AHDB February Vol 5 No 1 Special Issue

Hematologists Are Told toGet Ready for ACOsA Medical Home May Be a Viable Alternative By Neil Canavan

©2012 Engage Healthcare Communications, LLC

Hematologic Pipeline AbundantMany Drugs Show Impressive ResultsBy Caroline Helwick

Continued on page 8

Continued on page 5

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

February 2012 I Vol 5, No 1 I SPECIAL ISSUE

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

ASH 2011: PAYERS’ PERSPECTIVESAMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

Continued on page 10

HEALTH ECONOMICS . . . . . . . . . . .3First cost analysis of long-term management of CMLGuidelines for molecular testing canreduce costsThe cost of myeloproliferative disorders is significant

LEUKEMIA . . . . . . . . . . . . . . . . . . .9Could second-generation TKIs cure CML?Ponatinib overcomes T315I mutation in CML/ALL

MULTIPLE MYELOMA . . . . . . . .135-Year VISTA analysis confirms survival benefit with bortezomibPomalidomide a promising new agent

LYMPHOMA . . . . . . . . . . . . . . . .18Obinutuzumab shows promise inrelapsed indolent NHL

OTHER HIGHLIGHTS . . . . . . . . 19VTE prophylaxis during chemotherapycost-effectiveFavorable data for ruxolitinib and a newJAK inhibitor in myelofibrosis

IN THIS ISSUE

The hematology drug pipeline ischock full of novel agents thatare yielding impressive re -

sponses in patients with varioustumor types, often with less toxicitythan seen with standard agents and,in some cases, overcoming adversecytogenetic profiles.

Chronic Myeloid Leukemia

Ponatinib, an oral third-generationtyrosine kinase inhibitor (TKI),appears capable of overcoming theT315I mutation in chronic myeloidleukemia (CML), a mutation thatmakes it extremely difficult to treatthe tumor. In the PACE (PonatinibPh+ ALL and CML Evaluation) trial,major cytogenetic response was 47%after treatment with ponatinib, and

65% among patients with the muta-tion. PACE included 499 patients withCML or with Philadelphia-positive(Ph+) acute lymphoblastic leukemia(ALL) who were resistant to or intol-erant of nilotinib or dasatinib, or whohad the T315I mutation. High levelsof response were seen in all patienttypes, including major histologicresponses in 74% and major cytologicresponses in more than 50% (seearticle, page 12).

In the 12-month data from theBELA (Bosutinib versus Imatinib inNewly Diagnosed Chronic MyeloidLeukemia) trial, which evaluated theTKI bosutinib in 502 treatment-naïveCML patients, the rate of completeresponse (CR) plus major molecularresponse was 67% with bosutinib ver-

Accountable care organizations(ACOs) are the new model ofcare that has generated a buzz

in the industry, but their role in hema-tology and oncology practices remainsunclear. “They’re like unicorns,” saidLawrence A. Solberg, Jr, MD, PhD,of the Mayo Clinic, Jacksonville, FL.“We have an idea of what they’re sup-posed to look like, we’ve read aboutthem, but I’ve yet to meet a hematol-ogist who’s actually seen one.”

The healthcare reform focuses on

the formation of ACOs as key totransforming the current fee-for-ser-vice business model to a model inwhich provider groups will receivebundled payments, based on meas-ures of the quality and value of care.

Dr Solberg moderated a PracticeForum panel at ASH 2011, titled “Howto Prepare Your Practice for ACOs andOther Payment and Health Reforms.”

The Options for Hematologists

“The take-home is this,” said panel

Continued on page 8

A Large Study Sheds Light on the Cost of Managing NHLBy Caroline Helwick

Alarge, ongoing Canadianstudy provides an overviewof the cost of managing non-

Hodgkin lymphoma (NHL). “Ourstudy provides total and stage-specif-ic cost estimates for NHL, whereattributable costs were 3- to 7-foldhigher than those for non-NHL con-trols, and increased by stage,” saidPierre K. Isogai, BSc, of SunnybrookHealth Sciences Centre in Toronto.

Mr Isogai and colleagues identified13,336 patients with NHL in theOntario Cancer Registry (2005-2009)and compared them with 65,668matched controls from the Institutefor Clinical Evaluative Sciences data-base who were demographically sim-ilar and used healthcare resources butdid not have cancer.

Resources for the analysis includ-ed physician visits, hospitalizations,

The cure for chronic myeloidleukemia (CML) is a topic ofintense debate among hematol-

ogists these days, not only the possi-bility of achieving it but what cureactually means.

“What do we mean by ‘cure’?”asked Junia Melo, MD, PhD, ImperialCollege of Medicine, London, speak-ing at a CML education session atASH 2011.

One position is that a cure is theeradication of every leukemic cellfrom the body; a second perspectiveholds that what is needed is an “oper-ational cure,” meaning the disappear-ance of all signs of the disease, so thatthere is no further impact on thepatient’s quality of life.

“The first concept is overly sim-plistic,” said Dr Melo. “Not only is itdifficult to achieve; it’s impossible to

Chronic Myeloid Leukemia: AreWe Close to Finding a Cure?By Neil Canavan

Jaka� is a trademark of Incyte Corporation.© 2011, Incyte Corporation. All rights reserved. RUX-1004C 11/11

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jaka� can cause hematologic adverse

reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions.

Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modi� cation is recommended when administering Jaka� with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jaka� should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

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

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK

MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

3FEBRUARY 2012 www.AHDBonline.comVOL. 5 NO. 1 SPECIAL ISSUE

Health Economics

Few analyses to date have as -sessed the long-term costs asso-ciated with the management of

chronic myeloid leukemia (CML). At

ASH 2011, Shrividya Iyer, PhD, ofPfizer, presented results of a retro-spective analysis performed by agroup of researchers at Pfizer and the

Eliassen Group that looked at infor-mation from the Thomson ReutersMarketScan Commercial Claims andEncounters Database, and theMedicare Supple mental Database.Medical claims for the years 2002-

2009 were used for 2583 patients withCML who had ≥2 claims associatedwith a CML diagnosis.

Costs for the entire CML cohortwere analyzed first, followed by asubanalysis of costs related to patientswith ≥4 years of postdiagnosis follow-up. The average follow-up for theentire cohort of 2583 patients was 2.7years, with 509 (20%) patients having≥4 years of follow-up (mean age, 59years). More than 50% of the patientshad a point-of-service health planwith capitation coverage.

The proportion of patients with ≥1CML-related outpatient, inpatient, oremergency department visit annuallywere:• 94.9% for outpatient visits (55.1

actual outpatient and office visitscombined, per patient-year)

• 32.4% for inpatient visits (1.3 aver-age number of actual visits)

• 15.1% for emergency departmentvisits (1.6 visits). The average number of drug pre-

scriptions for the entire CML cohortwas 6.7 annually, with the tyrosinekinase inhibitor (TKI) imatinib ac -counting for 85% of those claims.

The average annual costs for CML-related healthcare utilization perpatient were: • $24,391 for outpatient care • $24,462 for inpatient care• $15,588 for prescription drugs

(CML drugs accounted for 73% ofoverall prescription costs). Data for patients with ≥4 years of

follow-up indicated an increase inoutpatient visits, but with nearlyequivalent rates for inpatient andemergency department care; forpatients with ≥1 CML-related visit,98% had an outpatient visit, 31% hadinpatient care, and 15% had presentedto the emergency department on anannual basis.

This analysis did not address thepotential cost and utilization impactof the newer TKIs; improved efficacyand reduced side effects may have apositive impact on overall healthcareutilization and costs in the long-termmanagement of CML, but this remainsto be seen. �

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

The average annualhealthcare utilization costsfor a patient with CML were $24,391 for outpatientcare, $24,462 for inpatientcare, and $15,588 forprescription drugs.

