapse between consecutive doses of bortezomib.5

Dosage in Patients With Relapsed MM or Mantle Cell Lymphoma In patients with relapsed MM or mantle cell lymphoma, bortezomib 1.3 mg/m2 per dose is administered twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 through 21). For extended ther-

Y DA O T ER $100 T GISAVE E R S

apy of more than 8 cycles, bortezomib may be administered according to the standard schedule or on a maintenance, once-weekly schedule for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period.5

Dose Modifications A patient’s platelet count should be ≥70 ¥ 109/L and his or her absolute neutrophil count should be ≥1.0 ¥

109/L before receiving any cycle of therapy with bortezomib in combination with melphalan and prednisone. All nonhematologic toxicities should have resolved to grade 1 or to baseline level.5 Dose modification guidelines for patients with relapsed MM or mantle cell lymphoma state that bortezomib therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hematologic toxicities

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 • JW Marriott • Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES • 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 it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that 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

Gary Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS

DESIGNATION OF CREDIT STATEMENTS

President, CEO OncoMed

excluding neuropathy, which is discussed separately. Once the symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated at a 25% reduced dose.5 Administration Precautions When the SC route of administration is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.5 If local injection site reactions occur after SC bortezomib administration, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be used for SC administration. Alternatively, the IV route of administration may be considered.5

Prevention rather than treatment is the best approach to use when addressing bortezomibrelated neuropathy. Conclusion MM is an incurable hematologic cancer with great clinical burden. The use of bortezomib, and lenalidomide and thalidomide, as well as zoledronic acid and pamidronate, has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects. A 3-drug combination therapy is the preferred approach to treatment, but some 2-drug combinations are also recommended in current guidelines. Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. A paradigm shift regarding bortezomib use has emerged, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. ●

Physician Accreditation – Joint Sponsor

References

The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 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 (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. 2. Munshi NC, Anderson AC, Bergsagel PL, et al; for the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:46964700. 3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple Myeloma, Version 1. 2012. www.nccn.org. Accessed February 5, 2012. 4. CenterWatch. Drug information. Velcade (bortezomib). www.centerwatch.com/druginformation/fdaapprovals/drug-details.aspx?DrugID=830. Accessed February 5, 2012. 5. Velcade prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012. 6. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit. This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

February 2012 I VOL 5, NO 1

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

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Breast Cancer BOLERO-2: Practice-Changing Results With Exemestane... Continued from cover First results of this study, called BOLERO-2, were presented in September 2011 at ECCO/ESMO/ ESTRO. Updated results with additional follow-up, presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, confirm the PFS benefit of adding everolimus to exemestane in this group of women. Overall survival (OS) data are not yet mature. â&#x20AC;&#x153;We believe these results underline that everolimus is the first agent to significantly enhance the efficacy of hormonal therapy in patients with HR+ breast cancer. The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population,â&#x20AC;? stated Gabriel N. Hortobagyi, MD, professor of medicine and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, Texas â&#x20AC;&#x153;Endocrine therapy is the treatment of choice for the majority of breast cancers that express the estrogen receptor, which represents about 75% of patients over age 50. The standard is to use multiple endocrine regimens in sequence to get multiple mileage. But the sad truth is that after a few months of suppression of tumor cells on one agent, tumor cells become smarter and resistant and we need to change agents,â&#x20AC;? Hortobagyi explained. Everolimus is an mTOR inhibitor. This pathway is activated in hormoneresistant advanced breast cancer. Phase 2 clinical trials of everolimus monotherapy and in combination with endocrine therapy were encouraging in advanced HR+ breast cancer, Hortobagyi explained. Positive results of phase 2 trials with everolimus added to hormonal therapy led to the strategy tested in BOLERO-2, he said. BOLERO-2 was a prospective, double-blind, placebo-controlled, phase 3 trial. The study population included 724 postmenopausal women with HR+ metastatic breast cancer with disease progression on previous hormonal therapy (ie, resistance). Patients were randomized 2:1 to exemestane plus everolimus (n=485) versus exemestane plus placebo (n=279). Baseline demographics and disease characteristics were similar between the arms. At baseline, median age was 62 years, 56% had visceral metastases, and 84% had documented benefit from previous endocrine therapy with letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%). Sixty percent had excellent performance status. The study popula-

