February 2010, Vol 3, No 1 SPECIAL ISSUE

Some degree of healthcare reformseems likely to be enacted, butwhat is shaping up as reform will

likely be a failure in terms of “seriouscost-containment,” suggested Paul B.Ginsburg, PhD, President of theCenter for Studying Health System

Change, a “think tank” that analyzeschanges in financing and the deliveryof healthcare (www.hschange.org). DrGinsburg was the main speaker at thesession on Healthcare Costs andReform at the 2009 annual meeting ofthe American Society of Hematology.

Healthcare Reform: Cost-Containment Not Very LikelyBy Caroline Helwick

©2010 Engage Healthcare Communications, LLC

Ahost of investigational drugsin the pipeline for the treat-ment 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 dabigatranetexilate and rivaroxaban, whichshowed impressive success for theprevention of recurrent venous throm-boembolic events (see article, page 21).

Omacetaxine mepesuccinate isbeing studied for the treatment ofchronic myelogenous leukemia (CML)that is resistant to imatinib because ofthe development of the BCR-ABLT315I genetic mutation. In an ongoingphase 2/3 study of 81 patients withCML (49 in chronic-phase CML, 17 inthe accelerated phase, and 15 in theblast phase), omacetaxine produced

durable hematologic and cytogeneticresponses, reported Jorge E. Cortes,MD, Deputy Chair and Professor ofMedicine, Department of Leukemia,University of Texas M.D. AndersonCancer Center.“Omacetaxine works by a complete-

ly different mechanism, inhibiting thesynthesis of certain oncoproteinsinstead of directly attacking BCR-ABL,” Dr Cortes said.Previous imatinib therapy had

failed in all the patients, and ≥2 previous tyrosine kinase inhibitorsfailed in 79%. A baseline BCR-ABLT315I gene mutation was confirmed in all patients.In chronic-phase CML patients,

complete hematologic responses oc -curred in 86% (median response dura-tion, 9 months) and the total cytoge-netic response rate was 41%, with amajor cytogenetic response in 27%.

Hematologic Drug Pipeline Diverse and PromisingBy Wayne Kuznar

Continued on page 21

Continued on page 5

The costs of treating multiplemyeloma (MM) can present asmuch 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 forMM with bortezomib (Velcade), aninjectable drug, and with the oral med-ications lenalidomide (Revlimid) andthalidomide (Thalomid).

The Costs of Multiple MyelomaTreatment Vary WidelyBy Caroline Helwick

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE

New Regimen Challenges StandardTreatment of Indolent LymphomaBy Wayne Kuznar

Bendamustine (Treanda) plus rituximab (Rituxan) (B/R) wasmore effective and better tolerat-

ed than the standard first-line regimenof CHOP-R—cyclophosphamide (Cy -toxan), hydroxydaunorubicin (Adri -amycin), vincristine (Oncovin), andprednisone (Deltasone), plus ritux-imab—for indolent lymphoma andmantle-cell lymphoma (MCL), accord-ing to a phase 3 German trial in whichB/R reduced the risk of tumor pro-gression by 43%. The study was high-lighted at a special press conference

during ASH.“Bendamustine

plus rituximab hasthe potential tobecome a treatmentof first choice inthese disease enti-ties,” said MathiasJ. Rummel, MD, of the UniversityHospital in Giessen,Germany.“I think there will be a great deal of

interest in this study. The findings are

Paul B. Ginsburg, PhD

INSIDEHEALTH ECONOMICS 4LYMPHOMA 8

LEUKEMIA 12MULTIPLE MYELOMA 17OTHER ASH HIGHLIGHTS 21

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Continued on page 4

Mathias J. Rummel, MD

Continued on page 8

ASH 2009: PAYER’S PERSPECTIVESTHE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 1:12 PM Page c1

For more information, visit www.cllinformation.com

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

*Refractory to fl udarabine and alemtuzumab

11:12:39 AM

AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 12:58 PM Page c2

3www.AHDBonline.comVOL. 3 NO. 1 SPECIAL ISSUE

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorLara J. [email protected]

Senior Production ManagerRobyn Jacobs

Business ManagerBlanche Marchitto

Editor-in-ChiefRobert E. [email protected]

CONTENTS

Mission StatementAmerican Health & Drug Benefits is founded on theconcept that health and drug benefits have undergonea transformation: the econo metric value of a drug is ofequal importance to clinical outcomes as it is to serv-ing as the basis for securing coverage in formulariesand benefit designs. Benefit designs are greatly affect-ed by clinical, business, and policy conditions.

This publication provides benefit design de cisionmakers the integrated industry information theyrequire to devise formularies and benefit designs thatstand up to today’s special healthcare delivery andbusiness needs.

Contact Information:For reprints, subscription information, and editorialqueries, please contact: [email protected]

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

American Health & Drug Benefits, ISSN 1942-2962(print); ISSN 1942-2970 (online), is published 6times a year by Engage Healthcare Communica -tions, LLC, 241 Forsgate Drive, Suite 205A, MonroeTownship, NJ 08831. Copyright © 2010 by EngageHealthcare Communications, LLC. All rightsreserved. American Health & Drug Benefits and ThePeer-Reviewed Forum for Evidence in Benefit Designare trademarks of Engage Healthcare Communi -cations, LLC. No part of this publication may bereproduced or transmitted in any form or by anymeans now or hereafter known, electronic ormechanical, including photocopy, recording, or anyinformational storage and retrieval system, withoutwritten permission from the Publisher. Printed inthe United States of America.

Address all editorial correspondence to: [email protected], Telephone: 732-992-1889.Fax: 732-992-1881.

Permission requests to reprint all or part of any articlepublished in this journal should be addressed to PER-MISSIONS DEPARTMENT. Fax: 732-992-1881.

The ideas and opinions expressed in American Health& Drug Benefits do not necessarily reflect those of theEditorial Board, the Editors, or the Publisher.Publication of an advertisement or other productmentioned in American Health & Drug Benefits shouldnot be construed as an endorsement of the product orthe manufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the Editorsnor the Publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGEOF ADDRESS should be directed to CIRCULA-TION DIRECTOR, American Health & DrugBenefits, 241 Forsgate Drive, Suite 205A, MonroeTownship, NJ 08831. Fax: 732-992-1881. YEARLYSUBSCRIPTION RATES: One year: $99.00 USD;Two years: $149.00 USD; Three years: $199.00 USD.

EDITORIAL BOARDCLINICAL EDITOR Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSr. Counselor, Fleishman-Hillard Washington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer Center, NorthwesternUniversityChair, Board of Directors, NCCN

Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan HealthSystems

CARDIOLOGY RESEARCH Michael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EMPLOYERSAlberto M. Colombi, MD, MPHCorporate Medical DirectorPPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE

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

F. Randy Vogenberg, RPh, PhDChief Strategy OfficerEmployer-based PharmaceuticalStrategiesSenior Scholar, Department of Health Policy, Thomas Jefferson University

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

Nirav R. Shah, MD, MPHAssistant Professor of MedicineNYU School of Medicine, NYCSenior Investigator, Geisinger HealthSystem, Danville, PA

HEALTH INFORMATION TECHNOLOGY J.B. Jones, PhD, MBAResearch Associate, Geisinger Health System, Danville, PA

HEALTH OUTCOMES RESEARCH Gordon M. Cummins, MSDirector, IntegriChain

Kavita V. Nair, PhDAssociate Professor, School ofPharmacyUniversity of Colorado at Denver

Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA

Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL

MANAGED CARE & GOVERNMENTAFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHPSenior Director, Customer Marketing & Innovation, US Specialty CustomersPfizer Specialty Business Unit, PA

Charles E. Collins, Jr, MS, MBAAssociate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA,PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. ofPharmacotherapyCollege of Pharmacy, Washington State UniversitySpokane, WA

PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, DistinguishedFellow, MIT Center for BiomedicalInnovation

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor ofPharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

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

William J. Cardarelli, PharmDDirector of PharmacyAtrius HealthHarvard Vanguard Medical AssociatesBoston, MA

Leslie S. Fish, PharmDSr. Director of Pharmacy ServicesFallon Community Health Plan, MA

Paul Anthony Polansky, BSPharm,MBAExecutive VP and Chief PharmacyOfficerSanovia Corp., Philadelphia, PA

Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in HealthCare Retirement PolicyAmerican Enterprise Institute

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School ofPharmacy University of Missouri,Kansas City

Alex Hathaway, MD, MPH,FACPMSenior Medical Policy AdvisorGovernment ProgramsGlaxoSmithKline, Philadelphia, PA

J. Warren Salmon, PhDProfessor of Health Policy &AdministrationSchool of Public HealthUniversity of Illinois at Chicago

REIMBURSEMENT POLICYGrant D. Lawless, BSPharm, MD,FACPExecutive Director for Payor RelationsCorporate AccountAmgen, Thousand Oaks, CA

Michael Schaffer, PharmD, MBADirector, Pharmacy ProgramsSanovia Corp., Philadelphia, PA

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and ScientificOfficer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics,Harvard-MIT Division of HealthSciences and Technology,Cambridge, MA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

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

FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE

ASH 2009: PAYER’S PERSPECTIVESTHE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

HEALTH ECONOMICS4 Healthcare Reform: Cost-Containment Not Very Likely

5 The Costs of Multiple Myeloma Treatment Vary WidelyPegfilgrastim with Transplant: Upfront Cost May Be Offset

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

7 Bortezomib Cost-Effective for Newly Diagnosed Patients with Multiple MyelomaAlemtuzumab Contributes 39% to Treatment Costs in CLL

LYMPHOMA8 New Regimen Challenges Standard Treatment of

Indolent LymphomaIn Challenging B-Cell Lymphoma, AggressiveChemotherapy plus Rituximab Show Best OutcomesTreatment Is Beneficial in Older Patients with Advanced Lymphoma

9 Hodgkin’s Lymphoma: No Changes in Standard of Care,but Emerging Therapies Are PromisingAdding Rituximab to Standard Therapy in Hodgkin’sLymphoma Improves Outcomes

10 Novel Agent Shows Impressive Outcomes in AggressiveNHLHow Much Rituximab Is Necessary in Advanced NHL?Long-Term Survival Achieved with Tositumomab/I-131

12 Emerging Strategies for Mantle-Cell Lymphoma

LEUKEMIA 12 First Head-to-Head Comparison of Targeted TKIs

13 Intermittent Dosing of Dasatinib May Cut Toxicity,Allow Continued Treatment in CMLBendamustine-Rituximab Combo an Effective First-LineTherapy for CLL

14 Statins Delay Treatment in CLLSecond-Generation TKIs Effective, Safe for Relapsed ALL

16 Advances in Treating MDSAdding Alemtuzumab to Fludarabine Doubles PFS inRelapsed CLLAntifungal Prophylaxis in AML Patients ReceivingInduction Chemotherapy

MULTIPLE MYELOMA17 Maintenance Therapy an Emerging Theme in Myeloma

High-Risk Smoldering Myeloma Responds to Treatment

20 Multiple Myeloma Management in 2010Weekly Bortezomib Effective, Less Toxic

OTHER ASH HIGHLIGHTS21 Hematologic Drug Pipeline Diverse and Promising

Investigational Alternatives to Warfarin Prevent VTEEvents

22 Stem-Cell Mobilization Strategies: What Works, What Doesn’tPositive Long-Term Data for 2 ITP Treatments

AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 12:58 PM

VOL. 3 NO. 1 SPECIAL ISSUE4 AMERICAN HEALTH & DRUG BENEFITS February 2010

Health Economics

Healthcare Reform: Cost-Containment... Continued from page 1

“A single approach to containingcosts is unlikely to be sufficiently suc-cessful,” he advised. “We need to pur-sue many distinct but consistent ap -proaches to offset risks that someap proaches will not succeed.”

Rising Healthcare Costs

On the national level, rising costs areundermining the mechanisms thatfinance healthcare and are a key factorin the country’s “dire public fiscal out-look,” Dr Ginsburg noted. On the indi-vidual level, private insurance isincreasingly unaffordable and theaffordability problem now affects themiddle class, he said.The costs of Medicare, Medicaid,

and tax expenditures for private healthinsurance are all growing faster thanthe gross domestic product (GDP), andthe result is that other priorities areneglected, taxes are higher, and thedeficit is growing. An international comparison pro-

vides the evidence of undue high costsin the United States. Healthcareaccounts for 16% of the GDP in thiscountry, compared with about 11% inmany other countries, including France,Germany, Switzerland, and Canada. “Adjusting for income, the United

States spends an extra $477 billion peryear on healthcare” compared withmany other countries, said DrGinsburg. Evidence of rising costscomes from a comparison of cost andincome trends. “There has been a 37%increase in earnings to support a 120%increase in premiums,” he said. “Thisgap explains three fourths of the long-term decline in the percent of theinsured population.”