First Cost Analysis of Long-Term Management of CMLWill Newer TKIs Change the Economic Landscape?By Neil Canavan

VOL. 5 NO. 1 SPECIAL ISSUE4 AMERICAN HEALTH & DRUG BENEFITS FEBRUARY 2012

EDITORIAL BOARD

PublisherNicholas [email protected] PublisherMaurice [email protected] DirectorDalia [email protected] EditorsBrett KaplanLara J. Lorton732-992-1892Editorial AssistantJennifer [email protected] AssistantZach CeretelleSenior Production ManagerLynn HamiltonQuality Control DirectorBarbara MarinoBusiness ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. Henry

Mission StatementAmerican Health & Drug Benefits is founded on theconcept that health and drug benefits have under-gone a transformation: the econo metric value of adrug is of equal importance to clinical outcomes as itis to serving as the basis for securing coverage in for-mularies and benefit designs. Because benefit designsare greatly affected by clinical, business, and policyconditions, this journal offers a forum for stakehold-er integration and collaboration toward theimprovement of healthcare.This publication further provides benefit design de -cision makers the integrated industry informationthey require to devise formularies and benefit designsthat stand up to today’s special healthcare deliveryand business needs.Contact Information:For subscription information and edi torial queries,please contact: [email protected]: 732-992-1892; F: 732-992-1881American Health & Drug Benefits, ISSN 1942-2962(print); ISSN 1942-2970 (online), is published 6 timesa year by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rights reserved. AmericanHealth & Drug Benefits and The Peer-Reviewed Forum forEvidence in Benefit Design are trademarks of EngageHealthcare Communications, LLC. No part of thispublication may be reproduced or transmitted in anyform or by any means now or hereafter known, elec-tronic or mechanical, including photocopy, recording,or any informational storage and retrieval system,without written permission from the Publisher. Printedin the United States of America. The ideas and opinions expressed in American Health& Drug Benefits do not necessarily reflect those ofthe Editorial Board, the Editors, or the Publisher.Publication of an advertisement or other productmentioned in American Health & Drug Benefitsshould not be construed as an endorsement of theproduct or the manufacturer’s claims. Readers areencouraged to contact the manufacturers about anyfeatures or limitations of products mentioned.Neither the Editors nor the Publisher assume anyresponsibility for any injury and/or damage to per-sons or property arising out of or related to any use ofthe material mentioned in this publication.For permission to reuse material from American Health& Drug Benefits (ISSN 1942-2962), please access www.copyright.com <http://www.copyright.com/> or con-tact the Copyright Clearance Center, Inc. (CCC), 222Rosewood Drive, Danvers, MA 01923, 978-750-8400.POSTMASTER: CORRESPONDENCE REGARDINGSUBSCRIPTIONS OR CHANGE OF ADDRESSshould be directed to CIRCULATION DIRECTOR,American Health & Drug Benefits, 241 Forsgate Drive, Suite205A, Monroe Township, NJ 08831. Fax: 732-992-1881.YEARLY SUBSCRIPTION RATES: One year: $99.00USD; Two years: $149.00 USD; Three years: $199.00 USD.

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

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSenior Counselor, Fleishman-HillardWashington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

AGING AND WELLNESSEric G. Tangalos, MD, FACP,AGSFProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer CenterNorthwestern UniversityImmediate Past President, ACCCPast Chair, NCCN Board of Directors

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

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, PhDPrincipal, Institute of IntegratedHealthcare, Sharon, MA

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

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDVice President, Research OperationsCenter for Health ResearchGeisinger Health System, Danville, PA

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

Victor J. Strecher, PhD, MPHProfessor and Director, Center forHealth Communications ResearchUniversity of Michigan Schools ofPublic Health and Medicine, AnnArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, OutcomesResearch Center, University of UtahCollege of Pharmacy, Salt Lake City

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

HEALTH & VALUE PROMOTION Albert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Milwaukee

MANAGED CARE & GOVERNMENT AFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas PacificGroup, FL

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA

Charles E. Collins, Jr, MS, MBAVice President, Managed MarketsStrategyFusion Medical Communications

PATIENT ADVOCACY William E. Fassett, BSPharm,MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, WashingtonState University, Spokane, WA

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

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor ofPharmacoeconomics& Pharmacoepidemiology, Collegeof Pharmacy, University ofCincinnati Medical Center, OH

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

William J. Cardarelli, PharmDDirector of Pharmacy, Atrius HealthHarvard Vanguard Medical Associates

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

Michael S. Jacobs, RPhNational Clinical Practice LeaderBuck Consultants, Atlanta

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Paul Anthony Polansky, BSPharm,MBASenior Field Scientist, HealthOutcomes and PharmacoEconomics(HOPE), Endo Pharmaceuticals,Chadds Ford, 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 of Pharmacy University of Missouri, Kansas City

Walid F. Gellad, MD, MPHAssistant Professor of Medicine,University of Pittsburgh, StaffPhysician, Pittsburgh VA MedicalCenter, Associate Scientist, RAND Health

Alex Hathaway, MD, MPH,FACPMPresident & Founder, J.D. BioEdgeHealth quality & biomedical research

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

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer andScientific OfficerWorldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics,Harvard-MIT Division of HealthSciences and TechnologyCambridge, MA

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

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

In This Issue

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™ ASH 2011: PAYERS’ PERSPECTIVES

HEALTH ECONOMICSFirst cost analysis of long-term CML managementGuidelines for molecular testing can reduce costsThe cost of myeloproliferative disorders is significantMore…..

LEUKEMIABosutinib shows superior results in CMLNovel oral B-cell receptor inhibitor effective in CLLPonatinib overcomes T315I mutation inCML/ALLMore…..

MULTIPLE MYELOMAPomalidomide a promising new immunomodulatorMaintenance strategies in elderly patientsNext-generation proteasome inhibitors cause lessperipheral neuropathyMore…..

LYMPHOMAMaintenance rituximab may be unnecessary in follicular lymphoma Obinutuzumab shows promise in relapsed indolent NHL

OTHER HIGHLIGHTSVTE prophylaxis during chemotherapy cost-effectiveFirst comparison of catheter-directed thrombosisversus standard careFavorable data for ruxolitinib and a new JAKinhibitor in myelofibrosisMore…..

WEB EXCLUSIVE Additional ASH 2011 coverage atwww.AHDBonline.com

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS


member Neil M. Barth, MD, FACP,Newport Pacific Medical Associates,Newport Beach, CA. “Going forward,to satisfy the needs or the reform leg-islation, efficiencies must be achieved,delivery systems must be integrated,overall utilization must be reduced,and new payment models must beemployed.”

The goal of the patient-centeredmodel of care is to improve outcomesat a lower cost. To achieve this, DrBarth sees several options.

Remaining an independent subspe-cialty provider. The first option is todo nothing: “If you choose to main-tain the status quo, be locked into asmall practice size, and be fiercelyindependent, you’re probably goingto be eaten alive,” warns Dr Barth.

At least based on his experience inCalifornia, the writing is on the wall,Dr Barth said. Not only is there a gen-eral decrease in reimbursement, butthere is also “narrow network pres-sure,” whereby providers who havehigh costs are being dropped by pay-ers and are losing their preferredprovider status.

“It started out quietly, but this prac-tice is no longer subtle,” said Dr Barth.The message is clear: when it comesto cost cutting, an individual cannotcompete with a group.

Becoming a subspecialty line con-sultant. The second option is becom-ing a consultancy. “This is the extrememakeover for the practicing hematolo-gist,” Dr Barth noted. Under thisoption, the hematologist identifiesstrengths and services to be offered tothe local healthcare system.

“This will require capitalization onservice line knowledge. You have tostudy and to dissect the service lineyou would manage,” Dr Barth advised.Some skills may have to be brought into round out a consultancy package,

such as actuaries or an MBA degree.The third option is clinically inte-

grated groups, including ACOs. “Thisis a legal structure of individuals oreven a corporation of corporations;but however it’s configured, the glueholding it all together is IT [informa-tion technology].”

“Integration” means the ability toshare medical records, allocate re -source utilization, and perform costaccounting. “One of the attractivethings about this is, most of my col-leagues are fiercely independent,”said Dr Barth. “Doing it this way youdo not have to give up financial sov-ereignty, because you’re not under acommon tax ID number.”

This model is outside the ACOstructure as proposed, but accordingto Dr Barth, with the blessing of theFederal Trade Commission, it can bedone, and such an entity may engagein collective bargaining.

Joining/creating a clinically inte-grated ACO. ACOs are integratedgroups under a financial umbrella, yetcannot be well defined. “If you’veseen one, you’ve seen one,” Dr Barthsaid, “and most of us have not seenany. Frankly, we’re not sure how thisis going to play out.”

Healthcare reform legislation is stillin flux, and ACOs, initially designedwith the primary care provider in mind,

remain to be tailored for the hematolo-gist. The final rules for ACOs wereissued in October 2011, and certainchanges have been made, including:• The Centers for Medicare & Med -

icaid Services will annually updateACO patient risk scores

• “Meaningful use” for electronic healthre cords is no longer a prerequisite

• Start-up funding will be availablefor physician-group–only ACOs

• There is no longer a downside riskin track 1

• The number of quality measureshas been reduced from 63 to 33.Joining a medical foundation. The

fourth option for hematologists isjoining medical foundations, whichare already well integrated and repre-sent the path of least risk and resis -tance, if available.

In addition, Dr Barth stressed theneed for integrated IT in any type ofpractice. “It’s the essential part that

helps any of these structures come tofruition.” Systems are going to needstandardization to store and thenshare medical records. Evidence-basedguide lines must be part of the integra-tion. Algorithms are needed to trackperformance metrics, and the resultswill have to be delivered in real time sothat providers can compare the resultsagainst the agreed-on benchmarks.

The Medical Home Gets Results

The definition of a patient-centeredmedical home (PCMH) varies, but ingeneral the medical home model pro-motes a team-based approach topatient care through a spectrum of dis-ease states and across various stages oflife. Care is led by the patient’s person-

al physician, with the patient servingas the focal point of all medical activity.

