FEBRUARY 2013 I VOL 6, NO 1 I SPECIAL ISSUE by Dalia Buffery

The Peer-Reviewed Forum for Evidence in Benefit Design ™ For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

February 2013 I Vol 6, No 1 I SPECIAL ISSUE

Payers’ Perspectives in Oncology Including Highlights from ASH 2012*

NIH Research Funding Cuts Would Have Devastating Impact on Hematology

Azacitidine Reduces Transfusions and Costs for Patients with High-Risk MDS

Future of care delivery at risk, says ASH president-elect

By Caroline Helwick

By Wayne Kuznar

Atlanta, GA—The use of azacitidine (Vidaza) in patients with high-risk myelodysplastic syndrome (MDS) is associated with the reduced need for red blood cell (RBC) transfusion and transfusion dependence, a report from the 2012 ASH meeting showed. “At 12 and 18 months after azaci tidine treatment, there were 26% and 38% reductions in RBC transfusion costs, respectively, per patient com-

ith the fiscal cliff in the rear-view mirror, the next economic pressure is the impending spending cuts and debt

ceiling crisis in the coming months. Although cuts to the budget of the National Institutes of Health (NIH) Continued on page 6

Hematologic Drug Pipeline Is Bustling By Caroline Helwick

argeted therapies, immunomodulatory agents, and monoclonal antibodies with impressive response rates for the treatment of various hematologic malignancies were among the agents in late-stage development that were featured during

oral and poster sessions at the ASH 2012 meeting. Success with some of these therapies was groundbreaking. Leukemias Quizartinib. A selective inhibitor of Continued on page 4

*This publication is neither endorsed by nor associated with the American Society of Hematology.

Continued on page 9

New Targeted Agent Shows Significant Success in Treating Refractory Form of AML Complete response seen in patients with FLT3 mutation By Wayne Kuznar

new selective inhibitor of the FLT3 gene, quizartinib, produced complete remission in more than 33% of patients with an aggressive form of acute myeloid leukemia (AML). The treatment allowed these patients to bridge to potential ly curative allogeneic stem-cell transplant, said principal investigator, Mark Levis, MD, PhD, Associate Professor of Oncology and Medicine, Johns Hop-

kins Kimmel Can cer Center, Baltimore, MD, at ASH 2012. Quizartinib is a potent and selective inhibitor of FLT3, a gene that produces an enzyme that Mark Levis, MD, PhD signals bone marrow stem cells to re populate after chemotherapy. In pa tients with AML, an FLT3-ITD (internal Continued on page 12

in th i s i s s u e Health Economics . . . . . . . . . . . 6 Selective JAK inhibitor cost-effective in myelofibrosis Faster rituximab infusion lowers cost

LEUKEMIA. . . . . . . . . . . . . . . . . . 12 Ponatinib shows high response rates Alternatives emerge for “7 + 3” induction therapy for AML

pared with the 6 months before therapy,” said Eric Tseng, MD, Department of Hematology, University of Toronto, Ontario, Canada. In 2009, azacitidine was shown in the AZA001 study to improve overall survival, leukemia-free survival, and hematologic response, while reducing transfusion dependence in intermediate- and high-risk MDS, compared with conventional care.

LYMPHOMA. . . . . . . . . . . . . . . . . Ara-C for young patients with mantle-cell lymphoma

MYELOMA . . . . . . . . . . . . . . . . . 24 Overall survival benefit of pomalidomide in advanced myeloma Four-drug induction and 2-drug maintenance improves survival PAYERS’ PERspECTIVE. . . . . . . 27 New data highlight challenges and opportunities for payers DRUG UPDATE . . . . . . . . . . . . . . Ponatinib a new option for CML or Ph+ ALL

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on the next page of this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

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. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Health Economics

Hematologic Drug Pipeline Is... FLT3, quizar tinib, cleared leukemia cells from the bone marrow in a significant proportion of patients with acute myeloid leukemia (AML), thereby permitting transplant in many of them. Quizartinib is currently in phase 2 trials showing a more than

33% remission rate in patients with refractory AML (see article on page 1). Inotuzumab ozogamicin is an antibody-drug conjugate in early development; it is composed of a monoclonal antibody targeting CD22 that is linked to a cytotoxic agent.

INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: 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. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%. 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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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 of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms. 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 of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) 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. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. 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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, 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) 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, VELCADE 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 bortezomib 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 VELCADEHCP.com.

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 © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

3779_milpro_fa3_hpayr_vbcc.indd 3

American health & drug benefits

Data from a phase 1 clinical trial of weekly inotuzumab in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) showed that a best overall response was achieved by 83% of the participating patients; a hematologic remission rate

Embryo-fetal: Pregnancy Category D. Women of reproductive 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.

Brief Summary

Continued from page 1

V-12-0306

11/12

was achieved by 74% of the patients. Response to therapy with inotuzumab ozogamicin was achieved shortly after induction therapy, with a median time to remission of 28 days.

“Blinatumomab as a single agent induced an unprecedented high rate of complete hematological and MRD responses in adult patients with relapsed/ refractory B-precursor ALL.” —Max S. Topp, MD Blinatumomab, a bispecific T-cell– engaging antibody construct that directs cytotoxic T-cells to CD19- expressing B-cells, induced complete remission in 12 of 18 (67%) of the patients within the first 2 cycles of treatment when used as a single agent in a phase 2 clinical trial of patients with B-precursor ALL. “Blinatumo mab as a single agent induced an unprecedented high rate of complete hematological and MRD [minimal residual disease] responses in adult patients with relapsed/refractory B-precursor ALL,” said lead investigator Max S. Topp, MD, from Wuerzburg University Medical Center, Wuerzburg, Germany. Lymphoma Ibrutinib. The Bruton’s tyrosine kinase inhibitor ibrutinib demonstrated robust single-agent activity in patients with relapsed or refractory mantle-cell lymphoma, according to the international, phase 2 PCY-1104CA trial. “Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle-cell lymphoma,” said Michael Wang, MD, University of Texas M.D. Anderson Cancer Center. Among the 115 patients, including those with and without previous exposure to bortezomib, the overall response rate (ORR) was 68%, and complete response (CR), >20%. The median progression-free survival (PFS) was 13.9 months for the whole population and has not yet been reached among responders. Ibrutinib is active in other lymphomas as well, including in patients with diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. Response rates in patients with these tumors and relapsed or refractory disease ranged from 23% to 44%; these rose to 55% with optiContinued on page 6

11/8/12 11:06 AM

february 2013

VOL. 6

NO. 1

Special Issue

The Peer-Reviewed Forum For Evidence in Benefit Design™

Payers’ Perspectives in Oncology

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton 732-992-1892 Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 National Accounts Manager Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and edi torial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage 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. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright.com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VOL. 6

NO. 1

Special Issue

HEALTH ECONOMICS NIH research funding cuts would have devastating impact on hematology Hematologic pipeline is bustling Azacitidine reduces transfusions, costs for high-risk MDS Ruxolitinib cost-effective option for myelofibrosis More….. LEUKEMIA Quizartinib promising for refractory AML “Dramatic” responses with targeted agent in CLL More….. PERSONALIZED MEDICINE Newly discovered AML genes identify response to therapy Can prognostic factors guide DLBCL treatment? More…..

LYMPHOMA Ara-C for young patients with mantle-cell lymphoma Ibrutinib: it’s not just for leukemia More….. MYELOMA Overall survival benefit with pomalidomide in advanced myeloma Host factors are important in myeloma patients More….. PAYERS’ PERspeCTIVE New data highlight challenges and opportunities for payers DRUG UPDATE Ponatinib a new treatment option for TKIresistant/intolerant CML or Ph+ ALL

EDITORIAL BOARD Editor-in-Chief David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health, Philadelphia, PA Deputy Editors Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research Jefferson School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy Philadelphia

J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship University of Michigan, School of Public Health and Medicine, Ann Arbor HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City

Aging and Wellness Joseph Couto, PharmD, MBA Eric G. Tangalos, MD, FACP, AGSF, CMD Clinical Program Manager Professor of Medicine Cigna Corporation, Bloomfield, CT Mayo Clinic, Rochester, MN Steve Miff, PhD CANCER RESEARCH Senior Vice President Al B. Benson III, MD, FACP, FASCO VHA, Inc., Irving, TX Professor of Medicine, Associate Director for Clinical Investigations Kavita V. Nair, PhD Robert H. Lurie Comprehensive Cancer Associate Professor, School of Pharmacy Center, Northwestern University, IL University of Colorado at Denver, CO Past Chair, NCCN Board of Directors Gary M. Owens, MD President, Gary Owens Associates Samuel M. Silver, MD, PhD, FASCO Glen Mills, PA Professor of Internal Medicine Hematology/Oncology Andrew M. Peterson, PharmD, PhD Assistant Dean for Research Associate Director, Faculty Group Practice Dean, Mayes School of Healthcare Business and Policy, Associate Professor University of Michigan Medical School University of the Sciences Philadelphia, PA EMPLOYERS Arthur F. Shinn, PharmD, FASCP Sarah A. Priddy, PhD President, Managed Pharmacy Director, Competitive Health Analytics Consultants, LLC, Lake Worth, FL Humana, Louisville, KY F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Health Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts care and Bentteligence, Sharon, MA Xcenda, Palm Harbor, FL ENDOCRINOLOGY Vincent J. Willey, PharmD James V. Felicetta, MD Associate Professor, Philadelphia School Chairman, Dept. of Medicine of Pharmacy, University of the Sciences Carl T. Hayden Veterans Affairs Philadelphia, PA Medical Center, Phoenix, AZ Paul Wilson Quang Nguyen, DO, FACP, FACE Senior VP, Health Consumer Insights Adjunct Associate Professor, Endocrinology and Analytics Blue Bell, PA Touro University Nevada, College of Osteopathic Medicine David W. Wright, MPH President, Institute for Interactive Patient EPIDEMIOLOGY Research Care, Bethesda, MD Joshua N. Liberman, PhD Executive Director, Research, Development health & value promotion & Dissemination Craig Deligdish, MD Sutter Health, Concord, CA Hematologist/Oncologist Oncology Resource Networks, Orlando, FL GOVERNMENT Kevin B. “Kip” Piper, MA, FACHE Thomas G. McCarter, MD, FACP President, Health Results Group, LLC Chief Clinical Officer Washington, DC Executive Health Resources, PA HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Waukesha, WI

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs Pfizer Specialty Care Business Unit, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy, Washington State University Spokane, WA Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine Amalia M. Issa, PhD, MPH Professor and Chair Department of Health Policy and Public Health Director, Program in Personalized Medicine & Targeted Therapeutics University of the Sciences, Philadelphia PHARMACOECONOMICs Josh Feldstein President & CEO CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate Menlo Park, CA Michael S. Jacobs, RPh Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute, Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy Practice and Administration, School of Pharmacy University of Missouri Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist RAND Health Paul Pomerantz, MBA Executive Director Drug Information Association Horsham, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY Atheer A. Kaddis, PharmD Senior Vice President Managed Markets/Clinical Services Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Paul Anthony Polansky, BSPharm, MBA Michael Kleinrock Senior Field Scientist, Health Outcomes Director, Research Development and PharmacoEconomics (HOPE) IMS Institute for Healthcare Informatics Endo Health Solutions, Chadds Ford, PA Collegeville, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA

february 2013

www.AHDBonline.com

Health Economics NIH Research Funding Cuts Would Have Devastating... Continued from page 1 have not been mentioned so far, the American Society of Hematology (ASH) is voicing its support of NIH funding at levels at least as high as the current levels to support hematology research, while ASH also initiates a program of funding bridge grants. “Our concern is that NIH funding will be an afterthought,” said ASH President-Elect Janis Abkowitz, MD, the Hematology Division Head, Clement A. Finch Professor of Medicine, and Adjunct Professor of Genome Sciences, University of Washington, Seattle. Dr Abkowitz believes that cuts to the NIH budget could have a lasting impact on research that ranges from clinically oriented “to research that might take place in zebra fish or mice…the NIH funds ideas, and the concern is that we will be sacrificing ideas for the future and the competitiveness we have not only in the world economy but in terms of healthcare delivery.” ASH Survey A survey unveiled at the ASH 2012 annual meeting demonstrates how crit-

“The NIH funds ideas, and the concern is that we will be sacrificing ideas for the future and the competitiveness we have not only in the world economy but in terms of healthcare delivery.” —Janis Abkowitz, MD ical NIH funding has been to the success of hematology research. The survey represented responses from 1040

Hematologic Drug Pipeline Is... mal dosing, according to other investigators at the meeting (see article on page 20). Multiple Myeloma MLN9708. The oral investigational proteasome inhibitor MLN9708 produced impressive results in a phase 1/2 study of patients with treatment-naïve multiple myeloma. MLN9708, given in combination with lenalidomide, achieved an ORR exceeding 90%, CRs in 25% of patients, and a low rate of peripheral neuropathy (grade 3 in 3%). As an oral proteasome inhibitor with a good tolerability profile, MLN9708 may help achieve the goal of having a convenient, all-oral, first-line treatment for myeloma (see article on page XX). Pomalidomide. In the phase 3 MM003 trial of patients with advanced multiple myeloma, the oral immunomodulatory agent pomalidomide was associated with an improvement not only in PFS but also in overall survival (OS). After a median follow-up of 18 months, the median PFS was 15.7 weeks versus 8 weeks with high-dose dexamethasone, a 55% reduction in risk (P <.001). The OS was 34 weeks with highdose dexamethasone, but has not been reached with pomalidomide plus lowdose dexamethasone, translating into a 47% risk reduction (P <.001).

february 2013

field, she says, leaving a gap in the medical science workforce.

Nearly 66% of the US presenters at ASH 2012 reported that they rely on NIH funding for their research. ASH Launches Bridge Grants Program In a recent editorial published in the Journal of the American Medical Association, Dr Abkowitz and her coauthors announced an ASH program designed to “assist medical research through this potential chasm in funding” (Hromas R, et al. JAMA. 2012;308:2343-2344). The ASH bridge grants totaling $9 million will support basic, clinical, and translational research in hematology; the grants will require that the researcher’s institution provides a 50% match of the funds. Dr Abkowitz and her coauthors caution, however, that bridge support from medical societies is not sustainable, and that federal and state funding is essential to maintain excellence. n

Continued from page 4

Pomalidomide combined with lowdose dexamethasone essentially doubled the median PFS versus high-dose dexamethasone alone. Pomalidomide is considered more potent than the 2 available immunomodulatory agents, thalidomide and lenalidomide, and is expected to become approved by the US Food and Drug Administration soon (see article on page 24). Daratumumab and elotuzumab. The data continue to accumulate for novel monoclonal antibodies in pa tients with myeloma. In a phase 1/2 study of 32 patients, daratumumab produced clinical benefit in almost 50% of the heavily pretreated relapsed/refractory population, and 47% of patients had a reduction in the amount of monoclonal protein in the blood or in the urine. Elotuzumab, another monoclonal antibody, given with lenalidomide and dexamethasone, was evaluated in a dose-finding study of 73 patients who had received a median of 2 previous lines of therapy, showing a 92% ORR and a median PFS that has not been reached after 21 months of follow-up. Phase 3 trials are evaluating 10-mg/kg elotuzumab and a lenalidomide plus dexamethasone combination in newly diagnosed patients.

