February 2010, Vol 3, No 1 SPECIAL ISSUE

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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE

ASH 2009: PAYER’S PERSPECTIVES THE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

Hematologic Drug Pipeline Healthcare Reform: CostContainment Not Very Likely Diverse and Promising

By Caroline Helwick

By Wayne Kuznar

A

Paul B. Ginsburg, PhD

S

ome degree of healthcare reform seems likely to be enacted, but what is shaping up as reform will likely be a failure in terms of “serious cost-containment,” suggested Paul B. Ginsburg, PhD, President of the Center for Studying Health System

Change, a “think tank” that analyzes changes in financing and the delivery of healthcare (www.hschange.org). Dr Ginsburg was the main speaker at the session on Healthcare Costs and Reform at the 2009 annual meeting of the American Society of Hematology.

Continued on page 4

The Costs of Multiple Myeloma Treatment Vary Widely

By Caroline Helwick

T

he costs of treating multiple myeloma (MM) can present as much of a burden on the patient and/or payers as on the disease itself.

In a recent cost analysis, investigators

compared the cost of treatment for MM with bortezomib (Velcade), an injectable drug, and with the oral medications lenalidomide (Revlimid) and thalidomide (Thalomid).

Continued on page 5

host of investigational drugs in the pipeline for the treatment of hematologic disorders were featured in many oral and poster presentations at ASH. The following is a sampling of agents that show particular promise.

Perhaps the 2 drugs that had the biggest reception were dabigatran etexilate and rivaroxaban, which showed impressive success for the prevention of recurrent venous thromboembolic events (see article, page 21).

Omacetaxine mepesuccinate is being studied for the treatment of chronic myelogenous leukemia (CML) that is resistant to imatinib because of the development of the BCR-ABL T315I genetic mutation. In an ongoing phase 2/3 study of 81 patients with CML (49 in chronic-phase CML, 17 in the accelerated phase, and 15 in the blast phase), omacetaxine produced

durable hematologic and cytogenetic responses, reported Jorge E. Cortes, MD, Deputy Chair and Professor of Medicine, Department of Leukemia, University of Texas M.D. Anderson Cancer Center.

“Omacetaxine works by a completely different mechanism, inhibiting the synthesis of certain oncoproteins instead of directly attacking BCRABL,” Dr Cortes said.

Previous imatinib therapy had failed in all the patients, and ≥2 previous tyrosine kinase inhibitors failed in 79%. A baseline BCR-ABL T315I gene mutation was confirmed in all patients.

In chronic-phase CML patients, complete hematologic responses occurred in 86% (median response duration, 9 months) and the total cytogenetic response rate was 41%, with a major cytogenetic response in 27%.

Continued on page 21

New Regimen Challenges Standard Treatment of Indolent Lymphoma

By Wayne Kuznar

B

endamustine (Treanda) plus rituximab (Rituxan) (B/R) was more effective and better tolerated than the standard first-line regimen of CHOP-R—cyclophosphamide (Cytoxan), hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and prednisone (Deltasone), plus rituximab—for indolent lymphoma and mantle-cell lymphoma (MCL), according to a phase 3 German trial in which B/R reduced the risk of tumor progression by 43%. The study was highlighted at a special press conference

during ASH. “Bendamustine plus rituximab has the potential to become a treatment of first choice in these disease entities,” said Mathias J. Rummel, MD, of the University Hospital in Giessen, Mathias J. Rummel, MD Germany.

“I think there will be a great deal of interest in this study. The findings are Continued on page 8

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LEUKEMIA 12 MULTIPLE MYELOMA 17 OTHER ASH HIGHLIGHTS 21

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For more information, visit www.cllinformation.com *

Refractory to fludarabine and alemtuzumab

Š 2009 The GlaxoSmithKline Group of Companies All Rights reserved. AZA140R0 October 2009

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ASH 2009: PAYER’S PERSPECTIVES

THE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

HEALTH ECONOMICS

LEUKEMIA

4 5

12 First Head-to-Head Comparison of Targeted TKIs 13 Intermittent Dosing of Dasatinib May Cut Toxicity,

6

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman lara@engagehc.com 732-992-1892 Senior Production Manager Robyn Jacobs

7

9

10

12

Indolent Lymphoma In Challenging B-Cell Lymphoma, Aggressive Chemotherapy plus Rituximab Show Best Outcomes Treatment Is Beneficial in Older Patients with Advanced Lymphoma Hodgkin’s Lymphoma: No Changes in Standard of Care, but Emerging Therapies Are Promising Adding Rituximab to Standard Therapy in Hodgkin’s Lymphoma Improves Outcomes Novel Agent Shows Impressive Outcomes in Aggressive NHL How Much Rituximab Is Necessary in Advanced NHL? Long-Term Survival Achieved with Tositumomab/I-131 Emerging Strategies for Mantle-Cell Lymphoma

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com

EDITORIAL BOARD

T: 732-992-1892 F: 732-992-1881

CLINICAL EDITOR Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 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.

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8 New Regimen Challenges Standard Treatment of

Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

This publication 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.

Healthcare Reform: Cost-Containment Not Very Likely The Costs of Multiple Myeloma Treatment Vary Widely Pegfilgrastim with Transplant: Upfront Cost May Be Offset For MDS Treatment, Azacitidine Enhances Cost-Effectiveness Compared with Decitabine Bortezomib Cost-Effective for Newly Diagnosed Patients with Multiple Myeloma Alemtuzumab Contributes 39% to Treatment Costs in CLL

LYMPHOMA

Business Manager Blanche Marchitto

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric 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. Benefit designs are greatly affected by clinical, business, and policy conditions.

FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

GOVERNMENT EDITOR Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

ACTUARY David Williams Milliman Health Consultant Windsor, CT

EPIDEMIOLOGY RESEARCH Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

CANCER RESEARCH Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Chair, Board of Directors, NCCN

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA

Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York ENDOCRINOLOGY RESEARCH James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EMPLOYERS Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

HEALTH INFORMATION TECHNOLOGY J.B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA HEALTH OUTCOMES RESEARCH Gordon M. Cummins, MS Director, IntegriChain

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL MANAGED CARE & GOVERNMENT AFFAIRS Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit, PA

Allow Continued Treatment in CML Bendamustine-Rituximab Combo an Effective First-Line Therapy for CLL Statins Delay Treatment in CLL Second-Generation TKIs Effective, Safe for Relapsed ALL Advances in Treating MDS Adding Alemtuzumab to Fludarabine Doubles PFS in Relapsed CLL Antifungal Prophylaxis in AML Patients Receiving Induction Chemotherapy

MULTIPLE MYELOMA

17 Maintenance Therapy an Emerging Theme in Myeloma 20

High-Risk Smoldering Myeloma Responds to Treatment Multiple Myeloma Management in 2010 Weekly Bortezomib Effective, Less Toxic

OTHER ASH HIGHLIGHTS

21 Hematologic Drug Pipeline Diverse and Promising

22

Investigational Alternatives to Warfarin Prevent VTE Events Stem-Cell Mobilization Strategies: What Works, What Doesn’t Positive Long-Term Data for 2 ITP Treatments

POLICY & PUBLIC HEALTH Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University Spokane, WA PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago REIMBURSEMENT POLICY Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Corp., Philadelphia, PA

PHARMACY BENEFIT DESIGN Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA

Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer Sanovia Corp., Philadelphia, PA

SPECIALTY PHARMACY Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System Danville, PA

James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates Boston, MA

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Health Economics

Healthcare Reform: Cost-Containment...

“A single approach to containing costs is unlikely to be sufficiently successful,” he advised. “We need to pursue many distinct but consistent ap proaches to offset risks that some approaches will not succeed.”

Rising Healthcare Costs On the national level, rising costs are undermining the mechanisms that finance healthcare and are a key factor in the country’s “dire public fiscal outlook,” Dr Ginsburg noted. On the individual level, private insurance is increasingly unaffordable and the affordability problem now affects the middle class, he said.

The costs of Medicare, Medicaid, and tax expenditures for private health insurance are all growing faster than the gross domestic product (GDP), and the result is that other priorities are neglected, taxes are higher, and the deficit is growing.

An international comparison provides the evidence of undue high costs in the United States. Healthcare accounts for 16% of the GDP in this country, compared with about 11% in many other countries, including France, Germany, Switzerland, and Canada.

“Adjusting for income, the United States spends an extra $477 billion per year on healthcare” compared with many other countries, said Dr Ginsburg. Evidence of rising costs comes from a comparison of cost and income trends. “There has been a 37% increase in earnings to support a 120% increase in premiums,” he said. “This gap explains three fourths of the longterm decline in the percent of the insured population.”

Dr Ginsburg. Additional drivers include the poorly functioning medical liability system and state insurance mandates.

At least one third of the trend in spending stems from technological “advances.” While new treatments are more effective—yielding better outcomes with lower risks—there is a tendency to overuse them to the point of limited or negative gains, he pointed out. Marginally effective, ineffective, or harmful treatments also add to rising costs, and there is little funding for effectiveness research to weed these out.

Unhealthy lifestyles create more health problems. Obesity alone is estimated to account for 12% of spending growth in recent years. Declines in smoking have held down cost trends, but the killer habit still contributes to spending growth, Dr Ginsburg said.

The prosperity of the economy largely derives from gains in productivity, but this is true only for certain industries, such as banking and airlines. “There is much less productivity in healthcare,” he noted.

One reason for this is the lack of the right incentives for healthcare providers. There are few incentives to produce episodes of treatment or to help improve a patient’s health more efficiently, he noted. And there is wide variation in the efficiency of the care that is delivered.

“New patterns of competition” refers to the “entrepreneurial delivery system” of today or to the expansion of services that are profitable but may not add true value. A failure of Medicare and private insurers to set

“A single approach to containing costs is unlikely to be sufficiently successful….We need to pursue many distinct but consistent approaches to offset risks that some approaches will not succeed.” —Paul Ginsburg, PhD Key Cost Drivers The key drivers of rising costs in the United States are: • Higher incomes (more money is available to spend on healthcare) • Developments in medical technology • Less-healthy lifestyles • Small gains in productivity related to the delivery of health services • New patterns of competition in healthcare • And to a lesser degree than is often assumed, the aging of the US population.

Aging contributes just ≤0.5% to the annual spending trend, according to

payment rates to appropriately reflect relative cost of services has led hospitals to expand services that are profitable, such as cardiac procedures, and special facilities, such as “heart hospitals.” It is possible that expansions of capacity are actually creating a demand for services, Dr Ginsburg noted.

Tied to this is an increase in physician self-referrals, for example, an increase in referrals to magnetic resonance imaging occurs when physicians use their own imaging centers.

“With ownership of facilities the scope of physician self-referral is wider, and this is worrisome to me,” he said.

Continued from page 1 will increase healthcare spending.”

The public plan option is also faulty.

“Only the robust version can impact costs through lower provider payment rates,” he noted. “The version in the current bills has little potential to reduce costs.” Increased competition in insurance markets has limited potential.

Cost-savings through increased wellness and prevention is another fallacy.

“The evidence on the lack of potential for savings is very strong. Many in Congress are unwilling to accept the evidence, but the Congressional Budget Office analysis found that prevention will not reduce federal outlays,” Dr Ginsburg said.

“Politicians claim there will be large savings through reducing waste. It’s a terrific idea, but it won’t solve the cost problem.”

—Paul Ginsburg, PhD Why Are Costs So Hard to Contain?

Cost-containment is complex and, for various reasons, is viewed by many sectors as threatening. “All spending pertains to someone’s income, and there is an increasingly effective lobby to protect incomes,” Dr Ginsburg observed.

Our political leaders are also “falling down on the job,” by fostering the notion that costs can be contained without sacrifice. “The concept of cutting waste, fraud, and abuse goes way back,” he said. “Politicians claim there will be large savings through reducing waste. It’s a terrific idea, but it won’t solve the cost problem.”

It is uncertain that such “painless solutions” will contain costs, he maintained. The other current proposals include the promotion of quality reporting and payment for quality, the advancement and adoption of health information technology, and the application of comparative effectiveness research.

“Red Herrings” of Current Reform The current motivator for healthcare reform is the expansion of insurance coverage; however, coverage expansion will exacerbate, not alleviate, the cost problem, according to Dr Ginsburg.

“Uninsured people spend less,” he pointed out. “More comprehensive in surance leads to higher spending. Bringing the uninsured up to insured status

Which Approaches May Work?

A single approach will not be the sole solution to cost-containment, and there are advantages and disadvantages to most of the strategies being discussed.

Increased patient cost-sharing (benefits “buydowns,” consumer-directed health plans, and health savings accounts) is part of a demand-side approach to cost-containment and is not favored by political liberals. In fact, patient cost-sharing does a fairly poor job of addressing spending trends, Dr Ginsburg added, because most spending is concentrated within a relatively small population of patients. “The burden of healthcare falls more on the sick and the poor.”

In contrast, patient financial incentives “clearly work,” but will not accomplish much, because healthcare use is not particularly sensitive to patient incentives. To be effective, the tools for patient incentives need refinement, he said.

One proposal is a value-based benefits design, which will vary costsharing by service type and patient condition—with low barriers to the management of chronic disease and higher barriers for elective services.

This approach would promote the choice of more efficient providers, because consumers would reap savings when they choose less-costly providers, and less-efficient providers would have incentives to improve care. Another tool is the excise tax on “Cadillac plans.”

Also part of the demand-side approach is more research on price and quality, which in theory is favored by all but providers but in practice may be less useful, because its impact would not be felt for years. The government’s role would be centered on data gathering rather than price setting; the latter would fall to insurers to customize and simplify.

Continued on page 5

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AMERICAN HEALTH & DRUG BENEFITS

February 2010

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Health Economics

The Costs of Multiple Myeloma Treatment...

Results showed that bortezomib was associated with less out-of-pocket (OOP) cost than the 2 oral medications.