“Applying this model to oncology iswhat we have been working on forthe last several years,” said John D.Sprandio, MD, Chief of Medical Oncol -ogy and Hematology at DelawareCounty Memorial Hospital, DrexelHill, PA. “Ours was the first in thecountry to be recognized as a level IIIpatient-centered medical home by theNational Committee for Quality As -surance in 2010.”

Dr Sprandio’s PCMH is responsiblefor coordinating all oncology services.A primary care provider addressesnononcologic issues, but everyone—surgeons, radiation oncologists, andeven hospice staff—is in “intense”communication as part of the overallcare unit.

Dr Sprandio described the goals foreach aspect of the PCMH: • A team approach that fosters collab-

oration within the team to assureadherence to treatment guidelines,proactive management of adverseevents, palliative care coordination,participation in clinical trials, andactive engagement with the patientto develop patient-directed thera-peutic goals

• The merger of operational and clin-ical decisions, which include stan-dardization of patient assessments,patient tracking, telephone triage ofpatients, and patient IT portals (forappointments, etc)

• Quality standards, including treat-ing according to guidelines, pro -active symptom management, co -ordinated end-of-life care (shareddecision-making), and the creationof high-risk registries

• Outcomes can be derived from toolssuch as the Consumer Assessment ofHealthcare Providers and Systems(CAHPS). “We use the CAHPS sur-veys,” Dr Sprandio said. “It’s a won-derful tool for looking at the actualdelivery of care.”Dr Sprandio shared his experience

with the integrated PCMH from 2004to 2010. “The effects have been sub-stantial in terms of emergency roomutilization per patient per year, as wellas hospital admissions.” There were2.6 emergency department visits perpatient in 2004, and only 1 visit perpatient in 2010; hospital admissionsdecreased from 1 per patient in 2004 to6 per patient in 2010.

There was a 23% increase in hospicestays, with 70% of patients in 2010dying in their own homes. In addi-tion, they had a 40% reduction in thenumber of admissions in the last 30days of life and 23% fewer evaluationsin the emergency department.

The cost-savings generated by thesereductions in utilization were substan-tial. Dr Sprandio estimates savings of$8.8 million in hospital admissions,$660,000 in emergency departmentvisits, and $12,000 in chemotherapy-related costs per patient. “Calculatedper provider, our hematologists aresaving about $1 million a year,” he said.

He advised hematologists to:• Define your clinical and financial

goals• Secure a buy-in from providers

(make it clear to them how yourintegration will be done)

• Engage payers• Standardize all processes of care• Overall, commit to continuous pro -

cess improvement.The panelists conceded that ques-

tions regarding the ideal modelremain and uncertainty regardingACOs abounds, especially with regardto hematology/oncology practices. �

Hematologists Are Told to Get Ready... Continued from page 1

“We have an idea of what[ACOs] are supposed to looklike, we’ve read about them,but I’ve yet to meet ahematologist who’s actuallyseen one.”—Lawrence A. Solberg, Jr, MD, PhD

Dr Sprandioestimatessavings of$8.8 millionin hospitaladmissions,

$660,000 in emergencydepartment visits, and$12,000 in chemotherapy-related costs per patient.

“If you choose to maintain the status quo, belocked into a small practice size, and befiercely independent, you’re probably going tobe eaten alive.” —Neil M. Barth, MD, FACP

Health Economics


Health Economics

Anew cost analysis of themanagement of the 3 sub-types of myeloproliferative

neoplasms (MPNs)—myelofibrosis,polycythemia vera, and essentialthrombocythemia—shows that asso-ciated medical and pharmaceuticalexpenses for patients with thesehematologic disorders in patientswith cancer are 2 to 6 times that ofmatched patients without cancer.Outpatient visits for MPN accountedfor more than 50% of the total costsincurred by patients with cancer.

“Some symptomatic treatmentoptions exist, but with the exceptionof hematopoietic stem-cell trans-plant, none are curative. And little isknown about healthcare costs associ-ated with these diseases,” accordingto Gregory L. Price, MPH, who pre-sented the data at ASH 2011.

The median survival in these MPNsubtypes ranges from months toyears for myelofibrosis, and as long

as a decade or more for patients withpolycythemia vera and essentialthrombocythemia.

To perform this cost analysis, datafor the years 2005-2008 were extractedfrom the Thomson Reuters MarketScandatabase, which includes claims datafrom more than 100 US payers.Patients eligible for analysis had tohave an MPN diagnosis code for thestudy period.

Data on matched patients with nocancer (ie, the control group) wereselected based on sex, year of birth,geographic region, and insurance type.

Calculated costs were based ontotal gross payments to the provider.

Total costs were defined as the sumof MPN- and non–MPN-related med-ical costs, including inpatient, outpatient, and emergency departmentservices and pharmacy. Costs relatedto pharmacy included chemotherapy(injectable and otherwise) and otherprescription supportive care.

A total of 25,145 patients withMPN were included in the analysis.As expected, all MPN-related costsfor the parameters selected exceededthose of noncancer controls. Resultsfor outpatient care cost, pharmaceuti-cal cost, and total cost are highlightedin the Table.

In November 2011, ruxolitinib(Jakafi), a Janus kinase (JAK) inhibitor,

was the first drug to be approved bythe US Food and Drug Administrationfor myelofibrosis and related diseases.New JAK inhibitors are currently indevelopment.

LY2784544, a JAK2 inhibitor, is cur-rently in phase 1 clinical trials. Pre -liminary data for the current 19patients enrolled have been presentedat the meeting. �

Table Mean Costs for MPNs: Patients with Cancer versus Controls

Costs

Patientswith cancer and MF

Controlgroup with MF

Patientswith cancer and PV

Controlgroup with PV

Patientswith cancer and ET

Controlgroup with ET

Outpatient $18,395 $3053 $5688 $2541 $8598 $2714

Pharmaceutical $7803 $1881 $2540 $1474 $2855 $1426

Total $34,690 $6899 $11,927 $5510 $19,672 $5683

ET indicates essential thrombocythemia; MF, myelofibrosis; MPNs, myeloproliferative neoplasms; PV, polycythemia vera.

Instituting guidelines-based testordering could lead to moreeffective, accurate, and complete

diagnosis and monitoring of hemato -lymphoid malignancies, while reduc-ing costs, according to hematopatholo-gists at Vanderbilt University MedicalCenter, Nashville, who said that testswere frequently overordered by theirhematologists.

Molecular and cytogenetic testing iscritical in the diagnosis and manage-ment of hematologic malignancies,but these can be complex and expen-sive. No comprehensive guidelinesexist for the disease- and patient-spe-cific selection of these tests.

The Hematopathology DiagnosticManagement Team explored thehypothesis that there is significantvariability in test-ordering patterns,including overordering of unneces-sary tests and underordering of neces-sary tests. They established evidence-based standard operating proceduresfor molecular and cytogenetic testordering, which pathologists wouldapply after a review of the patient’sclinical history and bone marrowmorphology. These standards werethen compared with current practicesat Vanderbilt.

“We found that if we followed the

guidelines in all cases, and eliminatedexcess testing, we would save ourpayers $1.25 million a year,” saidAdam C. Seegmiller, MD, PhD, ahematopathologist who led this study.

“Before we instituted this, we foundthat clinicians had a tendency tooverorder tests when doing molecularcytogenetic testing before the bonemarrow biopsy was done,” DrSeegmiller said. “We created a stan-dard operating procedure based oncurrent guidelines, best evidence, andbest clinical practice. We decidedwhat tests should be ordered for 6 cat-egories of disease and their stages. It’sa very simple chart.”

They evaluated 3007 ordered tests

on 804 bone marrow biopsy speci-mens; this included 769 karyotypes,1790 fluorescence in situ hybridiza-tion assays, and 448 molecular tests.Comparing how clinicians ordered

(or did not order) tests with thisnew standard operating procedureshowed that:• Only 1927 tests (64%) were concor-

dant with the new guidelines• 1080 tests (36%) were discordant• 307 tests were omitted that would

have been recommended by thenew guidelines. “Over one third were tests that the

guidelines would not have recom-mended [ie, overordered], while 307tests should have been ordered but

were not,” Dr Seegmiller noted. By stage and clinical scenario, for

example, there was 99% concordancebetween clinicians’ ordering andguidelines for the diagnosis of myelo-ma, but 0% concordance for testingduring follow-up, and 0% posttrans-plant. For lymphoma, concordancewas 81% for diagnosis, 41% for stag-ing, 13% for follow-up, 70% pretrans-plant, and 32% posttransplant.

“Among discordant tests, only 4%came back positive [ie, detected amutation], but more than one third ofthese were redundant. They were pos-itive, but we would have caught thesecases elsewhere,” he said. Only 1% ofcases were true positives that wouldhave been missed.

“We think we are not only eliminat-ing unnecessary tests, but also increas-ing the effectiveness of the tests we areusing,” Dr Seegmiller added.