Key Cost Drivers

The key drivers of rising costs in theUnited States are:• Higher incomes (more money isavailable to spend on healthcare)

• Developments in medical technology• Less-healthy lifestyles• Small gains in productivity relatedto the delivery of health services

• New patterns of competition inhealthcare

• And to a lesser degree than is often assumed, the aging of the USpopulation.Aging contributes just ≤0.5% to the

annual spending trend, according to

Dr Ginsburg. Additional drivers in -clude the poorly functioning medicalliability system and state insurancemandates.At least one third of the trend in

spending stems from technological“advances.” While new treatments aremore effective—yielding better out-comes with lower risks—there is a tendency to overuse them to the pointof limited or negative gains, he point-ed out. Marginally effective, ineffec-tive, or harmful treatments also add torising costs, and there is little fundingfor effectiveness research to weedthese out. Unhealthy lifestyles create more

health problems. Obesity alone is esti-mated to account for 12% of spendinggrowth in recent years. Declines insmoking have held down cost trends,but the killer habit still contributes tospending growth, Dr Ginsburg said. The prosperity of the economy

largely derives from gains in produc-tivity, but this is true only for certainindustries, such as banking and air-lines. “There is much less productivityin healthcare,” he noted. One reason for this is the lack of

the right incentives for healthcareproviders. There are few incentives toproduce episodes of treatment or tohelp improve a patient’s health moreefficiently, he noted. And there is widevariation in the efficiency of the carethat is delivered.“New patterns of competition”

refers to the “entrepreneurial deliverysystem” of today or to the expansionof services that are profitable but maynot add true value. A failure ofMedicare and private insurers to set

payment rates to appropriately reflectrelative cost of services has led hospi-tals to expand services that are prof-itable, such as cardiac procedures, andspecial facilities, such as “heart hospi-tals.” It is possible that expansions ofcapacity are actually creating a de -mand for services, Dr Ginsburg noted. Tied to this is an increase in physi-

cian self-referrals, for example, anincrease in referrals to magnetic reso-nance imaging occurs when physi-cians use their own imaging centers.“With ownership of facilities the scopeof physician self-referral is wider, andthis is worrisome to me,” he said.

Why Are Costs So Hard

to Contain?

Cost-containment is complex and,for various reasons, is viewed by manysectors as threatening. “All spendingpertains to someone’s income, andthere is an increasingly effective lobbyto protect incomes,” Dr Ginsburgobserved.Our political leaders are also “falling

down on the job,” by fostering thenotion that costs can be containedwithout sacrifice. “The concept of cut-ting waste, fraud, and abuse goes wayback,” he said. “Politicians claim therewill be large savings through reducingwaste. It’s a terrific idea, but it won’tsolve the cost problem.”It is uncertain that such “painless

solutions” will contain costs, he main-tained. The other current proposalsinclude the promotion of qualityreporting and payment for quality, theadvancement and adoption of healthinformation technology, and the appli-cation of comparative effectivenessresearch.

“Red Herrings” of Current Reform

The current motivator for healthcarereform is the expansion of insurancecoverage; however, coverage expansionwill exacerbate, not alleviate, the costproblem, according to Dr Ginsburg.“Uninsured people spend less,” hepointed out. “More comprehensive in -sur ance leads to higher spending. Bring - ing the uninsured up to insured status

will increase healthcare spending.”The public plan option is also faulty.

“Only the robust version can impactcosts through lower provider paymentrates,” he noted. “The version in thecurrent bills has little potential toreduce costs.” Increased competitionin insurance markets has limitedpotential.Cost-savings through increased well-

ness and prevention is another fallacy.“The evidence on the lack of potentialfor savings is very strong. Many inCongress are unwilling to accept theevidence, but the Congres sionalBudget Office analysis found that pre-vention will not reduce federal out-lays,” Dr Ginsburg said.

Which Approaches May Work?

A single approach will not be thesole solution to cost-containment, andthere are advantages and disadvan-tages to most of the strategies beingdiscussed.Increased patient cost-sharing (ben-

efits “buydowns,” consumer-directedhealth plans, and health savingsaccounts) is part of a demand-sideapproach to cost-containment and isnot favored by political liberals. In fact,patient cost-sharing does a fairly poorjob of addressing spending trends, DrGinsburg added, because most spend-ing is concentrated within a relativelysmall population of patients. “The bur-den of healthcare falls more on the sickand the poor.” In contrast, patient financial incen-

tives “clearly work,” but will notaccomplish much, because healthcareuse is not particularly sensitive topatient incentives. To be effective, thetools for patient incentives need refine-ment, he said.One proposal is a value-based bene-

fits design, which will vary cost-sharing by service type and patientcondition—with low barriers to themanagement of chronic disease andhigher barriers for elective services.This approach would promote thechoice of more efficient providers,because consumers would reap sav-ings when they choose less-costlyproviders, and less-efficient providerswould have incentives to improvecare. Another tool is the excise tax on“Cadillac plans.”Also part of the demand-side

approach is more research on priceand quality, which in theory is favoredby all but providers but in practicemay be less useful, because its impactwould not be felt for years. The gov-ernment’s role would be centered ondata gathering rather than price set-ting; the latter would fall to insurers tocustomize and simplify.

“A single approach to containing costs is unlikely to be sufficiently successful….We needto pursue many distinct but consistentapproaches to offset risks that some approaches will not succeed.” —Paul Ginsburg, PhD

“Politicians claim there will be large savings throughreducing waste. It’s a terrificidea, but it won’t solve thecost problem.”

—Paul Ginsburg, PhD

Continued on page 5



Finally, many today believe that pro-grams aimed at wellness and preven-tion will help contain costs, but theeffect of prevention has not beenproved, Dr Ginsburg cautions.

Improved Payment Structure

As a supply-side approach, thecrafting of a more accurate paymentstructure is widely proposed, based onthe unintended wide variation in prof-itability by service. Medicare is well-positioned to make structures moreaccurate (and private insurers andMedicaid programs will follow), butMedicare needs to apply more politicaland financial resources to this, whichis problematic, because many hold anegative view of Medicare gover-nance, 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 byhaving incentives for service volumeand lacking motivations or rewards forcoordinated services. BPUs introduce

elements of capitation in the form ofaccountable care organizations. Thestrategy can incorporate episode-based payments in which actual per-episode payments can be made to ajoint entity or by fee-for-service, withincentives for all involved. But Dr Ginsburg questions whether

BPUs will be implemented, andwhether the idea will succeed. “BPUshave opportunities for physicians—rewards for reducing spending onhospital care, pharmaceuticals, anddevices. They can save money byreducing hospitalizations, choice ofdrugs, and so forth and not just by reducing the physician’s own services. They can capture rewardsfrom this.”Although the debate once focused

on “competition versus regulation,”Dr Ginsburg pointed out that thecountry proved unwilling to embraceeither. He concluded that the searchfor a solution is geared toward “prag-matism that recognizes the need tobuild on present institutions.” �

The Costs of Multiple Myeloma Treatment... Continued from page 1

Results showed that bortezomib wasassociated with less out-of-pocket(OOP) cost than the 2 oral medications.Bortezomib is a proteasome inhibitor,and lenalidomide and thalidomide areimmunomodulatory drugs. Thesemedications are sometimes combinedwith other agents into 1 regimen.“Multiple myeloma is a complex dis-

ease. Improved outcomes have beenachieved with these novel agents; how-ever, few studies have reported theeconomic burden on patients,” saidBrett W. Pinsky, MPH, Senior Resear -cher at i3 Innovus, Eden Prairie, MN.

The investigators drew from a claimsdatabase of a large national, commer-cial health plan with 14 million mem-bers. Treatment episodes, defined aseach course of therapy, were identifiedfrom claims records for each patient.Patient OOP costs and patient visitdata were examined for 1 year from thebeginning of each treatment episode.Descriptive analyses were supple-

mented with multivariate regressionanalyses to control for patient charac-teristics, comorbidities, and line oftreatment. A total of 2642 treatmentepisodes were identified for the 1900patients. The majority of episodes wereclassified as “other chemotherapy orradiation therapy” (66.6%), followedby thalidomide (20.8%), bortezomib(9.2%), and lenalidomide (3.4%).Ambulatory visits accounted for

much of the patient visit burden. As expected, patients treated withbortezomib for injection had more visitsthan those treated with oral lenalido-mide, but the difference was not signif-icant after adjusting for patient charac-teristics, line of treatment, and comorbidities by a multivariate analysis.A significant number of outpatient

hospital visits occurred with all theseagents but most frequently withthalidomide. Because patients mustvisit doctors to receive bortezomibinjections more often than for the oralmedications, it is often assumed thatbortezomib injection is a more expen-sive treatment. The data, however, donot support that assumption, MrPinsky said.

Patient Out-of-Pocket Costs

“Direct out-of-pocket costs were sig-nificantly higher for patients treatedwith the oral drugs thalidomide andlenalidomide compared with borte-zomib for injection,” said Mr Pinsky.The total adjusted patient OOP costs

for the year after treatment initiationare shown in the Table. These costs,and the differences between treatmenttype, were even greater for MedicareAdvantage patients (Table). For theMedicare group, treatment with borte-zomib amounted to less than half thecost of oral drug therapy with eitherdrug, he said. The OOP cost discrepancy was mag-

nified in the Medicare population like-ly because of the coverage gap, knownas the doughnut hole in Medicare PartD, noted Henry Henk, PhD, also of i3

Innovus. “For the Medicare Advantagegroup, there is the doughnut holeeffect that is causing a huge spike inthe cost of the oral drugs,” Dr Henkpointed out. The investigators concluded that

because patients with MM require agreat deal of care and resources, themajority of patients will not see a sig-nificant difference in the number ofhealthcare visits, regardless of the typeof treatment, but they may feel thepinch of higher OOP costs with theoral drugs. �

“Direct out-of-pocket costswere significantly higher forpatients treated with the oraldrugs thalidomide andlenalidomide compared withbortezomib for injection.”

—Brett W. Pinsky, MPH

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 $12,568OOP indicates out-of-pocket.

Continued on page 6

Healthcare Reform... Continued from page 4

Health Economics

High-dose chemotherapy fol-lowed by autologous stem-celltransplantation (ASCT) is the

standard of care for subgroups ofpatients with multiple myeloma orlymphoma. Granulocyte colony-stim-ulating factors (G-CSFs) are used toenhance neutrophil engraftment inthese patients. Compared with nogrowth factors, this reduces the num-ber of days with fever, antibiotic use,and duration of hospitalization. Ran -domized trials have shown that fur-ther cost reduction can be obtained bydelaying the start of G-CSF therapyfrom day 1 to days 5 to 7 after trans-plant, without significantly changingthe time to neutrophil recovery.Although the G-CSF agent pegfil-

grastim (Neulasta) costs approximate-ly 25% more up front than filgrastim(Neupogen), the cost is offset by afaster neutrophil engraftment, shortertime on antibiotics, and a tendency toshorter hospitalization time comparedwith filgrastim, according to severalstudies presented at ASH. G-CSFs are regularly used after

ASCT to accelerate neutrophil engraft-ment. Swiss investigators evaluatedthe safety and efficacy of pegfilgras-tim, a long-acting form of filgrastim given as a single, fixed dose, in 40patients with multiple myeloma,Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. “This is a more patient-friendly

approach, and since the drug is given

in a single shot, there is no need todelay the therapy to decrease treat-ment costs,” said Luciano Wannesson,MD, of the Oncology Institute ofSouthern Switzerland, Bellinzona.

Pegfilgrastim 6 mg was given ontransplant day 1. Results were com-pared with a matched historical con-trol group of 40 patients who receivedfilgrastim 5 μg/kg daily starting on anaverage of 7 days after transplant.The median time to achieve a neu-

trophil count >500 μL (ie, neutrophilengraftment) was 9.5 days for the pegfilgrastim group versus 11.3 daysfor the filgrastim control group, whichwas a highly significant difference (P <.001). Median duration of neutropenia

was 5.8 days versus 7.4 days (P = .001),median duration of intravenousantibiotic therapy was 4.2 days versus6.5 days (P = .007), and median hospi-talization duration was 14.0 days ver-sus 14.8 days (P = .018). These differ-ences were most pronounced among

Pegfilgrastim with Transplant: Upfront Cost May Be OffsetBy Caroline Helwick

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

—Luciano Wannesson, MD



Health Economics

In a cost-effectiveness analysis forthe treatment of myelodysplasticsyndrome (MDS), azacitidine (Vi -

daza) was shown to be cost-saving orcost-effective compared with decita -bine (Dacogen). The analysis, fundedby Celgene, was presented by RishaGidwani, DrPH, lead health econo-mist at Abt Bio-Pharma Solutions,Lexington, MA. The National Comprehensive

Cancer Network 2010 guidelines rec-ommend the 2 agents, azacitidine anddecitabine, for the treatment of MDS,with azacitidine being the preferredCategory 1 treatment for intermediate-or high-risk patients ineligible fortransplant.“Although the clinical benefits of

azacitidine have been shown, this isthe first study to evaluate its cost-effec-tiveness relative to decitabine,” DrGidwani said.Investigators developed a decision-

analytic Markov model with 1-monthcycles, which was run alternatively for12- and 36-month periods. Patients inthe model replicated the demograph-ics of subjects enrolled in phase 3 trialsfor the drugs; based on these data, the

patients modeled in the decitabinearm had lower MDS severity thanthose in the azacitidine arm. During each cycle of the model,

patients could remain in or transitionamong 4 health states, including MDSand transfusion independence, MDSand transfusion dependence, progres-sion to acute myeloid leukemia(AML), or death. Therefore, in anygiven model cycle a patient could befound stable, become healthier,become sicker, or die. The analysisused model parameters derived frompublished studies, product labels, clin-ical trial data and drug pricing, andmedical services cost databases. “Despite a higher-risk profile in the

underlying data for azacitidine, treat-ment of MDS with azacitidine waseither cost-saving—meaning that itcost less and conferred greater clinicalbenefit—or was cost-effective com-pared with decitabine,” Dr Gidwanireported. “Azacitidine changed from domi-

nating decitabine in the 12-month sce-nario to being cost-effective in the 36-month scenario due to the survivaladvantage for azacitidine-treated

patients. Patients treated with azaciti-dine live longer, and therefore havemore opportunity to incur treatmentcosts,” she explained.In the 12-month and 36-month

scenarios, azacitidine-treated patientshad a greater number of life-years andquality-adjusted life-years (QALYs),attained a greater number of transfu-sion-independent months, and weremore 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 $11,534more than treatment with decitabinebut conferred a clinical benefit of0.2707 additional QALYs gained. Theincremental cost-effectiveness ratio of $42,615 per QALY is consideredcost-effective, Dr Gidwani noted. Thetotal costs per patient and QALYgained at 12 and 36 months are shownin the Table. �

For MDS Treatment, Azacitidine Enhances Cost-EffectivenessCompared with DecitabineBy Caroline Helwick

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

—Risha Gidwani, DrPH

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 1.175QALYs indicates quality-adjusted life-years.

patients with lymphoma. Median time to platelet engraftment

and median duration of fever weresimilar, and the 2 groups received anequal number of red blood cell andplatelet transfusions.“Starting pegfilgrastim on day 1 and

filgrastim on days 5 to 7 posttransplantmay have contributed to the accelerat-ed engraftment, in line with the resultsof studies comparing early versus latefilgrastim that showed a trend to betteroutcomes with early filgrastim,” DrWannesson said.