American health & drug benefits

presenters of abstracts at this year’s meeting, including 415 US presenters. Nearly 66% of the US presenters reported that they rely on NIH funding. In addition, 86% of American abstract presenters reported that they had referenced an NIH-funded study for their own research over the course of their careers. The survey also reveals a high level of concern among researchers and hematologists/oncologists about the impact of reduced NIH funding on the field of hematology and patient care. Of 412 US respondents, 75% said that when it comes to medical research and development, they are “extremely concerned” about the threat of NIH budget cuts and the impact on their future research. Of the 1040 respondents, 52% said that they have referenced an NIH-funded study for their own research, and 44% indicated that they were “extremely concerned” about the threat of NIH budget cuts. Mid-level researchers and their mentors are getting discouraged by the difficulty in obtaining federal research grants and are leaving the

ARRY-520. In a phase 2 clinical trial, the kinesin spindle protein inhibitor ARRY-520, given with or without dexamethasone, produced responses in 19% to 22% of enrolled patients with myeloma, with median response durations of 5.4 to 8.6 months. The side effect profile was mild, and no cases of peripheral neuropathy were reported. In a phase 1 clinical trial, therapy with ARRY-520 plus carfilzomib in patients with relapsed and/or refractory myeloma produced a 22% response rate, of which 11% were CRs. These studies further suggest that level of protein alpha-1-acid glycoprotein may serve as a biomarker for response in this patient population. Lorvotuzumab mertansine. A new class of drugs in early development has also impressed myeloma specialists at the meeting. Lorvotuzumab mertansine is a chemotherapy agent that is attached to an antibody. In a phase 1 clinical trial of 44 pretreated patients with myeloma, lorvotuzumab mertansine, in combination with len alidomide plus dexamethasone, led to a very high response rate—57%; however, peripheral neuropathy was reported by 56% of the patients. Myelofibrosis SAR302503. An open-label phase 2

study showed that a novel, investigational selective Janus kinase (JAK)2 inhibitor, SAR302503, reduced spleen size and improved constitutional symptoms in patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The reductions in spleen size from baseline were 30% to 42% depending on the dosage of SAR302503. A phase 3 trial of 289 patients is ongoing, with results expected in the second quarter of 2013. CYT387. An investigational selective JAK1/JAK2 inhibitor in early development, CYT387 produced dur able responses in anemia, splenomegaly, and constitutional symptoms in a phase 1/2 open-label study of 166 patients with myelofibrosis. At 12 weeks, the proportion of patients with transfusion independence ranged from 57% to 75%, depending on the dose of CYT387 that was used. The median duration of the transfusion-free period has not yet been reached. The median spleen decrease ranged from 36% to 46% with this new agent, with a median duration of response of 744 days. Fever resolved in 100% of the patients, and night sweats and pruritus either resolved or were markedly improved in more than 70% of the patients. n VOL. 6

NO. 1

Special Issue

Health Economics

Selective JAK Inhibitor Cost-Effective Option for Patients with Myelofibrosis By Wayne Kuznar

eneficial treatment options for patients with myelofibrosis are significantly lacking, although 1 drug, ruxolitinib (Jakafi), has proved effective in clinical trials. Compared with best available therapy, ruxolitinib proved to be a cost-effective option for patients with myelofibrosis, according to the findings from a cost-effectiveness study that was presented by Khalid El Ouagari, PhD, of Novartis Pharmaceuticals Canada, and colleagues. Ruxolitinib is an orally available, se lective inhibitor of Janus kinase (JAK)1 and JAK2 of the JAK-STAT signaling pathway. In the clinical trial COMFORT-II, ruxolitinib was proved to be clinically efficacious and was superior to best available therapy at diminishing splenomegaly and its condition-associated symptoms, while also enhancing patient quality of life. The latest trial was designed to determine the cost value of adding ruxolitinib to other myelofibrosis drug treatment options and the cost-effectiveness of ruxolitinib compared with best available therapy for the treatment of myelofibrosis. A Markov model was used to determine the cost, health outcomes, and

the cost-effectiveness of ruxolitinib versus best available therapy, consisting of a treatment or a combination treatment that is selected based on the COMFORT-II trial guidance.

Patients who were receiving ruxolitinib had less resource-use cost, mainly because patients with reduced spleens usually had less physician visits and less hospital admissions. All patients started the model having myelofibrosis with splenomegaly. The model tracked the progression of 4 health states—responder, nonresponder, leukemic transformation, and death—for 12 weeks during the patients’ lifetime. The rate by which patients navigated through the 4 health states was influenced by risk status at the study’s start, as well as by the success in or the inability of achieving responder state

(≥35% reduced spleen volume and/ or a lack of symptoms, such as weight loss, fever, or night sweats). Using a 1-way sensitivity analysis and a probabilistic sensitivity analysis, the outcomes measured were cost over time, life-years, quality of lifeyears, time when the patient did not have leukemic transformation, and the time as a treatment responder. All patients had intermediate-2 risk (51%) or high-risk (49%) myelofibrosis, according to the International Working Group for Myelofibrosis Research and Treatment risk categorization. Treatment Cost, QALY: Ruxolitinib versus Best Available Therapy The average treatment cost of a patient receiving ruxolitinib was $494,859, of which $205,484 was attributed to the drug cost. By comparison, the cost of managing a patient with best available therapy was $421,755, of which $59,289 was drug cost. Patients who were receiving ruxolitinib had less resource-use cost, mainly because patients with reduced spleens usually had less physician

visits and less hospital admissions, according to the model assumptions, resulting in similar overall cost between the 2 approaches. The ruxolitinib treatment arm produced a higher financial burden for leukemic transformation as a result of enhanced overall survival. Consequently, more adverse events and more transfusion-dependency costs were also seen in the ruxolitinib arm. Quality-adjusted life-years (QALYs) were 4.01 in the ruxolitinib arm and 2.82 in the best available therapy arm. The overall incremental cost- effectiveness ratio of ruxolitinib was $61,444 per QALY. Because there is a better survival outcome for intermediate-2 risk patients than for high-risk patients, the ruxolitinib group ended up with greater QALYs and subsequent additional costs over the patients’ lifetimes. In addition, although there may be no survival advantage with the removal of constitutional symptoms, such as weight loss or fever, because patients with less symptomatic issues sustain treatment with ruxolitinib for a longer duration, there is more drug-related cost. n

Faster Rituximab Infusion Lowers Cost By Caroline Helwick

n the treatment of non-Hodgkin lymphoma, faster infusion of rituximab (Rituxan) results in direct cost-savings for providers and for patients, reported John Hornberger, MD, of Cedar Associates, Menlo Park, CA, and a consultant to Genentech, at the 2012 ASH meeting. This is especially important “in an era of landmark legislation designed to address concerns about rising costs of healthcare and place more emphasis on patient-centered research,” noted Dr Hornberger. Although the direct medical cost- savings were relatively small, the savings in indirect costs were almost 40%, the study showed. “The most influential parameters included cost to treat grade 3/4 ad verse events, administration costs, and patient’s foregone income due to time for infusions. The savings per course may be greater if infusion centers are able to spread fixed costs, such as

VOL. 6

NO. 1

Special Issue

overhead, among a greater number of patients, resulting from the increased capacity to schedule more patients,” Dr Hornberger said.

for patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in cycles 2 to 8.

“The most influential parameters included cost to treat grade 3/4 adverse events, administration costs, and patient’s foregone income due to time for infusions. The savings per course may be greater if infusion centers are able to spread fixed costs, such as overhead, among a greater number of patients resulting from the increased capacity to schedule more patients.” —John Hornberger, MD The 90-Minute Infusion Data According to its US prescribing information, rituximab is typically given over 4 to 6 hours for the first infusion and over 3 to 4 hours for subsequent infusions. Recently, the US Food and Drug Administration approved 90-minute infusions

This new study assessed the cost from a US societal perspective of the faster infusion versus the conventional 4- to 6-hour infusion schedule in patients scheduled to receive rituximab 375 mg/m2 plus standard chemotherapy. The model included the direct

medical resources—chemotherapy administration, chemotherapy, pretreatment drugs (wholesale acquisition cost), and grades 3 and 4 adverse events—and the indirect visits for infusion costs to patients and caregivers. The data came from the phase 3 RATE clinical trial that evaluated alternative dosing of rituximab in 451 untreated patients. The target population was projected to be 23,519 newly diagnosed patients with DLBCL and FL. The estimated total direct medical cost for conventional infusion was $825,005,088; the cost of foregone income for patients and caregivers was $9,217,527. The 90-minute infusion reduced the direct medical costs by $2,205,689 (0.3%) and foregone income by $3,598,649 (39%). This resulted in an average cost-savings of $42 per infusion and $247 per course of treatment. n

february 2013

www.AHDBonline.com

Health Economics

Internet-Based Tool Helps Guide Treatment Decisions in Patients with CML See also Leukemia By Wayne Kuznar

n online tool may increase the number of oncologists who make optimal treatment decisions for patients with chronic myeloid leukemia (CML) based on their response to first-line tyrosine kinase inhibitor (TKI) therapy, according to Kevin L. Obholz, PhD, Senior Managing Editor, Clinical Care Options, Reston, VA. The tool is designed to provide customized, patient-specific expert advice similar to one developed for the adjuvant treatment of breast cancer. The breast cancer tool had a positive impact on treatment decisions, notes Dr Obholz. “Current treatment guidelines (European LeukemiaNet and National Comprehensive Cancer Network [NCCN]) lack definitive recommendations for patients who have suboptimal responses to first-line TKI therapy,” he said. “Furthermore, in a recent survey, only 58% of community oncologists made treatment decisions in line with expert recommendations for clinical scenarios in which patients had a suboptimal response to

first-line therapy with imatinib.” The interactive web-based decision support tool was developed with input from 5 CML experts who made treatment recommendations for 42 different patient scenarios. The tool requires

“In a recent survey, only 58% of community oncologists made treatment decisions in line with expert recommendations for clinical scenarios in which patients had a suboptimal response to first-line therapy with imatinib.” —Kevin L. Obholz, PhD the user to input the patient’s age and the duration of first-line TKI therapy, along with hematologic, cytogenetic, and/or molecular responses to the TKI therapy at 3, 6, 12, and 18 months. Recommendations are provided by the CML experts, and the user is

then asked whether the recommendations confirmed or changed his or her intended management approach, to determine whether the online tool helped community providers make more informed therapeutic decisions. The analysis included 291 cases. Impact questions were answered for 154 of the 291 cases, with the following results: • 21 (14%) indicated that the experts’ recommendations changed their intended clinical approach • 16 (approximately 10%) indicated that they had changed their approach from continuing their first-line TKI to switching therapy; of these cases, 8 responses were defined as failure and 8 were cases with suboptimal responses • 3% answered that they changed their approach from switching the current therapy to continuing the current therapy • Of the total users, 58% indicated that the online support tool confirmed their clinical approach • Only 28% said that the tool did not have an impact on their approach.

“A separate analysis of the in-tool recommendations showed that the experts considered not only guidelines, but also emerging data and their own clinical experience in making recommendations for specific patient scenarios,” Dr Obholz pointed out. For example, experts recommended using quantitative polymerase chain reaction of peripheral blood with a BCR-ABL/ABL ratio of 10% as the threshold for guiding a therapeutic change at 3 months, which predated similar recommendations that were included in the most recent update to the NCCN treatment guidelines for CML. Furthermore, 4 of 5 experts recommended a therapeutic change for patients in complete cytogenetic remission without major molecular response (MMR) at 12 months if there was a concomitant increase in the BCR-ABL ratio of ≥1 log. In addition, 3 of 5 experts recommended a therapeutic change for patients without a MMR at 18 months, regardless of whether their BCR-ABL/ABL ratio was increasing. n

Rasburicase Cost-Effective for Tumor Lysis Syndrome By Caroline Helwick

study using real-world data for patients with tumor lysis syndrome (TLS) showed that treatment with rasburicase (Elitek) was associated with significantly greater reductions in uric acid, length of hospital stay, and total hospitalization costs per patient compared with allopurinol (Zyloprim). TLS, which is a consequence of either tumor treatment or spontaneous tumor death, is an oncologic emergency. TLS can lead to renal failure, seizures, severe muscle weakness, tetany, cardiac arrhythmias, and death. The treatment options for TLS include allopurinol and rasburicase. “Although rasburicase is a higherpriced drug, it holds the potential for reduced inpatient costs and may, therefore, provide a more costeffective treatment option than allopurinol,” said Mitchell S. Cairo, MD, Chief, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, at New York Medical College, Valhalla, NY, and Director of the Children’s and Adolescent Cancer and Blood Diseases Center and Medical and Scientific Director of the

Stem and Cellular Therapy Laboratory at Westchester Medical Center, New York. Dr Cairo presented the results of a retrospective cohort study of administrative data from the Health Facts database, which includes comprehensive pharmacy, laboratory, admission, and billing records from more than 400 hospitals. Using propensity scores, patients treated with rasburicase were matched 1 to 4 with patients treated with allopurinol according to multiple factors. The study evaluated the potential cost-effectiveness of rasburicase compared with allopurinol in patients with TLS who were identified by laboratory values and by clinical markers. The investigators determined the difference, by treatment arm, in the reduction of uric acid level, alteration in renal function, length of hospital stay, and the total hospitalization cost in cancer patients with laboratory values or clinical markers and hyperuricemia. The changes were calculated as the difference between the uric acid level at treatment initiation, as well as 2 days later.

American health & drug benefits

february 2013

The evaluable population included 26 patients who received rasburicase and 104 receiving allopurinol. The mean baseline uric acid levels were 11.4 mg/dL in the rasburicase group and 11.2 mg/dL in the allopurinol group.

“Although rasburicase is a higher-priced drug, it holds the potential for reduced inpatient costs and may, therefore, provide a more cost-effective treatment option than allopurinol.” —Mitchell S. Cairo, MD

The investigators determined that patients treated with rasburicase had significantly greater mean reductions in uric acid levels, intensive care unit lengths of stay, hospital lengths of stay, and total hospitalization costs per patient than those treated with allopurinol.

By the second day of treatment, the mean uric acid levels were significantly lower with rasburicase (2.7 mg/ dL) compared with allopurinol (8.0 mg/dL; P <.001). Changes in potassium, phosphorus, and creatinine levels were comparable between the groups by the second day of treatment. The mean total lengths of stay were 11.5 days with rasburicase and 16.5 days with allopurinol; the mean intensive care unit stays were 1.4 days and 3.9 days, respectively; and the mean total costs per patient for inpatient hospitalization were $35,065 and $54,103, respectively. The mean total costs per percentage of uric acid reduction were $3915 with rasburicase and $16,907 with allopurinol (P <.001). “Although the drug cost of rasburicase is higher than allopurinol, treatment with rasburicase in patients with laboratory values TLS and clinical markers TLS was more cost-effective, because it reduced length of stay and overall costs,” Dr Cairo concluded. He suggested that future analyses of cost-effectiveness should consider differences in outpatient costs as well. n VOL. 6

NO. 1

Special Issue

Health Economics

Combined Chemoradiation Cost-Effective in Younger Patients with Primary CNS Lymphoma Chemotherapy alone favored in older patients

SPONSORS

COMMERCIAL SUPPORT ACKNOWLEDGMENT

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

SATURDAY, MAY 4, 2013

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

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

11:00 am - 11:45 am

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

PHYSICIAN CREDIT DESIGNATION

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

REGISTERED NURSE DESIGNATION

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

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

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

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

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

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

9:15 am - 10:00 am

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

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

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

11:00 am - 11:45 am

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

11:45 am - 12:00 pm

Summary and Conclusion of Conference

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

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

www.regonline.com/avbcc2013

*Agenda is subject to change. AVBCCKsize20413

Leukemia tandem duplication) mutation occurs in approximately 33% of patients, and constitutively activates FLT3. The FLT3 mutation is associated with high blast counts, frequent and rapid relapse, and reduced overall survival (OS), said Dr Levis. “We have been trying to inhibit this enzyme for the last 10 years,” he stated. “Quizartinib is the first drug designed as a FLT3 inhibitor. It’s extremely selective; it tends to just hit FLT3 and a few others. It’s 10 to 50 times more potent in humans than any of the other FLT3 inhibitors.” The phase 2 open-label trial included 271 patients with AML who were divided into 2 cohorts. Cohort 1 consisted of patients aged ≥60 years who failed to achieve remission with standard chemotherapy or who had recently relapsed for the first time. Cohort 2 consisted of patients aged ≥18 years who presented with relapsed or refractory AML and were administered salvage chemotherapy after failing to respond to prior treatment, or had