“We have now given hematologiststhe option to turn over all the testingdecisions to the hematopathologists,and about 80% of the time our clini-cians do that,” he said. Using this newstandard, “the hematopathologistmakes a decision for testing based onthe patient’s clinical history, theappearance of the bone marrow mor-phology, and the guidelines.” �

Guidelines for Molecular/Cytogenetic Tests CouldEliminate Overordering, Reduce CostsVanderbilt Hematologists Institute New Standards, Improve OutcomesBy Caroline Helwick

“We found that if wefollowed the guidelinesin all cases, andeliminated excesstesting, we would saveour payers $1.25 milliona year.”—Adam C. Seegmiller, MD, PhD

Cost of Treating Myeloproliferative Neoplasms Is SignificantBy Neil Canavan


Health Economics

Patients with early-stage non-bulky classic Hodgkin lym-phoma (HL) receive intensive

radiologic surveillance after treat-ment, despite a low risk for relapse. Astudy from Memorial Sloan-KetteringCancer Center (MSKCC) concludedthat routine imaging is unnecessary.

The study evaluated the risk forrelapse and value of imaging in asubset of patients who achieved com-plete remission (by positron-emis-sion tomography [PET]) after 6 cyclesof standard chemotherapy withABVD (doxorubicin, bleomycin, vin-blastine, and dacarbazine).

“We asked whether achieving aPET-negative complete remissionwould obviate the need for radiologicsurveillance,” said Sidonie Hartridge-Lambert, MBBS. “We found thatomitting radiologic surveillancewould reduce healthcare costs andalso radiation exposure, which isimportant in guarding against secondmalignancies.”

Dr Hartridge-Lambert said thatinterim and end-of-therapy PETscanning can provide prognosticinformation in predicting relapse inHL, but practice and surveillance pat-terns vary considerably. The pretest

probability for relapse in patients withnonbulky classic HL is low, and theincidence of relapse in early-stage

patients after a negative posttreat-ment PET is extremely low.

“Research suggests that mostrelapses are identified without imag-ing,” she said, “and relapse patternssuggest that imaging may be of limit-ed benefit 2 years after therapy.”

The study included 47 patients whowere treated at MSKCC with initialstaging by PET and interim and/orposttreatment PET, plus adequate fol-low-up. All patients achieved com-plete remission. Interim restagingincluded 39 PET and 8 computedtomography (CT) scans, identifying 1positive result. Posttreatment restag-ing involved 33 PET and 14 CT scans,with 1 positive.

The 2 patients with positive PETscans were biopsy-proven sarcoid.Two patients relapsed at 7 and 24months: the first relapse was identi-fied by surveillance scan, the secondoccurred simultaneously with theresumption of disease symptoms.The 2 relapsed patients are currentlyin complete remission after stem-celltransplant.

The other 45 patients had a du -rable complete remission, of whom21 had additional unscheduled imag-ing or work-up during surveillance

for various reasons; 5 patients hadfurther PET scans to confirm com-plete remission.

Financial Implications of

Surveillance

The costs per scan for each patientduring the posttreatment surveillancewere based on standard, nationalMedicare reimbursements of $770 perCT and $1181 per PET.

Multiplied by the number of scansper patient, and excluding relapses,the cost of follow-up was $181,720 forCT (median, $3850), rising 16% to$210,064 including PET (median,$4620).

Extrapolating to the US populationof patients with early-stage classic HL,the national cost over the 5 years of thestudy reaches $13 million, she said.

“Our results, in conjunction withthe growing concerns about radiationdose from medical imaging studies,suggest that surveillance imaging inthis subset of patients treated with 6cycles of ABVD alone could be ceasedaltogether,” she said.

Instead, patients should be closelymonitored with history, physicalexamination, and routine bloodwork. �

Radiologic Surveillance for Early-Stage Hodgkin Lymphomaan Unnecessary Expense?Most Relapses Identified without ImagingBy Caroline Helwick

“We found that omittingradiologic surveillance wouldreduce healthcare costs andalso radiation exposure,which is important inguarding against secondmalignancies.”—Sidonie Hartridge-Lambert, MBBS

Graft-versus-host disease (GVHD)remains a common complica-tion of hematopoietic stem-cell

transplant, but little is known aboutthe rate of hospital admissions and theassociated costs. Fiona L. Dignan,MD, of the Royal Marsden Hospital,United Kingdom, presented a studycomparing readmission rates andassociated costs between patientswith GVHD and controls.

The analysis included all patientsundergoing allogeneic stem-cell trans-plant (two thirds for leukemia) at thehospital between 2006 and 2009, andfollowed for a median of 3.2 years.

Costs were based on hospitalizationcharges in 2010 currency. Additionaldrug or procedural costs were notincluded.

Of 187 patients receiving trans-plant, 118 (63%) developed GVHD,

49% of which was grade 4. The onlysignificant difference between pa -tients with and without GVHD wasthe increased use of alemtuzumab inthe non-GVHD group, 71% versus54%. Of the 118 patients, 38% hadbiopsy-proven GVHD, 88% requiredsteroid treatment, and 52% weresteroid-refractory.

Acute GVHD was present in 44% ofpatients, chronic GVHD in 19%, andacute and chronic GVHD in 30%.Seven percent developed GVHD afterdonor lymphocyte infusion.

Costs and Services Increased

2-fold or More in GVHD Patients

Patients developing GVHD had asignificantly higher overall hospitalreadmission rate after transplant,89% versus 68% for controls, and ahigher mean cost of readmission,

€32,217 compared with €15,622, DrDignan reported.

They also had a significantly highermean total number of readmissiondays, 42 versus 18, and a higheradmission rate to the critical care unit,34% versus 12%.

For patients with grade 3/4 GVHD,

compared with grade 1/2, differenceswere also apparent. More severepatients had a higher mean total num-ber of readmission days, 57 versus 37(P = .054), and a numerically higherreadmission rate, 96% versus 88%.The mean cost of admission for thisgroup was almost double, €44,535 ver-sus €27,001.

“This study shows the high read-mission rates and costs associatedwith the development of GVHD, andhighlights the need for new treatmentapproaches for this condition,” DrDignan concluded.

Severe GVHD greatly compro-mised survival. At 3 years posttrans-plant, approximately 40% of patientsdid not develop GVHD, but that pro-portion dropped to <20% for patientswith grade 3/4. Grade 1/2 disease didnot diminish survival odds.—CH �

Graft-versus-Host Disease Often Leads to PosttransplantReadmission, High Costs

“This study shows the highreadmission rates and costsassociated with thedevelopment of GVHD, andhighlights the need for newtreatment approaches forthis condition.”

—Fiona L. Dignan, MD


Health Economics

sus 52% with imatinib. The US Foodand Drug Administration has accept-ed a new drug application for bosu-tinib on January 27, 2012 (see article,page 9).

Other Leukemias

Blinatumomab more than doubledthe CR rate in adult patients withrelapsed or refractory B-precursorALL compared with standard thera-pies. Blinatumomab is a BiTE (bispe-cific T-cell engager) antibody thatdirects the patient’s cytotoxic T-cellsto attack CD19-expressing cancercells. In a phase 2 study of 25 patients,68% achieved a CR or a CR with par-tial hematologic recovery with blina-tumomab. Median duration of CRwas 7.1 months, and median overallsurvival (OS) has not been reached(see article, page 12).PCI-32765, a novel inhibitor of B-

cell receptor signaling, this oral drugin early development achieved highrates of remission and was well toler-ated in patients with chronic lympho-cytic leukemia who were refractory toat least 2 previous treatments, accord-ing to updated results of a phase 1b/2study. This drug represents the first inclass of Bruton’s TKIs. In a phase 1b/2study of 61 patients, response ratesapproached 50%, depending on dose,and seemed independent of molecu-lar risk features. The 6-month progres-sion-free survival is >90%. Phase 3 tri-als are planned (see article, page 11).

Updated interim results of a phase 2monotherapy study of quizartinib(AC220), a new FLT3 inhibitor, sug-gest that this drug can achieve clini-cally meaningful responses in patientswith both refractory and relapsedFLT3-ITD–positive acute myeloidleukemia (AML). In an exploratoryanalysis of the 62-patient trial, manypatients who were treated with this

drug were able to go on to hematopoi-etic stem-cell transplant. The compos-ite CR rate reached 46%, with partialresponses (PRs) in up to 22%.Quizartinib is one of the first drugs toinduce CRs as a single agent in AML.

Multiple Myeloma

Data are maturing for carfilzomib,the next-generation proteasome in -hibitor, and US Food and DrugAdministration approval is expectedsoon. High response rates and mini-mal toxicity (including less peripheralneuropathy) were observed whencarfilzomib was combined withlenalidomide and low-dose dexa m-ethasone in a phase 2 study of 53patients. PRs or greater (≥PR) wereobserved in 94% of pa tients after 1cycle, and 53% achieved CR or a strin-gent CR. Response was not affectedby stage or cytogenetics (see article,page 16).

Still in early-phase studies butalready generating excitement is thefirst oral proteasome inhibitor,MLN9708. In a phase 1 study of 56heavily pretreated patients (46 can beevaluated), 6 achieved ≥PR, 1 patientachieved a minimal response, and 28patients achieved stable disease, somelasting >16 months. In previouslyuntreated patients, the drug is highlyactive, according to a phase 1/2 studythat showed 9 of 10 patients achieved≥PR. No peripheral neuropathy grade3 or higher has been reported withMLN9708. Phase 3 trials will beginnext year (see article, page 16).