Pegfilgrastim Frees Up BedsIn a study from the United King -

dom, investigators assessed theimpact on pegfilgrastim on bed avail-ability. “Busy hematology centers

have severe pressure on bed availabil-ity, which can limit their ability todeliver multiple cycles of intensivechemotherapy on time,” said NeilPhillips, MD, of the Heart of EnglandNHS Trust, Birmingham, UK.

“G-CSF use in ASCT has been shownto hasten neutrophil engraftment andto shorten the number of days of febrile

neutropenia,” Dr Phillips added.This retrospective study explored

the effect of a single injection of pegfil-grastim 6 mg on engraftment andinpatient stay of 55 patients undergo-ing ASCT for the treatment of multiplemyeloma, comparing those whoreceived the drug with those notreceiving it. The use of pegfilgrastimwas associated with shorter durationto neutrophil engraftment (P = .06),less need for antibiotics (P = .04), andreduced hospital stay (P = .004).“This is very useful, considering the

pressure on the bed availability in thetertiary referral centers,” Dr Phillipssaid. “Cost-effectiveness due to re -duced inpatient stay may lead to theuse of this agent post-ASCT as a standard practice.” �

“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

SEE ALSO Advances in Treating MDS, page 16.

Pegfilgrastim with Transplant... Continued from page 5

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


The bortezomib (Velcade)-basedregimen with melphalan (Al -keran) and prednisone (Del -

tasone)—the VMP regimen—is cost-ef-fective despite greater upfront costs. “Our study showed that while

adding bortezomib to melphalan andprednisone increases cost a good bit, itis actually cost-effective in patientswith myeloma,” said Si-Tien Wang,MSc, of the Analysis Group, Boston,MA, a consulting firm specializing in health economics and outcomesresearch. The study’s senior authorwas Louis Garrison, PhD, Professor of Pharmacy at the University ofWashington, Seattle. Phase 3 trials have shown a survival

advantage with the MPT regimen—thalidomide (Thalomid) plus melpha-lan and prednisone—over melphalanand prednisone (MP) alone, and thephase 3 VISTA trial showed the clinicalsuperiority of VMP over MP for front-line treatment in elderly patients whowere not eligible for transplantation.Results of a survival analysis of the

VISTA trial after a median of morethan 3 years were presented at ASH,confirming the benefits of the VMPregimen compared with MP alone.Overall survival rates in patients withhigh-risk cytogenetics were 74.5%with VMP versus 55.5% with MP. The incremental cost-effectiveness

of VMP over MP and MPT as initialtreatment, however, had not beenassessed; that was the aim of this cost-effectiveness analysis. The primary data sources were

patient-level data from VISTA after 26months of follow-up. The source ofdata for VMP versus MPT was thephase 3 IFM 99-06 trial, with a medianfollow-up of 51 months. Cost data wereobtained from published studies/sources. The cost analyses, adjusted to2009 dollars, included per- protocoldrug and medical costs, treatment-related adverse event costs, second-linetreatment costs, and resource utiliza-tion during treatment-free intervalsand progressive disease states.

Health outcomes were expressed inlife-years and quality-adjusted life-years (QALYs). Cost/health outcomeswere discounted at 3%. Incrementalcost-effectiveness ratios were calculat-ed for VMP versus MP, and VMP ver-sus MPT, over a lifetime horizon. A Markov model, with a 20-year

lifetime horizon, was developed froma US payers’ perspective. Patientsentered the model in the stable dis-ease/minimal disease (SD/MD) state.In subsequent monthly cycles, patientsmoved to their best response state orremained in SD/MD until they discon-

tinued treatment, progressed, or died.Patients in the second-line therapystate received a maximum of 6 monthsof treatment. Compared with MP and MPT, VMP

was associated with more time on treatment in complete response, a longertreatment-free interval, and less timein a progressive disease state or death. Overall survival was estimated to be

longest with VMP and MPT versus MP.Lifetime direct medical costs werehighest for MPT, followed by VMP;they were much lower for MP (Table).

“The incremental cost-effectivenessof VMP versus MP, however, wasfound to be within the generally accept-

ed cost-effectiveness range of $50,000 to$100,000 per QALY, suggesting thatVMP is cost-effective compared withMP,” Ms Wang said. “And comparedwith MPT, the VMP regimen was dom-inant in the model, meaning it was cost-saving and had better outcomes, cost-ing 17.7% less and providing slightlymore QALYs on average.”Compared with MPT, the drug cost

of VMP was lower by $13,277, and thecost of managing treatment-relatedadverse events was $10,213 lower. Thisdrove much of the dominance. A

1-way sensitivity analysis of VMP ver-sus MP pointed to the general robust-ness of the findings, with the key driv-er being the VMP versus MP hazardratio for the transition from second-line treatment to death. The results may actually be conser-

vative for the VMP regimen, said MsWang, because the study populationswere not completely comparable. TheIFM 99-06 population was youngerand had less-advanced disease thanthe VISTA population. She acknowledged several limita-

tions of the study—the indirect com-parison of VMP to MPT (no head-to-head trials were available); the use ofjust 1 of 5 phase 3 trials comparingMPT with MP (only 1 provided neces-sary results); and the different baselinecharacteristics of VISTA and IFM 99-06. The researchers concluded that

adding bortezomib to the standard MPregimen improves long-term out-comes with a survival benefit, whileremaining cost-effective. �


Health Economics

Bortezomib Cost-Effective for Newly Diagnosed Patients with Multiple MyelomaBy Caroline Helwick

“While adding bortezomib to melphalan and prednisoneincreases cost a good bit, it is actually cost-effective in patients with myeloma.” —Si-Tien Wang, MSc

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

ICER (vs VMP)Per life-yearPer QALY

$40,051$56,109

VMP dominantVMP dominant

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.

The cost of alemtuzumab(Campath) contributes 39% oftotal healthcare costs once it is

initiated for the treatment of chroniclymphocytic leukemia (CLL). Othercost drivers in this setting includeoncology services and medicalresources for cytopenia, infection, andcardiac dysfunction, said Marie-Hélène Lafeuille, MA, of Grouped’analyse, Ltée, Montreal.Her study used electronic claims

data of Medicare Part A and Part Bservices to quantify the incrementalcosts associated with alemtuzumab, bycalculating costs within 6 months afteralemtuzumab initiation versus 6months before its initiation.

The study assessed costs for 81patients with CLL. After alemtuzumabinitiation, mean total healthcare costsincreased from $4272 to $10,385 per-patient per-month (PPPM) in thenext 6 months, a $6113 increase. Themean cost for alemtuzumab in thepost–alemtuzumab initiation periodwas $4006 PPPM, representing 39% oftotal costs.The cost for oncology-related services

(ie, office visits, hospitalizations, homehealthcare) jumped from $3759 to$9602 PPPM from the prealemtuzum-ab to postalemtuzumab periods, anincrease of $5842.In the prealemtuzumab period, the

cost associated with a diagnosis of cytopenia was $1658 PPPM com-pared with $4441 postalemtuzumab—

a $2456 difference.Costs associated with medical

resources for diagnoses of infectionand cardiac dysfunction increased by$734 and $926, respectively, in the 6months after alemtuzumab initiationcompared with prealemtuzumab. �

After alemtuzumab initiation, mean total healthcare costs increasedfrom $4272 to $10,385 per-patient per-month.

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

SEE ALSO Weekly BortezomibEffective, Less Toxic, page 20.

SEE ALSO Adding Alemtuzumab to Fludarabine Doubles PFS in Relapsed CLL, page 16.

Alemtuzumab Contributes 39% to TreatmentCosts in CLLBy Wayne Kuznar



The addition of rituximab toeither conventional or high-dose chemotherapy for B-cell

lymphoma yielded “unexpectedlyhigh efficacy,” particularly in untreat-ed, young, high-risk patients withaggressive disease, according to inves-tigators from the MegaCHOEP Trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group.

“The 3-year event-free and overallsurvivals are the best ever reported forthis group of patients,” said NorbertSchmitz, MD, of the Asklepios KlinikenSt. Georg, Hamburg, Germany.This was an interim analysis of 216

patients in the phase 3 study thatincluded young (18-60 years old), high-risk patients with aggressive B-cell lymphoma. The study compared8 cycles of CHOEP-14 (cyclophos-phamide [Cytoxan], doxorubicin

[Adriamycin], vincristine [Oncovin],and prednisone [Deltasone] plus etopo-side [Eposin] given every 2 weeks) withhigh-dose MegaCHOEP, which usedhigher doses of the same drug givenevery 21 days, followed by stem-celltransplantation. Half of the patientsalso received rituximab (Rituxan).After a median follow-up of 29

months, the estimated 3-year overallsurvival was 84% with the CHOEPplus rituximab regimen and 75% withMegaCHOEP plus rituximab; prog -ression-free survival rates were 76%and 64%, respectively. These survivalrates were significantly higher than inthe treatment arms that did not receiverituximab; therefore, the arms notincluding rituximab were discontin-ued, Dr Schmitz noted. “Eight cycles of CHOEP-14 plus 6

cycles of rituximab gave excellentresults in young, high-risk patientswith untreated aggressive B-cell lym-phoma. Because of higher toxicity andinferior survival, the MegaCHOEParm was discontinued. High-dosetherapy and transplant has no role toplay as part of first-line therapy forthese patients if rituximab is combinedwith aggressive conventional chemo -therapy,” he said. �

In Challenging B-Cell Lymphoma,Aggressive Chemotherapy plusRituximab Show Best OutcomesBy Caroline Helwick

“The 3-year event-free andoverall survivals are the bestever reported for this group of patients.”

—Norbert Schmitz, MD

potentially practice changing,” con-curred press briefing moderatorRichard Van Etten, MD, of TuftsUniversity. “I would like to see anoverall survival benefit, and the studyneeds longer follow-up, but I don’tthink we need to wait for this.”

Large Randomized Study

Population

The trial by the German StudyGroup on Indolent Lymphoma in -cluded 549 symptomatic patientsenrolled at 82 centers. Patients wererandomized to B/R or CHOP-R.Approxi mately 50% of patients ineach arm had follicular lymphoma;the remainder had other indolent lym-phoma or MCL.B/R caused significantly less hema-

tologic toxicity, although just 4% of thepatients in this arm received growthfactors compared with 20% in theCHOP-R arm. As for side effects, alopecia did not

occur with B/R but was frequent withCHOP-R. Paresthesia, stomatitis, in -fec tious complications, and sepsis were

less frequent with B/R. Skin rashesand allergic reactions, however, weremore common with B/R than withCHOP-R, Dr Rummel reported.Overall response rates were similar

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

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

were translated into better progres-sion-free survival with B/R—54.9months (median) versus 34.8 monthsfor CHOP-R—a significant difference(P = .001).“There was a 20-month gain with

bendamustine. This was clearly a sur-prise. It was not just noninferior, butwas statistically significantly betterthan CHOP-R and better tolerated,”Dr Rummel commented.He added that the dose of

bendamustine used (90 mg/m2) waslower than the dose of 120 mg/m2

currently approved in the UnitedStates for lymphoma. The lower dosedid not compromise efficacy but didimprove tolerability, he said.Dr Rummel said the B/R regimen

would be economical, because it isassociated with fewer complicationsand reduced use of growth factor support. �

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

—Mathias J. Rummel, MD

New Regimen Challenges... Continued from page 1

In older patients with advanced fol-licular lymphoma, a brief course ofchemotherapy followed by main -

tenance therapy with rituximab(Rituxan) led to high response rates,including complete remissions, andwas well-tolerated in an Italian studypresented at ASH.

Umberto Vitolo, MD, of theUniversity of Torino, Italy, noted thatin elderly patients, “the goal is toreduce the chemotherapy that patientssometimes don’t tolerate and in themeantime, to maintain the efficacy ofthe treatment.” He added that, basedon his study’s findings thatchemotherapy is beneficial, it is notappropriate to withhold treatmentsonly because of age.Investigators at 33 Italian centers

enrolled 242 patients aged 61 to 75years with advanced or aggressivenon-Hodgkin’s lymphoma that had notbeen treated. The regimen consisted of4 weekly administrations of chemo -

immunotherapy—with fludarabine(Fludara), mitoxantrone (Novantrone),and dexamethasone (Decadron)—plusrituximab. Patients who achieved acomplete response or partial responsewere randomized to 4 consolidationdoses of rituximab at months 9, 11, 13,and 15, or to observation.