Bortezomib is a proteasome inhibitor, and lenalidomide and thalidomide are immunomodulatory drugs. These medications are sometimes combined with other agents into 1 regimen.

“Multiple myeloma is a complex disease. Improved outcomes have been achieved with these novel agents; however, few studies have reported the economic burden on patients,” said Brett W. Pinsky, MPH, Senior Researcher at i3 Innovus, Eden Prairie, MN.

“Direct out-of-pocket costs were significantly higher for patients treated with the oral drugs thalidomide and lenalidomide compared with bortezomib for injection.”

—Brett W. Pinsky, MPH The investigators drew from a claims database of a large national, commercial health plan with 14 million members. Treatment episodes, defined as each course of therapy, were identified from claims records for each patient.

Patient OOP costs and patient visit data were examined for 1 year from the beginning of each treatment episode.

Descriptive analyses were supple-

mented with multivariate regression analyses to control for patient characteristics, comorbidities, and line of treatment. A total of 2642 treatment episodes were identified for the 1900 patients. The majority of episodes were classified as “other chemotherapy or radiation therapy” (66.6%), followed by thalidomide (20.8%), bortezomib (9.2%), and lenalidomide (3.4%).

Ambulatory visits accounted for much of the patient visit burden.

As expected, patients treated with bortezomib for injection had more visits than those treated with oral lenalidomide, but the difference was not significant after adjusting for patient characteristics, line of treatment, and comorbidities by a multivariate analysis.

A significant number of outpatient hospital visits occurred with all these agents but most frequently with thalidomide. Because patients must visit doctors to receive bortezomib injections more often than for the oral medications, it is often assumed that bortezomib injection is a more expensive treatment. The data, however, do not support that assumption, Mr Pinsky said.

Patient Out-of-Pocket Costs “Direct out-of-pocket costs were significantly higher for patients treated with the oral drugs thalidomide and lenalidomide compared with bortezomib for injection,” said Mr Pinsky.

The total adjusted patient OOP costs

Healthcare Reform... Continued from page 4 Finally, many today believe that programs aimed at wellness and prevention will help contain costs, but the effect of prevention has not been proved, Dr Ginsburg cautions.

Improved Payment Structure As a supply-side approach, the crafting of a more accurate payment structure is widely proposed, based on the unintended wide variation in profitability by service. Medicare is wellpositioned to make structures more accurate (and private insurers and Medicaid programs will follow), but Medicare needs to apply more political and financial resources to this, which is problematic, because many hold a negative view of Medicare governance, Dr Ginsburg noted.

The supply-side approach also in cludes broader payment units (BPUs) as a means of reducing the role of fee-for-service, which is faulted by having incentives for service volume and lacking motivations or rewards for coordinated services. BPUs introduce

elements of capitation in the form of accountable care organizations. The strategy can incorporate episodebased payments in which actual perepisode payments can be made to a joint entity or by fee-for-service, with incentives for all involved.

But Dr Ginsburg questions whether BPUs will be implemented, and whether the idea will succeed. “BPUs have opportunities for physicians— rewards for reducing spending on hospital care, pharmaceuticals, and devices. They can save money by reducing hospitalizations, choice of drugs, and so forth and not just by reducing the physician’s own services. They can capture rewards from this.”

Although the debate once focused on “competition versus regulation,” Dr Ginsburg pointed out that the country proved unwilling to embrace either. He concluded that the search for a solution is geared toward “pragmatism that recognizes the need to build on present institutions.” ■

Continued from page 1

Table Adjusted Patient OOP Cost 1 Year after Treatment Initiation Patient OOP Cost Patient type

Bortezomib

Thalidomide

Lenalidomide

Non-Medicare

$3504

$4443

$4766

Medicare Advantage

$4395

$8824

$12,568

OOP indicates out-of-pocket.

for the year after treatment initiation are shown in the Table. These costs, and the differences between treatment type, were even greater for Medicare Advantage patients (Table). For the Medicare group, treatment with bortezomib amounted to less than half the cost of oral drug therapy with either drug, he said.

The OOP cost discrepancy was magnified in the Medicare population likely because of the coverage gap, known as the doughnut hole in Medicare Part D, noted Henry Henk, PhD, also of i3

Innovus. “For the Medicare Advantage group, there is the doughnut hole effect that is causing a huge spike in the cost of the oral drugs,” Dr Henk pointed out.

The investigators concluded that because patients with MM require a great deal of care and resources, the majority of patients will not see a significant difference in the number of healthcare visits, regardless of the type of treatment, but they may feel the pinch of higher OOP costs with the oral drugs. ■

Pegfilgrastim with Transplant: Upfront Cost May Be Offset

By Caroline Helwick

H

igh-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) is the standard of care for subgroups of patients with multiple myeloma or lymphoma. Granulocyte colony-stimulating factors (G-CSFs) are used to enhance neutrophil engraftment in these patients. Compared with no growth factors, this reduces the number of days with fever, antibiotic use, and duration of hospitalization. Randomized trials have shown that further cost reduction can be obtained by delaying the start of G-CSF therapy from day 1 to days 5 to 7 after transplant, without significantly changing the time to neutrophil recovery.

Although the G-CSF agent pegfilgrastim (Neulasta) costs approximately 25% more up front than filgrastim (Neupogen), the cost is offset by a faster neutrophil engraftment, shorter time on antibiotics, and a tendency to shorter hospitalization time compared with filgrastim, according to several studies presented at ASH. G-CSFs are regularly used after ASCT to accelerate neutrophil engraftment. Swiss investigators evaluated the safety and efficacy of pegfilgrastim, a long-acting form of filgrastim given as a single, fixed dose, in 40 patients with multiple myeloma, Hodgkin’s lymphoma, and nonHodgkin’s lymphoma.

“This is a more patient-friendly approach, and since the drug is given

in a single shot, there is no need to delay the therapy to decrease treatment costs,” said Luciano Wannesson, MD, of the Oncology Institute of Southern Switzerland, Bellinzona.

“This is a more patient-friendly approach, and since the drug is given in a single shot, there is no need to delay the therapy to decrease treatment costs.”

—Luciano Wannesson, MD Pegfilgrastim 6 mg was given on transplant day 1. Results were compared with a matched historical control group of 40 patients who received filgrastim 5 μg/kg daily starting on an average of 7 days after transplant.

The median time to achieve a neutrophil count >500 μL (ie, neutrophil engraftment) was 9.5 days for the pegfilgrastim group versus 11.3 days for the filgrastim control group, which was a highly significant difference (P <.001).

Median duration of neutropenia was 5.8 days versus 7.4 days (P = .001), median duration of intravenous antibiotic therapy was 4.2 days versus 6.5 days (P = .007), and median hospitalization duration was 14.0 days versus 14.8 days (P = .018). These differences were most pronounced among Continued on page 6

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Health Economics

For MDS Treatment, Azacitidine Enhances Cost-Effectiveness Compared with Decitabine

By Caroline Helwick

I

n a cost-effectiveness analysis for the treatment of myelodysplastic syndrome (MDS), azacitidine (Vidaza) was shown to be cost-saving or cost-effective compared with decitabine (Dacogen). The analysis, funded

by Celgene, was presented by Risha Gidwani, DrPH, lead health economist at Abt Bio-Pharma Solutions, Lexington, MA. The National Comprehensive Cancer Network 2010 guidelines recommend the 2 agents, azacitidine and decitabine, for the treatment of MDS, with azacitidine being the preferred Category 1 treatment for intermediateor high-risk patients ineligible for transplant.

“Although the clinical benefits of azacitidine have been shown, this is the first study to evaluate its cost-effectiveness relative to decitabine,” Dr Gidwani said.

Investigators developed a decisionanalytic Markov model with 1-month cycles, which was run alternatively for 12- and 36-month periods. Patients in the model replicated the demographics of subjects enrolled in phase 3 trials for the drugs; based on these data, the

patients modeled in the decitabine arm had lower MDS severity than those in the azacitidine arm.

During each cycle of the model, patients could remain in or transition among 4 health states, including MDS and transfusion independence, MDS and transfusion dependence, progression to acute myeloid leukemia (AML), or death. Therefore, in any given model cycle a patient could be found stable, become healthier, become sicker, or die. The analysis used model parameters derived from published studies, product labels, clinical trial data and drug pricing, and medical services cost databases.

“Despite a higher-risk profile in the underlying data for azacitidine, treatment of MDS with azacitidine was either cost-saving—meaning that it cost less and conferred greater clinical benefit—or was cost-effective compared with decitabine,” Dr Gidwani reported.

“Azacitidine changed from dominating decitabine in the 12-month scenario to being cost-effective in the 36month scenario due to the survival advantage for azacitidine-treated

Table Comparisons for Azacitidine and Decitabine Parameter

Azacitidine

Decitabine

Total costs per patient: 12 months

$53,518

$62,760

Total costs per patient: 36 months

$154,112

$142,578

QALYs gained: 12 months

0.579

0.526

QALYs gained: 36 months

1.446

1.175

QALYs indicates quality-adjusted life-years.

“Azacitidine changed from dominating decitabine in the 12month scenario to being cost-effective in the 36-month scenario due to the survival advantage for azacitidine-treated patients.”

—Risha Gidwani, DrPH patients. Patients treated with azacitidine live longer, and therefore have more opportunity to incur treatment costs,” she explained.

In the 12-month and 36-month scenarios, azacitidine-treated patients had a greater number of life-years and quality-adjusted life-years (QALYs), attained a greater number of transfusion-independent months, and were more likely to avoid progression to AML. In the 12-month scenario, the use of azacitidine resulted in $9242 saved per

patient. In the 36-month scenario, azacitidine treatment cost $11,534 more than treatment with decitabine but conferred a clinical benefit of 0.2707 additional QALYs gained. The incremental cost-effectiveness ratio of $42,615 per QALY is considered cost-effective, Dr Gidwani noted. The total costs per patient and QALY gained at 12 and 36 months are shown in the Table. ■ SEE ALSO Advances in Treating MDS, page 16.

Pegfilgrastim with Transplant... Continued from page 5 patients with lymphoma.

Median time to platelet engraftment and median duration of fever were similar, and the 2 groups received an equal number of red blood cell and platelet transfusions.

“Starting pegfilgrastim on day 1 and filgrastim on days 5 to 7 posttransplant may have contributed to the accelerated engraftment, in line with the results of studies comparing early versus late filgrastim that showed a trend to better outcomes with early filgrastim,” Dr Wannesson said.

Pegfilgrastim Frees Up Beds In a study from the United King dom, investigators assessed the impact on pegfilgrastim on bed availability. “Busy hematology centers

6

have severe pressure on bed availability, which can limit their ability to deliver multiple cycles of intensive chemotherapy on time,” said Neil Phillips, MD, of the Heart of England NHS Trust, Birmingham, UK.

“G-CSF use in ASCT has been shown to hasten neutrophil engraftment and to shorten the number of days of febrile neutropenia.”

—Neil Phillips, MD “G-CSF use in ASCT has been shown to hasten neutrophil engraftment and to shorten the number of days of febrile

AMERICAN HEALTH & DRUG BENEFITS

February 2010

neutropenia,” Dr Phillips added.

This retrospective study explored the effect of a single injection of pegfilgrastim 6 mg on engraftment and inpatient stay of 55 patients undergoing ASCT for the treatment of multiple myeloma, comparing those who received the drug with those not receiving it. The use of pegfilgrastim was associated with shorter duration to neutrophil engraftment (P = .06), less need for antibiotics (P = .04), and reduced hospital stay (P = .004).

“This is very useful, considering the pressure on the bed availability in the tertiary referral centers,” Dr Phillips said. “Cost-effectiveness due to reduced inpatient stay may lead to the use of this agent post-ASCT as a standard practice.” ■

“There’s nothing to laugh about but I laugh all the time.”

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Health Economics

Bortezomib Cost-Effective for Newly Diagnosed Patients with Multiple Myeloma

By Caroline Helwick

T

he bortezomib (Velcade)-based regimen with melphalan (Alkeran) and prednisone (Deltasone)—the VMP regimen—is cost-effective despite greater upfront costs.

“Our study showed that while adding bortezomib to melphalan and prednisone increases cost a good bit, it is actually cost-effective in patients with myeloma,” said Si-Tien Wang, MSc, of the Analysis Group, Boston, MA, a consulting firm specializing in health economics and outcomes research. The study’s senior author was Louis Garrison, PhD, Professor of Pharmacy at the University of Washington, Seattle.

Phase 3 trials have shown a survival advantage with the MPT regimen— thalidomide (Thalomid) plus melphalan and prednisone—over melphalan and prednisone (MP) alone, and the phase 3 VISTA trial showed the clinical superiority of VMP over MP for frontline treatment in elderly patients who were not eligible for transplantation.

Results of a survival analysis of the VISTA trial after a median of more than 3 years were presented at ASH, confirming the benefits of the VMP regimen compared with MP alone.

Overall survival rates in patients with high-risk cytogenetics were 74.5% with VMP versus 55.5% with MP. The incremental cost-effectiveness of VMP over MP and MPT as initial treatment, however, had not been assessed; that was the aim of this cost-effectiveness analysis.

The primary data sources were

patient-level data from VISTA after 26 months of follow-up. The source of data for VMP versus MPT was the phase 3 IFM 99-06 trial, with a median follow-up of 51 months. Cost data were obtained from published studies/ sources. The cost analyses, adjusted to 2009 dollars, included per-protocol drug and medical costs, treatmentrelated adverse event costs, second-line treatment costs, and resource utilization during treatment-free intervals and progressive disease states.

Compared with MPT, the drug cost of VMP was lower by $13,277, and the cost of managing treatment-related adverse events was $10,213 lower.

Health outcomes were expressed in life-years and quality-adjusted lifeyears (QALYs). Cost/health outcomes were discounted at 3%. Incremental cost-effectiveness ratios were calculated for VMP versus MP, and VMP versus MPT, over a lifetime horizon.