Monoclonal antibodies are alsoentering the treatment arena formyeloma. Elotuzumab, the first ofthese agents, led to very high responserates (82%) and prolonged remissionswhen combined with lenalidomide in73 relapsed/refractory patients in aphase 2 study. Median progression-

free survival had not been reached bythe time of the report, and the respons-es were highly durable. The drug alsoappears active even in cytogeneticallyhigh-risk patients. Phase 3 trials areongoing, both in previously untreatedpatients and in relapsed/refractorypatients (see article, page 16).

A novel immunomodulatory drug,pomalidomide, also earned highpraise from myeloma experts. In aphase 2 study in 221 relapsed/refrac-tory patients, pomalidomide pluslow-dose dexamethasone led to PRsin 34% of patients, and minor respons-es in 11%. Median OS was nearly 17months. In treatment-refractory pa -tients, a French phase 2 study ofpomalidomide plus low-dose dexa -methasone showed similar activity,with median OS of 13 months. Phase 3trials are currently evaluating poma-lidomide in various combinations (seearticle, page 14).

Two histone deacetylase inhibitorsshowed activity in patients withrelapsed/refractory myeloma. In theglobal phase 3 VANTAGE trial of 635patients, vorinostat plus bortezomibsignificantly prolonged remissioncompared with bortezomib alone,reducing the risk of progression by23% (P = .01) and improving responserates from 41% to 56% (P <.001).

In the phase 2 PANORAMA-2 studyof 55 treatment-refractory patients,panobinostat plus bortezomib anddexa methasone produced a clinicalbenefit rate of 49%. Panobinostat isbeing combined with a number of dif-ferent drugs in ongoing studies inmyeloma (see article, page 14).

Lymphoma

In patients with relapsed indolentnon-Hodgkin lymphoma (NHL), a“glycoengineered” humanized anti-body against CD20, obinutuzumab

(GA101) produced comparable out-comes to rituximab in the first head-to-head comparison of these drugs,the phase 2 GAUSS trial of 175 pa -tients. Response rates to inductionwere significantly higher with obinu-tuzumab than with rituxumab byindependent radiology review: 44.6%versus 26.7% (P = .01). The primaryend point, however, response accord-ing to local investigators, was numer-ically although not significantly differ-ent: 44.6% and 33.3% (P = .08). Medianprogression-free survival was approx-imately 17 months in each arm. Thestudy was not designed to show supe-riority, but to determine if a random-ized trial was justified, and trials arenow under way comparing the 2drugs, which are given withchemotherapy (see article, page 18).

In systemic anaplastic large-celllymphoma, an aggressive subtype ofmature T-cell NHL, a multicenterphase 2 study in relapsed/refractorypatients found durable clinical remis-sions and high response rates aftertreatment with brentuximabvedotin,an anti-CD30 antibody conjugated toan antimicrotubule agent. Overallresponse rates were 86%, and CRswere achieved by 56% of patients,with a median duration of responsethat had not been reached by the timeof the analysis.

Myelofibrosis

CYT387, a new Janus kinase (JAK)inhibitor, proved capable of keepingpatients with myelofibrosis free oftransfusion in a phase 1/2 trial of 166patients. In the study, 54% of the 68patients who were transfusion-depen-dent at baseline became transfusion-independent by 12 weeks, with a meanduration of response >6 months. Phase3 trials for CYT387 are slated to beginsoon (see article, page 23). �

Hematologic Pipeline Abundant... Continued from page 1

emergency department visits, drugs,home care, and same-day surgeries.Costs were inflated to 2009 Canadiandollars ($0.88 US) and were presentedas the mean annual cost for all patientsand by clinical stage. A public payer’sperspective was used.

The participants’ median age was68 years, and 55% were male. Geo -graphically, 86% of both groups werefrom urban areas.

The mean cost difference betweenthe NHL and the control groups rep-resents the mean cost attributable toNHL diagnosis and treatment.

The mean annual cost of managingNHL was $16,778; the cost by stage at

diagnosis ranged from $9575 for stageI to $26,099 for stage IV.

“So, for a typical patient, we spentabout $16,000 extra per year,” MrIsogai noted. “By stage, end of life wasthe most expensive, costing up to$25,000 versus less than $10,000 forstage I patients.”

Five cost categories were analyzedby the time for reporting at the meet-ing: health insurance plan, hospital-ization, same-day surgery, drug, andhome care (Table).

The study is ongoing; the re -searchers will be analyzing addition-al data, including cancer clinic visits,other drugs, and radiation therapy. �

A Large Study Sheds Light... Continued from page 1

Table Mean Annual Costs of Managing Patients with NHL versus Controls

Cost category

Patients with non-Hodgkin lymphoma,

$Control group,

$Difference,

$

Ontario HealthInsurance Plan

3509 1375 2134

Hospitalization 10,401 1811 8590

Same-day surgery 384 189 195

Drugs 6283 1174 5109

Home care 667 260 407

Total 21,244 4809 16,435

NHL indicates non-Hodgkin lymphoma.


The newest data presented fromthe BELA (Bosutinib Efficacyand Safety in Chronic Myeloid

Leukemia) trial show a superior cumu-lative complete cytogenetic responserate (CCyR) for bosutinib versus thestandard-of-care agent, imatinib, whenused as frontline treatment for pa -tients with chronic myeloid leukemia(CML), with 87% and 81% responserates, respectively, at 24 months.

“Given these results, bosutinib maysoon offer a new therapeutic optionfor patients with newly diagnosedchronic-phase CML,” said lead inves-tigator Jorge E. Cortes, MD, of theUniversity of Texas M.D. AndersonCancer Center, Houston.

The way was not always so clearfor bosutinib, the most clinicallyadvanced, investigational second-gen-eration tyrosine kinase inhibitor in thepipeline. The initial report of the piv-otal BELA trial was a sensation for thewrong reason; the trial failed to meetits primary end point.

The reason that the 12-month data(presented in 2010) fell short ofexpectations was not for the drug’slack of efficacy, but because of a con-flict between the planned intent-to-treat (ITT) analysis, and because thetrial was conducted in more than 100locations, where some cliniciansfailed to proactively manage treat-ment-related adverse events. Thissuboptimal care led to an inordinatenumber of patient discontinuations,thereby driving down the otherwiseencouraging treatment responserates. This critical issue has beenaddressed, and results at 24 monthshave improved significantly.

BELA Trial at 24 Months

The BELA trial was designed tolook at the use of bosutinib versusimatinib in 502 patients with treat-ment-naïve, chronic-phase CML. Thestudy’s primary end point was CCyRat 12 months, with secondary endpoints including major molecular

response (MMR), progression-freesurvival (PFS), overall survival (OS),and safety and tolerability. Theplanned follow-up period for BELAis 8 years.

At 24 months, the initial ITT analy-sis for CCyR indicated that theresponse to both drugs was nearlyidentical: 79% for bosutinib and 80%for imatinib. However, when patientswho discontinued unnecessarily wereexcluded from the calculation, thecumulative CCyR was 87% for bosu-tinib versus 81% for imatinib.

Further analysis showed a completeresponse rate plus MMR of 67% for

bosutinib versus 52% for imatinib, DrCortes reported.

Although median PFS and OS havenot yet been reached, at 24 monthsbosutinib has a lower rate of treatmentfailure: 4% versus 13% for imatinib.

Regarding adverse events, as ex -pected (and now effectively man-aged), individuals in the bosutinibcohort had more grade 3/4 diarrhea,whereas patients in the imatinib armhad more edema and myalgia.Hematologic events were more com-mon in the imatinib treatment arm,especially for neutropenia (24% vs10% for bosutinib).

New Drug Application

On January 27, 2011, the US Foodand Drug Administration accepted anew drug application for bosutinib fora standard review as a treatmentoption for patients with previouslytreated Philadelphia chromosome–positive CML; the drug was submittedfor approval in Europe late last year. �

Bosutinib Shows Superior Results in CMLBy Neil Canavan

“Bosutinib may soon offer anew therapeutic option forpatients with newly diagnosedchronic-phase CML.”

—Jorge E. Cortes, MD

Leukemia

Two studies presented at ASH2011 reached different con- clusions regarding the cost-

effectiveness of routine use of the up -front stem-cell mobilizer, plerixafor(Mozobil), before the use of autolo-gous stem-cell transplant.

Reserve Plerixafor for Poor

Mobilizers

The addition of chemotherapy togranulocyte colony-stimulating factor(G-CSF) for stem-cell mobilization canincrease cell yield and improve mobi-lization outcomes relative to G-CSFalone. A multicenter study investigatedthe use of mid-dose VP-16 (etoposide)plus G-CSF in patients with lymphomaand whether plerixafor might be incor-porated into this chemo-mobilizationbackbone in a cost-effective way.