New Targeted Agent Shows Significant Success... Continued from page 1

“Quizartinib is the first drug designed as a FLT3 inhibitor. It’s extremely selective; it tends to just hit FLT3 and a few others. It’s 10 to 50 times more potent in humans than any of the other FLT3 inhibitors.” —Mark Levis, MD, PhD

relapsed after a stem-cell transplant. Dr Levis presented data from the 138 patients in cohort 2, of whom 100 had the FLT3-ITD mutation. “These patients are essentially the equivalent of those on death row,” said Dr Levis. “We don’t have a cure rate to even report in this group.” Patients were treated with 28-day cycles of quizartinib monotherapy. In the 100 patients with the confirmed FLT3-ITD mutation, 46% had a complete response (CR)—6% had a CR with or without full platelet recovery, and 40% had a CR without full hematologic recovery. In the group with a CR, the median duration of response was 12.1 weeks. A composite complete remission occurred in 46% of patients with the FLT3ITD mutation and in 32% of patients in whom the mutation was not detectable. Of the patients with the FLT3-ITD mutation who were refractory to their most recent therapy, 79% had at least a partial response to quizartinib. Of the patients who had a CR to

quizartinib and were then bridged to potentially curative bone marrow transplant, 18 have survived at least 60 weeks, Dr Levis noted. The median OS was 22.9 weeks and 25.6 weeks in patients with the FLT3ITD mutation and in whom the mutation was not detectable, respectively. “Our focus with this drug is to clear the leukemia out of the patient’s bone marrow to a sufficient degree to allow them to go to transplant,” Dr Levis explained. Overall, 34% of patients were successfully bridged to transplantation. The median OS was 33.3 weeks in the patients who were FLT3-ITD positive and were bridged to transplantation compared with 17.7 weeks among those who did not receive a stem-cell transplant. In patients in whom the FLT3ITD mutation was not detectable, the median OS has not yet been reached in the patients who were bridged to transplantation, whereas the median OS was 20.8 weeks in those without stemcell transplant. n

New Oral TKI Ponatinib Produces High Response Rates in Hard-to-Treat Leukemia Atlanta, GA—The new oral tyrosine kinase inhibitor (TKI) ponatinib (Iclusig) has significant activity and is well tolerated in patients with highly pretreated chronic myeloid leukemia (CML) or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who otherwise lack therapeutic options. Twelvemonth follow-up data from a pivotal phase 2 trial of ponatinib in this population were reported by Jorge E. Cortes, MD, Professor of Medicine and Deputy Chair, Department of Leukemia, at M.D. Anderson Cancer Center, Houston, at the 2012 ASH meeting. “This therapy may be able to transform highly fatal forms of leukemia into a curable disease in these patients—we have simply never had

at a glance ➤ Ponatinib is the newest TKI that was recently approved by the FDA for the treatment of patients with CML or Ph+ ALL ➤ In clinical studies, the response rate to ponatinib was 56% in patients with chronicphase CML ➤ Overall, 57% of patients achieved a major cytogenetic response

any treatment produce such high rates of durable response in such a heavily treated group of patients,” he said. As a result of these data, the US Food and Drug Administration (FDA) approved ponatinib for the treatment of CML and Ph+ ALL in adults under its accelerated approval program. Approximately 5% to 20% of pa tients with CML and Ph+ ALL have the “gatekeeper” T315I BCR-ABL mutation, which confers resistance to dasatinib or nilotinib. Ponatinib binds to the BCR-ABL active site and had shown potent activity against native BCR-ABL and BCR-ABL mutants, including T315I, in earlier clinical trials. In addition, high levels of response to ponatinib had been observed in patients with no mutations who have experienced resistance or intolerance to the other TKIs. The international, open-label clinical trial Ponatinib Ph+ ALL and CML Evaluation (PACE) measured the safety and efficacy of ponatinib, 45 mg daily, in 449 patients with Ph+ leukemia (CML or Ph+ ALL) who were in various stages of disease. Among this heavily treated cohort, more than 90% of patients had been administered at least 2 TKIs, and approximately 60% of the patients in the chronic phase had received 3 TKIs. A significant predictor of response

American health & drug benefits

february 2013

By Wayne Kuznar

“This therapy may be able to transform highly fatal forms of leukemia into a curable disease in these patients— we have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients.” —Jorge E. Cortes, MD to a new drug for CML is how well a patient responds to previous drugs, said Dr Cortes. Only 25% of patients with CML in the trial had any response at all to previous TKIs. The primary end point for chronic phase was a major cytogenetic re sponse at any time within 12 months for CML, and a major hematologic response within 6 months after treat-

ment for patients with advanced-phase CML or Ph+ ALL. “For patients in more advanced stages of disease, who can be difficult to treat or are more likely to be resistant to all therapies, the goal is to generate a major hematologic response,” said Dr Cortes. In the chronic phase, which included 267 patients, the rate of response to ponatinib was 56%. In the 83 patients in the accelerated phase, almost 60% of patients achieved a major hematologic response. In addition, Dr Cortes pointed out, “We’re already getting deep molecular responses—one third are getting major molecular responses.” A significant 91% of these patients are predicted to maintain their responses. “These are very encouraging, sustained responses,” he acknowledged. “Of note, responses are happening regardless of mutations. Patients with mutations other than T315I respond very well.” A total of 57% have achieved a major cytogenetic response. Among the patients with no mutations, the response rate was 49%. Of note, “the drug is very well tolerated,” Dr Cortes said. Common side effects, which are usually mild and manageable, included skin rash and dry skin. Only 1 patient had to leave the study because of pancreatitis. n VOL. 6

NO. 1

Special Issue

Leukemia

“Dramatic” Responses with Targeted Agent for Patients with CLL A 22-month survival in 96% of treatment-naïve patients By Charles Bankhead Atlanta, GA—Targeting Bruton’s tyrosine kinase (BTK) in patients with chronic lymphocytic leukemia (CLL) resulted in high response rates, without severe toxicity, according to the results of 2 studies that were presented at the 2012 ASH meeting. Data from one trial showed a 70% response rate in 116 patients treated with ibrutinib and a 22-month survival of 96% in previously untreated patients and 76% in the subgroup with relapsed/refractory CLL. A second study reported at the meeting demonstrated objective responses in 83% of patients with high-risk CLL who were treated with ibrutinib. “Ibrutinib has the potential to change the treatment landscape in CLL,” said John C. Byrd, MD, Director of Hematology at The Ohio State University Comprehensive Cancer Center in Columbus during a press conference. BTK has emerged as a key player in the abnormal B-cell antigen receptor signaling that drives CLL and certain other B-cell diseases. Ibrutinib is one of

“Ibrutinib has the potential to change the treatment landscape in CLL.” —John C. Byrd, MD several BTK inhibitors in development and is the farthest along in clinical investigation. Dr Byrd presented results from a trial of ibrutinib monotherapy involv-

ing 85 patients with previously treated CLL and 31 treatment-naïve patients. All patients received 420 mg daily orally, which was associated with a 68% objective response rate (10% complete response [CR]) in the previously untreated patients and 70% (2% CR) in the relapsed/refractory group. In addition, 13% of the treatment-naïve patients and 4% of patients in the relapsed/refractory group had stable disease. At 22 months, 96% of the treated subgroup remained alive, as did 85% of the patients with relapsed/ refractory disease. The second trial involved 40 patients with poor-prognosis CLL. The cohort included patients with a history of poor response to therapy and those with unfavorable genetics, said Jan Burger, MD, PhD, a hematologic oncologist at The University of Texas M.D. Anderson Cancer Center in Houston. All patients received ibrutinib daily plus weekly infusions of rituximab during the first month, followed by

once-monthly infusions thereafter. The regimen resulted in 1 CR, 32 partial responses, 2 minor responses, and no response in 2 patients. Two other patients had not been treated long enough for a response assessment. Dr Burger characterized the ibrutinib- rituximab combination as highly active, not that several patients had particularly dramatic responses. In both trials, ibrutinib was associated with low rates of severe toxicity. Dr Byrd reported a 13% incidence of grade 3/4 myelosuppression and grade 3/4 infection in 10% of untreated and 40% of relapsed/refractory patients. Dr Burger reported 13 cases of grade 3/4 toxicity, including neutropenia, fatigue, pneumonia, insomnia, and bone pain. Diarrhea was the most common adverse effect associated with ibrutinib in both trials, and cases were grade 1/2 in severity. “Most side effects were modest and went away after the first couple of cycles of therapy,” noted Dr Byrd. n

Fast Response Identifies Patients with CML for Entry into Studies of Imatinib Discontinuation By Wayne Kuznar

n early major molecular re sponse (MMR) identifies pa tients with chronic myeloid leukemia (CML) who are more likely to achieve undetectable BCR-ABL1 transcripts while receiving imatinib therapy, and represent candidates for entry into studies of discontinuing therapy, said Susan Branford, PhD, Department of Genetics and Molecular Pathology, University of Adelaide School of Medicine, Australia. “The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients,” she said. Some patients have long-term treatment-related side effects, which is especially problematic for younger patients, whereas others become pregnant. The cost of therapy is also a consideration for many patients who wish to discontinue treatment with imatinib. “Some carefully selected patients can sustain remission after imatinib discontinuation,” said Dr Branford.

VOL. 6

NO. 1

Special Issue

The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive real-time quantitative polymerase chain reaction (PCR) assay. In the French Stop Imatinib (STIM) study, the overall probability of maintaining a response after discontinuation of imat inib was 39% versus 42.7% in the Australian CML8 (TWISTER) study. The studies had similar enrollment criteria: patients received imatinib for at least 3 years and had stable undetectable BCR-ABL1 for at least 2 years, with a PCR sensitivity of 5 log and 4.5 log, respectively, she said. It is not known how many patients receiving imatinib will eventually meet these PCR criteria for a discontinuation trial, noted Dr Branford. For this analysis, the CML8 PCR discontinuation criteria are defined as “stable UMR4.5.” To determine the number of patients who were treated with first-line imat inib and who achieve the CML8 PCR discontinuation criteria and the fac-

tors that predict its achievement, Dr Branford and her colleagues examined the MMR of 415 de novo patients with chronic-phase CML who were enrolled in consecutive clinical trials of imatinib since July 2000.

“An estimated 58 of the 415 patients would maintain response if imatinib was discontinued after stable UMR.”

—Susan Branford, PhD

The assigned daily imatinib doses were 400 mg (n = 90), 600 mg (n = 202), and 800 mg (n = 123). Of the 415 patients, 117 had confirmed undetectable BCR-ABL1 (MR4.5). Of these patients, 80 had follow-up of at least 24 months: 64% had stable MR4.5 for 24 months, only 1 patient lost MMR, and the remainder had fluctuating positive BCR-ABL1.

At 8 years of imatinib therapy, the cumulative incidence of stable UMR4.5 was 43%. The cumulative incidence of stable UMR4.5 was >60% for all patients who achieved MMR by 12 months and only 16% for patients with MMR between 12 and 18 months, which suggests that the speed of the response is an important factor. “An estimated 58 of the 415 [14%] patients would maintain response if imatinib was discontinued after stable UMR4.5,” she said. During imatinib therapy, females had significantly lower median BCRABL1 values at every assessment up to 42 months. Dr Branford speculated that women may be more compliant with their therapy, resulting in a better response, or that biological differences may influence the response. The 3-month BCR-ABL1 value also predicted stable UMR4.5. A stable UMR4.5 was achieved by 59% of patients with a BCR-ABL1 value of <1.0% at 3 months. n

february 2013

www.AHDBonline.com

Leukemia

Alternatives to “7 + 3” Induction Therapy for AML Are Emerging Molecular profiling may help patient selection, improve outcomes

he combination of the nucleoside analog cytarabine (Cytosar-U) and the anthracycline daunorubicin (Daunoxome), the so-called “7 + 3” schedule, has been the standard of care for the treatment of acute myeloid leukemia (AML) for several years. Recent data suggest that better induction options exist, especially for younger patients, said Alan K. Burnett, MD, Head of Hematology, Department of Medical Genetics, Hematology and Pathology, Cardiff University, Heath Park, United Kingdom. He challenged the current 7 + 3 paradigm during the Ham-Wasserman Lecture delivered at ASH 2012. Unresolved issues around the “conventional” approach include alternative anthracyclines or nucleoside analogs in induction, dose, and number of courses of consolidation, and which patients should receive an allograft in first remission. Survival has improved in younger patients over the past 2 or 3 decades— although improvements in supportive care may be primarily responsible— but this improvement in survival may be limited to those with favorable-risk disease, Dr Burnett said. Little evidence of improved survival exists for older patients. Molecular studies may help define the patients who are to receive an allogeneic transplant in first remission. “The ability to accurately monitor treatment by molecular or immunophenotypic techniques has the potential to enhance a personalized approach to treatment,” said Dr Burnett. Because conventional chemotherapy has probably reached its potential, there is interest in novel treatments, particularly for older patients. Higher Anthracycline Dose Intensifying daunorubicin administration is an option that may improve overall remission rate and overall survival (OS), Dr Burnett pointed out. In the E1900 trial, daunorubicin dosed at 90 mg/m2 in a 7 + 3 schedule for the first induction course resulted in a significantly higher overall remission rate, with more patients in complete remission after the first course, and a better OS rate compared with the 45-mg/m2 dose (23.7 vs 15.7 months, respectively). In 2 other studies, a similar approach improved the overall remission rate but not OS, except in patients aged 60 to 65 years. Whether a higher daunorubicin dose should be the standard of care

is not clear, noted Dr Burnett. Recent multigene mutation characterization may be useful in identifying those who benefit from the escalated dose. Antibody-Directed Chemotherapy Gemtuzumab ozogamicin (Mylotarg) is a monoclonal antibody to CD33 that is conjugated to the powerful intercalating agent calicheamicin. A single dose of gentuzumab ozogamicin (6 mg/m2) to augment daunorubicin and cytarabine failed to show benefit in clinical studies of patients with AML, with a concern about an excess of induction death in one trial (SWOG-106). Three European randomized trials of nearly 3000 patients show a survival benefit when gentuzumab ozogamicin was given at lower daily dose levels (3 mg/m2) in combination with induction chemotherapy, with little increase in toxicity. These studies demonstrated improved survival in favorable and in intermediate-risk patients, but not in poor-risk patients. Alternative Nucleoside Analogs in Induction Novel nucleoside analogs under recent investigation include cladri bine (Litak), fludarabine (Fludara), and clofarabine (Clolar).

“The ability to accurately monitor treatment by molecular or immunophenotypic techniques has the potential to enhance a personalized approach to treatment.”

By Wayne Kuznar

“The inclusion of cladribine, but not fludarabine, improved the remission rate and overall survival. In a subgroup analysis, the addition of either nucleoside appeared to be beneficial in patients with an adverse karyotype.” —Alan K. Burnett, MD ulocyte colony-stimulating factor, and idarubicin in younger patients reduced the rate of relapse significantly compared with daunorubicin or daunorubicin plus etoposide, but had no effect on remission rate or OS; however, this reduction in risk was offset by an increase in the rate of myelosuppression. Clofarabine 20 mg/m2 in combination with daunorubicin did not improve response or OS in any risk group when compared with cytarabine plus daunorubicin in the United Kingdom NCRI AML16 trial.