A Markov model, with a 20-year lifetime horizon, was developed from a US payers’ perspective. Patients entered the model in the stable disease/minimal disease (SD/MD) state.

In subsequent monthly cycles, patients moved to their best response state or remained in SD/MD until they discon-

Table Cost-Effectiveness of VMP vs MP and VMP vs MPT over a Lifetime VMP

MP

MPT

Cost

$110,870-$57,864

$129,902

$129,902

Life-years

4.187

2.864

4.140

QALYs

2.994

2.049

2.951

$40,051 $56,109

VMP dominant VMP dominant

ICER (vs VMP) Per life-year Per QALY

ICER indicates incremental cost-effectiveness ratio; MP, melphalan and prednisone; MPT, thalidomide, melphalan, and prednisone; QALY, quality-adjusted life-year; VMP, bortezomib, melphalan, and prednisone.

tinued treatment, progressed, or died.

Patients in the second-line therapy state received a maximum of 6 months of treatment.

Compared with MP and MPT, VMP was associated with more time on treatment in complete response, a longer treatment-free interval, and less time in a progressive disease state or death.

Overall survival was estimated to be longest with VMP and MPT versus MP. Lifetime direct medical costs were highest for MPT, followed by VMP; they were much lower for MP (Table).

“While adding bortezomib to melphalan and prednisone increases cost a good bit, it is actually cost-effective in patients with myeloma.”

—Si-Tien Wang, MSc “The incremental cost-effectiveness of VMP versus MP, however, was found to be within the generally accept-

Alemtuzumab Contributes 39% to Treatment Costs in CLL

By Wayne Kuznar

T

he cost of alemtuzumab (Campath) contributes 39% of total healthcare costs once it is initiated for the treatment of chronic lymphocytic leukemia (CLL). Other cost drivers in this setting include oncology services and medical resources for cytopenia, infection, and cardiac dysfunction, said MarieHélène Lafeuille, MA, of Groupe d’analyse, Ltée, Montreal.

Her study used electronic claims data of Medicare Part A and Part B services to quantify the incremental costs associated with alemtuzumab, by calculating costs within 6 months after alemtuzumab initiation versus 6 months before its initiation.

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The study assessed costs for 81 patients with CLL. After alemtuzumab initiation, mean total healthcare costs increased from $4272 to $10,385 per-patient per-month (PPPM) in the next 6 months, a $6113 increase. The mean cost for alemtuzumab in the post–alemtuzumab initiation period was $4006 PPPM, representing 39% of total costs.

The cost for oncology-related services (ie, office visits, hospitalizations, home healthcare) jumped from $3759 to $9602 PPPM from the prealemtuzumab to postalemtuzumab periods, an increase of $5842.

In the prealemtuzumab period, the cost associated with a diagnosis of cytopenia was $1658 PPPM compared with $4441 postalemtuzumab—

ed cost-effectiveness range of $50,000 to $100,000 per QALY, suggesting that VMP is cost-effective compared with MP,” Ms Wang said. “And compared with MPT, the VMP regimen was dominant in the model, meaning it was costsaving and had better outcomes, costing 17.7% less and providing slightly more QALYs on average.”

Compared with MPT, the drug cost of VMP was lower by $13,277, and the cost of managing treatment-related adverse events was $10,213 lower. This drove much of the dominance. A

After alemtuzumab initiation, mean total healthcare costs increased from $4272 to $10,385 per-patient per-month. a $2456 difference.

Costs associated with medical resources for diagnoses of infection and cardiac dysfunction increased by $734 and $926, respectively, in the 6 months after alemtuzumab initiation compared with prealemtuzumab. ■ SEE ALSO Adding Alemtuzumab to Fludarabine Doubles PFS in Relapsed CLL, page 16.

1-way sensitivity analysis of VMP versus MP pointed to the general robustness of the findings, with the key driver being the VMP versus MP hazard ratio for the transition from secondline treatment to death.

The results may actually be conservative for the VMP regimen, said Ms Wang, because the study populations were not completely comparable. The IFM 99-06 population was younger and had less-advanced disease than the VISTA population.

She acknowledged several limitations of the study—the indirect comparison of VMP to MPT (no head-tohead trials were available); the use of just 1 of 5 phase 3 trials comparing MPT with MP (only 1 provided necessary results); and the different baseline characteristics of VISTA and IFM 99-06.

The researchers concluded that adding bortezomib to the standard MP regimen improves long-term outcomes with a survival benefit, while remaining cost-effective. ■ SEE ALSO Weekly Bortezomib Effective, Less Toxic, page 20.

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Lymphoma

New Regimen Challenges...

Continued from page 1

potentially practice changing,” concurred press briefing moderator Richard Van Etten, MD, of Tufts University. “I would like to see an overall survival benefit, and the study needs longer follow-up, but I don’t think we need to wait for this.”

Large Randomized Study Population The trial by the German Study Group on Indolent Lymphoma included 549 symptomatic patients enrolled at 82 centers. Patients were randomized to B/R or CHOP-R. Approximately 50% of patients in each arm had follicular lymphoma; the remainder had other indolent lymphoma or MCL. B/R caused significantly less hematologic toxicity, although just 4% of the patients in this arm received growth factors compared with 20% in the CHOP-R arm.

As for side effects, alopecia did not occur with B/R but was frequent with CHOP-R. Paresthesia, stomatitis, infectious complications, and sepsis were

“Bendamustine plus rituximab has the potential to become a treatment of first choice in these disease entities….There was a 20-month gain with bendamustine. This was clearly a surprise. It was not just noninferior, but was statistically significantly better than CHOP-R and better tolerated.”

—Mathias J. Rummel, MD less frequent with B/R. Skin rashes and allergic reactions, however, were more common with B/R than with CHOP-R, Dr Rummel reported.

Overall response rates were similar

In Challenging B-Cell Lymphoma, Aggressive Chemotherapy plus Rituximab Show Best Outcomes

By Caroline Helwick

T

he addition of rituximab to either conventional or highdose chemotherapy for B-cell lymphoma yielded “unexpectedly high efficacy,” particularly in untreated, young, high-risk patients with aggressive disease, according to investigators from the MegaCHOEP Trial of the German High-Grade NonHodgkin’s Lymphoma Study Group.

“The 3-year event-free and overall survivals are the best ever reported for this group of patients.”

—Norbert Schmitz, MD “The 3-year event-free and overall survivals are the best ever reported for this group of patients,” said Norbert Schmitz, MD, of the Asklepios Kliniken St. Georg, Hamburg, Germany.

This was an interim analysis of 216 patients in the phase 3 study that included young (18-60 years old), high-risk patients with aggressive B-cell lymphoma. The study compared 8 cycles of CHOEP-14 (cyclophosphamide [Cytoxan], doxorubicin

8

[Adriamycin], vincristine [Oncovin], and prednisone [Deltasone] plus etoposide [Eposin] given every 2 weeks) with high-dose MegaCHOEP, which used higher doses of the same drug given every 21 days, followed by stem-cell transplantation. Half of the patients also received rituximab (Rituxan).

After a median follow-up of 29 months, the estimated 3-year overall survival was 84% with the CHOEP plus rituximab regimen and 75% with MegaCHOEP plus rituximab; progression-free survival rates were 76% and 64%, respectively. These survival rates were significantly higher than in the treatment arms that did not receive rituximab; therefore, the arms not including rituximab were discontinued, Dr Schmitz noted.

“Eight cycles of CHOEP-14 plus 6 cycles of rituximab gave excellent results in young, high-risk patients with untreated aggressive B-cell lymphoma. Because of higher toxicity and inferior survival, the MegaCHOEP arm was discontinued. High-dose therapy and transplant has no role to play as part of first-line therapy for these patients if rituximab is combined with aggressive conventional chemo therapy,” he said. ■

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February 2010

between the 2 regimens—92.7% with B/R and 91% with CHOP-R—but patients receiving B/R were more like-

ly to have a complete response (39.6% vs 30%, respectively).

Improved complete response rates were translated into better progression-free survival with B/R—54.9 months (median) versus 34.8 months for CHOP-R—a significant difference (P = .001).

“There was a 20-month gain with bendamustine. This was clearly a surprise. It was not just noninferior, but was statistically significantly better than CHOP-R and better tolerated,” Dr Rummel commented.

He added that the dose of bendamustine used (90 mg/m2) was lower than the dose of 120 mg/m2 currently approved in the United States for lymphoma. The lower dose did not compromise efficacy but did improve tolerability, he said.

Dr Rummel said the B/R regimen would be economical, because it is associated with fewer complications and reduced use of growth factor support. ■

Treatment Is Beneficial in Older Patients with Advanced Lymphoma

I

n older patients with advanced follicular lymphoma, a brief course of chemotherapy followed by maintenance therapy with rituximab (Rituxan) led to high response rates, including complete remissions, and was well-tolerated in an Italian study presented at ASH.

immunotherapy—with fludarabine (Fludara), mitoxantrone (Novantrone), and dexamethasone (Decadron)—plus rituximab. Patients who achieved a complete response or partial response were randomized to 4 consolidation doses of rituximab at months 9, 11, 13, and 15, or to observation.

These findings show that chemotherapy is beneficial in this older patient population, and withholding treatments because of age is therefore inappropriate.

—Umberto Vitolo, MD Umberto Vitolo, MD, of the University of Torino, Italy, noted that in elderly patients, “the goal is to reduce the chemotherapy that patients sometimes don’t tolerate and in the meantime, to maintain the efficacy of the treatment.” He added that, based on his study’s findings that chemotherapy is beneficial, it is not appropriate to withhold treatments only because of age.

Investigators at 33 Italian centers enrolled 242 patients aged 61 to 75 years with advanced or aggressive non-Hodgkin’s lymphoma that had not been treated. The regimen consisted of 4 weekly administrations of chemo-

The 4 cycles of chemoimmunotherapy led to complete responses in 55% of patients, and partial responses in 37%.

After rituximab consolidation therapy, 69% of patients achieved complete responses and 18% of patients achieved partial responses. At the 22-month follow-up, 2-year survival was 92%, and 2-year progression-free survival was 75%.

The data, however, are not mature enough to assess the value of maintenance versus observation over time. The most common toxicity in patients was neutropenia (65%), but it was severe in only 25% of those patients.—CH ■

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Lymphoma

Hodgkin’s Lymphoma: No Changes in Standard of Care, but Emerging Therapies Are Promising

By Caroline Helwick

H

odgkin’s lymphoma is a very curable malignancy, because the majority of patients present with localized disease. But advanced Hodgkin’s lymphoma is associated with failure rates of 30% to 40% in response to anthracycline-based polychemotherapy. Current clinical trials are focusing on improving this outcome with the use of multiple first-line agents, said John Kuruvilla, MD, of the University of Toronto, who presented an update on the treatment of Hodgkin’s lymphoma at ASH 2009.

For advanced Hodgkin’s lymphoma, the initial gold-standard regimen is ABVD—doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban), and dacarbazine (DTIC). Many groups have developed alternate regimens based on doseintensive or dose-dense chemotherapy, or by using a similar approach that dose-intensifies certain drugs while minimizing leukemogenic or gonadotoxic drugs.

The results from clinical trials applying these approaches indicate that dose-intensifying chemotherapy improves disease control, but at the cost of acute toxicity and possibly delaying toxicity. The BEACOPP regimen— bleomycin, etoposide (Eposin), doxorubicin, cyclophosphamide (Endoxan), procarbazine (Matulane), vincristine (Oncovin), prednisone (Meticorten)—largely used in Europe,

One interesting approach being evaluated is the use of novel, risk-adapted strategies using FDG-PET imaging to identify patients who are deemed at risk for treatment failure after 2 cycles of ABVD. is the only regimen that has shown an overall survival advantage over the ABVD regimen.

An alternative strategy to altering the primary chemotherapy for Hodgkin’s lymphoma is to attempt to “consolidate” the response, using high-dose chemotherapy, autologous stem-cell transplantation (ASCT), or radiation, but clinical trial results show no role for consolidation in advanced Hodgkin’s lymphoma.

One interesting approach being evaluated is the use of novel, riskadapted strategies using FDG-PET imaging to identify patients who are deemed at risk for treatment failure after 2 cycles of ABVD and who may need more intensive treatment, Dr Kuruvilla said.

Treatment of Relapsed or Refractory Hodgkin’s Lymphoma Relapsed or refractory HL is another

common problem associated with treatment of the disease. Second-line (ie, salvage) chemotherapy followed

by ASCT is the standard of care, but there is a lack of consensus about the type of salvage chemotherapy to use before the transplant. ASCT carries significant toxicity and may be limited in application, because of the patient’s age and medical fitness.

Several interesting approaches are currently being evaluated, including high-dose sequential therapy and tandem ASCT approaches. But few large or prospective series are studying strategies that are not based on transplantation, Dr Kuruvilla pointed out.

bendamustine as front-line therapy is very interesting. At ASH, we heard many presentations on this agent. It’s a very active drug and one that will be widely used in lymphoma,” he stated.

“This is just one of many therapies we now have for indolent lymphoma, including a number of new biologics and new immune-based therapies.

Among the emerging drugs of interest are new fully humanized monoclonal anti-CD20 antibodies that aim to improve upon the activity of rituximab [Rituxan],” he pointed out.

“We are also hearing about some new antibody/toxin conjugates, and some completely new approaches, such

“In clinical care, the use of bendamustine as front-line therapy is very interesting. At ASH, we heard many presentations on this agent….Among the emerging drugs of interest are new fully humanized monoclonal anti-CD20 antibodies…some new antibody/toxin conjugates, and some completely new approaches.”