Using a predictive modeling ap -proach, plerixafor could be reservedfor patients predicted to be “poormobilizers,” said William Wood, MD,University of North Carolina Line -berger Comprehensive Cancer Center,Chapel Hill.

“Poor mobilizers” were defined aspatients failing to produce 5 × 106

cells in ≤2 days. The researchers iden-tified certain predictors for poormobilization.

Of 159 patients in this study:

• 90 (57%) were identified as “goodmobilizers”

• 43% were “poor mobilizers.” Average costs were:• $14,923 for good mobilizers • $27,044 for poor mobilizers (P <.05).

The first peripheral blood CD34+count (obtained between days 9 and15) accurately predicted good versuspoor mobilizers, Dr Wood said.

“Using our data, we estimated thatit would not be cost-effective to give

plerixafor to all patients, even if 100%of patients subsequently became goodmobilizers,” he said.

Instead, by reserving plerixafor foronly predicted poor mobilizers at thetime of first CD34+ count, the investi-gators estimated that 64% of thesepatients would need to become goodmobilizers to achieve cost neutrality.

The researchers are still determin-

ing the cost-effectiveness of addingplerixafor in patients predicted to bepoor mobilizers.

Plerixafor Upfront Is Cost-Neutral

By contrast, the researchers fromMount Sinai Medical Center, NY, con-cluded that upfront use of plerixafordoes not add a substantial cost burdenin the setting of transplant for multi-ple myeloma.

This prospective study included 50patients with myeloma who under-went transplant, 25 of whom receivedplerixafor in combination with G-CSFand 25 received G-CSF alone as anupfront mobilization strategy.

Compared with G-CSF alone, pler-ixafor mobilizations yielded highernumbers of CD34+ cells/kg, highernumbers of CD34+ cells infused,required fewer G-CSF doses for stem-cell collection and for neutrophilrecovery, and less apheresis. Theplerixafor group had a longer time toneutrophil engraftment; however,this did not translate to longer daysof hospitalization posttransplant,said Luis Isola, MD.

The plerixafor group required fewerG-CSF doses for mobilization and forneutrophil recovery, and fewerapheresis sessions. Therefore, thisgroup had a lower cost of G-CSF per

patient for stem-cell collection (mean,$2212 vs $2765) and stem-cell recov-ery (mean, $1677 vs $2653), as well asa lower cost of apheresis per patient(mean, $889 vs $1476).

The mean number of plerixafordoses per patient was 1.8, with a $9081cost per patient.

“Based on our interim data for over-all cost analysis, the plerixafor grouphad similar cost for blood products perpatient, overall cost of medications,overall cost of hospitalization, andcost of hospitalization and apheresiscombined per patient,” Dr Isola said.

“These data suggest that using pler-ixafor for upfront autologous stem-cell mobilization in patients with mul-tiple myeloma significantly improvessuccess rate of mobilization, decreasesthe number of apheresis sessions, anddoes not have a substantial pharma-coeconomic impact.” �

“Using plerixafor for upfrontautologous stem-cellmobilization...does not havea substantialpharmacoeconomic impact.”

—Luis Isola, MD“We estimated that it wouldnot be cost-effective to giveplerixafor to all patients,even if 100% of patientssubsequently became goodmobilizers.”—William Wood, MD

Is Plerixafor Cost-Effective for Stem-Cell Mobilization?By Caroline Helwick

Health Economics


prove.” There is no assay that canensure that every last leukemic cellpresent can be detected.

Dr Melo asked if a treatment-freecure is truly that important. “Thereare 3 things to look at: chronic toxicitywith treatment and late-emerging tox-icities; cost of continuing treatment;and the threat of lingering, althoughminimal, disease.”

Toxicities and Cost of

Continuing Treatment

One recent study has shown thatmany patients with CML are tired ofreceiving treatment. When asked tostratify their treatment’s side effects,patients said they “minded verymuch” fatigue (29%), muscle cramps(30%), pain (30%), and edema (24%).“We need to consider this when we’rekeeping patients on treatment foryears at a time,” Dr Melo said.

The cost of years-long treatment isalso no small matter. Dr Melo esti-mates that the cost to treat CMLpatients using tyrosine kinase in -hibitors (TKIs) in the United Kingdomranges from £18,000 to £32,000($27,000-$48,000) annually.

As for the lingering potential forrelapse—should a few active leukemiccells survive treatment—what thresh-old of risk is acceptable? There is noway to say. “So, maybe an operationalcure is only a partial success and weshould aim higher.”

Treating CML with an allogeneictransplant is defined as curative.However, as Dr Melo pointed out,although the relapse-free rate withtransplant is as high as 70% at 10years, only 25% of patients are ableto find the necessary human leuko-cyte antigen–matched donor. Further -more, those who re ceive a transplantrisk developing chronic graft-versus-host disease, and, according to verysensitive testing methods, 30% oftransplant patients still harbor aber-rant BCR-ABL (potentially disease-causing) transcripts.

Can CML Actually Be Cured?

Accepting the premise that a curecannot be proved, Dr Melo consideredwhether cures have been seen in prac-tice. Two clinical trials involvedpatients who achieved a completemolecular response (CMR) and wereallowed to stop treatment with TKIs—the CML8 trial and the STIM (StopImatinib) study. Both showed thatapproximately 40% of patients wereable to discontinue treatment andmaintain CMR for 5 years.

“This tells us that for some propor-tion of patients, the TKIs can be safelywithdrawn,” Dr Melo said, adding

that stopping treatment in the STIMtrial is estimated to have saved asmuch as €4 million ($5.2 million),“even in this short period of time.”

In both trials, patients receivedimatinib. The potential for cure withsecond-generation TKIs may holdeven greater promise (see below). Inone study, 64% of patients in CMRwho stopped treatment with dasa-tinib or nilotinib have maintainedresponses for 10 months of follow-up. “Although the numbers are verysmall [N = 33], it is still very encour-aging,” Dr Melo said.

Can Cures Be Predicted?

Evidence continues to accrue thatsome patients can be treatment-freeand cured, but predicting who may becured remains a challenge. A smallsubset of patients from the STIM trialwho successfully stopped treatment(N = 66) displayed a few identifiablecommonalities. Significant factors fortreatment-free individuals with sus-

tained CMR were lower Sokal prog-nostic scores, imatinib treatment >50months, and (barely significant forreasons unknown) male sex.

The molecular mechanism of cure isalso coming into focus. Citing a recentanalysis of data from the IRIS(International Randomized IFN ver-sus STI571) and TIDEL (Trial ofImatinib with Dose Escalation) trials(both with imatinib), Dr Melo favorsthe idea of a triphasic response totreatment that results in “stem-cell

exhaustion,” in which 3 distinct can-cer-cell–killing time intervals havebeen observed. “In the first 3 to 4months you kill all the mature cells,then after 3 to 4 years the progenitorcells die off, then finally you get to the(cancer-originating) stem cells.”

“Can we consolidate CMR withmore intense use of TKIs?” asked DrMelo. Several approaches that arebeing considered include change ofdose, schedule, and adding animmunotherapy. The answer may liein new drugs that target the stem cellsthemselves.

“There are several new agents indevelopment that target the onco-gene BCR-ABL, stop the formation ofstem cells, and induce apoptosis inquiescent cells,” said Dr Melo. But ifno method can ensure the detectionof no residual, potentially life-threat-ening CML stem cells, then the reali-ty of achieving a cure will remain amatter of faith and ongoing patientobservation. �

Chronic Myeloid Leukemia... Continued from page 1

“There are several newagents in development thattarget the oncogene BCR-ABL, stop the formation ofstem cells, and induceapoptosis in quiescent cells.”

—Junia Melo, MD, PhD

Patients with chronic myeloidleukemia (CML) who are incomplete molecular remission

(CMR) can safely discontinue theirtreatment with imatinib, accordingto data from the Stop Imatinib(STIM) and Aus tralasian Leukaemia& Lymphoma Group CML8 clinicaltrials. As a result, researchers arenow asking whether second-genera-tion tyrosine kinase inhibitors (TKIs)can accomplish this at an even high-er rate.

Delphine Rea, MD, PhD, of theHôpital Saint Louis, Paris, presentedthe initial data from the French CMLStudy Group that looked at sus-tained, treatment-free CMR afterextended treatment with the second-generation TKIs dasatinib or nilo-tinib, which showed high rates ofCMR for up to 24 months after treat-ment discontinuation.

The results demonstrated thatthese newer TKIs have superiorpotency against cancer-causing BCR-

ABL transcripts compared with ima-tinib, as well as being effective as sal-vage therapy for patients with CMLresistant to or intolerant of imatinib.

STIM Study

To perform her study, Dr Reaenrolled adult patients with chronic-

phase or accelerated-phase CML whohad been treated with dasatinib ornilotinib for at least 36 months, andhad achieved and sustained a CMRfor at least 24 months (N = 33). Twopatients in the cohort had receivedtreatment with frontline nilotinib; the

remaining 31 individuals started withimatinib, but were switched to sec-ond-generation TKIs as salvage ther-apy. All active treatment was haltedon study entry (N = 33).