Cytogenetics and Personalized Therapy Determining which patients should undergo allogeneic transplantation may depend on predicting relapse using molecular studies, Dr Burnett claimed. Patients with a cKIT mutation have an increased risk of relapse. Biallelic CEBPα and NPM1 mutations without an FLT3 mutation have a favorable prognosis, similar to the core-binding factor leukemias, and therefore do not require a transplant. Adverse cytogenetics include chromosomes 5 and 7 abnormalities, inv3, and complex and monosomal karyotypes, and predict rapid relapse. Allograft is recommended for such patients, but it only cures 30% to 40% of these patients, Dr Burnett cautioned. Molecular data have emerged to estimate prognosis. An FLT3 mutation balances out the favorable effect of an NPM1 mutation, but “the impact of FLT3 mutations is complex and is influenced by the association with NPM1, whether it occurs alone and by the allelic ratio,” he said. “It is likely that the prognostic impact of each mutation will be modified by its association with other mutations.” Dr Burnett added that the utility of allogeneic transplantation for FLT3 mutations has not been settled, “particularly when the allelic ratio and association (or not) with NPM1 is considered.” FLT3 has been a target for the development of pharmaceuticals. Targeting FLT3 with quizartinib proved beneficial in patients with AML who have a mutation in FLT3 in an open-label study that was also reported at the meeting (see article on page 15). n

—Alan K. Burnett, MD

Cancer Death Rates Still Declining Compared with cytarabine, clad ribine significantly increased the proportion of patients who achieved complete remission with 1 course, but did not improve survival. In a more recent study, adding cladri bine or fludarabine to 7 + 3 cytarabine was compared with 7 + 3 alone in a 3-arm study of patients aged <60 years. “The inclusion of cladribine, but not fludarabine, improved the remission rate and overall survival,” Dr Burnett said. “In a subgroup analysis, the addition of either nucleoside appeared to be beneficial in patients with an adverse karyotype.” Adding fludarabine to induction therapy with cytarabine, gran-

American health & drug benefits

february 2013

Cancer death rates continue to decline in the United States for men and women, according to the National Cancer Institute’s Annual Report to the Nation on the Status of Cancer, 1975-2009. New data released on January 1, 2013, show that between 2000 and 2009, the overall incidence of cancer: • Decreased by 0.6% for men, remained stable for women, and increased by 0.6% for children aged ≤14 years • Increased for HPV-associated oropharyngeal cancer in white

men and women, and for anal cancer in white and black men and women. The annual death rates from cancer: • Declined by 1.8% in men and children, and by 1.4% in women • Declined for 10 of the 17 most common cancers in men, including lung, prostate, and colon cancer; and for 15 of the 18 most common cancers in women, including lung, breast, and colon cancer • Increased for melanoma (for men only) and for cancers of the liver, pancreas, and uterus for both sexes.

VOL. 6

NO. 1

Special Issue

Leukemia

Initial Choice of TKI in Patients with CML Probably Not Important With 3 agents showing similar efficacy, drug cost and early response matter By Mark Knight

he initial choice of therapy for patients with chronic myeloid leukemia (CML) is probably not important, because differences in efficacy are not dramatic. What matters is that response is assessed early, and that side effects are managed swiftly, said David Marin, MD, Hammersmith Hospital, Imperial College London, United Kingdom. Similar Efficacy “The current data do not justify paying a premium price for any of the tyrosine kinase inhibitors” (TKIs), Dr Martin stressed. An inadequate response or the emergence of side effects should prompt a change to an alternate TKI. Furthermore, long-term follow-up suggests that a small proportion of patients with CML are candidates for treatment discontinuation without the disease recurring. Imatinib (Gleevec) has more than 12 years of experience behind it as firstline therapy for CML, and its side- effect profile is therefore well known, said Dr Marin. The achievement of a complete cytogenetic response (CCyR) is the major objective of therapy. Approximately 70% of patients who receive imatinib as first-line therapy achieve a CCyR by 12 months, and 80% do so by 5 years. The proportion of patients who achieve a CCyR at 1 year is higher with nilotinib (Tasigna) or dasatinib (Sprycel), but by 2 years, the rate of treatment failure is similar

between these 3 drugs, making the initial choice of therapy in the chronic phase (CP) less dependent on efficacy than on price, Dr Marin pointed out.

“The current data do not justify paying a premium price for any of the tyrosine kinase inhibitors.” —David Marin, MD Although the rate of molecular response is greater with nilotinib and dasatinib compared with imatinib, there is no proof that achieving a molecular response or complete molecular response (CMR) in patients who already achieved CCyR has any added benefit on overall survival or progression to advanced disease, he said. Assessing Response Early Is Key Regardless of the choice as first-line therapy, assessing the response early and acting on this assessment is of utmost importance, Dr Marin emphasized. Perhaps the main advantage to using nilotinib or dasatinib as initial therapy is that they may prove to reduce the number of patients who progress early after diagnosis. Monitoring for side effects and changing the medication when necessary does not seem to diminish efficacy in responding patients. Among the minority of patients who present with advanced disease,

Dr Marin prefers dasatinib, although the use of TKIs in this setting should be in conjunction with a more complex strategy that includes conventional chemotherapy and allogeneic stem-cell transplantation, if possible. Is a Cure Possible? “Attempting a cure in CML may be possible, as long as a very low level of residual disease is achieved and sustained,” said François-Xavier Mahon, MD, Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Bordeaux, France. Achieving a CMR for at least 2 years appears to be a key criterion in predicting the success of discontinuation. Among patients with undetectable peripheral blood BCR-ABL transcripts for at least 2 years who stopped imat inib in the Stop Imatinib (STIM) trial, the overall probability of maintaining a CMR was 39% at 36 months. Most patients who experienced molecular relapses did so within 6 months, but late relapse at 19, 20, and 22 months occurred in 3 cases. “It is clearly necessary to perform molecular assessments using qualitative RT-PCR [reverse transcription polymerase chain reaction] to detect early those patients who exhibit a fast molecular relapse to retreat them as soon as possible,” he said. In the STIM trial, patients in the low Sokal risk group were more likely to remain in stable CMR than those in intermediate or high Sokal risk groups, Dr Mahon noted.

Candidates for discontinuation represent only approximately 10% of patients with CP-CML, according to enrollment in STIM. The use of a second-generation TKI or combining imatinib with recombinant interferon-alfa may expand the number of patients who will reach the criteria for discontinuing treatment, but each approach requires further study. When used in patients with newly diagnosed CP-CML, molecular responses have been faster and deeper with nilotinib and dasatinib compared with imatinib.

“Attempting a cure in CML may be possible, as long as a very low level of residual disease is achieved and sustained.” —François-Xavier Mahon, MD The potential for safe treatment discontinuation relies on close molecular monitoring, commented Susan Branford, PhD, Department of Genetics and Molecular Pathology and Centre for Cancer Biology, University of Adelaide School of Medicine, Australia. Even among patients who continue therapy, long-term molecular monitoring is necessary. Although the loss of response to imatinib is rare after 18 months of achieving a major molecular response, the benefit is dependent on continuous drug adherence, she noted. n

Molecular and Cytogenetic Assessments Infrequently Performed in Patients with CML Receiving First-Line Imatinib

any patients with chronic myeloid leukemia (CML) in the United States are being treated with imatinib (Gleevec) as first-line therapy without molecular or cytogenetic assessments being performed by their physicians, according to the US findings from an international registry. The routine monitoring of newly diagnosed patients with CML receiving a tyrosine kinase inhibitor as primary treatment is recommended by the National Comprehensive Cancer Network (NCCN). Robert C. Hermann, MD, FACP, from Northwest Georgia Oncolo-

gy Centers, Marietta, and colleagues evaluated the alignment of registry patients enrolled at US sites with current NCCN guidelines. Approximately 377 patients (median age, 53 years) who were diagnosed with any-phase Philadelphia chromosome–positive (Ph+) or BCR-ABL–confirmed CML within 6 months of entry into the registry were enrolled in the analysis. “Physicians treating patients with CML should be made aware of key recent updates to the NCCN guidelines, such as the importance of assessing early molecular response by polymerase chain reaction at 3 months,” Dr Hermann said.

“Physicians treating patients with CML should be made aware of key recent updates to the NCCN guidelines, such as the importance of assessing early molecular response by polymerase chain reaction at 3 months.” —Robert C. Hermann, MD, FACP Patient Population Nearly all of the patients (96.3%) in the main analysis were in chronic

phase; 2.7% were in acute phase, and 1.1% were in blast crisis. Evaluations used to establish the CML diagnosis were hematologic (85%), bone marrow (84%), cytogenetic (82%), and molecular (polymerase chain reaction; 52%). Most patients (91.0%) had no prognostic risk score assigned at baseline. Imatinib was used as first-line therapy in 73% of patients in chronic phase, 80% in acute phase, and 75% of patients in blast phase. The median duration of imatinib treatment in chronic-phase patients was 7.6 months. Nilotinib (Tasigna) was used in 2.8% of patients in chronic phase, 10% in acute phase, and 25% Continued on page 18

VOL. 6

NO. 1

Special Issue

february 2013

www.AHDBonline.com

Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment benefits in clinical trials.2,3 Use of a PRO instrument can evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. Incorporating PROs into a clinical trial program provides a means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make betterinformed decisions.4

Myelofibrosis (MF) is a life-threatening, progressive disease characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, double-blind placebo-controlled study, COMFORT-I, for Jakafi. Spleen reduction, as measured by imaging (MRI or CT), was the primary and biologic endpoint, and a reduction in total symptom score (TSS), the PRO measure, was a key secondary endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

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 • Patients with platelet counts <200 × 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 × 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

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patient’s response.

WORSENING

100

IMPROVEMENT

Change From Baseline (%)

WORSENING

IMPROVEMENT

Change From Baseline (%)

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

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 References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials. 3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901. 6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Leukemia Molecular and Cytogenetic Assessments Infrequently Performed... Continued from page 15 of patients in blast phase. Dasatinib (Sprycel) was used in 1.1% of patients in chronic phase. Of the patients with chronic-phase 1INC007 JK0 BS 12P_Layout 1 11/16/11 AM firstPage 1 CML who were treated 9:16 with line imatinib, 10.9% had their dose increased, with the primary reasons being physician request and lack of

efficacy. Of the patients, 12.1% had their imatinib dose decreased, mainly as a result of adverse events (AEs) and physician request, and 3.8% had treatment interrupted, primarily as a result of AEs. Imatinib was switched to nilotinib in 7.9% of patients and to dasatinib in

7.5% of patients, with the primary reasons being lack of efficacy and AEs. Molecular Assessment Disease burden during the time the patients were receiving imatinib was most frequently assessed using blood counts. Only 15.5% of patients had a

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). Reactions Gradesa 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 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 Urinary Tract Infectionsd 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)], f Herpes Zoster 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

American health & drug benefits

february 2013

molecular assessment at 3 months. Molecular assessments were most frequently (in 46.7%-64.1% of patients) performed between 12 months and 36 months. Cytogenetic assessment was even rarer, and was performed in 12.5% of patients at 3 months since the start of imatinib, 34.3% at 6 months, 32.1% at 12 months, 25.2% at 18 months, 28.3% at 24 months, and 33.3% at 36 months. “Approximately one fourth of patients with chronic-phase CML receiving first-line imatinib achieved a complete cytogenetic response by 12 and 18 months,” said Dr Hermann. The rates are lower than those that were historically reported in clinical trials of imatinib, he noted, with the difference potentially being a result of a lower percentage of cytogenetic assessments being performed. Of the 141 patients who were treated with first-line imatinib and were assessed at 12 months for cytogenetic response, 66 had a complete cytogenetic response (CCyR). At 18 months, 71 of the 144 patients who were assessed for cytogenetic response had a CCyR. Approximately 25% of patients with chronic-phase CML who were receiving imatinib as first-line treatment achieved a major molecular response (MMR). Of the 152 patients who were assessed for molecular response at 12 months, 66 had an MMR, and of the 157 who were assessed at 18 months, 78 had an MMR. Again, these rates are lower than those historically reported in clinical trials. The estimated 3-year overall survival (OS) was 88.4% among the US patients with chronic-phase CML who were treated with first-line imatinib; the estimated event-free survival at 3 years for this group was 77.8%. The estimated 3-year OS was higher in patients who received imatinib on at least 85% of days compared with those who received it on <85% of days (95.8% vs 67.3%, respectively). Adverse Events The AEs that were reported in ≥1% of all patients included nausea (3%), fatigue (2%), rash (2%), diarrhea (2%), headache (2%), thrombocytopenia (2%), neutropenia (1%), and dyspnea (1%). Of the 17 deaths, 5 were related to CML progression, 1 was suspected to be related to CML treatment (necrotizing pneumonia), 7 were unrelated to CML treatment, and 4 had unknown causes. The findings may reflect the lack of readily available molecular testing during part of the period evaluated by the registry (February 2008-December 31, 2010), Dr Hermann noted.—MK n VOL. 6

NO. 1

Special Issue

Personalized Medicine

Newly Discovered Genes in AML Can Identify Likely Response to Therapies By Mark Knight

rofiling mutations in patients with acute myeloid leukemia (AML) can be used to inform therapeutic approaches. Because most patients with AML who achieve complete remission with induction therapy eventually relapse, and most die from relapsed disease, new treatment options must be evaluated. Ross L. Levine, MD, a physician and scientist at Memorial Sloan-Kettering Cancer Center, New York City, reviewed the prognostic significance of novel AML alleles. Risk Stratification Integrated genetic analysis from 502 patients with AML who were enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 clinical trial revealed genes with prognostic importance. Mutations within 18 genes were analyzed. Mutations in IDH2 R140, but not in IDH2 R172 or IDH1, were associated with improved survival, and mutations in ASXL1 and PHF6 were associated with worse overall survival (OS). The risk can be further refined in patients with intermediate-risk AML by more extensive analysis of genetic mutations than is currently used in the clinical setting, Dr Levine said.

Extensive mutations analysis could be used to identify the patients who Ross L. Levine, MD are most likely to benefit from standard AML therapy. He said that 3 distinct risk groups can be identified in FLT3 internal tandem duplication (ITD)-negative intermediate-risk AML based on mutation status; TET2, ASXL1, PHF6, and partial tandem duplications in MLL are high-risk mutations that are associated with worse survival in the group of intermediate-risk patients with wildtype FLT3-ITD. Patients without FLT3-ITD mutations and with NPM1 and IDH mutations represent a favorable-risk subset. In contrast, patients who were negative for FLT3-ITD mutations but had NPM1 mutation and no IDH mutations had a much less favorable outcome. In the ECOG E1900 trial, a post hoc analysis of mutational status

showed that high-dose daunorubicin improved outcomes markedly for patients with DNMT3A mutations. Patients with NPM1 or DNMT3A mutations, or MLL translocations, had a 3-year OS of 44% with highdose daunorubicin induction chemotherapy compared with a 25% OS in patients treated with standard-dose daunorubicin. Extensive mutations analysis could be used to identify the patients who are the most likely to benefit from standard AML therapy or from allogeneic stemcell transplantation, believes Dr Levine. Minimal Residual Disease Minimal residual disease (MRD) after treatment in patients with AML predicts failure to maintain a morphologic complete response (CR) and negatively affects survival. The best method to monitor MRD is still controversial, said Elisabeth Paietta, PhD, Professor, Department of Oncologic Medicine, Albert Einstein College of Medicine, Bronx, NY. MRD assessment assays are immunophenotypic or are done by multiparameter flow cytometry or by polymerase chain reaction to detect recurrent gene mutations or leukemia fusion transcripts. Even if clones that are present at the time of an AML diagnosis can be detected through sensitive assays, therapeutic options for patients with MRD

are limited at present. Intensive therapeutic approaches have not worked in patients with MRD, noted Dr Paietta. Immunotherapy may represent a promising approach to managing patients with MRD after chemotherapy. Newer cytotoxic chemotherapies for the treatment of relapsed AML include clofarabine with or without cytarabine; tosedotat, an orally available aminopeptidase inhibitor associated with a 27% overall response rate in a phase 1/2 study of patients with relapsed AML; and FLT3 inhibitors, which may have a role as a bridge to transplantation, said Jeffrey Szer, MBBS, FRACP, MD, Professor and Director, Department of Clinical Hematology and Bone Marrow Transplant Service, the Royal Melbourne Hospital, Parkville, Australia. Inhibitors of mTOR, such as everolimus (Zortress, Afinitor) and sirolimus, have potential benefit, given the role of the mTOR pathway in cytarabine activity. Hypomethylating agents are being studied as maintenance therapy after allogeneic stem-cell transplant. Allogeneic stem-cell transplant has an established track record in the cure of patients with relapsed and refractory AML, although subsequent relapse does occur. The successful use of transplant will require patients with relapsed AML to achieve a state of a second CR or MRD. n