—Lawrence Kaplan, MD Emerging Trends in Lymphoma Lawrence Kaplan, MD, Director of the Lymphoma Program at the University of California, San Francisco, mentioned the importance of emerging trends in the treatment of lymphoma, such as bendamustine (Treanda). “In clinical care, the use of

as the bidirectional antibody blinatumomab [MT103]. How all these new approaches will impact the long-term outcome is not known, but with advances in treatment, our lymphoma patients are now able to survive for many years,” Dr Kaplan concluded. ■

Adding Rituximab to Standard Therapy in Hodgkin’s Lymphoma Improves Outcomes

T

he addition of rituximab (Rituxan) to the standard ABVD regimen (R-ABVD) of doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban), and dacarbazine (DTIC) for Hodgkin’s lymphoma can improve outcomes, according to the final report of a phase 2 study in newly diagnosed patients with advanced-stage Hodgkin’s lymphoma.

The large, multicenter US study compared outcomes of patients treated with R-ABVD with those of institutional historical controls and found that R-ABVD yielded a higher 5-year event-free survival rate in every category of the International Prognostic Score (IPS), an indication of disease severity (Table), according to lead

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investigator Amanda R. Copeland, MS, of the University of Texas M.D. Anderson Cancer Center, Houston.

With a median follow-up of 5 years, the projected event-free survival for RABVD was 87% overall, “which is significantly better than institutional re-

sults with ABVD,” Ms Copeland noted.

The findings form the rationale for a multicenter randomized comparison of ABVD with R-ABVD, which is currently enrolling patients with stage II bulky, stage III, or stage IV disease.—CH ■

Table 5-Year Event-Free Survival by IPS and Treatment IPS group

Institutional ABVD, %

R-ABVD, %

All patients

66

87

0-1 >1–<2 >2–<3 >3

73 62 55 47

96 79 79 65

ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; IPS, International Prognostic Score; R-ABVD, rituximab, doxorubicin, bleomycin, vinblastine, and dacarbazine.

With a median follow-up of 5 years, the projected event-free survival for R-ABVD was 87% overall, “which is significantly better than institutional results with ABVD.” —Amanda R. Copeland, MS

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Lymphoma

Novel Agent Shows Impressive How Much Rituximab Is Outcomes in Aggressive NHL Necessary in Advanced NHL?

By Caroline Helwick

T

reatment with the investigational anthracycline pixantrone achieved significant increases in complete and overall response rates and a trend toward improved survival, compared with current agents, in patients with relapsed or refractory non Hodgkin’s lymphoma (NHL) in the phase 3 randomized open-label EXTEND trial.

Pixantrone is an analogue of mitoxantrone that has reduced cardiotoxicity. “An anthracycline with reduced cardiotoxicity that can be used for salvage therapy of aggressive NHL meets a significant unmet medical need,” noted lead researcher Ruth Pettengell, MD, of St George’s Hospital, London.

EXTEND enrolled 140 patients who had previous treatment for relapsed aggressive NHL. They were randomized to pixantrone for up to 6 cycles or to a single-agent comparator at the treating physician’s discretion. In the United States, the only comparators

permitted were gemcitabine (Gemzar) and rituximab (Rituxan). The patients were followed up to 18 months after treatment completion.

“An anthracycline with reduced cardiotoxicity that can be used for salvage therapy of aggressive NHL meets a significant unmet medical need.”

—Ruth Pettengell, MD The Table shows results after at least 9 months of follow-up. A trend for improved survival at 9 months was shown with pixantrone, at 10.2 months, compared with 6.9 months for the comparators; 1-year survival was 45% for pixantrone and 35% for the comparators, Dr Pettengell reported. ■

Table Pixantrone vs Single-Agent Comparators: 9-Month Follow-Up Response rate

Pixantrone

Comparators

Complete/unconfirmed complete response

25.7%

7%

Overall response

40%

14.3%

Median progression-free survival

5.6 months

2.6 months

All P <.001.

First Comparison of Fewer Courses of Therapy than Current Standard

F

or the treatment of advanced nonHodgkin’s lymphoma (NHL), there was no advantage of giving multiple courses of rituximab (Rituxan) compared with just 1 course, in a multicenter German study.

“The addition of rituximab to standard chemotherapy has substantially improved the prognosis of NHL. Over the past few years, a trend toward intensified protocols with multiple applications of rituximab has been observed,” said Fabienne McClanahan, MD, of the University of Heidelberg, Germany. “We are able to report a unique cohort that has also been treated with only 1 or 3 courses within a prospective randomized phase 2 trial, contrasting with the current standard procedure.”

This study may be the first to randomize patients to fewer courses than are currently applied in standard protocols. Included were 126 patients with stage III or IV cluster of differentiation (CD) 20+ follicular lymphoma.

Patients were classified as low risk (22%), intermediate risk (39%), or high risk (39%).

Patients were randomized to receive 1 of 3 treatment options: 1 course (arm A), 3 courses (arm B), or 6 courses (arm C) of rituximab, along with 6 courses of standard CHOP—cyclophosphamide (Cytoxan), hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and prednisone (Deltasone)—chemotherapy. In addition,

Long-Term Survival Achieved with Tositumomab/I-131 Regimen

P

atients with indolent lymphoma that progresses after treatment with rituximab (Rituxan) can achieve long-term survival after switching to tositumomab and iodine (I)-131 tositumomab (Bexxar regimen), based on results from a multicenter phase 2 study of the Eastern Cooper ative Oncology Group.

This treatment is already approved for certain groups of patients with relapsed or refractory low-grade, follicular or transformed, non-Hodgkin’s lymphoma. The regimen pairs the targeting ability of a monoclonal antibody with the therapeutic potential of radiation. Combined, these agents form a radiolabeled monoclonal antibody regimen that binds to the target

10

antigen CD20 found on B-cells and delivers the radiation.

In this study, median overall survival was 6.7 years for patients who received the Bexxar regimen after relapsing. Response rates to the regimen were high and durable, said Sandra Horning, MD, of Stanford University, CA. The study included 40 patients with indolent, follicular large-cell or transformed B-cell lymphoma that had progressed while using a median of 4 previous therapies. Patients received a therapeutic dose of the I-131 tositumomab based on totalbody dosimetry.

Responses were seen in 72% of patients, 38% of which were complete

AMERICAN HEALTH & DRUG BENEFITS

February 2010

responses. Median response duration was nearly 19 months; 40% of patients responded for 5 years.

“Across 10 years, we are seeing a consistent result and effect on survival by treating patients with this approach.”

—Mark Kaminski, MD Consistent Responses in Treatment-Naïve Patients In another phase 2 study of I-131 tositumomab in 79 untreated patients

60% of the patients also received radiotherapy. Patients were followed for a median of 60 months, after which 94% of patients in each arm had achieved at least a partial response.

“We are able to report a unique cohort that has also been treated with only 1 or 3 courses...contrasting with the current standard.”

—Fabienne McClanahan, MD There were no significant differences in remission rates, remission duration, progression-free survival, or overall survival according to the number of courses the patients received. Relapses occurred in 36 patients, with no difference in remission duration among the 3 arms. Six-year progression-free survival rates were 45% in arm A, 60% in arm B, and 65% in arm C, and 6-year overall survival rates were 72%, 82%, and 80%, respectively.

“More-frequent applications did not differ from less-frequent applications, and a noninferiority of fewer applications of rituximab could not be detected,” Dr McClanahan said.

“The advantage of multiple courses of rituximab, therefore, remains uncertain.”—CH ■

with indolent lymphoma, the 10-year survival rate was 83% and the 10-year progression-free survival rate was 38%. Responses were observed in 97% of patients, and 75% had complete responses with a median duration of response of 9 years.

“Across 10 years, we are seeing a consistent result and effect on survival by treating patients with this approach,” said Mark Kaminski, MD, Director of the Leukemia/Lymphoma Program at the University of Michigan, Ann Arbor. “Rarely are there data to show a treatment can produce a durable response over a decade, and what is most exciting is that these results were achieved after a single treatment.”—CH ■ Lymphoma continued on page 12

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Lymphoma

Emerging Strategies for Mantle-Cell Lymphoma

By Caroline Helwick

M

antle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin’s lymphoma characterized by a certain chromosomal translocation and nuclear cyclin D1 overexpression. Most patients present with advanced-stage disease and undergo an aggressive clinical course.

Recent improvement has been achieved with the use of monoclonal antibodies and dose-intensified approaches, including autologous stem-cell transplantation (ASCT) strategies.

Allogeneic hematopoietic stem cell transplantation remains the only curative option for patients with advanced MCL. Recent improvement has been seen with the introduction of reducedintensity conditioning, offering a 50% chance of being disease-free at 5 years.

With the exception of this approach, advanced disease is not curable; most

patients have a delayed but continuous decline, with average survival of 4 to 6 years, although a subset of patients (15%) may have a more indolent course and long-term survival. In these asymptomatic patients, close monitoring is recommended, with treatment initiated if symptoms or progression occur, said Martin Dreyling, MD, of Ludwig-Maximilians University, Munich, Germany, in an update of the disease.

Emerging strategies, such as proteasome inhibitors, immunomodulating drugs, and mTOR inhibitors, are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy with these compounds achieves efficacy comparable with conventional chemotherapy in relapsed MCL. Combination strategies are being studied,

although their introduction into clinical practice remains a challenge, Dr Dreyling pointed out.

Various regimens are being evaluated as consolidation after transplant to further improve outcomes.

Radioimmunotherapy is also promising.

Based on its favorable toxicity profile, rituximab (Rituxan) remains a valuable treatment option in combination with standard chemotherapy or with bendamustine (Ribomustin, Treanda), which is better tolerated. In younger patients, dose-intensified

schemes in combination with rituximab are the standard of care. Various regimens are being evaluated as consolidation after transplant to further improve outcomes. Radioimmunotherapy is also promising.

Molecular-targeted approaches that capitalize on the underlying biology of MCL are very encouraging. Bortezomib (Velcade) in combination with conventional chemotherapy has shown encouraging results in re lapsed or refractory disease. Thalidomide (Thalomid) and lenalidomide (Revlimid) have produced high response rates. The mTOR inhibitors temsirolimus and everolimus are being evaluated as well, as are flavopiridol, inhibitors of the Bcl-2 family, antisense approaches, and approaches that directly target apoptosis (programmed cell death). ■

Leukemia

First Head-to-Head Comparison of Targeted TKIs Nilotinib Potential First-Line Option for Chronic-Phase CML

By Wayne Kuznar

I

n the first head-to-head comparison of targeted oral tyrosine kinase inhibitors (TKIs) as initial treatment for early-stage chronic myeloid leukemia (CML), molecular and cytogenetic remissions were more common with nilotinib (Tasigna) than with imatinib (Gleevec), the previous standard for treating early-stage CML, said lead study investigator Giuseppe Saglio, MD, of the University of Turin, Italy, at ASH. New Standard of Care?

This finding could elevate nilotinib to first-line treatment for early CML. Nilotinib is currently approved for the treatment of patients with Philadelphia chromosome-positive (Ph+) CML in the chronic phase and accelerated phase in patients who are resistant to previous therapy, including imatinib.

“The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML,” said Dr Saglio. In the open-label study, 846 patients with newly diagnosed Ph+ CML in chronic phase were randomized to receive either 400 mg of imatinib once daily, or 300 mg or 400 mg of nilotinib twice daily. Follow-up lasted about 5 years.

nilotinib groups compared with the imatinib group.

Dr Saglio noted that molecular monitoring is the most sensitive measure of CML disease burden. “Major molecular response is associated with an extremely low rate of disease progression,” he said. Of the patients who experienced progression of disease in this study, none achieved a major molecular response.

Complete cytogenetic responses at 12 months were also significantly better with nilotinib.

“The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML.” —Giuseppe Saglio, MD At 12 months, the rates of major molecular response (the primary end point) were 44% with 300 mg of nilotinib twice daily, 43% with 400 mg of nilotinib twice daily, and 22% with 400 mg of imatinib once daily. The median time to a major molecular response was faster by about 2.5 months in the

Disease Progression Rates of progression to accelerated phase or blast crisis were 3.9% in the imatinib group compared with less than 0.7% and 0.4% in the patients treated with 300 mg and 400 mg of nilotinib, respectively.

The difference between nilotinib and imatinib in progression to accelerated phase or blast crisis is the most meaningful finding of the study, “because people who go into accelerated phase or blast phase don’t really have the opportunity for second-line therapy,” according to Bayard L. Powell, MD, Head of Hematology and Oncology, Wake Forest University, Winston-Salem, NC. The importance of progression to

accelerated phase or progression to blast phase is not questioned, Dr Powell said. “Survival is negatively influenced by progression. It was accomplished with no additional toxicity.”

Nilotinib was superior to imatinib on efficacy end points across all risk groups of patients based on their Sokal score (a risk index based on 6 criteria).

Molecular and cytogenetic remissions were more common with nilotinib than with imatinib.

Side Effects Both drugs were well tolerated. In each group, 7% to 11% of patients discontinued their study drug because of adverse events or abnormalities in laboratory values, with no significant differences between groups. In the imatinib group, 4% of patients discontinued because of treatment failure, 4% discontinued because of disease progression, and 2% discontinued because of suboptimal response.

Edema and weight gain occurred more often with imatinib therapy. Grade 3 or 4 toxicities were rare in any group.

In commenting on the study, Rick Continued on page 13

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Leukemia

Intermittent Dosing of Dasatinib May Cut Toxicity, Allow Continued Treatment in CML

By Wayne Kuznar

I

ntermittent dosing of dasatinib may reduce toxicity, while allowing patients with chronic myelogenous leukemia (CML) to continue treatment, according to Paul La Rosée, MD, Professor, Division of Hematology/ Oncology, Universitätsklinikum Jena, Germany.

Dasatinib (Sprycel) is approved for second-line treatment of CML after imatinib (Gleevec) failure. Dose reduction beyond the labeled reduced continuous dosing is mandated in select patients with chronic-phase CML who experience dasatinib-induced toxicity.