The 4 cycles of chemoimmunothera-py led to complete responses in 55% ofpatients, and partial responses in 37%.After rituximab consolidation therapy,69% of patients achieved complete re -sponses and 18% of patients achievedpartial responses. At the 22-month follow-up, 2-year survival was 92%,and 2-year progression-free survivalwas 75%. The data, however, are not mature

enough to assess the value of main -tenance versus observation over time. The most common toxicity inpatients was neutropenia (65%), but itwas severe in only 25% of thosepatients.—CH �

Treatment Is Beneficial in Older Patients with Advanced Lymphoma

These findings show thatchemotherapy is beneficial in thisolder patient population, andwithholding treatments because ofage is therefore inappropriate.

—Umberto Vitolo, MD

Lymphoma


The addition of rituximab (Rit -uxan) to the standard ABVDregimen (R-ABVD) of doxoru-

bicin (Adriamycin), bleomycin (Blen -oxane), vinblastine (Velban), anddacarbazine (DTIC) for Hodgkin’slymphoma can improve outcomes,according to the final report of a phase 2 study in newly diagnosedpatients with advanced-stage Hodg -kin’s lymphoma.The large, multicenter US study

compared outcomes of patients treatedwith R-ABVD with those of institu-tional historical controls and foundthat R-ABVD yielded a higher 5-yearevent-free survival rate in every cate-gory of the International PrognosticScore (IPS), an indication of diseaseseverity (Table), according to lead

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 R-ABVD was 87% overall, “which is sig-nificantly better than institutional re -

sults with ABVD,” Ms Copeland noted.The findings form the rationale

for a multicenter randomized compar-ison of ABVD with R-ABVD, which is currently enrolling patients withstage II bulky, stage III, or stage IV disease.—CH �


Lymphoma

Hodgkin’s lymphoma is a verycurable malignancy, becausethe majority of patients present

with localized disease. But advancedHodgkin’s lymphoma is associatedwith failure rates of 30% to 40% inresponse to anthracycline-based poly-chemotherapy. Current clinical trialsare focusing on improving this out-come with the use of multiple first-lineagents, said John Kuruvilla, MD, of theUniversity of Toronto, who presentedan update on the treatment ofHodgkin’s lymphoma at ASH 2009.For advanced Hodgkin’s lym-

phoma, the initial gold-standard regimen is ABVD—doxorubicin (Adri -amycin), bleomycin (Blenoxane), vin-blastine (Velban), and dacarbazine(DTIC). Many groups have developedalternate regimens based on dose-intensive or dose-dense chemothera-py, or by using a similar approach thatdose-intensifies certain drugs whileminimizing leukemogenic or gonado-toxic drugs. The results from clinical trials apply-

ing these approaches indicate thatdose-intensifying chemotherapy im -proves disease control, but at the costof acute toxicity and possibly delayingtoxicity. The BEACOPP regimen—bleomycin, etoposide (Eposin), dox-orubicin, cyclophosphamide (End -oxan), procarbazine (Matulane),vincristine (Oncovin), prednisone(Meticorten)—largely used in Europe,

is the only regimen that has shown anoverall survival advantage over theABVD regimen.An alternative strategy to altering

the primary chemotherapy forHodgkin’s lymphoma is to attempt to“consolidate” the response, usinghigh-dose chemotherapy, autologousstem-cell transplantation (ASCT), orradiation, but clinical trial results showno role for consolidation in advancedHodgkin’s lymphoma. One interesting approach being

evaluated is the use of novel, risk-adapted strategies using FDG-PETimaging to identify patients who aredeemed at risk for treatment failureafter 2 cycles of ABVD and who mayneed more intensive treatment, DrKuruvilla said.

Treatment of Relapsed or

Refractory Hodgkin’s Lymphoma

Relapsed or refractory HL is another

common problem associated withtreatment of the disease. Second-line(ie, salvage) chemotherapy followedby ASCT is the standard of care, butthere is a lack of consensus about thetype of salvage chemotherapy to usebefore the transplant. ASCT carriessignificant toxicity and may be limitedin application, because of the patient’sage and medical fitness. Several interesting approaches are

currently being evaluated, includinghigh-dose sequential therapy and tan-dem ASCT approaches. But few largeor prospective series are studyingstrategies that are not based on trans-plantation, Dr Kuruvilla pointed out.

Emerging Trends in Lymphoma

Lawrence Kaplan, MD, Director ofthe Lymphoma Program at theUniversity of California, San Fran -cisco, mentioned the importance ofemerging trends in the treatment oflymphoma, such as bendamustine(Treanda). “In clinical care, the use of

bendamustine as front-line therapy isvery interesting. At ASH, we heardmany presentations on this agent. It’sa very active drug and one that will bewidely used in lymphoma,” he stated.“This is just one of many therapies

we now have for indolent lymphoma,including a number of new biologicsand new immune-based therapies.Among the emerging drugs of interestare new fully humanized monoclonalanti-CD20 antibodies that aim toimprove upon the activity of ritux-imab [Rituxan],” he pointed out. “We are also hearing about some newantibody/toxin conjugates, and somecompletely new approaches, such

as the bidirectional antibody blinatu-momab [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 tosurvive for many years,” Dr Kaplanconcluded. �

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

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

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

IPS group Institutional ABVD, % R-ABVD, %

All patients 66 87

0-1 73 96>1–<2 62 79>2–<3 55 79>3 47 65ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; IPS, International PrognosticScore; R-ABVD, rituximab, doxorubicin, bleomycin, vinblastine, and dacarbazine.

With a median follow-up of 5years, the projected event-freesurvival for R-ABVD was 87%overall, “which is significantlybetter than institutional results with ABVD.”

—Amanda R. Copeland, MS

“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

One interesting approachbeing evaluated is the use of novel, risk-adaptedstrategies using FDG-PETimaging to identify patientswho are deemed at risk for treatment failure after 2cycles of ABVD.



Patients with indolent lymphomathat progresses after treatmentwith rituximab (Rituxan) can

achieve long-term survival afterswitching to tositumomab and iodine(I)-131 tositumomab (Bexxar regimen),based on results from a multicenterphase 2 study of the Eastern Cooper -ative Oncology Group. This treatment is already approved

for certain groups of patients withrelapsed or refractory low-grade, fol-licular or transformed, non-Hodgkin’slymphoma. The regimen pairs the tar-geting ability of a monoclonal anti-body with the therapeutic potential ofradiation. Combined, these agentsform a radiolabeled monoclonal anti-body regimen that binds to the target

antigen CD20 found on B-cells anddelivers the radiation. In this study, median overall sur-

vival was 6.7 years for patients whoreceived the Bexxar regimen afterrelapsing. Response rates to the regi-men were high and durable, saidSandra Horning, MD, of StanfordUniversity, CA. The study included 40 patients

with indolent, follicular large-cell or trans formed B-cell lymphoma thathad progressed while using a medianof 4 previous therapies. Patientsreceived a therapeutic dose of the I-131 tositumo mab based on total-body dosimetry.Responses were seen in 72% of

patients, 38% of which were complete

responses. Median response durationwas nearly 19 months; 40% of patientsresponded for 5 years.

Consistent Responses inTreatment-Naïve PatientsIn another phase 2 study of I-131

tositumomab in 79 untreated patients

with indolent lymphoma, the 10-yearsurvival rate was 83% and the 10-yearprogression-free survival rate was38%. Responses were observed in 97%of patients, and 75% had completeresponses with a median duration ofresponse of 9 years. “Across 10 years, we are seeing a

consistent result and effect on survivalby treating patients with thisapproach,” said Mark Kaminski, MD,Director of the Leukemia/LymphomaProgram at the University ofMichigan, Ann Arbor. “Rarely arethere data to show a treatment canproduce a durable response over adecade, and what is most exciting isthat these results were achieved after asingle treatment.”—CH �

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

“Across 10 years, we areseeing a consistent result and effect on survivalby treating patients with this approach.”

—Mark Kaminski, MD

Treatment with the investiga -tional anthracycline pixantroneachieved significant increases in

complete and overall response ratesand a trend toward improved survival,compared with current agents, inpatients with relapsed or refractorynon Hodg kin’s lymphoma (NHL) inthe phase 3 randomized open-labelEXTEND trial. Pixantrone is an analogue of mitox-

antrone that has reduced cardiotoxici-ty. “An anthracycline with reducedcardiotoxicity that can be used for sal-vage therapy of aggressive NHL meetsa 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 relapsedaggressive NHL. They were random-ized to pixantrone for up to 6 cycles orto a single-agent comparator at thetreating physician’s discretion. In theUnited States, the only comparators

permitted were gemcitabine (Gemzar)and rituximab (Rituxan). The patientswere followed up to 18 months aftertreatment completion.

The Table shows results after at least9 months of follow-up. A trend forimproved survival at 9 months wasshown with pixantrone, at 10.2months, compared with 6.9 months forthe comparators; 1-year survival was 45% for pixantrone and 35% for the comparators, Dr Pettengellreported. �

Novel Agent Shows ImpressiveOutcomes in Aggressive NHLBy Caroline Helwick

“An anthracycline withreduced cardiotoxicity thatcan be used for salvagetherapy of aggressive NHLmeets a significant unmetmedical need.”

—Ruth Pettengell, MD

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.

For the treatment of advanced non-Hodgkin’s lymphoma (NHL),there was no advantage of giving

multiple courses of rituximab (Rit -uxan) compared with just 1 course, ina multicenter German study.“The addition of rituximab to stan-

dard chemotherapy has substantiallyimproved the prognosis of NHL.Over the past few years, a trendtoward intensified protocols withmultiple applications of rituximabhas been observed,” said FabienneMcClanahan, MD, of the Universityof Heidelberg, Germany. “We are ableto report a unique cohort that has alsobeen treated with only 1 or 3 courseswithin a prospective randomizedphase 2 trial, contrasting with the cur-rent standard procedure.”This study may be the first to ran-

domize patients to fewer courses thanare currently applied in standard pro-tocols. Included were 126 patientswith stage III or IV cluster of differen-tiation (CD) 20+ follicular lymphoma.Patients were classified as low risk(22%), intermediate risk (39%), or highrisk (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—cyclo -phosphamide (Cytoxan), hydroxy-daunorubicin (Adriamycin), vincristine(Oncovin), and prednisone (Delta -sone)—chemotherapy. In addition,

60% of the patients also receivedradiotherapy. Patients were followedfor a median of 60 months, after which94% of patients in each arm hadachieved at least a partial response.

There were no significant differencesin remission rates, remission duration,progression-free survival, or overallsurvival according to the number ofcourses the patients received. Relapsesoccurred in 36 patients, with no differ-ence in remission duration among the 3arms. Six-year progression-free sur-vival rates were 45% in arm A, 60% inarm B, and 65% in arm C, and 6-yearoverall survival rates were 72%, 82%,and 80%, respectively.“More-frequent applications did

not differ from less-frequent applica-tions, and a noninferiority of fewerapplications of rituximab could not be detected,” Dr McClanahan said. “The advantage of multiple courses of rituximab, therefore, remains uncertain.”—CH �

How Much Rituximab IsNecessary in Advanced NHL?First Comparison of Fewer Courses of Therapy than Current Standard

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

—Fabienne McClanahan, MD

Lymphoma continued on page 12

Lymphoma


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Mantle-cell lymphoma (MCL) isa unique subtype of B-cellnon-Hodgkin’s lymphoma

characterized by a certain chromoso-mal translocation and nuclear cyclinD1 overexpression. Most patients pre -sent with advanced-stage disease andundergo an aggressive clinical course.Recent improvement has been achievedwith the use of monoclonal antibodiesand dose-intensified ap proaches, in -cluding autologous stem-cell trans-plantation (ASCT) strategies.Allogeneic hematopoietic stem cell

transplantation remains the only cura-tive option for patients with advancedMCL. Recent improvement has beenseen with the introduction of reduced-intensity 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 continu-ous decline, with average survival of 4 to 6 years, although a subset ofpatients (15%) may have a more indo-lent course and long-term survival. Inthese asymptomatic patients, closemonitoring is recommended, withtreatment initiated if symptoms orprogression occur, said MartinDreyling, MD, of Ludwig-MaximiliansUniver sity, Munich, Germany, in anupdate of the disease.Emerging strategies, such as protea-

some inhibitors, immunomodulatingdrugs, and mTOR inhibitors, are basedon the dysregulated control of cellcycle machinery and impaired apop-totic pathways. Monotherapy withthese compounds achieves efficacycomparable with conventional chemo -therapy in relapsed MCL. Combina -tion strategies are being studied,

although their introduction into clini-cal practice remains a challenge, DrDreyling pointed out.