The primary end point for thestudy was stable major molecularresponse (MMR) at 6 months. Pa -tients are monitored by polymerasechain reaction once a month for thefirst year, then every 2 to 3 monthsthereafter. TKIs were reintroduced ifMMR is lost.

After second-generation TKI cessa-

tion, 8 patients lost MMR at 2-monthmedian intervals; all 8 regained MMRwithin 12 months of resuming TKItherapy.

The other 25 patients remained offtherapy for a median of 6 months(range, 0-25 months); 15 of the 25patients have sustained MMR to amedian of 13 months. From these ini-tial findings, Dr Rea concluded thatsecond-generation TKIs could bediscontinued without jeopardizingshort-term outcomes, and that evenif patients lost an MMR, theyremained sensitive (nonresistant) tosuch treatment when reintroduced.

What Would a “Cure” Mean

to Patients?

“Even defining cure is a real chal-lenge,” said Dr Rea. “Is cure a totaleradication of leukemic cells, or iscure being able to stop therapieswithout disease relapse? These are2 different points.” This uncertaintyhas become an issue among pa -tients. “One of the very first ques-tions patients ask is ‘How long is thetreatment going to last?’ ‘When am Igoing to be cured?’ So, from thepatient’s perspective, being curedmeans being able to stop the thera-py without disease recurrence,” DrRea said. �

Second-Generation TKIs Have Potential to Cure CML

“Is cure a total eradication ofleukemic cells, or is curebeing able to stop therapieswithout disease relapse?These are 2 different points.”

—Delphine Rea, MD, PhD

Leukemia


Novel Oral B-Cell Receptor Inhibitor Very Effective inChronic Lymphocytic LeukemiaResponse Rates Increasing Over Time, with Low Toxicities By Caroline Helwick

Anovel inhibitor of B-cell recep-tor signaling, PCI-32765, pro-duced high rates of remission

and was well tolerated in patientswith chronic lymphocytic leukemia(CLL) whose disease was refractory toat least 2 previous treatments, report-ed Susan O’Brien, MD, of theUniversity of Texas M.D. AndersonCancer Center, Houston.

“To have agents that are this effec-tive and that are not myelosuppres-sive is very exciting,” Dr O’Brien said.“These agents will change the para-digm for the treatment of CLL.”

PCI-32765 is the first drug designedto target Bruton’s tyrosine kinase, aprotein that is essential for CLL cellsurvival and proliferation.

A total of 61 patients with relapsed orrefractory CLL received oral PCI-32765daily (420 mg in previously untreatedand 840 mg in previously treatedpatients) for 28-day cycles or until dis-ease progression. At least 1 poor-riskmolecular feature was present in 72% ofpatients. Median follow-up was 10.2months for the 420-mg cohort and 6.5months for the 840-mg cohort.

Response rates were 70% in the 420-mg cohort and 44% in the 840-mggroup. Nodal partial responses (PRs)were reported in 35% of patients(>50% reduction in aggregate lymphnode size), with residual lymphocyto-sis. Reponses appear to be independ-ent of molecular risk features.

Dr O’Brien noted that responserates have steadily increased over theduration of the study. “At ASCO, wereported a PR rate of 48%. Now wereport a response rate of about 70%.The responses have evolved overtime,” she said.

Some 82% of the original patientsare still using this treatment; only 8%of patients have progressed so far. The6-month progression-free survivalwas 92% in the 420-mg cohort and90% in the 840-mg cohort.

PCI-32765 is well tolerated, with

most adverse events reported beinggrade 1 or 2. Myelosuppression hasnot been a problem with this agent, DrO’Brien said. Phase 3 clinical trialswith PCI-32765 are planned.

Jane Winter, MD, Professor of Med -icine at Northwestern Univer sityFeinberg School of Medicine, Chicago,who moderated the press briefing,commented, “This appears to be a

highly effective new agent, with a newstrategy that targets the B-cell receptor.It has a very low toxicity profile andhigh efficacy, and it is just the begin-ning of many new agents in CLL.” �

“To have agents that are thiseffective and that are notmyelosuppressive is veryexciting. These agents willchange the paradigm for thetreatment of chroniclymphocytic leukemia.”

—Susan O’Brien, MD

Leukemia

Locate the mutation.Stay one step ahead of CML resistance.

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Leukemia

Preliminary data from the phase2 PACE (Ponatinib Ph+ALL andCML Evaluation) trial show that

ponatinib (Ariad Pharmaceuticals)can overcome the difficult-to-treatT315I mutation in patients with chron-ic myeloid leukemia (CML). Currently,patients with this genetic mutationhave no effective treatment options.

In PACE, the tyrosine kinaseinhibitor (TKI) ponatinib achieved a47% major cytogenetic response(MCyR). For patients with the T315I

mutation, ponatinib induced a 65%MCyR. This drug was specificallydesigned to overcome the T315I

mutation.“Ponatinib has the potential to

become a promising new treatmentoption for patients with multi-refrac-tory/relapsed CML,” said PACE leadinvestigator Jorge E. Cortes, MD, ofthe University of Texas M.D. AndersonCancer Center, Houston.

This open-label study enrolled 499patients with CML or with Philadel -

phia chromosome–positive (Ph+)acute lymphoblastic leukemia (ALL)who had previously been treatedwith nilotinib or dasatinib, but theirdisease was resistant or intolerant tothose drugs, or they had the T315I

mutation. Patients were stratified into 1 of 6

groups, according to disease, diseasephase, and mutation status. Allpatients were treated with the samedose and schedule. The primary endpoints were MCyR for chronic-phase(CP)-CML, and major histologic re -sponse for accelerated-phase (AP)-CML, blast-phase (BP)-CML, orPh+ALL.

After a median follow-up of 5months, Dr Cortes reported high lev-els of response being observed in allpatient types. Patients with AP-CMLachieved a major histologic responseof 74%, and MCyRs ranging up to53%. For patients with the most severe

prognosis, the BP-CML and Ph+ALLcohorts, both groups achieved a majorhistologic response of 37%, and MCyRsof 34% and 37%, respectively.

A major molecular response rate of33% was reported in patients with theT315I mutation and those with CP-CML/T315I.

Treatment-related adverse eventswere generally mild; the most com-mon serious events were thrombocy-topenia and neutropenia.

“Extremely exciting,” said TimBrümmendorf, MD, of the UniversityHospital, Aachen, Germany, in re -sponse to the ponatinib data. “It is themost promising approach to target themost problematic mutation that wecurrently see—the T315I mutation.This mutation confers absolute resis -tance to all TKIs that we currentlyhave approved in clinical use. So,from what I have seen, it [ponatinib]looks extremely promising.” �

Ponatinib Overcomes Hard-to-Treat T315I Mutation in Patients with CML/ALLBy Neil Canavan

“Ponatinib has the potentialto become a promising newtreatment option for patientswith multi-refractory/relapsed CML.”

—Jorge E. Cortes, MD

The novel agent blinatumomabmore than doubled the com-plete response (CR) rate in

adult patients with relapsed orrefractory B-precursor acute lym-phoblastic leukemia (ALL) comparedwith standard therapies. If validated,these findings offer significant hopeto patients with an otherwise dismalprognosis after having failed toachieve CR with standard treatment.

Blinatumomab is a member of theBiTE (bispecific T-cell engager) drugclass, a bispecific monoclonal anti-body designed to direct the cytotoxicT-cells of the host’s immune system,via CD3, to attack CD19-expressingcancer cells.

In this open-label, single-arm, dose-ranging, phase 2 clinical trial, 25patients with ALL were randomizedto 1 of 3 doses of blinatumomab.Results for all tested doses showedthat 17 (68%) of the patients achieveda CR or a CR with partial hematologicrecovery with blinatumomab.

For the 12 patients who received thedose selected for further investigation,9 achieved a CR or partial hematologicrecovery. All responders achieved min-imal residual disease status, meaningthat there were no detectable leukemiccells in their blood or bone marrow.

Treatment effect with blinatu m omabwas lasting, with a median complete

hematologic remission of 7.1 months.At a median follow-up of 9.7 months,median survival time has not beenreached. This ongoing measurealready exceeds median survivaltimes typically seen with combinationchemotherapy in ALL.

The most common adverse eventsobserved with initial blinatumomabtreatment were mild, and were pre-dominantly flulike symptoms of feverand headache.

More serious, but reversible, eventsincluded cytokine release syndromein 2 patients with high tumor burden,and 5 patients with central nervous

system events (3 with seizures and 2with disorientation). Events for all 7patients were managed with treat-ment interruption, and all 7 continuedthe trial after event resolution. Therewere no treatment-related deaths.