In a retrospective analysis, treatment response was assessed in 33 patients with CML who were intolerant/resistant to imatinib and who received a weekly on/off regimen (3-5 days on/2-4 days off) of dasatinib.

The median weekly intermittent dose was 500 mg.

Patients were followed by routine hematologic and cytogenetic assess-

ment and molecular monitoring for a median of 23 months. Resistant patients were regularly screened for BCR-ABL mutations. Of those evalu-

“This retrospective analysis in patients resistant or intolerant to imatinib…suggests good, and in many cases even improved, efficacy of interval treatment compared with continuous dosing.”

—Paul La Rosée, MD

able for response, 18 of 31 patients (58%) showed either maintenance of or an improved response to dasatinib with the intermittent-dosing schedule.

Of the 18 patients, 14 achieved or maintained a major molecular response; 5 patients repeatedly tested negative by polymerase chain reaction. The other 4 patients achieved a complete cytogenetic remission.

Bendamustine-Rituximab Combo an Effective First-Line Therapy for CLL

A

new study presented at ASH examined the use of bendamustine HCl (Treanda) in combination with rituximab (Rituxan) as first-line therapy in 117 patients with newly diagnosed, advanced chronic lymphocytic leukemia (CLL).

One third of the patients achieved complete responses with this combination therapy, and another 56% of the patients had partial responses, said lead investigator Kirsten Fischer, MD, Center of Integrated Oncology, University of Cologne, Germany. Of the 117 patients, 48% had Binet stage C disease and 41% had Binet stage B. Bendamustine had already been shown to have considerable activity as monotherapy in CLL and other lymphoid cancers, and in combination with rituximab in patients with relapsed/refractory CLL. In this study, rituximab was given as four 6-week cycles, with 2 doses of bendamustine with each cycle. Some 72% of patients in the study were treated with all 6 cycles.

The median observation time was 15.4 months. Overall response rate was 90.9%. A complete response was observed in 32.7% of patients, and a partial response in 55.5%. All other

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“Of note, 10 of 12 patients with improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens, without having achieved the response level observed after allowing drug hol-

patients (9.1%) had stable disease; none had progressive disease.

With up to 26 months of follow-up, 75.8% of the patients were still in remission; the median progressionfree survival has not been reached.

Objective response rates of approximately 90% were achieved among the different genetic subgroups, except those with chromosome 17p deletion, a high-risk subgroup whose partial response rate was 42.9%.

Complete responses occurred most often in patients with unmutated IGHV gene, about 25%. The overall response rate in this group was 88.9%.

Hematologic toxicities were grade 3/4 anemia (4.9%), grade 3/4 leukopenia (14.6%), and grade 3/4 neutropenia and thrombocytopenia (6.5% and 6.1% of all given courses, respectively). Twenty-nine episodes of Common Toxicity Criteria grade >3 infections were documented (5.1%).

There were 2 treatment-related deaths during the study.

The group is now conducting a phase 3 trial in which the efficacy of bendamustine-rituximab is being compared with fludarabine-based immunochemotherapy for the firstline treatment of CLL.—WK ■

iday,” said Dr La Rosée. “This retrospective analysis in patients resistant or intolerant to imatinib with up to 5 preceding treatment modalities suggests good, and in many cases even improved, efficacy of interval treatment compared with continuous dosing. These data mandate the initiation of clinical trials to investigate alternative intermittent targeting regimens.”

Increasing Imatinib Dose May Induce Response in CML Failures In another study of patients with chronic-phase CML who had suboptimal response or failure with 400 mg of imatinib, dose escalation achieved a major molecular response, according

to Katia B.B. Pagnano, MD, PhD, Hematology and Hemotherapy Center, Faculdade de Ciências MédicasUniversity of Campinas, Brazil.

This study evaluated the efficacy of imatinib dose increase in 120 patients who were treated with 400 mg of imatinib between March 2002 and December 2008. Imatinib was escalated to between 600 mg and 800 mg in cases of suboptimal response.

The dose was escalated in 55 patients because of unsatisfactory response after 36 months of imatinib treatment. Twenty-eight of the 55 patients (51%) were treated with imatinib as first-line therapy and 28 patients (51%) had previously taken interferon. Median time between diagnosis and start of imatinib therapy was 5.0 months.

After the dose was increased, 31 patients (56%) responded, and 58% of the patients with previous suboptimal molecular response achieved major molecular response, said Dr Pagnano.

“Most of the patients with hematologic failure did not respond to dose escalation,” implying a change to a second-line agent, such as nilotinib (Tasigna) or dasatinib (Sprycel), was needed, Dr Pagnano pointed out.

Patients who do not achieve major molecular response may also be candidates for second-line treatment. ■

First Head-to-Head Comparison...

Continued from page 12 Van Etten, MD, PhD, Director of the Tufts Medical Center Cancer Center in Boston, agreed that the finding “could be used to argue for nilotinib as firstline therapy.”

Potent Agents Show Impressive Complete Cytogenetic Responses Additional studies of nilotinib and dasatinib, another oral TKI that is several times as potent as imatinib, show favorable efficacy on major molecular response in patients with newly diagnosed CML. The sets of data were reported by Jorge E. Cortes, MD, Deputy Chair and Professor of Medicine, Department of Leukemia, at the University of Texas M.D. Anderson Cancer Center. The 2 studies he presented were identical in the nature of their design.

In the open-label, single-agent trials, the efficacy of either nilotinib 400 mg twice daily or dasatinib 100 mg/day (50 mg twice daily or 100 mg once daily) were investigated as first-line therapy in chronic-phase CML. In the nilotinib study, 32 of 51

Jorge E. Cortes, MD patients (63%) who were followed for at least 3 months achieved a complete molecular response, and 98% achieved a complete cytogenetic response.

In the dasatinib study, major molecular response was achieved in 70% of the 50 patients who were followed for at least 3 months, and a complete cytogenetic response was achieved in 98% of the 50 patients.

Dr Cortes noted that the cytogenetic response rates with nilotinib and dasatinib in these studies compare favorably with that observed in imatinib-treated patients. ■

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Leukemia

Statins Delay Treatment in CLL

By Wayne Kuznar

P

atients who take statins at the time they are diagnosed with chronic lymphocytic leukemia (CLL) are less likely to have their disease progress to the point of requiring therapy, said Daphne Friedman, MD, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC. Of 355 patients in the Duke University/Durham Veterans Affairs Medical Center’s CLL database (1999present), statin use/lack of use at the time of CLL diagnosis was known in 254 patients—65 statin users, 189 nonusers.

In these patients, CLL therapy was not required in 132 (52%) patients; 122

(48%) patients received at least 1 treatment. Indications for therapy were recorded in 117 of the 122 patients, and included increasing lymphocyte count in 49 patients, anemia in 14 patients, thrombocytopenia in 8 patients, splenomegaly in 8 patients, and lymphadenopathy in 49 patients.

Follow-up ranged from 0.05 years to 25 years from diagnosis, with a shorter follow-up time in the patients who were taking a statin at the time of diagnosis.

Patients taking a statin at the time of diagnosis were significantly less likely to require therapy; this applied primarily to women and patients with low-risk (CD38-negative) CLL.

“Notably, even though patients taking a statin at the time of diagnosis were less likely to ever require therapy,

CLL treatment was not significantly associated with progression or time to progression.

“Even though patients taking a statin at the time of diagnosis were less likely to ever require therapy, statin use was not associated with a significant improvement in overall or treatment-free survival.”

—Daphne Friedman, MD statin use was not associated with a significant improvement in overall or treatment-free survival,” said Dr Friedman.

In addition, statin use at time of first

There was no significant correlation between lipid levels at diagnosis and the need for CLL treatment. But data for this lipid analysis were only available for 26 patients. ■

Second-Generation TKIs Effective, Safe for Relapsed ALL

T

he use of second- and thirdgeneration tyrosine kinase inhibitors (TKIs) is a valid and safe approach to treating relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in adult and elderly patients, said Cristina Papayannidis, MD, Department of Hematology and Medical Oncology, Institute L. and A. Seràgnoli, University of Bologna, Italy.

About 30% of patients with ALL have Ph+. “The prognosis of this subset of patients treated with standard therapies, including multiagent chemotherapy, imatinib [Gleevec], and

allogeneic stem-cell transplantation is still dismal, due to a high risk of relapse,” she said.

Dasatinib (Sprycel) and nilotinib (Tasigna) are second-generation TKIs that were developed to overcome resistance to imatinib in patients with Ph+ ALL. This retrospective analysis evaluated the use of second-generation and experimental third-generation TKIs in 29 adult patients (median age at diagnosis, 49 years) with relapsed Ph+ ALL. Of these patients, 14 were in first relapse, 11 were in second relapse, and 4 were in third relapse.

All the patients were previously treated with imatinib; 10 patients had also received allogeneic bone marrow transplantation. Of the 29 patients, 13 reached a hematologic response—11 patients with dasatinib, 1 patient with nilotinib, and 1 patient with a thirdgeneration experimental TKI. Ten patients also obtained a cytogenetic response and 9 patients obtained a molecular response.

With a median follow-up of 10.8 months, the median durations of hematologic response, cytogenetic response, and molecular response were each 5.5 months.

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The median overall survival was 25.8 months, and progression-free survival was 5.5 months.

In the near future, combination treatment— including novel agents (ie, aurora kinase inhibitors)— with standard TKIs may reduce the risk of relapse.

Although these TKIs proved effective, “relapse is unavoidable due to the emergence of additional ABL mutations,” Dr Papayannidis said.

In the near future, combination treatment— including novel agents (ie, aurora kinase inhibitors)— with standard TKIs may reduce the risk of relapse and overcome the genomic instability of Ph+ ALL, she speculated.—WK ■

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Leukemia

Advances in Treating MDS

By Caroline Helwick

M

yelodysplastic syndromes (MDS), formerly known as preleukemia, is a diverse collection of hematologic conditions united by the ineffective production or abnormality of bone marrow cells and the risk of transformation to acute lymphocytic leukemia (AML). Although many patients with MDS have an indolent disease, approximately one third eventually progress to AML. Significant advances have been made in the understanding of the disease. For example, several new molecular abnormalities have been identified, including loss of function mutations in TET2. For patients with bone marrow failure syndromes who do not meet the World Health Organization 2008 criteria for MDS, and who also do not meet any other disease classification, a category of idiopathic cytopenias of undeter-

mined significance has been proposed.

Currently, 3 drugs are approved by the Food and Drug Administration for MDS—azacitidine (Vidaza), lenalidomide (Revlimid), and decitabine (Dacogen). In addition, clinicians are using multiple hematopoietic growth factors, immunosuppressants, and cytotoxic agents for MDS. Investigative agents include thrombopoietin agonists that stimulate platelet production, other drugs that target novel pathways in MDS, and drugs that show promise for combination approaches, said Mikkael Sekeres, MD, of the Cleveland Clinic Taussig Cancer Institute.

Heather Leitch, MD, from the University of British Columbia, Vancouver, presented data suggesting that iron overload is a factor in MDS. Since humans lack a physiologic mechanism for excreting excess iron, the accumulation of iron can occur

from repeated red blood cell transfusions and can contribute to morbidity and even mortality of patients with MDS. There is the potential, therefore, to derive iron-lowering benefits from iron chelation therapy, which has helped in similar conditions, she said, but this requires more study.

Important findings on novel treatments for MDS were reported at the ASH meeting: • Lenalidomide, currently used in low-risk MDS patients with certain cytogenetic features, was evaluated in high-risk patients in a phase 2 European study. Used as a single agent, but in doses higher than are used in low-risk patients, lenalidomide produced a 30% response rate.

• Alemtuzumab (Campath), an antiCD52 antibody, produced a very high response rate in patients with intermediate-risk disease, with transfusion independence and normalization of blood counts and cytogenetic

remissions in a high proportion.

• An oral formulation of azacitidine was active and well tolerated, with a manageable side effect profile, in patients with MDS. • An oral formulation of clofarabine (Clolar), a deoxyadenosine nucleoside analog, produced responses in 46% of patients with high-risk MDS. • Compared with the 5-day intravenous schedule used in high-risk MDS, decitabine given subcutaneously in a very low dose daily or weekly was safe and active, with significantly less myelotoxicity in a phase 2 study of patients with lower risk disease.

• In trisomy 8 MDS patients refractory to other treatments, experimental treatment with the styryl sulfone ON 01910 (which decreases cyclin D1 accumulation in bone marrow) improved blood counts and in some cases led to transfusion independence and long-term remission. ■

Adding Alemtuzumab to Fludarabine Antifungal Prophylaxis in AML Patients Receiving Induction Doubles PFS in Relapsed CLL Chemotherapy

By Wayne Kuznar

A

dual regimen of alemtuzumab (Campath) and fludarabine phosphate (Fludara) reduces the risk of disease progression or death compared with single-agent fludarabine as second-line therapy for patients with chronic lymphocytic leukemia (CLL), according to Andreas Engert, MD, Professor of Internal Medicine, Hematology and Oncology, University Hospital of Cologne, Germany.

Dr Engert is principal investigator of a phase 3 study that compared the 2 regimens in 335 patients with relapsed or refractory CLL. Progression-free survival (PFS) was the end point of the study; PFS more than doubled with the alemtuzumabfludarabine combination compared with fludarabine alone. As a result, Genzyme indicated that it would seek a new indication for alemtuzumab for use in this combination regimen.

Until this study, there was no clear standard of care for second-line therapy for CLL, said Dr Engert. To be eligible for the study, patients must not have had an active infection within the 3 months before randomization.

Patients were randomized to alemtuzumab in escalating doses followed by up to 6 cycles of fludarabine, or up to 6 cycles of fludarabine alone.

A similar number of patients in each group completed all 6 cycles of fludarabine, and the percentage of patients who discontinued the study drugs because of adverse events was

16

similar—23% with alemtuzumab/fludarabine and 22% with fludarabine alone. The trial’s data safety monitoring panel recommended that the study be closed early as a result of these data.