Based on its favorable toxicity pro-file, rituximab (Rituxan) remains avaluable treatment option in combina-tion with standard chemotherapy or with bendamustine (Ribomustin,Treanda), which is better tolerated. Inyounger patients, dose-intensified

schemes in combination with ritux-imab are the standard of care. Variousregimens are being evaluated as con-solidation after transplant to furtherimprove outcomes. Radioimmuno -therapy is also promising.Molecular-targeted approaches that

capitalize on the underlying biologyof MCL are very encouraging. Borte -zomib (Velcade) in combination withconventional chemotherapy hasshown encouraging results in re -lapsed or refractory disease. Thali -domide (Tha lomid) and lena lidomide(Revlimid) have produced highresponse rates. The mTOR inhibitorstemsirolimus and everolimus arebeing evaluated as well, as areflavopiridol, inhibitors of the Bcl-2family, antisense approaches, andapproaches that directly target apo p-tosis (programmed cell death). �

Emerging Strategies for Mantle-Cell LymphomaBy Caroline Helwick

Various regimens are beingevaluated as consolidation after transplant to furtherimprove outcomes. Radioimmuno therapy is also promising.

Leukemia

First Head-to-Head Comparison of Targeted TKIsNilotinib Potential First-Line Option for Chronic-Phase CMLBy Wayne Kuznar

In the first head-to-head comparisonof targeted oral tyrosine kinaseinhibitors (TKIs) as initial treatment

for early-stage chronic myeloidleukemia (CML), molecular and cyto-genetic remissions were more com-mon with nilotinib (Tasigna) than withimatinib (Gleevec), the previous stan-dard for treating early-stage CML, saidlead study investigator GiuseppeSaglio, MD, of the University of Turin,Italy, at ASH.

New Standard of Care?

This finding could elevate nilotinibto first-line treatment for early CML.Nilotinib is currently approved for thetreatment of patients with Philadelphiachromosome-positive (Ph+) CML inthe chronic phase and acceleratedphase in patients who are resistant toprevious therapy, including imatinib.“The superior efficacy and favorable

tolerability profile of nilotinib com-pared with imatinib suggests that nilotinib may become the standard ofcare in newly diagnosed CML,” saidDr Saglio. In the open-label study, 846patients with newly diagnosed Ph+CML in chronic phase were random-ized to receive either 400 mg of ima-tinib once daily, or 300 mg or 400 mg ofnilotinib twice daily. Follow-up lastedabout 5 years.

At 12 months, the rates of majormolecular response (the primary endpoint) were 44% with 300 mg of nilo-tinib twice daily, 43% with 400 mg ofnilotinib twice daily, and 22% with 400mg of imatinib once daily. The mediantime to a major molecular responsewas faster by about 2.5 months in the

nilotinib groups compared with theimatinib group. Dr Saglio noted that molecular mon-

itoring is the most sensitive measure ofCML disease burden. “Major molecu-lar response is associated with anextremely low rate of disease progres-sion,” he said. Of the patients whoexperienced progression of disease inthis study, none achieved a majormolecular response.Complete cytogenetic responses at

12 months were also significantly bet-ter with nilotinib.

Disease ProgressionRates of progression to accelerated

phase or blast crisis were 3.9% in theimatinib group compared with lessthan 0.7% and 0.4% in the patientstreated with 300 mg and 400 mg ofnilotinib, respectively.The difference between nilotinib

and imatinib in progression to acceler-ated phase or blast crisis is the mostmeaningful finding of the study,“because people who go into accelerat-ed phase or blast phase don’t reallyhave the opportunity for second-linetherapy,” according to Bayard L.Powell, MD, Head of Hematology andOncology, Wake Forest University,Winston-Salem, NC.The importance of progression to

accelerated phase or progression toblast phase is not questioned, DrPowell said. “Survival is negatively in -fluenced by progression. It was accom-plished with no additional toxicity.”Nilotinib was superior to imatinib

on efficacy end points across all riskgroups of patients based on their Sokalscore (a risk index based on 6 criteria).

Side EffectsBoth drugs were well tolerated. In

each group, 7% to 11% of patients dis-continued their study drug because ofadverse events or abnormalities in laboratory values, with no significantdifferences between groups. In theimatinib group, 4% of patients discon-tinued because of treatment failure, 4%discontinued because of disease progression, and 2% discontinuedbecause of suboptimal response.Edema and weight gain occurred moreoften with imatinib therapy. Grade 3 or4 toxicities were rare in any group.In commenting on the study, Rick

“The superior efficacy andfavorable tolerability profile ofnilotinib compared withimatinib suggests that nilotinibmay become the standard ofcare in newly diagnosed CML.”

—Giuseppe Saglio, MD

Molecular and cytogeneticremissions were morecommon with nilotinib thanwith imatinib.


Lymphoma



Leukemia

Intermittent dosing of dasatinibmay reduce toxicity, while allowingpatients with chronic myelogenous

leukemia (CML) to continue treat-ment, according to Paul La Rosée, MD,Professor, Division of Hematology/Oncology, Universitätsklinikum Jena,Germany.Dasatinib (Sprycel) is approved for

second-line treatment of CML afterimatinib (Gleevec) failure. Dose reduc-tion beyond the labeled reduced con-tinuous dosing is mandated in selectpatients with chronic-phase CML whoexperience dasatinib-induced toxicity.In a retrospective analysis, treat-

ment response was assessed in 33patients with CML who were intoler-ant/resistant to imatinib and whoreceived a weekly on/off regimen (3-5 days on/2-4 days off) of dasatinib.The median weekly intermittent dosewas 500 mg.Patients were followed by routine

hematologic and cytogenetic assess-

ment and molecular monitoring for amedian of 23 months. Resistantpatients were regularly screened forBCR-ABL mutations. Of those evalu-

able for response, 18 of 31 patients(58%) showed either maintenance ofor an improved response to dasatinibwith the intermittent-dosing schedule.Of the 18 patients, 14 achieved or

maintained a major molecular re -sponse; 5 patients repeatedly testednegative by polymerase chain reac-tion. The other 4 patients achieved acomplete cytogenetic remission.

“Of note, 10 of 12 patients withimproved response have been treatedfor a minimum of 6 months with con-tinuous dosing dasatinib regimens,without having achieved the responselevel observed after allowing drug hol-

iday,” said Dr La Rosée. “This retro-spective analysis in patients resistantor intolerant to imatinib with up to 5preceding treatment modalities sug-gests good, and in many cases evenimproved, efficacy of interval treat-ment compared with continuous dos-ing. These data mandate the initiationof clinical trials to investigate alterna-tive intermittent targeting regimens.”

Increasing Imatinib Dose

May Induce Response in

CML Failures

In another study of patients withchronic-phase CML who had subopti-mal response or failure with 400 mg ofimatinib, dose escalation achieved amajor molecular response, according

to Katia B.B. Pagnano, MD, PhD,Hematology and Hemotherapy Cen -ter, Faculdade de Ciências Médicas-University of Campinas, Brazil.This study evaluated the efficacy of

imatinib dose increase in 120 patientswho were treated with 400 mg of ima-tinib between March 2002 andDecember 2008. Imatinib was escalat-ed to between 600 mg and 800 mg incases of suboptimal response.The dose was escalated in 55

patients because of unsatisfactoryresponse after 36 months of imatinibtreatment. Twenty-eight of the 55patients (51%) were treated with ima-tinib as first-line therapy and 28patients (51%) had previously takeninterferon. Median time between diag-nosis and start of imatinib therapy was5.0 months. After the dose was increased, 31

patients (56%) responded, and 58% ofthe patients with previous suboptimalmolecular response achieved majormolecular response, said Dr Pagnano.“Most of the patients with hemato-

logic failure did not respond to doseescalation,” implying a change to asecond-line agent, such as nilotinib(Tasigna) or dasatinib (Sprycel), wasneeded, Dr Pagnano pointed out.Patients who do not achieve majormolecular response may also be candi-dates for second-line treatment. �

“This retrospective analysis in patients resistant or intolerantto imatinib…suggests good, and in many cases evenimproved, efficacy of interval treatment compared with continuous dosing.” —Paul La Rosée, MD

Intermittent Dosing of Dasatinib May Cut Toxicity, Allow Continued Treatment in CMLBy Wayne Kuznar

Bendamustine-RituximabCombo an Effective First-Line Therapy for CLL

Anew study presented at ASHexamined the use of ben-damustine HCl (Treanda) in

combination with rituximab (Rituxan)as first-line therapy in 117 patientswith newly diagnosed, advancedchronic lymphocytic leukemia (CLL). One third of the patients achieved

complete responses with this combi-nation therapy, and another 56% of thepatients had partial responses, saidlead investigator Kirsten Fischer, MD,Center of Integrated Oncology, Uni -versity of Cologne, Germany. Of the117 patients, 48% had Binet stage Cdisease and 41% had Binet stage B.Bendamustine had already been

shown to have considerable activity asmonotherapy in CLL and other lymphoid cancers, and in combinationwith rituximab in patients withrelapsed/refractory CLL.In this study, rituximab was given

as four 6-week cycles, with 2 doses ofbendamustine with each cycle. Some72% of patients in the study weretreated with all 6 cycles.The median observation time was

15.4 months. Overall response ratewas 90.9%. A complete response wasobserved in 32.7% of patients, and apartial response in 55.5%. All other

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 inremission; the median progression-free survival has not been reached.Objective response rates of approxi-

mately 90% were achieved among thedifferent genetic subgroups, exceptthose with chromosome 17p deletion,a high-risk subgroup whose partialresponse rate was 42.9%.Complete responses occurred most

often in patients with unmutated IGHVgene, about 25%. The overall responserate in this group was 88.9%.Hematologic toxicities were grade

3/4 anemia (4.9%), grade 3/4leukopenia (14.6%), and grade 3/4neutropenia and thrombocytopenia(6.5% and 6.1% of all given courses,respectively). Twenty-nine episodes ofCommon Toxicity Criteria grade >3infections were documented (5.1%).There were 2 treatment-related deathsduring the study.The group is now conducting a

phase 3 trial in which the efficacy of bendamustine-rituximab is beingcompared with fludarabine-basedimmunochemotherapy for the first-line treatment of CLL.—WK �

First Head-to-Head Comparison...Continued from page 12

Van Etten, MD, PhD, Director of theTufts Medical Center Cancer Center inBoston, agreed that the finding “couldbe used to argue for nilotinib as first-line therapy.”

Potent Agents Show Impressive

Complete Cytogenetic Responses

Additional studies of nilotinib anddasatinib, another oral TKI that is several times as potent as imatinib,show favorable efficacy on majormolecular response in patients withnewly diagnosed CML. The sets ofdata were reported by Jorge E. Cortes,MD, Deputy Chair and Professor ofMedicine, Department of Leukemia, atthe University of Texas M.D. AndersonCancer Center. The 2 studies he pre-sented were identical in the nature oftheir design. In the open-label, single-agent trials,

the efficacy of either nilotinib 400 mgtwice daily or dasatinib 100 mg/day(50 mg twice daily or 100 mg oncedaily) were investigated as first-linetherapy in chronic-phase CML.In the nilotinib study, 32 of 51

patients (63%) who were followed forat least 3 months achieved a completemolecular response, and 98% achieveda complete cytogenetic response. In the dasatinib study, major molec-

ular response was achieved in 70% ofthe 50 patients who were followed forat least 3 months, and a complete cyto-genetic response was achieved in 98%of the 50 patients.Dr Cortes noted that the cytogenet-

ic response rates with nilotinib anddasatinib in these studies comparefavorably with that observed in ima-tinib-treated patients. �

Jorge E. Cortes, MD



Patients who take statins at thetime they are diagnosed withchronic lymphocytic leukemia

(CLL) are less likely to have their dis-ease progress to the point of requiringtherapy, said Daphne Friedman, MD,Division of Medical Oncology, Depart -ment of Medicine, Duke University,Durham, NC.Of 355 patients in the Duke

University/Durham Veterans AffairsMedical Center’s CLL database (1999-present), statin use/lack of use at thetime of CLL diagnosis was known in254 patients—65 statin users, 189nonusers. In these patients, CLL therapy was

not required in 132 (52%) patients; 122

(48%) patients received at least 1 treat-ment. Indications for therapy wererecorded in 117 of the 122 patients, andincluded increasing lymphocyte countin 49 patients, anemia in 14 patients,thrombocytopenia in 8 patients, spleno -megaly in 8 patients, and lympha -denopathy in 49 patients.Follow-up ranged from 0.05 years

to 25 years from diagnosis, with ashorter follow-up time in the patientswho were taking a statin at the time ofdiagnosis.Patients taking a statin at the time

of diagnosis were significantly lesslikely to require therapy; this appliedprimarily to women and patientswith low-risk (CD38-negative) CLL.

“Notably, even though patients tak-ing a statin at the time of diagnosiswere less likely to ever require therapy,

statin use was not associated with a sig-nificant improvement in overall ortreatment-free survival,” said DrFriedman.In addition, statin use at time of first

CLL treatment was not significantlyassociated with progression or time toprogression.

There was no significant correlationbetween lipid levels at diagnosis andthe need for CLL treatment. But datafor this lipid analysis were only avail-able for 26 patients. �

Statins Delay Treatment in CLLBy Wayne Kuznar

“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

The use of second- and third-generation tyrosine kinaseinhibitors (TKIs) is a valid and

safe approach to treating relapsedPhiladelphia chromosome-positive(Ph+) acute lymphoblastic leukemia(ALL) in adult and elderly patients,said Cristina Papayannidis, MD,Department of Hematology and Med -ical 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 stan-dard therapies, including multiagentchemotherapy, imatinib [Gleevec], and

allogeneic stem-cell transplantation isstill dismal, due to a high risk ofrelapse,” she said.Dasatinib (Sprycel) and nilotinib

(Tasigna) are second-generation TKIsthat were developed to overcomeresistance to imatinib in patients withPh+ ALL. This retrospective analysis evaluat-

ed the use of second-generation andexperimental third-generation TKIs in29 adult patients (median age at diag-nosis, 49 years) with relapsed Ph+ALL. Of these patients, 14 were in firstrelapse, 11 were in second relapse, and4 were in third relapse.