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tion reflects a variety of ethnic groups, he said. At a median follow-up of 12.5 months, median PFS was 7.4 months for the combination versus 3.2 months for exemestane plus placebo. The percentage of patients who experienced clinical benefit (complete response, partial response, stable disease, amount

of pain, and overall benefit of the drug) was almost double in the combination arm: 50.5% for the combination versus 25.5% for exemestane plus placebo. The combination of exemestane plus everolimus was well tolerated, Hortobagyi told listeners. The most common grade 3 or higher adverse events for the combination versus

exemestane plus placebo, respectively, were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs <1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%). Adverse events were manageable with dose delays or dose reductions. Quality of life was almost identical in both arms of the study. â&#x2014;?

April 20-22, 2012 â&#x20AC;˘ Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: â&#x20AC;˘ Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or 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

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. CORE PRINCIPLE SOLUTIONS, LLC

Teresa Petrella, BSc, MD, MSc, FRCPC Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-089-L01-P.

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Breast Cancer

Eribulin Associated With Less Neuropathy Than Ixabepilone in a Prospective, Randomized Study By Caroline Helwick

n a randomized phase 2 study of metastatic breast cancer patients, peripheral neuropathy (PN) was less likely to occur in patients receiv-

ing eribulin mesylate than with ixabepilone. “Peripheral neuropathy is a big problem in the treatment of breast cancer.

Across the spectrum, patients have it, and we don’t know how to treat it,” said Linda T. Vahdat, MD, of Weill Cornell Medical College in New York,

Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: • Newly Diagnosed Patients • Maintenance Therapy • Transplant-Eligible Patients • Retreatment • Transplant-Ineligible Patients • Cytogenetics • Side-Effect Management • Bone Health

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

Topics include: • Hodgkin Lymphoma • Follicular Lymphoma • Mantle Cell Lymphoma • Waldenstrom’s Macroglobulinemia • Diffuse Large B-Cell Lymphoma • T-Cell Lymphoma

PN was less likely to occur in patients receiving eribulin mesylate than with ixabepilone.

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEAsize40611MM

February 2012 I VOL 5, NO 1

who presented the study at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium (Poster P5-19-02). “If we want to be able to identify patients at risk for peripheral neuropathy and develop strategies to manage it we need to characterize it better. This trial was conceived and started after the close of the EMBRACE trial. It gave us the opportunity to get a better handle on how eribulin performed from the perspective of side effects. The endpoint was the incidence of neuropathy.” EMBRACE demonstrated that eribulin treatment significantly improved median overall survival by 2.5 months compared with standard treatments in heavily pretreated metastatic breast cancer patients. The overall incidence of PN in eribulin-treated patients was 35% and was mostly mild; grade 3 was seen in 8% and grade 4 in <1%.

The current study prospectively evaluated PN in 101 heavily pretreated metastatic breast cancer patients who were randomized to eribulin or ixabepilone as single agents on an every-3-week schedule; the mean number of treatment cycles was 6.2 in the eribulin group and 4.8 in the ixabepilone group. Almost one-third of patients in each arm had received at least 6 prior agents. “We found the incidence of neuropathy was about 13% lower with eribulin,” Vahdat reported. PN of any grade occurred in 31% of the eribulin group and 44% of the ixabepilone group. Grade 3/4 PN occurred in 10% versus 20%, respectively. The difference numerically favored eribulin, though it was not statistically significant, she added. “Most importantly,” she said, “the median time to the onset of treatment-emergent neuropathy was

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Breast Cancer longer in the eribulin group: 36 weeks versus only about 12 weeks with ixabepilone. By cycle 4, only 24% of patients receiving eribulin had developed neuropathy, compared to 44% receiving ixabepilone.” In addition, safety end points, including objective response rate and progression-free survival, based on Response Evaluation Criteria in Solid Tumors, showed greater reduction in the longest diameter of target lesions (ie, reducing tumor size) with eribulin (~80%) compared with ixabepilone (~70%) from baseline to nadir, as well as faster rate of change with eribulin, as shown in the Figure. Vahdat acknowledged that if ixabepilone were given weekly, as it often is, the Figure. Waterfall graphs of percent change in summed longest diameter of target lesions from baseline to nadir in incidence of PN would be lower. The patients receiving a) eribulin or b) ixabepilone according to RECIST (ITT population) study followed the FDA-approved dos- Figure courtesy of Prash Krishna, MBBS, MRCS. ing schedule. ●