Can Prognostic Factors Guide the Treatment of DLBCL?

iffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and is readily curable, even in the most advanced cases. Nevertheless, the treatment of DLBCL can be a challenge, according to Laurie H. Sehn, MD, MPH, FRCPC, a medical oncologist at the British Columbia Cancer Agency, Vancouver, Canada, who discussed DLBCL at ASH 2012. Advanced Disease and Personalized Medicine When relapse or progression occurs, high-dose chemotherapy and autologous stem-cell transplantation offer the best chance of cure for many patients, although only 50% of all patients are eligible for an intensive approach. As the treatment options for patients with advanced disease increase, “improved prognostication will be crucial to allow for the possibility of individualized risk-adapted therapy,” she suggested. There is a need to identify patients with advanced disease in whom the

VOL. 6

NO. 1

Special Issue

combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) will prove insufficient so that alternate treatment approaches, especially targeted therapies, can be considered. The question of whether reliable prognostic or predictive markers exist and should be used to guide initial treatment choice deserves consideration. Today’s clinical tools “do not provide the necessary biologic insight to allow for tailored therapy approaches with novel targeted agents,” Dr Sehn said. Molecular prognostic markers are emerging for patients with DLBCL who are receiving the R-CHOP regimen. BCL2 is an antiapoptotic protein that is associated with worse survival (although rituximab may overcome its negative influence). Myc oncogene rearrangement is identified in up to 10% of patients with typical DLBCL morphology. This may be associated with worse outcomes with R-CHOP treatment, although some studies suggest that coexpression

of BCL2 is necessary for this. “Currently, the one subgroup of patients that should be considered for alternate initial therapy outside of a clinical trial is the subset with a concurrent translocation involving BCL2 and Myc (ie, a double hit),” Dr Sehn suggested. “These patients have a remarkably poor outcome after R-CHOP, with a median survival of less than 1 year.” Gene-expression profiling has identified molecularly distinct subtypes within patients with DLBCL, and these distinctions have prognostic implications. Gene-expression profiling is not routinely available in patient care, but immunohistochemistry (IHC)-based algorithms have been developed to mimic the molecular designations that are obtained through gene-expression profiling. “Unfortunately, these IHC algorithms remain an imperfect substitution for microarray-based gene-expression profiling because of their inherent oversimplification and poor reproducibility,” Dr Sehn said.

Novel Targeted Therapies Predictive markers will become paramount in making treatment decisions,” she added. Gene-expression profiling studies have identified potential targets, leading to the development of targeted agents for patients who are too frail for R-CHOP or have relapsed or refractory disease. Molecular profiling has also demonstrated the importance of the microenvironment in DLBCL. Some of the novel agents and their postulated targets include bortezomib (nuclear factor [NF]-κB), fostamatinib (Syk), ibrutinib (Bruton’s tyrosine kinase), Cal-101 (PI3K), enzastaurin (protein kinase C-β), navitoclax (B-cell lymphoma 2), EZH2 inhibitors (EZH2), bevacizumab (vascular endothelial growth factor), and lenalidomide (angiogenesis, NF-κB). “Recognition of the biologic het erogeneity of DLBCL is of paramount importance and must be taken into consideration when investigating new therapies,” Dr Sehn concluded. n

february 2013

www.AHDBonline.com

Lymphoma

Ara-C Should Be Part of Conditioning Regimen in Young Patients with Mantle-Cell Lymphoma By Audrey Andrews

igh-dose Ara-C (also known as cytarabine) should be used in the induction regimen for younger patients with mantle-cell lymphoma (MCL) who are undergoing autologous stem-cell transplantation (ASCT), the final results of the MCL Younger Trial of the European MCL network showed. In this trial, the use of 3 alternating courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab plus dexamethasone, cytarabine, and cisplatin (R-DHAP) increased the clinical complete response (CR) rate and molecular responses compared with R-CHOP alone in patients with MCL after induction. The combined regimen also im proved time to treatment failure in all risk groups and was associated with increasing numbers of patients who were negative for minimal residual disease—which is a factor for good prognosis, said Olivier Hermine, MD, PhD, Head, Department of Hematolo-

gy at Hôpital Necker, and Professor of Hematology at the University of Paris Descartes, France. In addition, this regimen showed a trend toward improved overall survival, with a good safety profile. “Regimens that include high-dose Ara-C should become the new gold standard,” Dr Hermine maintained.

“Regimens that include highdose Ara-C should become the new gold standard.” —Olivier Hermine, MD, PhD Study Details The study compared 3 alternating courses of R-CHOP and R-DHAP followed by a high-dose Ara-C–containing myeloablative regimen and ASCT versus 6 courses of R-CHOP followed by myeloablative radiochemotherapy and ASCT in 497 younger patients (aged <65 years) with stage II to IV MCL.

After induction, the response rates were significantly higher in the Ara-C– containing arm, with CRs achieved by 25% in the R-CHOP arm versus 36% in the R-CHOP plus R-DHAP arm (P = .077); the rates of CR or unconfirmed CR (CRu) were 39% versus 55%, respectively (P = .013). The rates of CR, CRu, or partial re sponse (PR) were similar in both arms (90% and 95%, respectively). ASCT was possible for approximately 80% per arm, and posttransplant response rates were high in both arms (approximately 98%). After a median follow-up of 53 months, the median time to treatment failure was 46 months in the R-CHOP arm versus 88 months in the R-CHOP plus R-DHAP arm (P = .038), and R-CHOP–treated patients had almost twice the number of events related to treatment failure: 122 versus 69 with R-CHOP plus R-DHAP. In addition, the relapse rate after CR/Cru/PR was twice as high in the R-CHOP arm (88 vs 44, respectively).

Improved Outcomes The significant differences in time to treatment failure favoring the R-CHOP plus R-DHAP arm were present in the low-risk and in the intermediate-risk groups. The achievement of minimal residual disease after induction was the strongest independent prognostic factor of outcome, and other studies have suggested that this is significantly associated with prolonged remission. Compared with R-CHOP, inductions with R-CHOP plus R-DHAP were associated with higher rates of grade 3 or 4 myelosuppression and similar rates of other grades 3 and 4 toxicities. Transplant-related toxicities were similar between the arms. Median survival has not been reached in either arm, although the preliminary findings suggest that survival will be best for the low-risk group of younger patients with MCL, with a strong trend favoring treatment with R-CHOP plus R-DHAP. n

Ibrutinib: It’s Not Just for Leukemia Unprecedented success in mantle-cell lymphoma Atlanta, GA—The investigational agent ibrutinib, which is making news in the treatment of patients with leukemia, demonstrated “unprecedented” single-agent activity in patients with relapsed or refractory mantle-cell lymphoma (MCL), according to the lead author of an international phase 2 study that was reported at the 2012 ASH meeting. “Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle-cell lymphoma,” said Luhua (Michael) Wang, MD, Associate Professor, Department of Lymphoma/ Myeloma, Division of Cancer Medicine of the University of Texas M.D. Anderson Cancer Center, Houston. “Patients with all characteristics benefited across the board.” Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK), which is a critical kinase for lymphoma cell survival and proliferation. The drug is the first in the new class of BTK inhibitors. The PCYC-1104-CA study is an ongoing international, open-label, phase 2, single-agent trial of ibrutinib in patients with relapsed or refractory MCL. Currently, 115 patients

have been enrolled, including patients who are totally naïve to bortezomib (89.2%) or who have received fewer than 2 cycles of bortezomib (10.8%), and those who have been exposed to bortezomib (ie, have received at least 2 cycles). Patients were allowed to have received up to 5 prior lines of therapy.

“Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle-cell lymphoma.” —Luhua Wang, MD The overall response rate to single-agent ibrutinib 560 mg daily was 68%, including 65% among the bortezomib-naïve population and 72% for patients who were exposed to bortezomib; complete response rates in these cohorts were 21%, 23%, and 22%, respectively. “These responses have been durable, and the median duration of response has not been reached,” Dr Wang noted. “The response improved with longer follow-up, demonstrat-

American health & drug benefits

february 2013

ing the phenomenon of ‘incremental response.’” All patient subgroups derived benefit from the BTK inhibitor, with responses observed in 64% of patients with bulky disease, 65% of patients with refractory disease, 70% of those who were not disease refractory, 66% of those who had received at least 3 prior regimens, 76% of patients with prior lenalidomide exposure, and 74% of patients with a high-risk score. With longer follow-up among 51 patients treated for a median of 14.7 months, responses have increased over time, he emphasized. The overall response rate from the first analysis at 3.7 months to the 14.7-month point increased from 69% to 75%, with complete responses increasing from 16% of patients to 39%. This pattern was seen in bortezomib-naïve and bortez omib-exposed patients alike. “This is higher than the complete response rates we see in other subtypes of lymphoma, including [historically] in MCL. It is an unprecedented single-agent response rate,” Dr Wang pointed out. Median progression-free survival

was 13.9 months for the whole population. For responders, it has not been reached, whereas it is <7 months for patients who did not respond to treatment. Ibrutinib was well tolerated, and treatment-emergent adverse events were consistent with the safety data that were previously reported for this investigational agent. Grades 3 and 4 events occurred in <5% of patients. Approximately 10% of patients experienced grades 1 and 2 confusion, epistaxis, petechiae, and ecchymosis. Ibrutinib appears active in other lymphomas as well, including diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. Relapsed or refractory patients with these tumors demonstrated response rates ranging from 23% to 44%; response rates rose to 55% with optimal dosing, other investigators reported at the meeting. In summarizing his findings in patients with MCL, Dr Wang expressed much optimism about ibrutinib in hematologic cancer. “I look forward to the future with excitement, caution, and confidence,” he noted.—AA n VOL. 6

NO. 1

Special Issue

Lymphoma

PET-Directed Approach to Treating Early-Stage Hodgkin Lymphoma Produces Excellent Outcomes By Wayne Kuznar

he avoidance of involved-field radiotherapy (IFRT) is an acceptable strategy in patients with early-stage Hodgkin lymphoma who have a negative positron emission tomography (PET) scan after completing 3 cycles of doxorubicin, bleomycin sulfate, vinblastine, and dacarbazine (ABVD), reported John Radford, MD, Professor of Medical Oncology, School of Cancer and Imaging Sciences, University of Manchester, Christie National Health Service Foundation Trust, United Kingdom. In the United Kingdom’s RAPID trial, a PET-directed approach was a sufficiently robust biomarker of disease elimination, such that IFRT, the current standard of care after abbreviated chemotherapy for patients with stage IA or IIA Hodgkin lymphoma, could be avoided without significantly affecting the patient’s survival. “A response-adapted approach based on centrally reviewed PET imaging reduces treatment time and costs, improves tolerability, and, most important, removes the burden of early and late toxicity of radiotherapy from the PET-negative population,” said Dr Radford.

Study Details Overall, 602 patients with newly diagnosed stage IA or IIA Hodgkin lymphoma underwent PET imaging after 3 courses of ABVD. The PET scan was performed at 1 of 30 quality controlled PET scan centers across the United Kingdom.

“A response-adapted approach based on centrally reviewed PET imaging reduces treatment time and costs, improves tolerability, and, most important, removes the burden of early and late toxicity of radiotherapy from the PET-negative population.” —John Radford, MD

Patients with a positive PET scan received an additional course of ABVD followed by IFRT. Patients with a negative PET scan were ran-

domized to further treatment with IFRT applied to disease areas within 6 weeks of the completion of their chemotherapy or to no further treatment. A positive PET scan was defined as a score of 3, 4, or 5, as assigned at core laboratory review; a PET scan was considered negative if it had a score of 1 or 2. The trial was of a noninferiority design; “some reduction in primary disease control was considered acceptable because of the presumed benefits in terms of reduced late toxicity associated with not radiating everyone,” Dr Radford noted. Noninferiority was defined as a ≤7% difference in progression-free survival (PFS) from 95% in the arm continuing on to IFRT. Results In the trial, 426 (74.7%) PET scans were classified as negative, and 420 patients were randomized to either arm (6 patients with PET-negative scans were not randomized). Of 209 patients randomized to receive IFRT, 25 did not receive it: 19 patients declined after they became aware of the randomization decision, 5 died, and 1 patient developed pneumonia.

In an intent-to-treat analysis, the 3-year PFS was 94.5% in the group that was randomized to IFRT versus 90.8% in the arm that had no further treatment, a hazard ratio of 1.51 in favor of IFRT, which met the criterion for noninferiority for no further treatment. Overall survival was greater in the patients with no further treatment compared with those who received IFRT (99.5% vs 97.1%, respectively). In a per-protocol analysis of the 392 patients who received their allocated treatment, which included 2 patients in the arm that received no further treatment and who received radiotherapy, 3-year PFS was 97% in those treated with IFRT versus 90.7% in those with no further treatment, which again met the criterion for noninferiority of no further treatment. “Using PET, it is possible to identify a population of patients with stage IA and IIA Hodgkin lymphoma who have an excellent prognosis after 3 cycles of ABVD,” Dr Radford pointed out. A longer follow-up is required to establish the impact of a PET-directed approach on 10-year and 20-year survival rates, he said. n

Bendamustine plus Rituximab Noninferior to Standard Chemotherapy for Indolent Non-Hodgkin and Mantle-Cell Lymphomas By Caroline Helwick

he combination of bendamustine plus rituximab proved to be noninferior to standard first-line chemotherapy in patients with previously untreated, advanced, indolent non-Hodgkin lymphoma (NHL) and mantle-cell lymphoma (MCL) in the phase 3 BRIGHT clinical trial. The BRIGHT trial randomized 447 patients to bendamustine plus rituximab or to rituximab plus the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus the combination of cyclophosphamide, vincristine, and prednisone (R-CVP; physician’s choice). Similar Efficacy Complete response (CR) was the primary end point, which showed no difference between bendamustine plus rituximab and standard chemotherapy, reported Ian Flinn, MD, MPH, Director of Hematologic MaligVOL. 6

NO. 1

Special Issue

nancies Research at the Sarah Cannon Research Institute, Nashville, TN. In the absence of a single standard therapy for indolent NHL or MCL, the BRIGHT trial evaluated bendamustine plus rituximab, a regimen

“The overall response rate was high in both treatment groups. Bendamustine plus rituximab is an important treatment option for previously untreated indolent NHL and MCL.” —Ian Flinn, MD, MPH that is becoming standard in Germany, versus standard chemotherapy. The StiL NHL study, which was first reported on at the 2009 ASH annual meeting, showed a large difference

in progression-free survival (PFS) in patients with follicular, indolent NHL and MCL, favoring bendamustine plus rituximab over R-CHOP. In the current study, CR rates were 31% with bendamustine plus rituximab and 25% with standard chemotherapy. The CR ratio of 1.26 met the definition of noninferiority, Dr Flinn reported. It was not, however, statistically significant for the superiority of bendamustine plus rituximab over standard chemotherapy. The overall response rates were 97% for bendamustine plus rituximab versus 91% for R-CHOP/R-CVP. “The overall response rate was high in both treatment groups. Bendamustine plus rituximab is an impor tant treatment option for previously untreated indolent NHL and MCL,” said Dr Flinn. Although PFS is a more clinically meaningful end point than CR, the study was designed for a US Food

and Drug Administration application and is a supportive trial for existing data that have longer end points, Dr Flinn explained. “PFS is probably a better end point,” he acknowledged. Longer follow-up is needed to show PFS differences between the 2 arms, he noted. Different Toxicity Profiles The toxicity profiles of the 2 arms did, however, differ. Adverse events (AEs) of all grades included a higher incidence of nausea and vomiting, pyrexia, chills, drug hypersensitivity reactions, decreased appetite, rash, and pruritus for the bendamustine plus rituximab arm, and a higher incidence of constipation, paresthesia, peripheral neuropathy, and alopecia for the chemotherapy arms. With bendamustine plus rituximab, there were more ≥grade 3 hypersensitivity reactions, opportunistic infections, and respiratory and thoracic disorders.

february 2013

Continued on page 22

www.AHDBonline.com

Lymphoma

Evidence Lacking for Eliminating Prophylactic Platelet Transfusions Can cost be lowered by reducing unnecessary transfusions? By Audrey Andrews The results showed that hemostatic outcomes were comparable for the 2 approaches, and a new recommendation cannot be made at this time, Dr Stanworth said.

o prevent bleeding related to stem-cell transplant or intense induction and conditioning regimens, prophylactic platelet infusion remains the standard of care, according to a study that compared outcomes for patients who received prophylaxis versus those who did not. The results of the Noninferiority Trial of Prophylactic Platelet Transfusions (TOPPS) were presented by Simon J. Stanworth, MRCP, FRCPath, DPhil, Hematologist, Department of Transfusion Medicine, John Radcliffe Hospital, Oxford University Hospitals National Health Service Trust, Headington, United Kingdom. The investigators questioned whether a policy of no prophylaxis with platelet transfusions in adults with hematologic malignancies is not worse than (ie, noninferior to) a policy of prophylactic platelet infusion at 10 × 109/L, as judged by World Health Organization grades 2, 3, or 4 bleeding, up to 30 days from randomization. The study included 600 patients with hematologic malignancies and severe thrombocytopenia. The current practice is to give platelets prophylactically to patients when their platelet counts drop below 10,000/µL to protect against bleeding.