All the patients were previouslytreated with imatinib; 10 patients hadalso received allogeneic bone marrowtransplantation. Of the 29 patients, 13reached a hematologic response—11patients with dasatinib, 1 patient withnilotinib, and 1 patient with a third-generation experimental TKI. Tenpatients also obtained a cytogeneticresponse and 9 patients obtained amolecular response.With a median follow-up of 10.8

months, the median durations ofhematologic response, cytogeneticresponse, and molecular responsewere each 5.5 months.

The median overall survival was25.8 months, and progression-free sur-vival was 5.5 months.

Although these TKIs proved effec-tive, “relapse is unavoidable due to theemergence of additional ABL muta-tions,” Dr Papayannidis said.In the near future, combination

treatment— including novel agents (ie,aurora kinase inhibitors)— with stan-dard TKIs may reduce the risk ofrelapse and overcome the genomicinstability of Ph+ ALL, she specu -lated.—WK �

Second-Generation TKIs Effective, Safe for Relapsed ALL

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

Leukemia

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Myelodysplastic syndromes(MDS), formerly known aspreleukemia, is a diverse col-

lection of hematologic conditions unit-ed by the ineffective production orabnormality of bone marrow cells andthe risk of transformation to acute lym-phocytic leukemia (AML). Althoughmany patients with MDS have an indo-lent disease, approximately one thirdeventually progress to AML.Significant advances have been

made in the understanding of the dis-ease. For example, several new molec-ular abnormalities have been identi-fied, including loss of functionmutations in TET2. For patients withbone marrow failure syndromes whodo not meet the World HealthOrganization 2008 criteria for MDS,and who also do not meet any otherdisease classification, a category ofidiopathic cytopenias of undeter-

mined significance has been proposed.Currently, 3 drugs are approved by

the Food and Drug Administration forMDS—azacitidine (Vidaza), lenalido-mide (Revlimid), and decitabine(Dacogen). In addition, clinicians areusing multiple hematopoietic growthfactors, immunosuppressants, andcytotoxic agents for MDS. Investigativeagents include thrombopoietin agoniststhat stimulate platelet production,other drugs that target novel pathwaysin MDS, and drugs that show promisefor combination approaches, saidMikkael Sekeres, MD, of the ClevelandClinic Taussig Cancer Institute.Heather Leitch, MD, from the

University of British Columbia,Vancouver, presented data suggestingthat iron overload is a factor in MDS.Since humans lack a physiologicmechanism for excreting excess iron,the accumulation of iron can occur

from repeated red blood cell transfu-sions and can contribute to morbidityand even mortality of patients withMDS. There is the potential, therefore,to derive iron-lowering benefits fromiron chelation therapy, which hashelped in similar conditions, she said,but this requires more study.Important findings on novel treat-

ments for MDS were reported at theASH meeting:• Lenalidomide, currently used inlow-risk MDS patients with certaincytogenetic features, was evaluatedin high-risk patients in a phase 2European study. Used as a singleagent, but in doses higher than areused in low-risk patients, lenalido-mide produced a 30% response rate.

• Alemtuzumab (Campath), an anti-CD52 antibody, produced a very highresponse rate in patients with inter-mediate-risk disease, with transfu-sion independence and normaliza-tion of blood counts and cytogenetic

remissions in a high proportion.• An oral formulation of azacitidinewas active and well tolerated, with amanageable side effect profile, inpatients with MDS.

• An oral formulation of clofarabine(Clolar), a deoxyadenosine nucleo-side analog, produced re sponses in46% of patients with high-risk MDS.

• Compared with the 5-day intra-venous schedule used in high-riskMDS, decitabine given subcuta-neously in a very low dose daily orweekly was safe and active, with sig-nificantly less myelotoxicity in aphase 2 study of patients with lowerrisk disease.

• In trisomy 8 MDS patients refracto-ry to other treatments, experimentaltreatment with the styryl sulfoneON 01910 (which decreases cyclinD1 accumulation in bone marrow)improved blood counts and in somecases led to transfusion independ-ence and long-term remission. �

Advances in Treating MDSBy Caroline Helwick

Adual regimen of alemtuzumab(Campath) and fludarabinephosphate (Fludara) reduces

the risk of disease progression or deathcompared with single-agent fludara-bine as second-line therapy for patientswith chronic lymphocytic leukemia(CLL), according to Andreas Engert,MD, Professor of Internal Medicine,Hematology and Oncology, UniversityHospital of Cologne, Germany. Dr Engert is principal investigator of

a phase 3 study that compared the 2regimens in 335 patients with relapsedor refractory CLL. Progression-free survival (PFS) was

the end point of the study; PFS morethan doubled with the alemtuzumab-fludarabine combination comparedwith fludarabine alone. As a result,Genzyme indicated that it would seeka new indication for alemtuzumab foruse in this combination regimen.Until this study, there was no clear

standard of care for second-line thera-py for CLL, said Dr Engert. To be eligi-ble for the study, patients must nothave had an active infection within the3 months before randomization.Patients were randomized to alem-tuzumab in escalating doses followedby up to 6 cycles of fludarabine, or upto 6 cycles of fludarabine alone. A similar number of patients in each

group completed all 6 cycles of flu-darabine, and the percentage ofpatients who discontinued the studydrugs because of adverse events was

similar—23% with alemtuzumab/flu-darabine and 22% with fludarabinealone. The trial’s data safety monitor-ing panel recommended that the studybe closed early as a result of these data.With a median of 17 months follow-

up at the time of the second interimanalysis, the median PFS was 29.6months with alemtuzumab/fludara-bine compared with 20.7 with fludara-bine alone—a 39% risk reduction ofdisease progression. In the subgroupof patients with advanced CLL, themedian PFS was 26.1 months with thecombination regimen and 12.1 monthswith fludarabine only.

“The alemtuzumab/fludarabin safety profile compared with fludarabinemonotherapy resulted in no differencein the number of deaths and a similarfrequency of grade 3/4 infectious com-plications,” noted Dr Engert.Infection-related adverse events oc -

curred in 47.0% of patients assigned toalemtuzumab/fludarabine and 35.2%in patients assigned to fludarabinealone. �

Adding Alemtuzumab to FludarabineDoubles PFS in Relapsed CLLBy Wayne Kuznar

Antifungal Prophylaxis in AML Patients Receiving Induction Chemotherapy

Invasive fungal infections remain asignificant threat to patients withacute myelogenous leukemia (AML)

and myelodysplastic syndromes (MDS)who undergo induction chemotherapy.New evidence with voriconazole(Vfend) and posaconazole (Noxafil)supports the benefit of antifungal pro-phylaxis in this setting. In a retrospective study of patients

with AML or high-risk MDS, voricona-zole was superior to 7 other regimensas antifungal prophylaxis, reportedGloria Mattiuzzi, MD, AssistantProfessor, Department of Leukemia,University of Texas M.D. AndersonCancer Center.“An ideal antifungal prophylaxis

regimen should be effective, safe, anduncomplicated for the patients….Wehave explored several options, includ-ing different type of drugs and vari-ous delivery schedules,” Dr Mattiuzzisaid.M.D. Anderson’s experience with

antifungal prophylaxis for intensivechemotherapy from 1997 to 2009included 730 patients with AML orhigh-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 low-est among patients treated withvoriconazole, 400 mg intravenously(IV) twice daily followed by either 300mg IV twice daily or 400-mg tabletstwice daily for 1 day, then 200-mgtablets twice daily. Documented inva-sive fungal infections occurred at arate of 4% to 12% with the other regi-mens. The rates of possible or probableinvasive fungal infections were similarbetween the regimens.A significant difference was seen in

side effects among the 8 regimens,with caspofungin and voriconazolethe least toxic. Oral voriconazole wassignificantly less toxic than IVvoriconazole.In a separate analysis, investigators

at the H. Lee Moffitt Cancer Centerand Research Institute in Tampa, FL, looked at 195 patients receivingAML/MDS induction chemotherapywho received primary antifungal pro-phylaxis with voriconazole, 400 mgorally twice daily for 1 day followedby 200 mg orally twice daily, orposaconazole, 200 mg orally 3 timesdaily with meals. The median time onprophylaxis was about 2 weeks ineach group.Proved or probable invasive fungal

infection occurred in 7% of thevoriconazole group and 6.1% of theposaconazole group. The rates of seri-ous adverse events were 6% in thevoriconazole group and 7.5% in theposaconazole group.—WK �

PFS more than doubled withthe alemtuzumab-fludarabinecombination compared withfludarabine alone.

Leukemia

SEE ALSO Alemtuzumab Contributes39% to Treatment Costs in CLL, page 7.



Multiple Myeloma

The duration of treatment formultiple myeloma may belengthening, according to sever-

al studies that showed maintenancetherapy with lenalidomide (Revlimid)or bortezomib (Velcade) improves outcomes.

Maintenance with MPR Followedby Lenalidomide In a 10-month interim analysis of a

phase 3 study that garnered attentionat ASH, investigators reported goodresults with maintenance lenalidomidein newly diagnosed, elderly patients.Upfront induction therapy with

MPR (melphalan [Alkeran], pred-nisone [Deltasone], and lenalidomide)versus MP (melphalan and pred-nisone) alone produced more respons-es and less toxicity; however, the 3-drug combination did not improve therate of relapse. Until the studymatures, this comparison is likely to bea topic of debate, experts noted.The most interest was focused on

the maintenance approach with MPRfollowed by lenalidomide (MPR-R),which outperformed MPR withoutmaintenance. MPR-R reduced the riskof disease progression by 47% com-pared with MPR. Median progression-free survival (PFS) has not beenreached for MPR-R, and was 13.2months with MPR.“The study showed that continuous

lenalidomide was superior to regi-

mens of limited duration,” saidAntonio Palumbo, MD, of theUniversity of Torino, Italy. “MPR-Rcan be considered a new standard ofinitial therapy for patients older than65,” he pointed out.

Of the 469 patients, overall responserates were 77% for MPR-R, 67% forMPR, and 49% for MP; completeresponses were 18%, 13%, and 5%, re spectively. In the first 3 months oftreatment, 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 at17 months, suggesting that continuedimprovement is possible with contin-ued therapy.

4 Drugs plus bortezomib/thalidomide Maintenance Betterthan 3In another phase 3 study of 511 eld-

erly patients, Dr Palumbo reportedthat maintenance therapy after a 4-

drug regimen that included thalido-mide was superior to the same regimen without thalidomide or main-tenance. Patients were randomized tobortezomib, melphalan, and pred-nisone (VMP) without maintenance, orto VMP plus thalidomide (VMPT) fol-lowed by bortezomib and low-dosethalidomide for maintenance.VMPT plus maintenance therapy

was superior to VMP alone, with com-plete responses achieved by 34% and21% of patients, respectively. Theachievement of a complete responsesignificantly delayed relapses in bothregimens, but was most pronounced inthe VMPT arm; 2-year survival wassimilar (89%) for both arms. The study began with twice-weekly

bortezomib, but was amended to aonce-weekly dosage. This resulted in a“dramatic drop” in the incidence ofperipheral neuropathy without affect-ing the outcome, he said.Grade 3 to 4 neuropathy occurred in

just 4% of patients given bortezomibweekly versus 18% of patients givenbortezomib twice-weekly in the VMPTarm, and in 2% and 13% of patients,respectively, in the VMP arm. The 4-drug regimen was associated withsignificantly more grade 3 to 4 neu-tropenia and cardiotoxicity, but othertoxicities were similar for both arms. “VMPT followed by maintenance

with bortezomib and thalidomide wassuperior to VMP for response ratesand progression-free survival,” DrPalumbo concluded.

Bortezomib, then LenalidomidePosttransplantImproved outcomes were also

reported with a sequential approachusing bortezomib for induction andlenalidomide as posttransplant consol-idation maintenance. The investigatorssaid that bortezomib induction beforeautologous stem-cell transplantation(ASCT) has shown efficacy in newlydiagnosed patients, and lenalidomidemight be a less-toxic alternative tothalidomide for follow-up consolida-tion-maintenance. “This is the first phase 2 study of this

approach in newly diagnosed patientsaged 65 to 75 years old,” said FrancescaGay, MD, of the University of Torino.“We found that treatment was correlat-ed with an increase in response rateand in the depth of response, and wasgenerally well tolerated.”This multicenter phase 2 trial

included 102 newly diagnosed pa -tients (age 65-75 years). Inductionincluded 4 cycles of bortezomib, pegylated liposomal doxorubicin(Doxil), and dexamethasone (Deca -

dron), which was followed by ASCT,then consolidation with 4 cycles oflena lidomide plus prednisone, andfinally with lenalidomide for mainte-nance until relapse.VGPR or better was 58% in patients

after induction, which increased to>80% after consolidation and mainte-nance. Relapse-free rates were 88%after 1 year and 69% at 2 years; 93%and 75%, respectively, were still alive.Patients achieving a complete re -sponse had better outcomes. “Consolidation-maintenance was

well tolerated,” Dr Gay noted. “Only4% of patients required growth factorsupport, and no patient requiredplatelet transfusions. Skin toxicity waseasily manageable with dose reduc-tions and supportive therapy.”