Cancer Center Profile LSU Health Feist-Weiller Cancer Center Continued from cover Affiliate Programs located outside of Memphis, Tennessee. As an academic institute, there are more than 50 faculty members at work within the 3 divisions of the FeistWeiller Cancer Center. Each division— the Division of Clinical Cancer Research, the Division of Basic and Translational Cancer Research, and the Division of Cancer Prevention and Control—encourages strong collaboration among researchers and clinicians to increase the understanding of the mechanisms regulating cancer formation and progression, and to developing novel techniques to detect and treat cancer, all with the goal of providing better care for patients. Gary Jean, PharmD, BCOP, answered our questions about the Feist-Weiller Cancer Center and the role of oncology pharmacists in patient care and research.

What approach does your institution take to treating people with cancer? Gary Jean (GJ): LSU Health and FeistWeiller Cancer Center engage in evidence-based medicine and multidisciplinary, translational cancer research; provide patients cutting-edge treatment with access to national cancer clinical trials; and educate both physicians and the community about the prevention, treatment, and the science of cancer. How does that translate to better outcomes for your patients? GJ: The Feist-Weiller Cancer Center team is committed to bringing lifesaving discoveries about cancer to all of

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Louisiana and beyond. Collaboration between cancer researchers and treating physicians fosters a more comprehensive understanding of cancer. Feist-Weiller Cancer Center faculty: • Conduct laboratory and clinical research to discover better methods of preventing and treating cancer • Provide adult and pediatric patients with state-of-the-art cancer care, regardless of their ability to pay • Educate and train hematology/ oncology fellows, community physicians, and local residents about the most modern cancer treatments so all patients will receive the best possible cancer care • Supply Louisiana communities with cancer screenings and education materials for prevention through Partners in Wellness, a unique community cancer screening program

What are you excited about right now in the field of oncology? GJ: As a clinician, I am excited about the constantly changing aspect in the field of oncology. The evolution of cancer treatment provides a challenging and rewarding career in patient care. It is knowing that there is always going to be something new that keeps me enthusiastic about my work. How has the role of the oncology pharmacist changed over the past 5 years? GJ: As a relatively new practitioner, I have seen a change away from a dispensing model to one oriented more toward direct patient care. With so many new drugs and changes in the standard of

gy-related rotations as I could and studied the field at every opportunity. As my experience grew, getting to know the people behind the diseases increased my love for the field. While the success rate for a potential cure isn’t as high as we all hope for, being able to provide care for our patients in such a difficult time in their lives is a privilege.

Hong Nguyen, RPh, and Penny Crevoiserat, RPh, oncology pharmacists at Feist-Weiller Cancer Center.

care, pharmacists have to stay current to adequately take care of patients. Whether it’s verifying chemotherapy orders in clinic or making rounds on a medical oncology or bone marrow transplant service, every aspect of the patient has to be evaluated to ensure that patient care and safety come first.

What inspired you to become an oncology pharmacist? GJ: I was first exposed to oncology in my second year of pharmacy school during a pharmacotherapy lecture. It was then that I became intrigued about the level of complexity involved in leukemia, specifically, and I quickly came to understand, in all malignancies. The complex nature of the different disease states and constantly changing treatment regimens drew me even closer. By the time I had my first “oncology” rotation in my third year of pharmacy school, I was hooked. Through the mentorship of my future program director, Sachin Shah, PharmD, BCOP, I took as many oncolo-

Any advice for pharmacists just entering the field? GJ: There are a couple of things that I have noticed in my short tenure as an oncology pharmacist. Oncology is a field that you either love or hate. Regardless of the reason, if you choose the field of oncology, choose it for the right reason. In my opinion, being an oncology pharmacist requires a high level of commitment and caring for this population, because a simple mistake with these drugs could be catastrophic. The second piece of advice would be to never assume. We are human and are in no way perfect. If something doesn’t look right, a simple phone call can solve a lot of problems ahead of time. What are some areas of focus at your institution? GJ: Our population has continued to grow, even in the short time that I have been here. We are constantly engaged in physician-based and drug company– sponsored research. We are actively engaged in community outreach with cancer screening and prevention initiatives. In addition, we are actively involved in integrative medicine, which has taken patient care from being disease focused to being patient focused. ●

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New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

i dd

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UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

MP (n=338)

0 0

Kaplan-Meier estimate.