With a median of 17 months followup at the time of the second interim analysis, the median PFS was 29.6 months with alemtuzumab/fludarabine compared with 20.7 with fludarabine alone—a 39% risk reduction of disease progression. In the subgroup of patients with advanced CLL, the median PFS was 26.1 months with the combination regimen and 12.1 months with fludarabine only.

PFS more than doubled with the alemtuzumab-fludarabine combination compared with fludarabine alone.

“The alemtuzumab/fludarabin safety profile compared with fludarabine monotherapy resulted in no difference in the number of deaths and a similar frequency of grade 3/4 infectious complications,” noted Dr Engert.

Infection-related adverse events occurred in 47.0% of patients assigned to alemtuzumab/fludarabine and 35.2% in patients assigned to fludarabine alone. ■ SEE ALSO Alemtuzumab Contributes 39% to Treatment Costs in CLL, page 7.

AMERICAN HEALTH & DRUG BENEFITS

February 2010

I

nvasive fungal infections remain a significant threat to patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) who undergo induction chemotherapy.

New evidence with voriconazole (Vfend) and posaconazole (Noxafil) supports the benefit of antifungal prophylaxis in this setting.

In a retrospective study of patients with AML or high-risk MDS, voriconazole was superior to 7 other regimens as antifungal prophylaxis, reported Gloria Mattiuzzi, MD, Assistant Professor, Department of Leukemia, University of Texas M.D. Anderson Cancer Center.

“An ideal antifungal prophylaxis regimen should be effective, safe, and uncomplicated for the patients….We have explored several options, including different type of drugs and various delivery schedules,” Dr Mattiuzzi said.

M.D. Anderson’s experience with antifungal prophylaxis for intensive chemotherapy from 1997 to 2009 included 730 patients with AML or high-risk MDS patients.

The regimens involved various delivery methods and schedules of amphotericin B lipid complex (Abelcet), liposomal amphotericin B (Ambisome), fluconazole (Diflucan), itraconazole (Sporanox), caspofungin (Cancidas), and voriconazole.

The percentage of documented invasive fungal infections—0.7% (1

case of 137 patients treated) was lowest among patients treated with voriconazole, 400 mg intravenously (IV) twice daily followed by either 300 mg IV twice daily or 400-mg tablets twice daily for 1 day, then 200-mg tablets twice daily. Documented invasive fungal infections occurred at a rate of 4% to 12% with the other regimens. The rates of possible or probable invasive fungal infections were similar between the regimens.

A significant difference was seen in side effects among the 8 regimens, with caspofungin and voriconazole the least toxic. Oral voriconazole was significantly less toxic than IV voriconazole.

In a separate analysis, investigators at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, looked at 195 patients receiving AML/MDS induction chemotherapy who received primary antifungal prophylaxis with voriconazole, 400 mg orally twice daily for 1 day followed by 200 mg orally twice daily, or posaconazole, 200 mg orally 3 times daily with meals. The median time on prophylaxis was about 2 weeks in each group.

Proved or probable invasive fungal infection occurred in 7% of the voriconazole group and 6.1% of the posaconazole group. The rates of serious adverse events were 6% in the voriconazole group and 7.5% in the posaconazole group.—WK ■

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Multiple Myeloma

Maintenance Therapy an Emerging Theme in Myeloma

By Caroline Helwick he duration of treatment for multiple myeloma may be lengthening, according to several studies that showed maintenance therapy with lenalidomide (Revlimid) or bortezomib (Velcade) improves outcomes.

T

mens of limited duration,” said Antonio Palumbo, MD, of the University of Torino, Italy. “MPR-R can be considered a new standard of initial therapy for patients older than 65,” he pointed out.

Maintenance with MPR Followed

by Lenalidomide In a 10-month interim analysis of a phase 3 study that garnered attention at ASH, investigators reported good results with maintenance lenalidomide in newly diagnosed, elderly patients.

Upfront induction therapy with MPR (melphalan [Alkeran], prednisone [Deltasone], and lenalidomide) versus MP (melphalan and prednisone) alone produced more responses and less toxicity; however, the 3drug combination did not improve the rate of relapse. Until the study matures, this comparison is likely to be a topic of debate, experts noted.

The most interest was focused on the maintenance approach with MPR followed by lenalidomide (MPR-R), which outperformed MPR without maintenance. MPR-R reduced the risk of disease progression by 47% compared with MPR. Median progressionfree survival (PFS) has not been reached for MPR-R, and was 13.2 months with MPR. “The study showed that continuous lenalidomide was superior to regi-

“VMPT followed by maintenance with bortezomib and thalidomide was superior to VMP for response rates and progression-free survival.”—Antonio Palumbo, MD Of the 469 patients, overall response rates were 77% for MPR-R, 67% for MPR, and 49% for MP; complete responses were 18%, 13%, and 5%, respectively. In the first 3 months of treatment, partial response rate was 60% for the MPR-R arm and 30% for MP. Very good partial responses (VGPR) or better were still being observed at 17 months, suggesting that continued improvement is possible with continued therapy.

4 Drugs plus bortezomib/ thalidomide Maintenance Better than 3 In another phase 3 study of 511 elderly patients, Dr Palumbo reported that maintenance therapy after a 4-

High-Risk Smoldering Myeloma Responds to Treatment

H

igh interest was shown in a study of the best approach to managing patients with “smoldering” myeloma who were deemed to be at risk for progressing to symptomatic disease. This phase 3 clinical trial concluded that lenalidomide (Revlimid) plus dexamethasone (Decadron) is a promising treatment regimen compared with the usual approach of surveillance without treatment intervention.

All 94 patients had elevations in serum M-component and bone marrow plasma cells but no end-organ disease. Such patients typically develop symptomatic myeloma in slightly >2 years. The patients were randomized to nine 4-week induction cycles of lenalidomide plus dexamethasone followed by maintenance therapy with lenalidomide, or no treatment.

Results showed a significant benefit to treating high-risk smoldering patients, because 81% responded and

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14% achieved a “stringent” complete response or complete response after 4 cycles. After 9 cycles, response rates were 91% and 21%, respectively. At follow-up, patients in the no-treatment arm had a 19-month mean time to disease progression. In contrast, just 2 patients in the lenalidomide plus dexamethasone arm had progressed, reported Maria-Victoria Mateos, MD, of the University of Salamanca, Spain.

Lenalidomide plus dexamethasone is a promising treatment regimen compared with the usual approach.

Despite treatment, patients maintained a good quality of life, with few serious side effects, Dr Mateos added. The analysis, however, did not yet show an improvement in survival.—CH ■

drug regimen that included thalidomide was superior to the same regimen without thalidomide or maintenance. Patients were randomized to bortezomib, melphalan, and prednisone (VMP) without maintenance, or to VMP plus thalidomide (VMPT) followed by bortezomib and low-dose thalidomide for maintenance.

VMPT plus maintenance therapy was superior to VMP alone, with complete responses achieved by 34% and 21% of patients, respectively. The achievement of a complete response significantly delayed relapses in both regimens, but was most pronounced in the VMPT arm; 2-year survival was similar (89%) for both arms.

The study began with twice-weekly bortezomib, but was amended to a once-weekly dosage. This resulted in a “dramatic drop” in the incidence of peripheral neuropathy without affecting the outcome, he said.

Grade 3 to 4 neuropathy occurred in just 4% of patients given bortezomib weekly versus 18% of patients given bortezomib twice-weekly in the VMPT arm, and in 2% and 13% of patients, respectively, in the VMP arm. The 4-drug regimen was associated with significantly more grade 3 to 4 neutropenia and cardiotoxicity, but other toxicities were similar for both arms.

“VMPT followed by maintenance with bortezomib and thalidomide was superior to VMP for response rates and progression-free survival,” Dr Palumbo concluded.

Bortezomib, then Lenalidomide Posttransplant Improved outcomes were also reported with a sequential approach using bortezomib for induction and lenalidomide as posttransplant consolidation maintenance. The investigators said that bortezomib induction before autologous stem-cell transplantation (ASCT) has shown efficacy in newly diagnosed patients, and lenalidomide might be a less-toxic alternative to thalidomide for follow-up consolidation-maintenance.

“This is the first phase 2 study of this approach in newly diagnosed patients aged 65 to 75 years old,” said Francesca Gay, MD, of the University of Torino.

“We found that treatment was correlated with an increase in response rate and in the depth of response, and was generally well tolerated.”

This multicenter phase 2 trial included 102 newly diagnosed patients (age 65-75 years). Induction included 4 cycles of bortezomib, pegylated liposomal doxorubicin (Doxil), and dexamethasone (Deca-

dron), which was followed by ASCT, then consolidation with 4 cycles of lenalidomide plus prednisone, and finally with lenalidomide for maintenance until relapse.

VGPR or better was 58% in patients after induction, which increased to >80% after consolidation and maintenance. Relapse-free rates were 88% after 1 year and 69% at 2 years; 93% and 75%, respectively, were still alive.

Patients achieving a complete response had better outcomes.

“Consolidation-maintenance was well tolerated,” Dr Gay noted. “Only 4% of patients required growth factor support, and no patient required platelet transfusions. Skin toxicity was easily manageable with dose reductions and supportive therapy.”

“This is the first phase 2 study of this approach in newly diagnosed patients aged 65 to 75 years old.”

—Francesca Gay, MD Sequential VTD Maintenance Approach In another phase 2 study of sequential therapy, investigators from the City of Hope Cancer Center, Duarte, CA, evaluated the role of initiating bortezomib and dexamethasone for maintenance, followed by a second maintenance phase with thalidomide (VTD) after ASCT. Several studies have shown improved PFS, and possibly improved overall survival, with thalidomide (Thalomid) alone or in combination with steroids and chemotherapy as maintenance-consolidation therapy after ASCT. This study of 28 patients evaluated efficacy and toxicity with a prolonged course of sequential VTD maintenance.

After ASCT, patients received weekly bortezomib and dexamethasone monthly for 6 months. A second maintenance phase included thalidomide and dexamethasone monthly for an additional 6 months. Single-agent thalidomide was then continued until disease progression.

After 5-month follow-up, only 1 patient had died. Complete response rates were boosted after each sequence, and several patients remained in complete remission after the second maintenance phase. Toxicities were manageable: 10 patients had peripheral neuropathy at baseline; 3 developed it with bortezomib. ■ Multiple Myeloma continued on page 20

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Multiple Myeloma

Multiple Myeloma Management in 2010

By Caroline Helwick

T

he survival rates of patients with multiple myeloma (MM) have increased substantially over the past decade, as a result of high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) in young patients, and the new, highly efficient rescue treatments in young and elderly patients, said experts in a special update on this malignancy at ASH. The gold standard induction treatment, given before ASCT, is VAD (vincristine [Oncovin], doxorubicin [Adriamycin], and dexamethasone [Decadron]), but novel drug combinations are being evaluated for their ability to prolong remission. New strategies are based on thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) in combination with established antimyeloma agents.

Bortezomib/dexamethasone, with or without thalidomide, has proved to be very effective for debulking tumors, and is superior to VAD. Similar efficacy is expected for bortezomib plus lenalidomide and dexamethasone, said Jesus F. San-Miguel, MD, Uni-

versity Hospital of Salamanca, Spain.

Based on the number of studies evaluating maintenance strategies, this is an emerging concept that may become established (see article, page 17).

Although thalidomide has been effective for maintenance therapy, the more favorable toxicity profile of lenalidomide makes it an ideal maintenance agent. Other new studies are achieving good results, including higher response rates, with bortezomib.

Current investigations are showing that bortezomib can overcome the adverse prognosis of patients in the high-risk category based on cytogenetics or other factors. To a lesser degree, this is seen with lenalidomide as well.

Treatment of Elderly Patients Patients with MM aged ≥65 years have traditionally received an oral regimen of MP (melphalan [Alkeran] and prednisone [Deltasone]). The introduction of thalidomide, lenalidomide, and bortezomib has substantially changed this treatment paradigm, said Antonio Palumbo, MD, and Francesca Gay, MD, of the University of Torino, Italy.

With these novel agents on board for induction or consolidation after transplant, reduced-intensity transplantation is also now an option in some elderly patients. The choice of treatment (and level of aggressiveness) is tailored according to the patient’s biological age, comorbidities, and the expected toxicity profile of the regimen. When cost is a concern, MP plus thalidomide may be the best option, they said.

The introduction of thalidomide, lenalidomide, and bortezomib has substantially changed this treatment paradigm.

In elderly patients newly diagnosed with MM who are ineligible for transplantation, analysis of the VISTA trial showed that that the VMP regimen— bortezomib, melphalan, and prednisone—was superior to MP alone.

The 3-year overall survival rate with VMP was 68.5% compared with 54.0% for MP (see also article, page 7).

Weekly Bortezomib Effective, Less Toxic

U

sing bortezomib weekly rather than twice weekly appears to have comparable efficacy but less toxicity than the more-intensive regimen, according to presentations at a plenary session. Good results were reported with the less-intensive regimen in newly diagnosed older patients.

“We were trying to optimize the treatment of elderly patients, so we tried a less-intensive weekly administration for induction, followed by maintenance doses given every 3 months,” said lead investigator Maria-Victoria Mateos, MD, PhD, from University Hospital, Salamanca, Spain.

The 260 elderly patients (aged >65 years) were treated in 6 cycles with either VMP (bortezomib [Velcade], melphalan [Alkeran], and prednisone [Deltasone]) or VTP (bortezomib, thalidomide [Thalomid], and prednisone). In the first cycle, patients received bortezomib twice weekly, and once weekly in subsequent cycles.

For maintenance, patients received bortezomib plus thalidomide or prednisone for up to 3 years.

Both induction approaches were very effective, with response rates of about 80%; as maintenance, they increased complete responses from 23% to 42%.