Sequential VTD Maintenance ApproachIn another phase 2 study of sequen-

tial therapy, investigators from theCity of Hope Cancer Center, Duarte,CA, evaluated the role of initiatingbortezomib and dexamethasone formaintenance, followed by a secondmaintenance phase with thalidomide(VTD) after ASCT.Several studies have shown im -

proved PFS, and possibly improvedoverall survival, with thalidomide(Thalomid) alone or in combinationwith steroids and chemotherapy asmaintenance-consolidation therapyafter ASCT. This study of 28 patientsevaluated efficacy and toxicity with aprolonged course of sequential VTDmaintenance. After ASCT, patients received week-

ly bortezomib and dexamethasonemonthly for 6 months. A second main-tenance phase included thalidomideand dexamethasone monthly for anadditional 6 months. Single-agentthalidomide was then continued untildisease progression.After 5-month follow-up, only 1

patient had died. Complete responserates were boosted after each sequence,and several patients remained in complete remission after the secondmaintenance phase. Toxicities weremanageable: 10 patients had peripher-al neuropathy at baseline; 3 developedit with bortezomib. �

Maintenance Therapy an Emerging Theme in MyelomaBy Caroline Helwick

“VMPT followed bymaintenance with bortezomiband thalidomide was superiorto VMP for response ratesand progression-freesurvival.”—Antonio Palumbo, MD

“This is the first phase 2 studyof this approach in newlydiagnosed patients aged 65 to75 years old.”

—Francesca Gay, MD

High-Risk Smoldering MyelomaResponds to Treatment

High interest was shown in astudy of the best approach tomanaging patients with “smol-

dering” myeloma who were deemedto be at risk for progressing to sympto-matic disease. This phase 3 clinical trial concluded that lenalidomide(Revlimid) plus dexamethasone (De -cadron) is a promising treatment regimen compared with the usualapproach of surveillance without treat-ment intervention.All 94 patients had elevations in

serum M-component and bone mar-row plasma cells but no end-organ dis-ease. Such patients typically developsymptomatic myeloma in slightly >2years. The patients were randomizedto nine 4-week induction cycles oflenalidomide plus dexamethasone fol-lowed by maintenance therapy withlenalidomide, or no treatment. Results showed a significant benefit

to treating high-risk smolderingpatients, because 81% responded and

14% achieved a “stringent” completeresponse or complete response after 4cycles. After 9 cycles, response rateswere 91% and 21%, respectively. Atfollow-up, patients in the no-treatmentarm had a 19-month mean time to dis-ease progression. In contrast, just 2patients in the lenalidomide plus dex-amethasone arm had progressed,reported Maria-Victoria Mateos, MD,of the University of Salamanca, Spain.

Despite treatment, patients main-tained a good quality of life, with few serious side effects, Dr Mateosadded. The analysis, however, did not yet show an improvement in survival.—CH �

Lenalidomide plusdexamethasone is a promisingtreatment regimen comparedwith the usual approach.

Multiple Myeloma continued on page 20


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Multiple Myeloma

The survival rates of patientswith multiple myeloma (MM)have increased substantially

over the past decade, as a result ofhigh-dose chemotherapy followed byautologous stem-cell transplantation(ASCT) in young patients, and thenew, highly efficient rescue treatmentsin young and elderly patients, saidexperts in a special update on thismalignancy at ASH.The gold standard induction treat-

ment, given before ASCT, is VAD (vincristine [Oncovin], doxorubicin[Adriamycin], and dexamethasone[Decadron]), but novel drug combina-tions are being evaluated for their abili-ty to prolong remission. New strategiesare based on thalidomide (Thalomid),lenalidomide (Revlimid), and borte-zomib (Velcade) in combination withestablished antimyeloma agents. Bortezomib/dexamethasone, with

or without thalidomide, has proved tobe very effective for debulking tumors,and is superior to VAD. Similar effica-cy is expected for bortezomib pluslenalidomide and dexamethasone,said Jesus F. San-Miguel, MD, Uni -

versity Hospital of Salamanca, Spain. Based on the number of studies eval-

uating maintenance strategies, this isan emerging concept that may becomeestablished (see article, page 17). Although thalidomide has been

effective for maintenance therapy, themore favorable toxicity profile of lena -lidomide makes it an ideal maintenanceagent. Other new studies are achiev -ing good results, including higher re -sponse rates, with bortezomib.Current investigations are showing

that bortezomib can overcome theadverse prognosis of patients in thehigh-risk category based on cytogenet-ics or other factors. To a lesser degree,this is seen with lenalidomide as well.

Treatment of Elderly Patients

Patients with MM aged ≥65 yearshave traditionally received an oral reg-imen of MP (melphalan [Alkeran] andprednisone [Deltasone]). The introduc-tion of thalidomide, lenalidomide, andbortezomib has substantially changedthis treatment paradigm, said AntonioPalumbo, MD, and Francesca Gay,MD, of the University of Torino, Italy.

With these novel agents on board forinduction or consolidation after trans-plant, reduced-intensity transplanta-tion is also now an option in some eld-erly patients. The choice of treatment(and level of aggressiveness) is tailoredaccording to the patient’s biologicalage, comorbidities, and the expectedtoxicity profile of the regimen. Whencost is a concern, MP plus thalidomidemay be the best option, they said.

In elderly patients newly diagnosedwith MM who are ineligible for trans-plantation, analysis of the VISTA trialshowed that that the VMP regimen—bortezomib, melphalan, and pred-nisone—was superior to MP alone.The 3-year overall survival rate withVMP was 68.5% compared with 54.0%for MP (see also article, page 7).

Novel Therapies for Relapse

Despite extended periods of remis-sion after treatment with bortezomiband the immunomodulators thalido-mide and lenalidomide, most patientsdevelop drug resistance and eventual-ly relapse. Treatment for relapseshould be individualized to reflectprior drug exposure, prior drug toxici-ties, responsiveness, age, tempo ofrelapse, and genetic risk.The frequent occurrence of relapse

and potential for intolerable adverseeffects from current drugs make the development of newer agents with novel mechanisms of action, im proved efficacy, and better tolera-bility a pressing need, said A. KeithSteward, MD, of the Mayo ClinicArizona, Scottsdale.Bortezomib, the first proteasome

inhibitor to be approved for myeloma,elicits responses in about 50% ofpatients at the time of relapse. Newproteasome inhibitors are being devel-oped that differ somewhat from eachother in chemistry and in specificityfor the proteasome target, such ascarfilzomib, which has shown promisein early trials. New immunomodula-tors are also entering trials, includingpomalidomide (Actimid). The alkylat-ing agent bendamustine (Treanda) isalso being tested in combination withother active agents in MM.A review of the medical literature

reveals more than 180 different drugsin which preclinical results give ration-ale to proceed to clinical testing, withspecial interest in the AKT inhibitors,heat-shock protein inhibitors, and histone deacetylase inhibitors. It isprobable that the therapeutic arsenalfor MM will soon expand to helpimprove patient outcomes, Dr Stewardpredicted.

Questions Remain

Bart Barlogie, MD, PhD, Director ofthe Myeloma Institute for Researchand Therapy, University of Arkansasfor Medical Sciences, Little Rock, saidthat more radical questions need to beanswered about the future of MM, saying that we need “more decisivequestioning, at the end of which wehave crucially important information.” “One such question would be

wheth er to do transplant or not in thelow-risk myeloma patient. Somewould say they don’t need transplant,although personally I disagree. Thedownside is that once the patient hasa recurrence, we may have lost thecure potential. Also, we need to usemore gene arrays in research. If thiswere part and parcel of all evalua-tions of new agents, we could discov-er in 2 to 3 years an approach thatreally works. �

Weekly Bortezomib Effective, Less Toxic

Using bortezomib weekly ratherthan twice weekly appears tohave comparable efficacy but

less toxicity than the more-intensiveregimen, according to presentations at aplenary session. Good results werereported with the less-intensive regi-men in newly diagnosed older patients.“We were trying to optimize the treat-ment of elderly patients, so we tried aless-intensive weekly administrationfor induction, followed by maintenancedoses given every 3 months,” said leadinvestigator Maria-Victoria Mateos,MD, PhD, from University Hospital,Salamanca, Spain.The 260 elderly patients (aged >65

years) were treated in 6 cycles witheither VMP (bortezomib [Velcade],melphalan [Alkeran], and prednisone[Deltasone]) or VTP (bortezomib,thalidomide [Thalomid], and pred-nisone). In the first cycle, patientsreceived bortezomib twice weekly,and once weekly in subsequent cycles.For maintenance, patients receivedbortezomib plus thalidomide or pred-nisone for up to 3 years.Both induction approaches were

very effective, with response rates of about 80%; as maintenance, theyincreased complete responses from23% to 42%.A clear difference, however, was

seen in the toxicity profiles of the

induction regimens: VMP was as -sociated with more grade 3 neutrope-nia infections. VTP was associatedwith more serious cardiovascularevents and more severe peripheralneuropathy.

“We found that melphalan is proba-bly the best partner for bortezomib inelderly untreated myeloma patients,because the efficacy is similar to VTP,but the toxicity profile is different,” DrMateos said.“We asked whether we could

achieve similar efficacy with a lessintensive bortezomib regimen, and theanswer is that clearly we can,” DrMateos said. Perhaps the most impor-tant finding was that the poor progno-sis of high-risk elderly patients couldbe overcome with either regimen.

Comparing Regimens for Induction

Two prominent abstracts comparedTD (thalidomide [Thalomid] and dex-amethasone [Decadron]) with VTD

(TD plus bortezomib [Velcade]) asinduction therapy before autologousstem-cell transplantation (ASCT). Bothwere large randomized trials designedto assess the effect of using bortezomibin newly diagnosed patients.The study from the Italian Myeloma

Network, presented by Michele Cavo,MD, of the University of Bologna,showed significantly improved re -sponse rates with VTD. At all assess-ment points, patients receiving VTDhad better outcomes, and VTD con-ferred improved progression-free sur-vival—76% at 30 months comparedwith 58% in the TD arm.The addition of bortezomib added

little toxicity, except for more grade 3rash (16% vs 2%) and peripheral neu-ropathy (10% vs 2%). Few patients dis-continued VTD and 94% received allthe doses.In a similar phase 3 trial of 299

patients, the Spanish Myeloma Groupreported that VTD resulted in highercomplete response rates before andafter ASCT, as well as lower rates ofprogression compared with TD, partic-ularly in patients with high-risk cyto-genetics or soft-tissue extramedullaryplasmacytomas. Based on these andother findings, VTD appears to beemerging as a new standard foryounger myeloma patients who arecandidates for ASCT.—CH �

“We found that melphalan isprobably the best partner forbortezomib in elderlyuntreated myeloma patients.”

—Maria-Victoria Mateos, MD, PhD

The introduction ofthalidomide, lenalidomide,and bortezomib hassubstantially changed thistreatment paradigm.

Multiple Myeloma Management in 2010By Caroline Helwick



Hematologic Drug Pipeline... Continued from page 1

The overall hematologic response was35% (median duration, 7 months) inaccelerated-phase patients, and 47%(median duration, 2 months) in blast-phase patients.A new cancer vaccine GRNVAC1,

which targets telomerase, an enzymewhose activity is increased in acutemyelogenous leukemia (AML) andother cancers, has produced immuneresponses in more than half of vacci-nated AML patients. Complete clinicalremission has been maintained in 14 of20 vaccine recipients with AML inongoing complete remission or earlyrelapse. The median duration of clini-cal remission, including the patientswho have relapsed, is 12 months. Thevaccine was well tolerated, with theexception of 1 patient who developedimmune thrombocytopenic purpura.Elotuzumab, given with lenalido-

mide and low-dose dexamethasone,showed clinical activity in a study of28 patients with relapsed multiplemyeloma (MM). In the study, 23patients (82%) had an objectiveresponse. In 22 patients who had notpreviously received lenalidomide, 21patients (95%) achieved an objectiveresponse. No dose-limiting toxicitieswere reported up to the highest doselevel of 20 mg/kg, and a maximumtolerated dose was not established.Tositumomab and iodine I-131

tositumomab looked promising in 2phase 2 studies, one in patients withuntreated follicular lymphoma, and theother in patients with non-Hodgkin’slymphoma who no longer responded

to rituximab (see article, page 10).Less far along in the pipeline, but

very promising, are the bifunctional T-cell–engaging BiTE monoclonal anti-bodies, such as blinatumomab. In 50heavily pretreated patients withrelapsed NHL, blinatumomab, givenfor 4 to 8 weeks by continuous intra-venous infusion via port with a

portable pump produced responses inall 12 (100%) evaluable patients. Theduration of responses extended to 20months; response is ongoing in 7patients. Neurologic toxicity was aconcern, but this is being mitigated byslowing the infusion and using step-wise dosing. Voreloxin has a strong efficacy and

safety profile when used as a singleagent or in combination with chemo -therapy in patients with difficult-to-treat AML, according to Jeffrey Lancet,MD, Associate Member and Chief,Leukemia Section, Department ofHematologic Malignancies, H. LeeMoffitt Cancer Center and ResearchInstitute, Tampa, FL. In 64 evaluable patients with first

relapsed or refractory AML, voreloxinin combination with cytarabine was

associated with a preliminary medianoverall survival (OS) of 7.8 monthsand a remission rate of 31%. The medi-an OS in first relapsed or refractoryAML patients receiving currentlyavailable chemotherapies ranges from3.4 months to 5.9 months. In a trial of single-agent voreloxin in