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

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Leukemias Bruton’s Tyrosine Kinase Inhibitor... Continued from cover that induces apoptosis and inhibits cellular migration and adhesion in malignant B cells. “It is very exciting to have agents that are this effective and are not myelosuppressive. The efficacy of this agent increases over time, there is a relative lack of toxicity, and there is a

lack of myelosuppression. These agents should really change the paradigm for the treatment of CLL,” stated lead author Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston. An earlier analysis of the phase 1b/2 study showed that PCI-32765

was highly active and tolerable in patients with CLL. The data O’Brien presented at ASH were based on longer-term follow-up of a multicenter phase 1b/2 trial. The study enrolled 61 CLL patients aged 65 or older with previously untreated or relapsed/refractory CLL after at least

2 prior therapies. Patients received oral PCI-32765 daily in 28-day cycles until disease progression. Seventytwo percent of patients had at least 1 poor-risk molecular feature: del(17p) 31%, del(11q) 33%, or IgVH unmutated 57%. The study evaluated 2 doses of the Btk inhibitor: 420 mg and 840 mg daily. The analysis presented at ASH included patients with relapsed/refractory disease, but not those who were previously untreated. Median follow-up for the 420 mg cohort was 10.2 months and 6.5 months for the 840 mg cohort.

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy:: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension:: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders:: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders:: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS):: There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events:: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia:: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome:: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) m may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers:: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use:: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use:: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment:: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment:: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes:: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

Hepatic Events:: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment:: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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“The efficacy of this agent increases over time, there is a relative lack of toxicity, and there is a lack of myelosuppression.” —Susan O’Brien, MD

For the 420 mg cohort, objective response rates (ORRs) improved from 48% at 6 months of follow-up to 70% at 10 months; in the 840 mg cohort, ORR was 44% at a median follow-up of 6.5 months. The Btk inhibitor seems to be effective in shrinking CLL in the lymph node compartment. At the time of the ASH meeting, nodal partial response was observed in 35% of patients (>50% reduction in aggregate lymph node size), with residual lymphocytosis. ORR appears to be independent of molecular risk features, O’Brien commented. The novel agent was well tolerated. Two patients discontinued treatment due to adverse events; 6 patients required dose reductions. Grade 1/2 diarrhea, fatigue, nausea, and ecchymosis were the most frequently reported side effects. Ten percent of serious adverse events were attributed to PCI-32765, as were 21% of grade ≥3 adverse events. “Myelosuppression has not been a problem with this agent,” O’Brien said. At the time of the ASH meeting, 82% of patients remained on treatment with PCI-32765. Only 8% (5/61) progressed; 6-month progression-free survival was 92% in the 420 mg cohort and 90% in the 840 mg cohort. Pharmacyclics, the company developing the novel Btk inhibitor, is planning phase 3 trials of PCI-32765. ●

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Koeller’s Corner

Shooting from the Hip So You Want to Be an Oncology Pharmacist Specialist. What Are Your Options?

will say right up front that I am all in favor of specialty pharmacy training and the subsequent board certification. The real questions are: how much training is enough? how much is too much? and what options are available? I’ve been in the oncology business for over 30 years now and began when there was no real specialty training to speak of. In fact, my introduction into the specialty just happened; it wasn’t planned at all. I wanted to stay in Madison, Wisconsin, when I finished my hospital pharmacy residency, but I was actually more interested in emergency care. I happened to come across an announcement that the oncology department was looking for a coordinator to handle their new National Cancer Institute (NCI) contract, so on a fluke I went in and talked with the physician who was the principal investigator. We got along, and I was hired to manage the University of Wisconsin Comprehensive Cancer Center’s phase 1 NCI contract, working directly with the principal investigator. I had worked as a pharmacist on the oncology unit of the university hospital but had no additional formal oncology training. The rest, as they say, is history. The bottom line is that I learned on the job. I was allowed to do what I was able to do and demonstrate that I was competent. So, I basically did everything. I saw all the phase 1 patients, helped the fellows do workups, wrote all the orders for the patients, followed the patients, had my own clinic, started most of the IVs, kept all the experimental drugs, mixed and administered all the drugs, did all the pharmacokinetic blood drawing, sample handling, etc, and kept all the records for the program. I managed between 70 and 100 patients each year for 2 to 3 active phase 1 trials. I also went to the