“This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis.” —Simon J. Stanworth, MRCP, FRCPath, DPhil

“This multicenter study has not shown that a no-prophylaxis platelet

Bendamustine plus Rituximab... Continued from page 21 More frequent febrile neutropenia and alopecia were seen in the chemotherapy arms. Despite the use of growth factor support, patients treated with R-CHOP had a higher incidence of ≥grade 3 hematologic AEs, including neutropenia and lymphopenia. “There was a much greater use of growth factors in the R-CHOP arm, so lack of growth factor support could not explain the increased neutropenia observed with R-CHOP,” Dr Flinn noted. He said that the investigators expected less nausea and vomiting with the bendamustine plus rituximab combination, but they did not see that. Bendamustine plus rituximab and R-CHOP and R-CVP have distinct toxicity profiles, which should be considered in treatment selection, he said. A substudy of BRIGHT evaluated quality of life via patient-reported responses to 30 questions. Patients were surveyed at baseline and during intervals throughout treatment up to

cycle 6. The study found that patients treated with bendamustine plus rituximab had improved global health status, physical function, social and emotional function, fatigue, dyspnea, and constipation compared with the R-CHOP arm. Patients with Poor Performance Status Martin Dreyling, MD, Professor at the University of Munich in Germany, commented that the lack of a difference in PFS favoring bendamustine plus rituximab was surprising, based on the previous findings of substantial benefit in the StiL NHL trial. Dr Dreyling noted that bendamustine plus rituximab is better tolerated and noninferior to R-CHOP and, therefore, should be a good alternative for elderly patients and other patients with poor performance status. He said that he would not, however, consider this regimen to be the new standard of care, but an additional standard option. n

American health & drug benefits

february 2013

transfusion policy is noninferior to prophylaxis,” he pointed out. No Differences in Bleeding There were no significant differences between the arms in the period of thrombocytopenia, number of days in the hospital, or in the number of serious adverse events. Overall, grade 2 to 4 bleeding was seen in 43% of the prophylaxis group and in 50% of the no-prophylaxis group. Most bleeding was grade 2. “Serious bleeding complications were rare,” Dr Stanworth noted. “The proportion of patients with grade 2 to 4 bleeding was reduced by 7% with prophylactic platelets.” Significant differences were, however, seen in a couple of end points. Without prophylaxis, patients experienced significantly more days on which bleeding occurred (1.7 days vs 1.2 days; P = .004) and had a shorter time to the first occurrence of bleeding (P = .02). There was also no difference in the time to recovery from thrombocytopenia, he reported. Grades 3 and 4 bleeding were observed in 1 (0.3%) of the 298 patients who had prophylaxis and in 6 (2%) of the 300 patients who lacked prophylaxis. Although this amounted to a 6-fold increased risk, the difference was not significant (P = .13). In the group without prophylaxis, 1 intracranial bleeding event occurred. In a predefined subgroup analysis, patients were divided into patients who received autologous stem-cell transplant (ASCT) versus those who received “other” approaches. Dr Stanworth pointed out that the benefit of prophylaxis appeared to be most striking in the “other” group. Interestingly, this included more patients with acute myeloid leukemia. In the group receiving ASCT, which was mainly comprised of patients with lymphoma and myeloma, bleeding occurred in 45% and 47% of patients, respectively. In the “other” group, grades 2 to 4 bleeding occurred in 38% of patients with prophylaxis and in 58% without prophylaxis. “The role of prophylactic transfusions in autograft patients is less clear,” Dr Stanworth acknowledged. He noted that the rates of bleeding in the study were high overall, even when patients received platelet infusions, and he suggested that other approaches to the problem should be explored. Dr Stanworth added that factors other than those addressed by

prophylactic platelet transfusions are important in assessing bleeding risk in this population. Can Unnecessary Transfusions Be Eliminated? Although the results were considered a validation of the current standard of care, some experts at ASH commented that many patients receive prophylactic platelet transfusions unnecessarily. In the ASH Daily News, Andrew D. Leavitt, MD, Professor, Medical Director, Blood and Marrow Transplant Laboratory, Assistant Medical Director, Blood Bank Laboratory Medicine Cellular Therapy, University of California, San Francisco, noted, “With half of the no-prophylaxis group experiencing no significant bleeding, it is clear that we transfuse many patients unnecessarily,” yet this practice is actually increasing.

“The US healthcare system… spent more than $1.3 billion on prophylactic platelet transfusions in 2008, yet we lack good evidence that prophylactic platelet transfusions provide clinical benefit.”

—Andrew D. Leavitt, MD

Although there were no significant differences in outcomes, patients in the prophylaxis group received 61% more transfusions. Nationwide, approximately 1.5 million transfusions were administered in 1999, and a decade later, more than 2 million platelet transfusions were recorded by the US National Blood Collection and Utilization Survey Report, Dr Leavitt said. “It is estimated that about two thirds of the platelet transfusions are for prophylactic use, while approximately one third are administered to treat bleeding,” he said. “While product acquisition and infusion costs vary regionally and are difficult to determine, an average total cost of $1000 per platelet transfusion is a reasonable estimate,” Dr Leavitt noted. “The US healthcare system, therefore, spent more than $1.3 billion on prophylactic platelet transfusions in 2008, yet we lack good evidence that prophylactic platelet transfusions provide clinical benefit.” n VOL. 6

NO. 1

Special Issue

SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

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

8:15 am - 11:45 am

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

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

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

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

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

CONFERENCE OVERVIEW

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

TARGET AUDIENCE

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

LEARNING OBJECTIVES

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

DESIGNATION OF CREDIT STATEMENTS SPONSORS

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

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

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

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

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

3:00 pm

Departures

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

REGISTERED NURSE DESIGNATION

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

REGISTERED PHARMACY DESIGNATION

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

CONFERENCE REGISTRATION

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

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

GBCKsize20813

P O

PERSONALIZED MMEDICINE IN ONCOLOGY

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

Myeloma

New Data Demonstrate Overall Survival Benefit with Pomalidomide in Advanced Myeloma Atlanta, GA—Support for the oral immunomodulatory agent pomalidomide for the treatment of multiple myeloma took a giant step forward when new data from the phase 3 MM-003 trial showed a survival advantage in patients with advanced disease. The data were reported at the 2012 American Society of Hematology meeting by Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, Greece. In this open-label, phase 3 trial of 455 patients, pomalidomide 4 mg, in combination with low-dose dexamethasone, significantly improved progression-free survival (PFS) as well as overall survival (OS) compared with high-dose dexamethasone alone, Dr Dimopoulos reported in a late-breaking abstract. In patients with relapsed and/or refractory myeloma, treatment with the combination of pomalidomide and low-dose dexamethasone essentially doubled the PFS time compared with high-dose dexamethasone alone. “We saw a statistically significant increase in progression-free survival

By Caroline Helwick

“We believe this study provides the basis for considering this combination as a new standard of care for hard-to-treat patients who have exhausted most standard treatments for their refractory disease.” —Meletios Dimopoulos, MD

from about 2 months with high-dose dexamethasone to 4 months with this combination, and this difference translated to a significant overall survival advantage as well,” Dr Dimopoulos said. “The benefit of pomalidomide plus low-dose dexamethasone has now been shown in the context of a prospective randomized trial, and it is superior to the current standard of

care in patients with relapsed/refractory myeloma.” Pomalidomide is considered more potent than the other available immunomodulatory drugs, thalidomide and lenalidomide. A New Drug Application for pomalidomide has been accepted for review by the US Food and Drug Administration. The Prescription Drug User Fee Act date is February 10, 2013. Significant Overall Survival Benefit After a median follow-up of 18 months, the median PFS was 15.7 weeks with the pomalidomide plus low-dose dexamethasone combination versus 8 weeks with high-dose dexamethasone as a single agent, a 55% reduction in risk (P <.001). Although median OS was 34 weeks with high-dose dexamethasone, it has not been reached with pomalidomide plus low-dose dexamethasone. So far, this translates into a 47% risk reduction (P <.001). “We expect median overall survival with the combination to be around 11 or 12 months,” Dr Dimopoulos noted. The Data Safety and Monitoring Board, therefore, recommended that the monotherapy arm subsequently

receive the combination as a result of its high efficacy. The combination was well tolerated, and toxicities were as expected. Primarily, neutropenia was more common in the combination arm with pomalidomide than in the high-dose dexamethasone alone arm (42% vs 15%, respectively). At the time of the analysis, 45% of patients in the combination arm and 25% in the monotherapy arm remained in the study, with more patients receiving high-dose dexamethasone discontinuing because of disease progression than patients receiving pomalidomide plus low-dose dexamethasone (48% vs 35%, respectively). “We believe this study provides the basis for considering this combination as a new standard of care for hardto-treat patients who have exhausted most standard treatments for their refractory disease,” Dr Dimopoulos added. “And we believe pomalidomide may offer even greater benefit if studied among less heavily treated patients as a first-line therapy.” Clinical trials with pomalidomide in the first-line setting are now under way, Dr Dimopoulos said. n

Host Factors Important in Patients with Myeloma

edian overall survival (OS) for patients with multiple myeloma has improved substantially in the past 10 years, thanks to the approval of a number of new drugs. For patients who can undergo transplants, survival exceeds 80% at 5 years. But although many patients can live 7 to 10 years after diagnosis, outcomes can be highly variable, according to S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic in Rochester, MN. Patient factors are largely responsible for this variation, he said. Host factors that shift patients into the poor prognosis category include a performance status of 3 or 4, renal failure, advanced age, stage III disease (high tumor burden), and high-risk tumor biology. Although patients with hyperdiploidy t(11;14) and t(6;14) are considered to be at standard risk for disease progression, those with t(14;16), t(14;20), deletion 17p, and high-risk gene-expression profile signatures have a high risk. “Even with the

best-available therapy, these patients have a median survival of only about 2.5 years,” Dr Rajkumar noted. In the intermediate-risk range is the t(4;14) subset. Their risk is “intermediate,” he said, “not because survival falls between the standard-risk and high-risk patients, but because they can have better outcomes if they are treated in a particular manner.” Risk-Adapted Treatment “What we know about these subtypes is that standard-risk patients do very well regardless of the therapy, with a median survival of more than 7 to 10 years now,” Dr Rajkumar observed. “But intermediate-risk patients do well only if given bortez omib early in the disease, followed by transplant, followed by bortezomib-based consolidation, followed by maintenance therapy for 2 to 3 years. Many studies have shown that with this approach, survival in this group is similar to, if not the same as, standard-risk patients.”

American health & drug benefits

february 2013

“We should always put the patient in the center. We should look at host factors, stage, tumor burden, tumor biology, and patient tolerability and preference, and individualize therapy accordingly.” —S. Vincent Rajkumar, MD

“On the other hand, you can give high-risk patients all the therapies we have, and they still have a median survival of 2.5 years,” he noted. In this group, the achievement of a complete response (CR) is critical, Dr Rajkumar emphasized. In a study from the Arkansas group using the total therapy tandem transplant regimen, the 18-month survival rate was only 13% among high-risk patients when a CR was not achieved, whereas it exceeded 80% among complete responders (Haessler J, et al. Clin Cancer Res. 2007;13:7073-7079). In lowrisk patients, OS was 87% regardless of whether patients achieved a CR. Treatment should be adapted to this underlying risk, Dr Rajkumar emphasized. “Often, which approach the pa tient receives will depend on which physician they see, but we should always put the patient in the center. We should look at host factors, stage, tumor burden, tumor biology, and patient tolerability and preference, and individualize therapy accordingly,” he stressed.—CH n VOL. 6

NO. 1

Special Issue

Myeloma

Four-Drug Induction and 2-Drug Maintenance Boost Overall Survival in Patients with Newly Diagnosed Myeloma By Audrey Andrews

—Antonio Palumbo, MD

The 58-center study enrolled 511 patients aged >65 years or aged ≤65 years but not eligible for stem-cell transplant. The investigators compared a 4-drug induction regimen (bortezomib, melphalan [Alkeran], prednisone, thalidomide) followed by 2 years of maintenance therapy with bortezomib and thalidomide (VMPTVT) with a regimen that included 3 drugs for induction—bortezomib, melphalan, and prednisone (VMP)— and no maintenance therapy. Cytogenetic abnormalities were identified in approximately 30% of the patients in each arm. After a median follow-up of 54 months, the risk of progression was reduced by 42% in the experimental VOL. 6

NO. 1

Special Issue

Figure 1 Progression-Free Survival and Time to Next Therapy Median follow-up 54 months 42% Reduced risk of progression PFS

48% Reduced risk of next therapy TTNT 1.00

1.00

0.75

0.50

0.25

0.00

VMPT-VT: median 46.6 mo

VMPT-VT: median 35.3 mo

VMP: median 24.8 mo HR, 0.58 (95% CI, 0.47-0.71; P <.001) 0

VMP: median 27.8 mo HR, 0.52 (95% CI, 0.42-0.66; P <.001)

0.00

Time, months CI indicates confidence interval; HR, hazard ratio; PFS, progression-free survival; TTNT, time to next therapy: VMP, bortezomib/melphalan/prednisone; VMPT-VT, bortezomib/melphalan/prednisone/thalidomide followed by 2 years of maintenance therapy with bortezomib/thalidomide. Copyright © Antonio Palumbo, MD. Used with permission.