113 previously untreated elderly AML

patients (median age, 74 years), 3 dos-ing schedules were tested: once week-ly for 3 weeks (schedule A); onceweekly for 2 weeks (schedule B); andon days 1 and 4 at either 72 mg/m2 or90 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 sched-ule C (72 mg/m2 on days 1 and 4). Themedian duration of remission was 10.7months, and 1-year survival was 38%for schedule A. For the other sched-ules, median duration of remission hasnot been reached, and 1-year survivalis too early to evaluate.INCB018424, an investigational oral

inhibitor of the Janus-activated kinase(JAK) 1 and 2 enzymes, can reducespleen size and improve quality of lifeand symptoms associated with myelo -

fibrosis, according to Srdan Verstovsek,MD, PhD, Associate Professor, De -partment of Leukemia, University ofTexas M.D. Anderson Cancer Center.Recent evidence indicates that exag-

gerated JAK signaling plays an impor-tant role in the pathogenesis ofmyelofibrosis. Average life expectancyfor patients is 5 to 7 years. In 155patients with the disease, INCB018424treatment resulted in a rapid reductionin spleen volume, which was evidentas early as 1 month into therapy andlasted beyond 6 months of therapy.Some 48% of patients had spleen vol-ume reduction ≥35% after 6 months oftreatment. An improvement was alsoobserved in the 6-minute walk test.Carfilzomib, the second-generation

proteasome inhibitor, is showing note-worthy response rates and low levelsof adverse effects in patients with MM,according to updated data from a 17-center study.Carfilzomib induced a response in

45% of 51 evaluable patients with re -lapsed or resistant MM who received 1 to 3 previous therapies (but notbortezomib, the original proteasomeinhibitor). The response rate is consid-ered noteworthy for a single agent inpatients with tumor progressiondespite previous therapy, said leadinvestigator Michael Wang, MD,Associate Professor, Department ofLymphoma/Myeloma, M.D. Ander -son. He said 37% of the patients expe-rienced neuropathy from previous treatments, which was reduced to 12%with carfilzomib. �

Other Highlights

Investigational Alternatives to Warfarin Prevent VTE EventsBy Wayne Kuznar

More convenient options towarfarin (Coumadin) for theprevention of venous throm-

boembolism (VTE) events are a stepcloser, as suggested by encouragingresults of 2 phase 3 clinical trials pre-sented at ASH.

Dabigatran for VTE ProphylaxisTwo oral fixed-dose anticoagulants—

both inhibitors of factor Xa—showedefficacy in the prevention of VTEevents, with acceptable bleeding rates.In the RE-COVER trial, dabigatran

etexilate (Pradaxa) proved to be aseffective as warfarin in preventingrecurrent VTE in patients with acuteVTE. Current guidelines for the treat-ment of clinically documented VTErecommend a parenteral heparinpreparation for at least 5 days, fol-lowed by oral anticoagulation with avitamin K antagonist, such as warfarin.“In North America, 2 million people

are on warfarin at any time point,”

noted Sam Schulman, MD, lead investi-gator of RE-COVER and Director of theClinical Thromboembolism Program,Hamilton General Hospital, Ontario,Canada. “Patients on warfarin have togo for blood tests, called an internation-al normalized ratio [INR], every 2 to 3weeks, and adjust the dose….Warfarinhas been around for 60 years and hasnot really had any contester.”“There’s probably no more danger-

ous drug on the market than warfarin,”noted Bradford Schwartz, MD, Dean,University of Illinois College of Med -icine, Urbana-Champaign. “Warfarin isa direct competitor to vitamin K, soany thing you do that varies the amountof vitamin K you take in is going toaffect how much warfarin is there tohave an effect.” Many concomitantdrugs can also affect blood levels ofwarfarin. Unlike warfarin, dabigatranis not a vitamin K antagonist.RE-COVER was an international

phase 3 study of 2539 patients with

acute VTE who were randomized to 6months of therapy with oral dabiga-tran, 150 mg twice daily, or warfarin,after initial treatment with a parenter-al anticoagulant approved for thisindication. The warfarin dosage was adjusted

to maintain a 2.0 to 3.0 INR, whichrequired a blood test about every 11days; those randomized to dabigatranreceived a sham blood test as part of the double-blind, double-dummydesign of the study.At 6 months, dabigatran was “non-

inferior” to warfarin on the primaryend 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 withdabigatran than with warfarin (207 vs280 events, respectively); the major

bleeding incidence was similarbetween the 2 groups (1.6% vs 1.9%,respectively).


“Omacetaxine works by a completely different mechanism, inhibiting the synthesis of certain oncoproteins instead of directly attacking BCR-ABL.”

—Jorge E. Cortes, MD

“Patients on warfarin have to go for blood tests…every 2 to 3weeks and adjust the dose.Warfarin has been around for 60years and has not really had anycontester.” —Sam Schulman, MD



Investigational Alternatives... Continued from page 21

Adverse events leading to medica-tion discontinuation occurred in 115patients (9.0%) taking dabigatran and86 patients (6.8%) using warfarin.Death, myocardial infarctions, andabnormalities in liver function testswere infrequent in both groups.

Dabigatran is also being studied forthe primary prevention of VTE inpatients undergoing elective total hipand knee replacement surgeries, forthe prevention of atherothromboticevents in patients with acute coronarysyndrome, and for stroke preventionin atrial fibrillation.

Rivaroxaban for Recurrent VTEIn a second study, rivaroxaban

(Xarelto), the other direct oral factor Xa inhibitor, was compared withplacebo in 1197 patients who had completed 6 to 12 months of anticoag-ulant treatment for acute VTE. Theywere randomized to rivaroxaban, 20mg/day, or placebo for an additional12 months.

Recurrent VTE event rates were1.3% with rivaroxaban and 7.1% withplacebo—an 82% relative risk reduc-tion. After the study medication wasstopped, 6 symptomatic recurrent VTEevents occurred in each group duringa 1-month observational period.

Harry Büller, MD, lead investigatorand Professor of Medicine, AcademicMedical Center in Amsterdam, theNetherlands, said that the ideal dura-tion of VTE-related anticoagulationevent is still unknown. “The classicalway is 3 to 6 months,” he said.

Four patients treated with rivaroxa-ban and none receiving placebo had amajor bleeding episode, none of whichwere fatal or in a critical site. Nonmajorbleeding, such as nose bleeds, skinhematoma, or blood in the urine,occurred in 5.4% of the rivaroxabangroup and 1.2% of the placebo group.

Liver toxicity did not occur withrivaroxaban. Continued study of a previous factor Xa inhibitor, ximelaga-tran (Exanta), was halted after it wasfound to be associated with significantliver toxicity. �

New long-term data were pre-sented at ASH for 2 new drugsfor the treatment of immune

thrombocytopenic purpura (ITP).

Romiplostim

Long-term follow-up of patientswith chronic ITP treated with romi-plostim (Nplate), a peptibody proteinthat increases platelet production,shows maintenance of platelet countswithin the target range (50-200103/µL) in an open-label study.

“This is the longest running ITPextension study for a thrombopoietinmimetic agent by far, with up to 5years of continued romiplostim treat-ment,” said James Bussel, MD,Professor, Platelet Disorders Center,Division of Pediatric Hematology-Oncology, Weill Cornell MedicalCollege, New York City.

As of May 2009, 291 adults had beentreated with romiplostim for a medianof 2 years; 30 patients have been fol-lowed for >4 years. “The plateletcounts in general were very stable,”said Dr Bussel. “The great majority ofpatients maintained their dose, eitherat their most frequent dose or within

2 µg/kg of their most frequent dose.”Many patients receiving concurrent

ITP medications were able to taper thedoses or discontinue those other med-ications. “Rescue medication use wasless than 15% in most of the 12-weekperiods during the study. This wouldmean, on average…a rescue treatmentabout once a year,” Dr Bussel said.

Most common adverse events wereheadache (32%), nasopharyngitis (30%),and confusion and fatigue (each 28%).Twenty-six patients had venous orarterial thrombotic events, with no cor-relation to the platelet count level. Twoof the 13 deaths in the study were pos-sibly treatment-related, from unstableangina or myocardial infarction.

In a European phase 3b study, romi-plostim was compared with medicalstandard of care (SOC). Romiplostimreduced the rate of bleeding-relatedepisodes (BREs) and the need for intra-venous immunoglobulin rescue innonsplenectomized adults with ITP.“The risk of having a BRE was half aslikely in patients receiving romi-plostim than in patients receiving theSOC,” said Roberto Stasi, MD, of StGeorge’s Hospital, London. “Patients

Positive Long-Term Data for 2ITP TreatmentsBy Wayne Kuznar

Stem-Cell Mobilization Strategies: What Works, What Doesn’tBy Caroline Helwick

In mobilizing hematopoietic stemcells (HSCs) before proceeding toautotransplant, especially in chal-

lenging cases, the conventional ap -proach of intensifying cytokine-based(growth factor) strategies was found tobe futile. No advantage was seen fordose-escalated granulocyte colony-stimulating factors (G-CSFs) or thecombination of G-CSFs plus granulo-cyte macrophage colony-stimulatingfactor in mobilizing HSCs.

The strategies were evaluated as ameans of boosting HSC in patientsdeemed hard to mobilize based on priortherapy. “Unlike what is seen with nor-mal donors, there was no benefit to doseescalation of mobilization cytokines orthe use of 2 versus 1 cytokine in heavilypretreated patients,” said ElizabethBerger, BA, of Loyola University, IL.

“Given the cost of these cytokines,

we conclude that standard-dose G-CSF is the optimal method of stem-cell mobilization for hard-to-mobilizepatients,” she said. “Alternative ap -proaches, such as the combination ofplerixafor plus standard-dose G-CSF,might be the preferred method of ini-tial HSC mobilization.”

Plerixafor plus G-CSF

Several studies have shown thatplerixafor (a CXCR4 receptor inhibitorthat prevents the binding of the stemcell 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 myelomaand lymphoma.

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

mobilization of HSC. “The addition of plerixafor to G-CSF

predictably allows significantly morepatients to achieve the target cell col-lection within 1 day of apheresis com-pared with G-CSF alone,” said Brian J.Bolwell, MD, of the Cleveland Clinic.

In a trial of patients with non-Hodgkin’s lymphoma (NHL), 59.3% ofthe patients in the plerixafor group col-lected sufficient CD34+ cells on day 1of apheresis compared with 30.2% inthe placebo group. In a trial of patientswith myeloma, these percentages were85.8% versus 58.5%, respectively. Alldifferences were very significant.

Ivana N. Micallef, MD, of the MayoClinic, Rochester, MN, reported resultsfrom patients in the plerixafor compas-sionate use program who failed/pre-dicted to fail stem-cell collection withany mobilization regimen, stratifiedaccording to the presence or absence ofthrombocytopenia.

“We need to have a drug like this.It’s a very good drug, and it reducesthe number of mobilization failures,”said Dr Micallef. “We have shown that50% of patients needed this drug, andit has reduced our failure rate from22% to about 5%.”

In another study, the cost of usingplerixafor was compared for patientswith NHL or Hodgkin’s lymphoma inthe expanded-access program versusmatched historical controls receivingchemotherapy (cyclophosphamide)plus G-CSF. The median cost of plerix-afor plus G-CSF mobilization was nothigher than that of G-CSF pluschemotherapy for HSC mobilization:$19,644 versus $18,831. �

“It’s a very good drug…and ithas reduced our failure ratefrom 22% to about 5%.”

—Ivana N. Micallef, MD


“There’sprobably no moredangerous drugon the marketthan warfarin.”

Bradford Schwartz, MD

“The addition of plerixafor to G-CSFpredictably allows significantly morepatients to achieve the target cell collection within 1 day of apheresis.”

—Brian J. Bolwell, MD

Other Highlights



(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 single-agent 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)

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RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) 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; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; 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. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Infections Rituxan is not recommended for treatment of patients with severe active infections. The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoen cephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

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 institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by

NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Whole 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendages 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory System 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and Nutritional Disorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

11:27:51 PM

Positive Long-Term Data... Continued from page 22

receiving romiplostim spent more timewith platelet levels ≥50103/µL thanthose receiving the SOC,” said Dr Stasi.

Eltrombopag

Long-term follow-up data werealso presented for ITP therapy witheltrombopag (Promacta), an oralthrombopoietin receptor agonist thatincreases platelet production by in -creasing megakaryocyte proliferation.The study included 299 patients whowere treated with eltrombopag.Eltrombopag was started at 50

mg/day and adjusted to maintainplatelet counts within normal range.The follow-up period extended to 104 weeks.Overall, 86% of the patients a -

chieved a platelet count of ≥50103/µL. Response was similar betweensplenectomized and nonsplenec-tomized patients.

Median platelet counts increased to≥50103/µL by week 2; 30% of thepatients were able to stop concomitantITP therapies. No treatment-relateddeaths occurred. “At this point, we have 2 very

promising drugs,” said Joel AnneChasis, MD, from the LawrenceBerkeley National Laboratory, Berke -ley, CA. “We can say that these drugsare very effective in raising plateletcounts and maintaining these platelet

counts. The questions that still remainare—what about thrombosis, whatabout the development of reticulin in the marrow, and what about the development of hematologicmalignancies.” �

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Across approved NHL indications

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 InformationThe 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

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 GELA trial1‡

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

In the E1496 trial1

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)

In the Marcus trial1

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)

IndicationsRITUXAN® (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

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

DRIVING BETTEROUTCOMES IN NHL

PROVEN OUTCOMES ACROSS MULTIPLE ENDPOINTS1-3

* 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.

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