phase 1 meeting at the NCI and was expected to present our data. As I see it, specialty recognition is a 2-step process: one is training, and the other board certification. I know everyone is aware of the medical model with general medical/surgical training followed by specialty training and board certification. This is the model that pharmacy, for good or for bad, adopted years ago. First, the American Society of Health-System Pharmacists created accredited specialty residencies. The first accredited oncology specialty residency was in 1984. Once training was standardized to some degree through specialty residency training, it became easier to establish a scope of practice for oncology pharmacists. Once a scope of practice could be established, certification could be sought. So as far as oncology pharmacy goes, we have both accredited training and board certification available.

Everyone is aware of the medical model with general medical/surgical training followed by specialty training and board certification. This is the model that pharmacy, for good or for bad, adopted years ago. So, let’s add up the years. The average PharmD program in the US is now 6 years. Many students (like those at the University of Texas) have completed more than the 2-year pre-pharmacy program as our degree is now designed. A large percentage of our students already

have an undergraduate degree upon entering pharmacy. If the average pharmacy student has already put in between 6 and 8 years of college before completing both a PGY-1 and then an oncology specialty PGY-2 year, the total time of training can easily reach 10 years. Also, many students, some of whom are married and have children, have completed up to 8+ years of pharmacy training and need to “get out” of school, take a break, and earn some money. Note that the $40,000 to $60,000 generally earned during the residency process may not be adequate for many of these students. This leads to the question, is 8 to 10+ years of training to become an oncology pharmacist specialist reasonable? Apparently many would say yes, because this is the process and timeline today. As I tell the students I interact with, you do graduate work and residency training (or any type of extra training) so that you can hopefully have a better chance of landing that job that you will love getting up for every morning. Those with the most credentials will generally have the better chance and more options available for getting a job they love. This brings up the issue of money. As I also tell the students with whom I interact, all the extra training you do may not mean you will make a lot of extra money in terms of salary, but hopefully it will mean that you will be happy at work every day. I can say after 30+ years of doing this, loving what you do every day easily trumps the money. However, if you just cannot go straight through the 10+ years for your specialty training (including pharmacy school), is getting out and getting your oncology experience while you work as a pharmacist OK? My answer to this is yes!

Can someone learn oncology on the job? Absolutely! It just may not be the most efficient or ideal way of doing it. Trying to find a “clinical” position in a hospital or clinic may be difficult without residency training, but probably not impossible. Back in the day when there was no formal specialty training process, learning on the job was much more common. If you were a pharmacist who worked in oncology, sooner or later you were viewed as the oncology pharmacist (by default). Things have come a long way since then, and finding that perfect position where you can learn on the job is probably less common today. Many people hiring today want to bring in someone who can do the job right off the bat. Another issue with all the training required for specialization is that many young people may not know what area of specialization they want to settle into at the time of their graduation or even residency training. Many of these do PGY-1 general training, and some even do PGY2 specialty training in pharmacotherapy, yet they may not know exactly what they want to do for a living. From my years of training here in San Antonio, I can give you numerous examples of residents who completed their pharmacotherapy specialty residency training but are now “oncology pharmacists” in a variety of positions across the country. I have always called these my “recent converts” (those who swore they didn’t like oncology and did pharmacotherapy instead, only to “see the light” shortly after that and then “convert” to oncology). Even more recently, one of our master’s/pharmacotherapy residents is now an oncology specialist and lecturer at a college of pharmacy. Is all the training—either going straight through or learning on the job— worth it to be an oncology pharmacist? It has been for me, but I cannot answer for you. You will have to decide.... ●

Would you like straight-shooter Jim Koeller to respond to a particular topic? E-mail your ideas to editorial@greenhillhc.com. www.TheOncologyPharmacist.com

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Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®. Our Specialists can help you navigate the process.

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