Figure 2 Overall Survival Landmark Analysis VT maintenance

VMPT

Off therapy

1.00

0.75

Patients, %

“A proteasome inhibitor in conjunction with an immunomodulatory drug, taking advantage of the synergistic effect, basically doubled the progressionfree survival and time to next treatment. And more importantly, we were able to keep patients in an asymptomatic condition for up to 4 years.”

arm, and the time to next therapy was reduced by 48%, Dr Palumbo reported. The median progression-free survival (PFS) was 24.8 months with VMP, increasing to 35.3 months with VMPTVT, and the 5-year PFS rate rose from 13% to 29%, respectively (Figure 1; hazard ratio [HR], 0.58; P <.001). The median times to next therapy were 27.8 months and 46.6 months, respectively, and, at 5 years, the rates of time to next therapy were 19% and 41%, respectively (HR, 0.52; P <.001), he reported. Commenting on the implications of these numbers, Dr Palumbo noted, “We are now able to deliver treatment that can keep disease under control for 4 years, and we can maintain disease in an asymptomatic state.” The “most striking” observation, he said, is the divergence of the curve during maintenance, and even after maintenance. “When both groups are off treatment, the curves tend to continue to part,” Dr Palumbo noted. “There is evidence that continuous treatment can delay clonal evolution, whereas we see faster clonal evolution and relapse without maintenance,” he said. These differences led to an overall survival (OS) advantage with the 4-drug induction plus maintenance therapy. The 5-year OS rates were 61% with VMPT-VT versus 51% for the control arm, representing a 30% reduced mortality risk (P = .01). The median OS has not been reached in the experimental arm, whereas it is 60.6 months in the control arm, he reported. Dr Palumbo noted that the HR becomes even more impressive—0.63 (P = .006)—in the OS landmark analysis, which evaluates survival after induction and from the start of maintenance. Four-year OS from the start of maintenance was 67% with VMPT-VT versus 55% with VMP; median OS has not been reached with VMPT-VT and was 54.2 months with VMP. Most of the survival benefit seems to accrue during the maintenance period, he emphasized. The study did not show a survival benefit for the novel regimen from the time of first relapse. In those patients, 3-year OS rates were approximately 47% per arm, and the median OS time was 27 months (Figure 2). In the prespecified subgroup analysis, the benefit of the 4-drug combination and maintenance was the most obvious in several groups: patients

Patients, %

atients with newly diagnosed myeloma who received a 4-drug regimen for induction, followed by a 2-drug maintenance approach, demonstrated a significant survival benefit and a significant delay in developing symptomatic disease, according to a study from the Italian Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) network presented at ASH 2012. Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Torino, Italy, credited the good outcomes with a strategy that takes advantage of the synergy between bortezomib (Velcade) and an immunomodulatory drug, in this case thalidomide (Thalomid). He maintained that this duet given during maintenance was a more important factor to survival than the use of 4 drugs during induction.

0.50

0.25

4-year OS

Median OS

VMPT-VT

67%

Not reached

VMP

55%

54.2 months

HR, 0.63; 95% CI, 0.46-0.88; P = .006. 0.00 0

Time, months CI indicates confidence interval; HR, hazard ratio; OS, overall survival; VMP, bortezomib/melphalan/ prednisone; VMPT-VT, bortezomib/melphalan/prednisone/thalidomide followed by 2 years of maintenance therapy with bortezomib/thalidomide; VT, bortezomib/thalidomide. Copyright © Antonio Palumbo, MD. Used with permission.

who were aged 65 to 75 years (compared with older patients), in patients with complete responses (vs lesser responses), and in patients with International Staging System stages I and II (vs stage III). He said that the regimen appears to be too toxic for the elderly, who discontinued the study at a higher rate and received a lower dose intensity.

“A proteasome inhibitor in conjunction with an immunomodulatory drug, taking advantage of the synergistic effect, basically doubled the progression-free survival and time to next treatment,” Dr Palumbo emphasized in conclusion. “And more importantly, we were able to keep patients in an asymptomatic condition for up to 4 years.” n

february 2013

www.AHDBonline.com

Myeloma

Oral Proteasome Inhibitor MLN9708 a News Maker at ASH 2012 By Caroline Helwick ous formulation offers a much reduced incidence, with approximately 10% to 15% neuropathy, Dr Kumar said.

Atlanta, GA—MLN9708, an investigational oral proteasome inhibitor, produced impressive results in a phase 1/2 clinical trial of treatment-naïve patients with multiple myeloma that was featured in a press briefing at the 2012 American Society of Hematology (ASH) meeting. Used in combination with lenalidomide, MLN9708 achieved an overall response rate exceeding 90%, and complete responses were seen in 25% of patients, reported Shaji K. Kumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, MN. “There is increasing attention toward developing highly effective regimens that at the same time will be better tolerated, convenient, and able to be taken for a long time,” Dr Kumar said. As an oral proteasome inhibitor with a good tolerability profile, MLN9708 may help achieve this goal. It is the first oral drug among the proteasome inhibitors to enter clinical trials with patients with myeloma, which offers a convenient and tolerable treatment regimen. The incidence of peripheral neuropathy with this oral formulation is less than is seen with bortezomib. The twice-weekly intravenous form of bortezomib is associated with an overall rate of neuropathy of approximately 30%; however, the subcutane-

“While the follow-up is still very short, progression-free survival is 93%. The number of patients at risk beyond 1 year is very low, but the data need to mature.” —Shaji K. Kumar, MD “The peripheral neuropathy signal has been fairly low [with the oral drug] compared with what we expect with bortezomib-based regimens,” Dr Kumar said. He added that besides the good tolerability, MLN9708 rep-

resents a huge treatment advance by providing an oral therapy option. MLN9708 Studied with First-Line Combination Regimen “Given the activity and toxicity profile of MLN9708, we wanted to explore the feasibility and efficacy of combining MLN9708 with lenalidomide and dexamethasone,” Dr Kumar said. This mirrors the highly effective combination of the similar drug bortezomib plus lenalidomide and dexamethasone combination. “The goal was to develop a highly effective, safe, and convenient, all-oral regimen for the initial treatment of myeloma,” he said. After establishing the maximum tolerated dose of the drug, 65 patients were evaluated in the study, in which MLN9708 was given on days 1, 8, and 15 in combination with lenalidomide (25 mg daily on days 1-21) and with dexamethasone (40 mg on days 1, 8, 15, and 22). MLN9708 was then continued as maintenance therapy for up to 12 cycles. In the 20 patients who were to undergo an autologous stem-cell transplant, stem cells were successfully collected. Overall, 52 patients were evaluable for response after a median of 6 cycles of treatment; of these patients, 58% achieved at least a very good partial response (≥VGPR), 32% achieved a

partial response, and 23% had a complete response. The depth of response deepened with increasing exposure to treatment. After 8 cycles, the complete response rate was 32%, and in the 3 patients who completed all 12 cycles, 100% of patients achieved ≥VGPR. “While the follow-up is still very short, progression-free survival is 93%,” Dr Kumar added. “The number of patients at risk beyond 1 year is very low, but the data need to mature.” Twenty-one patients (32%) reported neuropathy, which was grade 1 in 20% of patients, grade 2 in only 9%, and grade 3 in 3% of patients. Mild rash, fatigue, nausea, vomiting, and diarrhea were reported by 40% of patients. These were well managed with dose reductions and supportive care, Dr Kumar said. Two serious adverse events (grade 4) were observed, including end-stage renal disease in 1 patient (resulting from disease progression) and deepvein thrombosis in 1 patient. In addition, 1 patient died from pneumonia while receiving treatment. In light of the promising results seen with MLN9708, the drug has entered a phase 3 trial, and 2 other trials are planned in newly diagnosed patients with myeloma and in those with relapsed and/or refractory disease. n

Request your subscription to American Health & Drug Benefits

q YES ! I would like to receive American Health & Drug Benefits q NO. Please discontinue my subscription. Signature (Required)

as well as related educational supplements.

Specialty

Date (Required) Address Name City/State/Zip Company E-mail Title

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

Fax to: 732.992.1881 26

American health & drug benefits

february 2013

VOL. 6

NO. 1

Special Issue

Payers’ Perspective

New Data Presented at Highlight Challenges and Opportunities for Payers Matthew Mitchell, PharmD, MBA, Manager, Pharmacy Services, SelectHealth, Salt Lake City, UT

he overall incidence of hematologic cancers is lower than that of solid tumor malignancies, such as lung, breast, and colorectal cancers, for payers who are responsible for keeping track of and for managing the entire portfolio of oncology. Hematologic cancers bring unique challenges from a treatment perspective and a supportive care perspective. These considerations translate to unique consideration requirements, challenges, and opportunities for payers. The 2012 ASH meeting brought with it much anticipated data supporting novel therapies. Several retrospective analyses were also shared that evaluated existing treatments, best-practice medical interventions (eg, hematopoietic-cell transplantation), the value of medications, and other interventions as seen through calculations of cost-effectiveness. Promising Emerging Medications One example of a novel medication with exciting phase 2 results is quizartinib. Quizartinib is being studied for the treatment of patients with high-risk, refractory acute myeloid leukemia (AML). The data presented show a 46% complete response rate after 28-day cycles of quizartinib monotherapy in a population that failed salvage chemotherapy or that had relapsed after stem-cell transplant. What makes this even more impressive is that the majority of patients were at very high risk as a result of their genetic profiles, including the FLT3-ITD mutation. In a population that previously did not have an opportunity to bridge to a potential curative allogeneic stem-cell transplant, 34% of the patients were successfully bridged to transplantation. Further development of quizartinib’s clinical profile will be important to monitor to define its place in therapy. This includes defining the appropriate patient, including a genetic profile, as well as when quizartinib is used within the continuum of therapy. These factors will influence the management and the potential value as defined by payers. Ross L. Levine, MD, presented data on newly discovered genes that have prognostic significance in treating patients with AML. Having the ability to classify patients into various risk profiles may help guide therapy. For example, a recent post hoc analysis

VOL. 6

NO. 1

Special Issue

found that high-dose daunorubicin had a greater 3-year overall survival compared with standard-dose daunorubicin in patients with high-risk mutations or translocations. These data may also help shape guideline development and corresponding coverage criteria. Payers will evaluate the sensitivity, specificity, and the cost of these genetic tests and consider the relative prognostic value in a realworld setting. Shaji K. Kumar, MD, presented data on an investigational oral proteasome inhibitor, MLN9708. This could be the first oral proteasome inhibitor for the treatment of multiple myeloma (MM). During a 12-month time frame, the overall response rate was more than 90%; however, MLN9708 was studied in combination with lenalidomide. Payers are familiar with the use of combination therapy for the treatment of patients with MM. However, if these data are confirmed in later phase studies, the US Food and Drug Administration (FDA) could approve combination therapy with novel agents for the treatment of

Further development of quizartinib’s clinical profile will be important to monitor to define its place in therapy. This includes defining the appropriate patient, including a genetic profile, as well as when quizartinib is used within the continuum of therapy. These factors will influence the management and the potential value as defined by payers. MM, which is primarily recommended by the National Comprehensive Cancer Network (NCCN), but without formal FDA approval. Determining the value of all of the various combinations of currently available therapy, as well as the most appropriate line of therapy, is very difficult in patients with MM. Cost Implications Mitchell S. Cairo, MD, presented

Payers will evaluate the sensitivity, specificity, and the cost of these genetic tests and consider the relative prognostic value in a real-world setting. interesting data demonstrating a cost reduction for inpatient stays, shorter lengths of stay, and lower corresponding charges when rasburicase was used in lieu of allopurinol for the treatment of acute tumor lysis syndrome. Regarding this relatively rare condition, records from more than 400 hospitals were evaluated to profile 130 patients, of which approximately 25% received rasburicase. The average lengths of stay were 5 days less for the group that received rasburicase. Hospitals with specific-use criteria for rasburicase should evaluate these data to validate their criteria. The outstanding question is the potential for the cost-effective use of rasburicase in the outpatient setting. Without these data, payers should continue to monitor the need to manage the use of rasburicase in the outpatient setting while keeping in mind the acquisition cost of these products as well as the available clinical data. Recently Approved Therapies Several recent advances have been reported in hard-to-treat leukemia. The FDA approved bosutinib in September 2012 and omacetaxine mepesuccinate in October 2012 to treat various phases of chronic myeloid leukemia (CML). Vincristine sulfate liposome injection was approved in

August 2012 to treat Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL). In December 2012, the FDA approved ponatinib 3 months ahead of schedule for the treatment of CML and Philadelphia chromosome–positive ALL. Jorge E. Cortes, MD, presented data on the use of ponatinib in patients who otherwise had no therapeutic alternatives. Ponatinib is a tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in patients who have failed other TKI therapies, including first- and second-line TKI therapies. In particular, if a patient has a T315I BCR-ABL mutation, the other existing TKIs, including bosutinib, dasatinib, nilotinib, and imatinib, are considerably less effective. According to Dr Cortes, patients with mutations other than T315I respond very well, with a total of 57% having a major cytogenetic response. Dr Cortes also noted that ponatinib is very well tolerated, but it does, however, carry a Boxed Warning about blood clots and liver toxicity. Opportunities for Payer Management These therapies for CML and ALL also provide opportunities for keen payer management. Particularly in patients with chronic-phase CML, oral TKI therapy may be used for years to maintain cytogenetic response. Robert C. Hermann, MD, FACP, presented data regarding the use of cytogenetic assessments from a registry of patients with newly diagnosed CML. The majority of patients (96%) in the analysis had chronic-phase CML, and 73% of patients were started with imatinib as first-line therapy. Disease burden while patients were receiving imatinib was most frequently assessed by blood counts, with only 16% having had a molecular assessment at 3 months, 47% at 12 months, and 64% at 36 months. Cytogenetic testing was even less common. According to Dr Hermann, only approximately 25% of the patients receiving imatinib had a complete cytogenetic response by 12 months and by 18 months, and approximately 25% achieved a major molecular response, which is lower than reported in clinical trials. What is not known from these data is if cytogenetic testing was completed more in populations of higher risk

february 2013

Continued on page 28

www.AHDBonline.com

Drug Update

Ponatinib: New Option for the Treatment of Adults with CML or Ph+ ALL that Is Resistant or Intolerant to Previous Therapy with Tyrosine Kinase Inhibitors By Lynne Lederman, PhD

eukemias are cancers involving the bone marrow and blood, and they account for approximately 4% of cancer deaths.1 The majority of leukemias occur in adults aged >20 years, and the incidence is a higher in men than in women. Leukemias are classified by the type of cell involved (ie, lymphocytic or myeloid) and the rate of progression (ie, acute or chronic). Chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) account for approximately 2.5% and 6%, respectively, of deaths resulting from leukemia.1 CML arises from the unregulated production of white blood cells in the bone marrow that results from a constitutively active tyrosine kinase that is the fusion product of the Abelson murine leukemia (ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22 after a reciprocal translocation between these chromosomes forms the Philadelphia chromosome (Ph). A related fusion protein occurs in a subset of cases of ALL (ie, Ph+ ALL).2-4 The Burden and Impact of CML and ALL The American Cancer Society esti-

mates that there will be almost 6000 new cases each of CML and ALL in 2013 in the United States, and that 610 deaths will result from CML and 1430 deaths from ALL.1 Leukemia is often associated with fatigue, pallor, bleeding, bruising, weight loss, and infections. In acute leukemia, these signs and symptoms may appear suddenly, whereas in chronic leukemia, there may be few symptoms that progress slowly.1 The 5-year survival rate for CML increased from 31% for patients diagnosed during 1990-1992 to 56% for those diagnosed during 2002-2008.1 The increase in survival for patients with CML is mainly the result of the development of targeted therapies,1 known as the BCR-ABLâ&#x20AC;&#x201C;specific tyrosine kinase inhibitors (TKIs).5 The 5-year relative survival rate for ALL overall has increased from 41% during the 1975-1977 period to 68% in the 2002-2008 period.1 The prognosis for Ph+ ALL is worse than that for other subtypes of ALL.4 The current treatment options for CML include the TKIs imatinib (Gleevec) and nilotinib (Tasigna), which are specific BCR-ABL TKIs; and dasatinib (Sprycel) and bosutinib

New Data Highlight Challenges... Continued from page 27 based on genetic profiles or on physical condition, or if molecular testing was more readily available in certain clinics that possibly have more specialized hematologists. This may have led to an adverse selection of patients being tested compared with those who were not tested. Either way, the NCCN now recommends the early assessment of molecular response. With the expanding treatment options for patients with CML, some payers are looking to TKI therapy as an opportunity to manage products. Imatinib is currently the least expensive TKI for CML on a monthly basis, and it is expected to become available as a generic in 2015. Dasatinib and nilotinib have similar FDA-approved indications, and they are considered by many payers to have similar efficacy. This is an area in oncology where payers may start to prefer an agent or agents through step therapy or prior authorization. Another initiative taken by sev-

eral specialty pharmacies and some payers is an effort to increase adherence. The importance of adherence is demonstrated by Dr Hermannâ&#x20AC;&#x2122;s presentation of improved 3-year survival in patients who received imatinib more than 85% of the days compared with those who were less adherent to therapy. These therapies are expensive, and poor adherence contributing to inadequate cytogenetic response may make the spending wasteful. It behooves payers to make efforts to tackle patient nonadherence. Meeting the Challenge Overall the ASH annual conference presented a large variety of data for upcoming new therapeutic entrants, as well as for existing treatment options. With these data, new challenges and opportunities emerge for payers who are charged with the responsibility of trying to manage this exciting realm in hematologic cancers. n

American health & drug benefits

february 2013

(Bosulif), which inhibit both ABL and SRC kinases.3 These agents may be used as a part of combination therapy for patients with Ph+ ALL.4 Although many patients with CML who receive imatinib have a complete cytogenetic response, 25% of patients have disease that either does not respond initially to imatinib (primary resistance) or that progresses after initial response (secondary resistance).