A clear difference, however, was seen in the toxicity profiles of the

20

induction regimens: VMP was associated with more grade 3 neutropenia infections. VTP was associated with more serious cardiovascular events and more severe peripheral neuropathy.

“We found that melphalan is probably the best partner for bortezomib in elderly untreated myeloma patients.”

—Maria-Victoria Mateos, MD, PhD “We found that melphalan is probably the best partner for bortezomib in elderly untreated myeloma patients, because the efficacy is similar to VTP, but the toxicity profile is different,” Dr Mateos said.

“We asked whether we could achieve similar efficacy with a less intensive bortezomib regimen, and the answer is that clearly we can,” Dr Mateos said. Perhaps the most important finding was that the poor prognosis of high-risk elderly patients could be overcome with either regimen.

Comparing Regimens for Induction Two prominent abstracts compared TD (thalidomide [Thalomid] and dexamethasone [Decadron]) with VTD

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(TD plus bortezomib [Velcade]) as induction therapy before autologous stem-cell transplantation (ASCT). Both were large randomized trials designed to assess the effect of using bortezomib in newly diagnosed patients.

The study from the Italian Myeloma Network, presented by Michele Cavo, MD, of the University of Bologna, showed significantly improved response rates with VTD. At all assessment points, patients receiving VTD had better outcomes, and VTD conferred improved progression-free survival—76% at 30 months compared with 58% in the TD arm.

The addition of bortezomib added little toxicity, except for more grade 3 rash (16% vs 2%) and peripheral neuropathy (10% vs 2%). Few patients discontinued VTD and 94% received all the doses.

In a similar phase 3 trial of 299 patients, the Spanish Myeloma Group reported that VTD resulted in higher complete response rates before and after ASCT, as well as lower rates of progression compared with TD, particularly in patients with high-risk cytogenetics or soft-tissue extramedullary plasmacytomas. Based on these and other findings, VTD appears to be emerging as a new standard for younger myeloma patients who are candidates for ASCT.—CH ■

Novel Therapies for Relapse Despite extended periods of remission after treatment with bortezomib and the immunomodulators thalidomide and lenalidomide, most patients develop drug resistance and eventually relapse. Treatment for relapse should be individualized to reflect prior drug exposure, prior drug toxicities, responsiveness, age, tempo of relapse, and genetic risk.

The frequent occurrence of relapse and potential for intolerable adverse effects from current drugs make the development of newer agents with novel mechanisms of action, improved efficacy, and better tolerability a pressing need, said A. Keith Steward, MD, of the Mayo Clinic Arizona, Scottsdale.

Bortezomib, the first proteasome inhibitor to be approved for myeloma, elicits responses in about 50% of patients at the time of relapse. New proteasome inhibitors are being developed that differ somewhat from each other in chemistry and in specificity for the proteasome target, such as carfilzomib, which has shown promise in early trials. New immunomodulators are also entering trials, including pomalidomide (Actimid). The alkylating agent bendamustine (Treanda) is also being tested in combination with other active agents in MM. A review of the medical literature reveals more than 180 different drugs in which preclinical results give rationale to proceed to clinical testing, with special interest in the AKT inhibitors, heat-shock protein inhibitors, and histone deacetylase inhibitors. It is probable that the therapeutic arsenal for MM will soon expand to help improve patient outcomes, Dr Steward predicted.

Questions Remain Bart Barlogie, MD, PhD, Director of the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, said that more radical questions need to be answered about the future of MM, saying that we need “more decisive questioning, at the end of which we have crucially important information.”

“One such question would be whether to do transplant or not in the low-risk myeloma patient. Some would say they don’t need transplant, although personally I disagree. The downside is that once the patient has a recurrence, we may have lost the cure potential. Also, we need to use more gene arrays in research. If this were part and parcel of all evaluations of new agents, we could discover in 2 to 3 years an approach that really works. ■

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Other Highlights

Hematologic Drug Pipeline...

The overall hematologic response was 35% (median duration, 7 months) in accelerated-phase patients, and 47% (median duration, 2 months) in blastphase patients.

A new cancer vaccine GRNVAC1, which targets telomerase, an enzyme whose activity is increased in acute myelogenous leukemia (AML) and other cancers, has produced immune responses in more than half of vaccinated AML patients. Complete clinical remission has been maintained in 14 of 20 vaccine recipients with AML in ongoing complete remission or early relapse. The median duration of clinical remission, including the patients who have relapsed, is 12 months. The vaccine was well tolerated, with the exception of 1 patient who developed immune thrombocytopenic purpura.

Elotuzumab, given with lenalidomide and low-dose dexamethasone, showed clinical activity in a study of 28 patients with relapsed multiple myeloma (MM). In the study, 23 patients (82%) had an objective response. In 22 patients who had not previously received lenalidomide, 21 patients (95%) achieved an objective response. No dose-limiting toxicities were reported up to the highest dose level of 20 mg/kg, and a maximum tolerated dose was not established.

Tositumomab and iodine I-131 tositumomab looked promising in 2 phase 2 studies, one in patients with untreated follicular lymphoma, and the other in patients with non-Hodgkin’s lymphoma who no longer responded

Continued from page 1

to rituximab (see article, page 10).

Less far along in the pipeline, but very promising, are the bifunctional T-cell–engaging BiTE monoclonal antibodies, such as blinatumomab. In 50 heavily pretreated patients with relapsed NHL, blinatumomab, given for 4 to 8 weeks by continuous intravenous infusion via port with a

associated with a preliminary median overall survival (OS) of 7.8 months and a remission rate of 31%. The median OS in first relapsed or refractory AML patients receiving currently available chemotherapies ranges from 3.4 months to 5.9 months.

In a trial of single-agent voreloxin in 113 previously untreated elderly AML

“Omacetaxine works by a completely different mechanism, inhibiting the synthesis of certain oncoproteins instead of directly attacking BCR-ABL.” —Jorge E. Cortes, MD portable pump produced responses in all 12 (100%) evaluable patients. The duration of responses extended to 20 months; response is ongoing in 7 patients. Neurologic toxicity was a concern, but this is being mitigated by slowing the infusion and using stepwise dosing.

Voreloxin has a strong efficacy and safety profile when used as a single agent or in combination with chemotherapy in patients with difficult-totreat AML, according to Jeffrey Lancet, MD, Associate Member and Chief, Leukemia Section, Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. In 64 evaluable patients with first relapsed or refractory AML, voreloxin in combination with cytarabine was

patients (median age, 74 years), 3 dosing schedules were tested: once weekly for 3 weeks (schedule A); once weekly for 2 weeks (schedule B); and on days 1 and 4 at either 72 mg/m2 or 90 mg/m2 (schedule C).

Median survival was 8.7 months in schedule A; 5.8 months in schedule B; and 7.3 months (preliminary) in schedule C (72 mg/m2 on days 1 and 4). The median duration of remission was 10.7 months, and 1-year survival was 38% for schedule A. For the other schedules, median duration of remission has not been reached, and 1-year survival is too early to evaluate.

INCB018424, an investigational oral inhibitor of the Janus-activated kinase (JAK) 1 and 2 enzymes, can reduce spleen size and improve quality of life and symptoms associated with myelo-

fibrosis, according to Srdan Verstovsek, MD, PhD, Associate Professor, Department of Leukemia, University of Texas M.D. Anderson Cancer Center.

Recent evidence indicates that exaggerated JAK signaling plays an important role in the pathogenesis of myelofibrosis. Average life expectancy for patients is 5 to 7 years. In 155 patients with the disease, INCB018424 treatment resulted in a rapid reduction in spleen volume, which was evident as early as 1 month into therapy and lasted beyond 6 months of therapy.

Some 48% of patients had spleen volume reduction ≥35% after 6 months of treatment. An improvement was also observed in the 6-minute walk test.

Carfilzomib, the second-generation proteasome inhibitor, is showing noteworthy response rates and low levels of adverse effects in patients with MM, according to updated data from a 17center study.

Carfilzomib induced a response in 45% of 51 evaluable patients with relapsed or resistant MM who received 1 to 3 previous therapies (but not bortezomib, the original proteasome inhibitor). The response rate is considered noteworthy for a single agent in patients with tumor progression despite previous therapy, said lead investigator Michael Wang, MD, Associate Professor, Department of Lymphoma/Myeloma, M.D. Anderson. He said 37% of the patients experienced neuropathy from previous treatments, which was reduced to 12% with carfilzomib. ■

Investigational Alternatives to Warfarin Prevent VTE Events

By Wayne Kuznar

M

ore convenient options to warfarin (Coumadin) for the prevention of venous thromboembolism (VTE) events are a step closer, as suggested by encouraging results of 2 phase 3 clinical trials presented at ASH.

Dabigatran for VTE Prophylaxis Two oral fixed-dose anticoagulants— both inhibitors of factor Xa—showed efficacy in the prevention of VTE events, with acceptable bleeding rates.

In the RE-COVER trial, dabigatran etexilate (Pradaxa) proved to be as effective as warfarin in preventing recurrent VTE in patients with acute VTE. Current guidelines for the treatment of clinically documented VTE recommend a parenteral heparin preparation for at least 5 days, followed by oral anticoagulation with a vitamin K antagonist, such as warfarin.

“In North America, 2 million people are on warfarin at any time point,”

noted Sam Schulman, MD, lead investigator of RE-COVER and Director of the Clinical Thromboembolism Program, Hamilton General Hospital, Ontario, Canada. “Patients on warfarin have to go for blood tests, called an international normalized ratio [INR], every 2 to 3 weeks, and adjust the dose….Warfarin has been around for 60 years and has not really had any contester.”

“There’s probably no more dangerous drug on the market than warfarin,” noted Bradford Schwartz, MD, Dean, University of Illinois College of Med icine, Urbana-Champaign. “Warfarin is a direct competitor to vitamin K, so anything you do that varies the amount of vitamin K you take in is going to affect how much warfarin is there to have an effect.” Many concomitant drugs can also affect blood levels of warfarin. Unlike warfarin, dabigatran is not a vitamin K antagonist.

RE-COVER was an international phase 3 study of 2539 patients with

acute VTE who were randomized to 6 months of therapy with oral dabigatran, 150 mg twice daily, or warfarin, after initial treatment with a parenteral anticoagulant approved for this indication.

The warfarin dosage was adjusted to maintain a 2.0 to 3.0 INR, which required a blood test about every 11 days; those randomized to dabigatran received a sham blood test as part of the double-blind, double-dummy design of the study.

At 6 months, dabigatran was “noninferior” to warfarin on the primary end point—the 6-month incidence of recurrent symptomatic VTE/death.

This end point occurred in 2.4% (30 patients) of the dabigatran group and 2.2% (27 patients) of the warfarin group.

The incidence of major/clinically relevant bleeding was 37% lower with dabigatran than with warfarin (207 vs 280 events, respectively); the major

“Patients on warfarin have to go for blood tests…every 2 to 3 weeks and adjust the dose.

Warfarin has been around for 60 years and has not really had any contester.” —Sam Schulman, MD bleeding incidence was similar between the 2 groups (1.6% vs 1.9%, respectively).

Continued on page 22

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Other Highlights

Stem-Cell Mobilization Strategies: What Works, What Doesn’t

By Caroline Helwick

I

n mobilizing hematopoietic stem cells (HSCs) before proceeding to autotransplant, especially in challenging cases, the conventional approach of intensifying cytokine-based (growth factor) strategies was found to be futile. No advantage was seen for dose-escalated granulocyte colonystimulating factors (G-CSFs) or the combination of G-CSFs plus granulocyte macrophage colony-stimulating factor in mobilizing HSCs. The strategies were evaluated as a means of boosting HSC in patients deemed hard to mobilize based on prior therapy. “Unlike what is seen with normal donors, there was no benefit to dose escalation of mobilization cytokines or the use of 2 versus 1 cytokine in heavily pretreated patients,” said Elizabeth Berger, BA, of Loyola University, IL. “Given the cost of these cytokines,

we conclude that standard-dose GCSF is the optimal method of stemcell mobilization for hard-to-mobilize patients,” she said. “Alternative approaches, such as the combination of plerixafor plus standard-dose G-CSF, might be the preferred method of initial HSC mobilization.”

Plerixafor plus G-CSF Several studies have shown that plerixafor (a CXCR4 receptor inhibitor that prevents the binding of the stem cell to the stroma in the bone marrow) plus G-CSF mobilizes more CD34+ cells in fewer apheresis days than G-CSF alone in patients with myeloma and lymphoma.

Two prospective, randomized, double-blind, placebo-controlled phase 3 trials compared plerixafor plus G-CSF with placebo plus G-CSF for

“The addition of plerixafor to G-CSF predictably allows significantly more patients to achieve the target cell collection within 1 day of apheresis.”

—Brian J. Bolwell, MD

Investigational Alternatives... Continued from page 21 Adverse events leading to medication discontinuation occurred in 115 patients (9.0%) taking dabigatran and 86 patients (6.8%) using warfarin.

Death, myocardial infarctions, and abnormalities in liver function tests were infrequent in both groups.

Dabigatran is also being studied for the primary prevention of VTE in patients undergoing elective total hip and knee replacement surgeries, for the prevention of atherothrombotic events in patients with acute coronary syndrome, and for stroke prevention in atrial fibrillation.

Rivaroxaban for Recurrent VTE In a second study, rivaroxaban (Xarelto), the other direct oral factor Xa inhibitor, was compared with placebo in 1197 patients who had completed 6 to 12 months of anticoagulant treatment for acute VTE. They were randomized to rivaroxaban, 20 mg/day, or placebo for an additional 12 months.

Recurrent VTE event rates were 1.3% with rivaroxaban and 7.1% with placebo—an 82% relative risk reduction. After the study medication was stopped, 6 symptomatic recurrent VTE events occurred in each group during a 1-month observational period.

“There’s probably no more dangerous drug on the market than warfarin.”

Bradford Schwartz, MD

Harry Büller, MD, lead investigator and Professor of Medicine, Academic Medical Center in Amsterdam, the Netherlands, said that the ideal duration of VTE-related anticoagulation event is still unknown. “The classical way is 3 to 6 months,” he said.

Four patients treated with rivaroxaban and none receiving placebo had a major bleeding episode, none of which were fatal or in a critical site. Nonmajor bleeding, such as nose bleeds, skin hematoma, or blood in the urine, occurred in 5.4% of the rivaroxaban group and 1.2% of the placebo group.

Liver toxicity did not occur with rivaroxaban. Continued study of a previous factor Xa inhibitor, ximelagatran (Exanta), was halted after it was found to be associated with significant liver toxicity. ■

mobilization of HSC. “The addition of plerixafor to G-CSF predictably allows significantly more patients to achieve the target cell collection within 1 day of apheresis compared with G-CSF alone,” said Brian J. Bolwell, MD, of the Cleveland Clinic.

In a trial of patients with nonHodgkin’s lymphoma (NHL), 59.3% of the patients in the plerixafor group collected sufficient CD34+ cells on day 1 of apheresis compared with 30.2% in the placebo group. In a trial of patients with myeloma, these percentages were 85.8% versus 58.5%, respectively. All differences were very significant.

Ivana N. Micallef, MD, of the Mayo Clinic, Rochester, MN, reported results from patients in the plerixafor compassionate use program who failed/predicted to fail stem-cell collection with any mobilization regimen, stratified according to the presence or absence of thrombocytopenia.

“We need to have a drug like this.

It’s a very good drug, and it reduces the number of mobilization failures,” said Dr Micallef. “We have shown that 50% of patients needed this drug, and it has reduced our failure rate from 22% to about 5%.”

“It’s a very good drug…and it has reduced our failure rate from 22% to about 5%.”

—Ivana N. Micallef, MD

In another study, the cost of using plerixafor was compared for patients with NHL or Hodgkin’s lymphoma in the expanded-access program versus matched historical controls receiving chemotherapy (cyclophosphamide) plus G-CSF. The median cost of plerixafor plus G-CSF mobilization was not higher than that of G-CSF plus chemotherapy for HSC mobilization: $19,644 versus $18,831. ■

Positive Long-Term Data for 2 ITP Treatments

By Wayne Kuznar

N

ew long-term data were presented at ASH for 2 new drugs for the treatment of immune thrombocytopenic purpura (ITP).

Romiplostim Long-term follow-up of patients with chronic ITP treated with romiplostim (Nplate), a peptibody protein that increases platelet production, shows maintenance of platelet counts within the target range (50-200 103/µL) in an open-label study.

“This is the longest running ITP extension study for a thrombopoietin mimetic agent by far, with up to 5 years of continued romiplostim treatment,” said James Bussel, MD, Professor, Platelet Disorders Center, Division of Pediatric HematologyOncology, Weill Cornell Medical College, New York City.

As of May 2009, 291 adults had been treated with romiplostim for a median of 2 years; 30 patients have been followed for >4 years. “The platelet counts in general were very stable,” said Dr Bussel. “The great majority of patients maintained their dose, either at their most frequent dose or within

2 µg/kg of their most frequent dose.”

Many patients receiving concurrent ITP medications were able to taper the doses or discontinue those other medications. “Rescue medication use was less than 15% in most of the 12-week periods during the study. This would mean, on average…a rescue treatment about once a year,” Dr Bussel said.

Most common adverse events were headache (32%), nasopharyngitis (30%), and confusion and fatigue (each 28%).

Twenty-six patients had venous or arterial thrombotic events, with no correlation to the platelet count level. Two of the 13 deaths in the study were possibly treatment-related, from unstable angina or myocardial infarction.

In a European phase 3b study, romiplostim was compared with medical standard of care (SOC). Romiplostim reduced the rate of bleeding-related episodes (BREs) and the need for intravenous immunoglobulin rescue in nonsplenectomized adults with ITP. “The risk of having a BRE was half as likely in patients receiving romiplostim than in patients receiving the SOC,” said Roberto Stasi, MD, of St George’s Hospital, London. “Patients Continued on page 23

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Positive Long-Term Data... receiving romiplostim spent more time with platelet levels ≥50103/µL than those receiving the SOC,” said Dr Stasi.

Eltrombopag Long-term follow-up data were also presented for ITP therapy with eltrombopag (Promacta), an oral thrombopoietin receptor agonist that increases platelet production by increasing megakaryocyte proliferation.

The study included 299 patients who were treated with eltrombopag.

Eltrombopag was started at 50 mg/day and adjusted to maintain platelet counts within normal range.

The follow-up period extended to 104 weeks.

Overall, 86% of the patients achieved a platelet count of ≥50 103/µL. Response was similar between splenectomized and nonsplenectomized patients.

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Median platelet counts increased to ≥50103/µL by week 2; 30% of the patients were able to stop concomitant ITP therapies. No treatment-related deaths occurred.

“At this point, we have 2 very

promising drugs,” said Joel Anne Chasis, MD, from the Lawrence Berkeley National Laboratory, Berkeley, CA. “We can say that these drugs are very effective in raising platelet counts and maintaining these platelet

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), institute appropriate treatment for complaints of abdominal pain, especially early in the SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of LEUKOENCEPHALOPATHY (PML) immunization with live viral vaccines following Rituxan therapy has not been studied and Infusion Reactions: Rituxan administration can result in serious, including vaccination with live virus vaccines is not recommended. Laboratory Monitoring fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have Because Rituxan binds to all CD20-positive B lymphocytes (malignant and nonoccurred. Approximately 80% of fatal infusion reactions occurred in malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals association with the first infusion. Carefully monitor patients during during Rituxan therapy and more frequently in patients who develop cytopenias [see infusions. Discontinue Rituxan infusion and provide medical treatment for Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse beyond the treatment period. ADVERSE REACTIONS The most common adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, Reactions: Severe, including fatal, mucocutaneous reactions can occur in mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other patients receiving Rituxan [see Warnings and Precautions, Adverse viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation.

Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are infection resulting in PML and death can occur in patients receiving Rituxan conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another [see Warnings and Precautions, Adverse Reactions]. drug and may not reflect the rates observed in practice. The data described below reflect ® INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan (rituximab) is exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up indicated for the treatment of patients with: Relapsed or refractory, low-grade or to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non–progressing DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after given as a single agent weekly for up to 8 doses, in combination with chemotherapy for first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, including fatal, infusion reactions. Severe reactions typically occurred during the first myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and reactions typically occurred within 30 to 120 minutes of beginning the first infusion and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, resolved with slowing or interruption of the Rituxan infusion and with supportive care pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate reactions was highest during the first infusion (77%) and decreased with each patients with an antihistamine and acetaminophen prior to dosing. Institute medical subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than reactions as needed. Depending on the severity of the infusion reaction and the required 5% of patients with NHL in the single-arm studies. The overall incidence of infections interventions, consider resumption of the infusion at a minimum 50% reduction in rate was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and after symptoms have resolved. Closely monitor the following patients: those with pre- Precautions.] In randomized, controlled studies where Rituxan was administered existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary following chemotherapy for the treatment of follicular or low-grade NHL, the rate of adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/ infection was higher among patients who received Rituxan. In diffuse large B-cell mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor lymphoma patients, viral infections occurred more frequently in those who received Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences administer supportive care, including dialysis as indicated. [See Boxed Warning.] of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of outcome, can occur in patients treated with Rituxan. These reactions include patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan who experience a severe mucocutaneous reaction. The safety of readministration of 375 mg/m2 weekly for 4 doses.

Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Table 1 Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b patients with hematologic malignancies or with autoimmune diseases. The majority of All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) patients with hematologic malignancies diagnosed with PML received Rituxan in Any Adverse Events 99 57 Respiratory System 38 4 Body as a Whole 86 10 Increased Cough 13 1 combination with chemotherapy or as part of a hematopoietic stem cell transplant. The Fever 53 1 Rhinitis 12 1 Chills 33 3 Bronchospasm 8 1 patients with autoimmune diseases had prior or concurrent immunosuppressive therapy.

Infection 31 4 Dyspnea 7 1 Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan.

Asthenia 26 1 Sinusitis 6 0 Headache 19 1 Metabolic and Nutritional Consider the diagnosis of PML in any patient presenting with new-onset neurologic Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 manifestations. Discontinue Rituxan and consider discontinuation or reduction of any Back Pain 10 1 Hyperglycemia 9 1 concomitant chemotherapy or immunosuppressive therapy in patients who develop Throat Irritation 9 0 Peripheral Edema 8 0 Flushing 5 0 LDH Increase 7 0 PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Heme and Lymphatic System 67 48 Digestive System 37 2 Lymphopenia 48 40 Nausea 23 1 Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death Leukopenia 14 4 Diarrhea 10 1 can occur in patients with hematologic malignancies treated with Rituxan. The median Neutropenia 14 6 Vomiting 10 1 Thrombocytopenia 12 2 Nervous System 32 1 time to the diagnosis of hepatitis was approximately 4 months after the initiation of Anemia 8 3 Dizziness 10 1 44 2 Anxiety 5 1 Rituxan and approximately one month after the last dose. Screen patients at high risk of Skin and Appendages Night Sweats 15 1 Musculoskeletal System 26 3 HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for Rash 15 1 Myalgia 10 1 Pruritus 14 1 Arthralgia 10 1 clinical and laboratory signs of active HBV infection for several months following Rituxan Urticaria 8 1 Cardiovascular System 25 3 therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who Hypotension 10 1 Hypertension 6 1 develop viral hepatitis, and institute appropriate treatment including antiviral therapy.

Insufficient data exist regarding the safety of resuming Rituxan in patients who develop aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Infections Rituxan is NCI-CTC criteria. not recommended for treatment of patients with severe active infections. The following In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to additional serious viral infections, either new, reactivated, or exacerbated, have been 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy identified in clinical studies or postmarketing reports. The majority of patients received Adverse reactions information below is based on 1250 patients who received Rituxan in Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell combination with chemotherapy or following chemotherapy. Rituxan in Combination transplant. These viral infections included cytomegalovirus, herpes simplex virus, With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, experienced a higher incidence of infusional toxicity and neutropenia compared to the viral infections occurred as late as one year following discontinuation of Rituxan and patients in the CVP arm. The following adverse reactions occurred more frequently have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan including fatal, renal toxicity can occur after Rituxan administration in patients with following CVP compared to patients who received no further therapy: fatigue (39% vs. hematologic malignancies. Renal toxicity has occurred in patients with high numbers of 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), lysis syndrome and in patients with NHL administered concomitant cisplatin therapy rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. during clinical trials. The combination of cisplatin and Rituxan is not an approved 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more treatment regimen. Use extreme caution if this non-approved combination is used in frequently (≥2%) in the Rituxan arm compared with those who received no further clinical trials and monitor closely for signs of renal failure. Consider discontinuation of therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Studies 6 and 7, the following adverse reactions, regardless of severity, were reported Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to to death, can occur in patients receiving Rituxan in combination with chemotherapy. In CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder

counts. The questions that still remain are—what about thrombosis, what about the development of reticulin in the marrow, and what about the development of hematologic malignancies.” ■

(29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving singleagent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection.

Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis).

DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan, or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. Because caution should be exercised in administering Rituxan to patients with active infections, it is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Rituxan is detectable in serum for up to six months following completion of therapy.

Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Revised 10/2009 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2009 Biogen Idec Inc. and Genentech, Inc. 7140918 November 2009

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Across approved NHL indications

DRIVING BETTER OUTCOMES IN NHL PROVEN OUTCOMES ACROSS MULTIPLE ENDPOINTS1-3

In the GELA trial1‡

In the Marcus trial 1

In the E1496 trial 1

At 5 years, OS increased from 46% with CHOP alone to 58% with R-CHOP

At 1.5-year median follow-up, there was a 71% improvement in median PFS (2.4 years R-CVP vs 1.4 years CVP alone)

At 2.3-year median follow-up, there was a 51% reduction in the risk of relapse, progression, or death with CVP→R vs CVP alone (p≤0.05)

Indications RITUXAN® (Rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent Weekly ×4

Weekly ×8

Bulky disease

Retreatment

Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy Across DLBCL trials in patients ≥60 years of age, the following Grade 3 or 4 adverse reactions were reported more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection and neutropenia. In the Marcus trial of first-line follicular NHL, patients in the R-CVP arm had higher incidences of infusional toxicity (71% vs 51%) and Grade 3–4 neutropenia (24% vs 14%) as compared with those in the CVP arm. In the E1496 trial of low-grade NHL, neutropenia was the only Grade 3 or 4 adverse event that occurred more frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%).

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse

©2009 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.

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Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.

For additional safety information, please see following page for brief summary of prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *In the ECOG 4494 and MInT DLBCL trials, 2-year OS was R-CHOP 74% vs CHOP 63% (p<0.05) and R-CHEMO 95% vs CHEMO 86% (p<0.05), respectively.1 † Improvement in overall PFS was calculated using the formula (1–HR)/HR. ‡ R-CHOP improved the primary endpoint of median event-free survival by 164% (2.9 years vs 1.1 years) vs CHOP alone.1 NHL=non-Hodgkin’s lymphoma; DLBCL=diffuse large B-cell lymphoma; R=RITUXAN; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; OS=overall survival; GELA=Groupe d’Etude des Lymphomes de l’Adulte; CVP=cyclophosphamide, vincristine, and prednisone; PFS=progression-free survival; HR=hazard ratio; ECOG=Eastern Cooperative Oncology Group; MInT=MabThera® (Rituximab) International Trial; CHEMO=CHOP, CHOEP (CHOP+etoposide), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) biweekly, or PMitCEBO (prednisolone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, and vincristine) biweekly.

References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 3. Marcus R, Imrie K, Solal-Céligny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579-4586.

December 2009