Ponatinib offers a new treatment option for patients with CML, especially those with the T315I mutation, whose disease is not responding to other agents. According to the FDA, these patients have had few therapeutic options. Secondary resistance may be caused by a mutation in the ABL kinase domain known as the T325I (or gate-keeper) mutation, because it prevents imatinib, dasatinib, and bosutinib from entering the ATP-binding pocket and inhibiting the kinase. Resistance to imatinib and other TKIs is associated with many other mutations and other as-yet unidentified causes. However, the presence of a kinase-domain mutation is associated with a high risk for disease progression.3,6 Patients may also develop intolerance to approved TKIs.3 Therefore, there remains a need for new agents that are effective in patients with resistant disease. Ponatinib Fills an Unmet Need On December 14, 2012, the US Food and Drug Administration (FDA) granted accelerated approval to ponatinib (Iclusig; ARIAD Pharmaceuticals) based on the results from a phase 2 clinical trial. Ponatinib is indicated for the treatment of adult patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML that is resistant to or is intolerant of previous TKI therapy or for patients with Ph+ ALL that is resistant to or intolerant of previous TKI therapy.7 Ponatinib offers a new treatment option for patients with CML, espe-

cially those with the T315I mutation, whose disease is not responding to other agents. According to the FDA, these patients have had few therapeutic options. This approval provides patients with earlier access to ponatinib, while the manufacturer conducts additional studies to confirm the clinical benefit and the safe use of this new agent.8 The prescribing information for ponatinib states that the indication was based on the response rate to the drug, and that no trials have confirmed an improvement in disease-related symptoms or increased survival with this drug.9 Dosing and Administration Ponatinib is administered orally once daily at a recommended dose of 45 mg.9

Dose Modification Dose modifications are suggested if patients experience neutropenia or thrombocytopenia that is unrelated to their leukemia. The dose of ponatinib should be modified or the treatment should be interrupted if serious nonhematologic reactions occur. Treatment may be resumed once the event has resolved, or if the benefit of resuming therapy outweighs the risk; in patients with serious ischemic reactions, in addition to considering the risk-benefit ratio, ponatinib should be resumed only if the patient has no other treatment options.9 Use with CYP3A Inhibitors The recommended dose should be reduced to 30 mg once daily when administering ponatinib with strong cytochrome (CY) P3A inhibitors.9 Clinical Pharmacology

Mechanism of Action Ponatinib is a TKI that was designed to inhibit the BCR-ABL genetic mutations, including drug-resistant mutations that arise during treatment.9 Ponatinib is the only TKI that is active against the T315I mutation of BCR-ABL,7 which is the most frequent mutation, occurring in up to 20% of patients with TKI resistance.2 In vitro, ponatinib inhibited the tyrosine kinase activity of ABL and T315I-mutant ABL, as well as that of additional kinases, including members of the vascular endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor VOL. 6

NO. 1

Special Issue

Drug Update receptors, and ephrin receptors; the SRC families of kinases; and KIT, RET, TIE2, and FLT3.9,10 Phase 2 Clinical Trial Ponatinib was approved on the basis of the pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial in patients with CML or Ph+ ALL whose disease was resistant to or intolerant of previous TKI therapy, or whose leukemia had the T315I mutation of BCR-ABL.7,9,11,12

Trial Design The phase 2 PACE trial was a single-arm, open-label, international, multicenter trial. The starting dose for all patients was 45 mg of ponatinib once daily. A total of 449 patients were enrolled, of whom 444 were evaluable for efficacy. Patients were assigned to 1 of 6 cohorts based on disease phase, resistance or intolerance to previous TKI therapy (ie, dasatinib or nilotinib), and the presence of the T315I mutation. Disease phases included CP-CML, APCML, and BP-CML/Ph+ ALL.9,11,12 The primary efficacy end point in CP-CML was major cytogenetic response, which included complete and partial cytogenetic responses. The primary efficacy end point in patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, defined as a complete hematologic response or no evidence of leukemia.9 Patient Population The study included 267 patients with CP-CML (resistant or intolerant cohort, N = 203; T315I mutation cohort, N = 64), 83 patients with APCML, 62 patients with BP-CML, and 32 patients with Ph+ ALL.9 Key baseline demographic and disease characteristics of the evaluable patients are listed in Table 1. Safety Profile At the time of the safety analysis, the median duration of treatment with ponatinib was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83% of the expected 45-mg dose. Overall, the most frequent nonhematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.9 The rates of treatment-emergent adverse events (AEs) resulting in discontinuation were 13% in the patients VOL. 6

NO. 1

Special Issue

with CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in the patients with Ph+ ALL. The most frequent AEs that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%). Dose modifications (delays or reduction) resulting from adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), increases in lipase (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and alanine aminotransferase, aspartate aminotransferase, or an increase in gamma glutamyl transferase (6%). Myelosuppression occurred in all patient populations. The frequencies of grade 3 or 4 thrombocytopenia, neutropenia, and anemia were higher in patients with AP-CML, BP-CML, and Ph+ ALL (47%, 57%, and 47%, respectively) than in patients with CP-CML (36%). Patients with Ph+ ALL had the highest rates of grades 3 and 4 neutropenia and leukopenia (63%); patients with BP-CML had the highest rates of grades 3 and 4 anemia (55%) and lymphopenia (37%).9

Response At the time of the analysis for response, the median follow-up was 10 months (with a minimum of 6 months of follow-up for all ongoing patients). The median duration of ponatinib treatment was 281 days in patients with CP-CML, 286 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL.9 The efficacy results for patients with CP-CML are summarized in Table 2. The efficacy results for patients with AP-CML, BP-CML, and Ph+ ALL are summarized in Table 3. Warnings and Precautions The ponatinib prescribing information contains a Boxed Warning about arterial thrombosis and hepatotoxicity, advising clinicians about the potential for these serious events with this medication:9 • Arterial thrombosis. Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, have occurred in patients receiving ponatinib. In clinical trials, serious arterial thrombosis occurred in 8% of patients receiving ponatinib. In patients receiving ponatinib who develop arterial thrombotic events, ponatinib should be interrupted and discontinuation should be considered.

aseline Demographics and Disease Characteristics in the Phase 2 Table 1 B Pivotal Trial Efficacy population N = 444

Characteristic Median age, yrs (range)

59 (18-94)

Men, N (%) Women, N (%)

236 (53) 108 (47)

Race, N (%) White Black Asian Other

349 (79) 25 (6) 57 (13) 13 (3)

ECOG performance status 0 or 1, N (%)

409 (92)

Median time from diagnosis to first dose, yrs (range)

6.1 (0.3-28.5)

Resistant to previous TKI therapy, N (%)

374 (88)

Presence of ≥1 BCR-ABL kinase domain mutations, N (%)

244 (55)

Previously approved TKIs, N (%) 1 2 ≥3

29 (7%) 166 (37%) 249 (56%)

ECOG indicates Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor. Adapted from Reference 9.

Table 2 E fficacy of Ponatinib in Patients with Resistant or Intolerant Chronic-Phase CML Cohort

Cytogenetic response

Total patients N = 267

Patients with resistant/ intolerant disease N = 203

Patients with T315I Mutation N = 64

MCyRa, % (95% CI)

54 (48-60)

49 (42-56)

70 (58-81)

CCyR, % (95% CI)

44 (38-50)

37 (31-44)

66 (53-77)

Median time to MCyR, days (range)

84 (49-334)

Median duration of MCyR

Not reached

The primary end point for chronic-phase CML cohorts was MCyR, which combines both complete (no detectable Ph+ cells) and partial (1%-35% Ph+ cells in at least 20 metaphases) cytogenetic responses. CCyR indicates complete cytogenetic response; CML, chronic myeloid leukemia; MCyR, major cytogenetic response; Ph+, Philadelphia chromosome–positive. Adapted from Reference 9.

Table 3 E fficacy of Ponatinib in Patients with Resistant or Intolerant Advanced Disease, (Including Resistant/Intolerant and T315I Mutation Cohorts) Hematologic response

AP-CML N = 83

BP-CML N = 62

Ph+ ALL N = 32

Major responsea, % (95% CI)

52 (41-63)

31 (20-44)

41 (24-59)

Complete response , % (95% CI)

47 (33-55)

21 (12-33)

34 (19-53)

Median time to major response, days (range)

21 (12-176)

29 (12-113)

20 (11-168)

9.5 (1.1-17.7)

4.7 (1.8-14.1+)

3.2 (1.8-8.8+)

Median duration of major response, months (range)

Primary end point for patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, which combines complete hematologic responses and no evidence of leukemia. b Complete hematologic response: white blood cell ≤institutional upper limit of normal, absolute neutrophil count ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, no extramedullary involvement (including no hepatomegaly or splenomegaly). ALL indicates acute lymphocytic leukemia; AP, accelerated phase; BP, blast phase; CI, confidence interval; CML, chronic myeloid leukemia; Ph+, Philadelphia chromosome–positive. Adapted from Reference 9. a

Continued on page 30 february 2013

www.AHDBonline.com

Drug Update Ponatinib: New Option for the Treatment of Adults with CML... Table 4 Summary of Ponatinib Warnings and Precautions Warnings and precautions

Description

Thrombosis/ thromboembolism

CV, cerebrovascular, and peripheral vascular thrombosis; serious arterial thrombosis, 8%a; MI, 5%; VTE, 3%; serious cerebral vascular or peripheral arterial events, 2% each

Other CV events

Congestive heart failure: any grade, 7%; serious, 4% Cardiac arrhythmias: includes bradyarrhythmias (1% required pacemaker implantation; tachyarrhythmias) Hypertension: overall, 67%; serious requiring urgent intervention, 2%Fluid retention: overall, 23%; serious, 3%; 1 fatal brain edema

Hepatotoxicity

Fatal in 3 patients; AST or ALT elevation, 56% (8% grades 3 or 4)

Pancreatitis

Clinical, 6%; grade 3, 5%; lipase elevation, 41%

Hemorrhage

Overall, 24%; serious including fatal events, 5%; most common with grade 4 thrombocytopenia

Myelosuppression

Severe, 48%

Tumor lysis syndrome

Serious in 2 patients (<1%); serious hyperuri cemia, 7%

Compromised wound healing

No formal studies, but could occur

Gastrointestinal perforation 1 patient with fistula 38 days postcholecystectomy Embryo-fetal toxicity

Can cause fetal harm based on method of operation and animal studies

Refers to proportion of patients in the pivotal trial (N = 444). ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; MI, myocardial infarction; VTE, venous thromboembolism. Source: Reference 9.

• Hepatotoxicity. Hepatotoxicity, liver failure, and death have occurred in patients receiving ponatinib. Hepatic function should be monitored before and during treatment. For hepatotoxicity, ponatinib should be interrupted and then reduced or discontinued. Other warnings and precautions are summarized in Table 4. Conclusion Ponatinib is now being further investigated in a phase 3 randomized clinical trial that is comparing ponatinib with imatinib in patients with newly diagnosed CP-CML.13 As the second-generation BCR-ABL inhibitors are replacing imatinib in the treatment of newly diagnosed CML, the aim of this trial is to determine if ponatinib is effective in this patient population, and if it has the ability to prevent the emergence of resistant mutations that occur with other TKIs.10,13 A recent commentary by J.M. Goldman regarding the multikinase activity of ponatinib, as well as the preliminary results in patients with CML that is resistant to imatinib and second-generation TKIs, suggest that ponatinib may be “another step forward in the march toward real success with molecularly targeted therapy for cancer.”6 n

Continued from page 29 References

1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013. 2. Cortez JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia. Version 3.2013. NCCN.org. Accessed December 19, 2012. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia. Version 2.2012. NCCN.org. Accessed: January 9, 2013. 5. Carella AM, Goldman JM, Martinelli G, et al. Chronic myeloid leukemia: the basis of treatment for tomorrow. Haematologica. 2011;96:1737-1739. 6. Goldman JM. Ponatinib for chronic myeloid leukemia. N Engl J Med. 2012;367:2148-2149. 7. ARIAD Pharmaceuticals. ARIAD announces accelerated approval by FDA of Iclusig (ponatinib) for patients with CML and Ph+ ALL resistant or intolerant to prior tyrosine kinase inhibitor therapy. December 14, 2012. http://phx.corporate-ir.net/phoenix.zhtml?c= 118422&p=irol-newsArticle_print&ID=1767523&highlight =. Accessed January 17, 2013. 8. FDA News Release. FDA approves Iclusig to treat two rare types of leukemia. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm332252.htm. Accessed January 17, 2013. 9. Iclusig (ponatinib) tablets for oral use. Prescribing information. ARIAD Pharmaceuticals, Inc: Cambridge, MA; December 2012. 10. O’Hare T, Shakespeare WC, Zhu X, et al. AP24535, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412. 11. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol. 2012; 30(suppl):Abstract 6503. 12. Cortes J, Kim DW, Pinilla J, et al. PACE: a pivotal phase 2 trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Haematologica. 2012; 97(suppl 1):453. 13. ARIAD EPIC PR. ARIAD announced initiation of randomized phase 3 trial of ponatinib in newly diagnosed patients with chronic myeloid leukemia. http:// phx.corporate-ir.net/phoenix.zhtml?c=118422&p= irol-newsArticle&ID=1719432&highlight=. Accessed January 17, 2013.

Call for Papers

Cancer Care Theme Issue American Health & Drug Benefits will be publishing a theme issue on cancer care in mid-2013 The growing focus on targeted therapies and diagnostics, and the ever-increasing cost of cancer care, require a thorough examination of current and emerging trends in oncology, focusing on benefit design, utilization, and health outcomes. Readers are invited to submit manuscripts for this issue, including original research, cost-effective analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends. All articles will undergo the journal’s rigorous peer-review process. Manuscripts must follow the format described in the Information for Authors at www.AHDBonline.com.

Areas of particular interest include: Benefit design for cancer therapies

➤

Best practices in oncology

➤

Cancer care and health disparities

➤

Cost considerations in cancer care

➤

Emerging trends in hematology/oncology

➤

End-of-life issues

➤

Health plan initiatives in oncology

➤

➤ ➤ ➤ ➤ ➤

Managing toxicities of cancer therapies Palliative care Pathways and practice guidelines Personalized medicine in oncology Survivorship programs Targeted cancer therapies

➤ ➤

Value-based cancer care

Submit articles to editorial@engagehc.com. For more information, call 732-992-1889.

American health & drug benefits

february 2013

VOL. 6

NO. 1

Special Issue

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer CareTM, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will explore a specific topic to be considered when developing value-based strategies. IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation. Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies. Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care , is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-ef topic to be considered when developing value-based newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5 By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6 By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

www.valuebasedcancer.com/myeloma AVBCC100Ksize21213

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it. Building confidence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made. After all, there’s so much at stake.

That’s why manufacturing matters. Learn more at

buildingbiologics.com