“Blinatumomab as a single agentinduced an unprecedented high rateof complete hematological and mini-mal residual disease responses inadult patients with relapsed/refracto-ry B-precursor ALL,” said the study’slead investigator, Max S. Topp, MD,at Wuerzburg University MedicalCenter, Wuerzburg, Germany, wherephase 2 studies are under way.—NC �

Investigational Blinatumomab Puts BiTE on AcuteLymphoblastic Leukemia

“Blinatumomab as a singleagent induced anunprecedented high rate ofcomplete hematological and MRD responses in adult patients withrelapsed/refractory B-precursor ALL.”

—Max S. Topp, MD

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Multiple Myeloma

The final analysis of the phase 3VISTA trial upheld a persistentand significant survival benefit

for bortezomib in patients with previ-ously untreated multiple myeloma.

Of the 655 patients in VISTA, thosetreated with bortezomib lived an aver-age of 13.3 months longer than thosereceiving a regimen lacking this agent,VISTA investigator Jesús F. SanMiguel, MD, PhD, of the HospitalClinico Universitario, Salamanca,Spain, reported.

“An overall survival [OS] benefitwas seen across multiple prespecifiedpatient subgroups and was main-tained after 5 years’ follow-up anddespite substantial use of novelagent–based salvage therapies,” saidDr San Miguel.

Data from the initial report of thisinternational phase 3 trial showed thatnine 6-week cycles of the bortezomib,melphalan, and prednisone (VMP)regimen were superior to the melpha-lan and prednisone (MP) regimen inpatients with previously untreatedmultiple myeloma. At 36.7 months offollow-up, a second analysis con-firmed a continued OS benefit. Thecurrent report was the final updatedOS analysis after 5 years of follow-up,which includes data on 95% of theoriginal cohort.

The 5-year follow-up also found noassociation between bortezomib treat-ment and the development of secondprimary cancers, at least above and

beyond the incidence of cancer in thegeneral healthy population. Sincereports surfaced at ASH last year thatlenalidomide seemed to be associatedwith a higher risk for second malig-

nancies, studies of myeloma therapiesall examine this potential risk.

Dr San Miguel said that based onthe findings of no excess cancers, he isconvinced that the long-term use of

bortezomib is “completely safe.”

5-Year Mortality Risk

Reduced by 31%

Mortality risk was reduced by 31%

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EDUCATIONAL OBJECTIVES• Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care

delivery• Define the barriers associated with cost, quality, and access as it relates to healthcare reform and

what solutions are currently being considered• Compare and contrast the different approaches/tools that providers and payers are utilizing to

manage and deliver care collaboratively• Examine the current trends in personalized care and companion diagnostics• Analyze the patient issues around cost, quality, and access to care

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VISTA Final Analysis Upholds Survival Benefit of Bortezomib at 5 YearsBy Caroline Helwick

“These findings demonstratethe importance of providingoptimal first-line treatmentincorporating bortezomib,rather than reservingbortezomib for salvagetherapy and usingconventional first-linetreatment.”

—Jesús F. San Miguel, MD, PhD

Continued on page 15


Multiple Myeloma

With so many new myelomadrugs of various classes inthe pipeline (Table), “my -

eloma is going to become a chronicill ness, with sustained completeresponses in a significant fraction ofpatients,” according to Kenneth C.Anderson, MD, of Dana-FarberCancer Institute and Harvard MedicalSchool, Boston.

In his presentation about treatmenttargets and niches, Dr Anderson pre-dicted that the future direction of multi-ple myeloma management will include:• Development of immune treat-

ments (vaccine and adoptiveimmunotherapy); these may bevery personalized

• Development of novel agentsaimed at the myeloma cell in thebone marrow microenvironment;these will target cell growth, sur-vival, and drug resistance

• Development of rationally basedcombination therapies, such asbortezomib plus histone deacety-lase inhibitors

• Utilization of genomics for im -proved classification; microRNAprofiles can already identify clinicalsubgroups with different survivaloutcomes

• Personalized treatment based ontumor genetics. Sonja Zweegman, MD, PhD, of VU

University Medical Center, Amster -

dam, and Erasmus University, Rotter -dam, the Netherlands, moderated thesession on new agents in myeloma.She elaborated on the future of per-sonalized treatment for myeloma:“We need many drugs to prolong thelife of these patients, and what youwill increasingly see happen is the use

of biologically determined treatment.”For example, she said, we heard

here at ASH 2011, that with the MEK(mitogen-activated protein kinase)inhibitor AZD6244 (selumetinib),only patients with activation of thesignaling transduction pathway willrespond.

“It will help to have a biologicaldetermination of the malignant plas-

ma cells, and a predictive model tohelp select the most appropriate treat-ment for a particular patient. That willbe the future,” said Dr Zweegman.

Dr Anderson agreed. “With wholegenome sequencing coming, and withso many novel agents—includingmany in phase 3 trials, as we saw dis-cussed at this meeting—I know thefuture is bright in myeloma.” �

Future Directions in MyelomaBy Caroline Helwick

Pomalidomide a Promising New Immunomodulatory Drug for Multiple Myeloma

Early-phase studies of the newimmunomodulatory drug pomalidomide drew considerable

interest at ASH 2011 and generatedenthusiasm from myeloma specialists.

Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, whohas led trials of pomalidomide, com-mented, “Over 40% clinical benefitrate and almost 17 months mediansurvival in heavily pretreated patientsis fantastic.”

A phase 2 study compared poma-lidomide alone versus pomalidomideplus low-dose dexamethasone in 221patients with relapsed/refractory dis-ease. Patients had received an averageof 5 previous lines of therapy, and mostof them had progressed with bortez -omib or with lenalidomide therapy.

Pomalidomide plus dexamethasoneled to a partial response in 34% ofpatients compared with 13% of patientsresponding to pomalidomide alone;

another 11% of patients had minorresponses to the combination regimen.

Median progression-free survivalrates were 4.7 months with the combi-nation and 2.7 months with pomalido-mide alone, and median overall sur-vival (OS) rates were 16.9 months and14 months, respectively.

Similar findings emerged from theFrench phase 2 IFM 2009-02 study ofpomalidomide plus low-dose dexa -methasone in 84 patients with dis-ease refractory to both lenalidomideand bortezomib.

Responses with the combinationwere observed in 34.5% of patients,and stable disease was present in 48%of patients. Median time to progressionwas 9.1 months, and median OS was13.4 months, according to XavierLeleu, MD, PhD, of Hôpital ClaudeHuriez, CHRU, Lille, France.

Pomalidomide Plus 2 Drugs

and Maintenance

Italian investigators combinedpomalidomide with 2 other agents,cyclophosphamide and prednisone,followed by maintenance with poma-lidomide plus cyclophosphamide in aphase 2 study of 29 relapsed/refracto-ry patients.

After a median of 4 cycles, partialresponse or better was observed in81% of the patients with refractory dis-ease and in 55.5% of the patients whorelapsed. Very good partial responseor better was seen in 27% and 28% of

patients, respectively, and completeresponses were documented in 9%and 5.5% of patients, respectively,according to Antonio Palumbo, MD, ofthe University of Torino in Italy, for theItalian Multiple Myeloma Network.

Dr Palumbo also suggested thatusing a combination with “a goodrisk-benefit ratio, where there is notmuch toxicity,” and continuing the 3drugs as maintenance therapy, “mayhelp explain the higher proportion ofresponses” in this study.

Pomalidomide was generally welltolerated in all studies. The mostcommon grade 3 or 4 toxicities wereneutropenia, anemia, pneumonia,thrombocytopenia, and fatigue. Moreunusual grade 3 or 4 nonhematologictoxicities include rash and centralneurologic toxicity in <10% of pa -tients. Phase 3 trials are currentlyevaluating pomalidomide in variousdrug combinations.—CH �

“Over 40% clinical benefitrate and almost 17 monthsmedian survival in heavilypretreated patients isfantastic.”

—Paul G. Richardson, MD

Table Novel Investigational Agents for Myeloma

Agent Mechanism of action

Carfilzomib,a MLN9708, marizomib Proteasome inhibitor

Pomalidomidea Immunomodulatory drug

Daratumumab, elotuzumab,a

siltuximab,a cetuximabMonoclonal antibody

BT062 Immunotoxin

Perifosine,a GSK 2110183 Akt inhibitor

Vorinostat,a panobinostat,a

romidepsin, ACY-1215Histone deacetylase inhibitor

ARRY-520 Kinesin spindle protein inhibitor

PD 0332991 Cyclin-dependent kinase 4/6 inhibitor

BMS-833923 Hedgehog pathway inhibitor

Everolimus mTOR

Hydroxychloroquine Aggresome/autophagy

Selumetinib (AZD6244) MEK inhibitoraCurrently in phase 3 clinical trials.

With so many new myelomadrugs of various classes inthe pipeline, “myeloma isgoing to become a chronicillness, with sustainedcomplete responses in asignificant fraction ofpatients.”

—Kenneth C. Anderson, MD


The value of continuous, or main-tenance, therapy in pa tientsnewly diagnosed with multiple

myeloma who are not eligible forstem-cell transplant (such as the elder-ly) is still debated. Studies presented atASH 2011 showed that maintenancetherapy can delay disease progres-sion, although an overall survival(OS) advantage is not yet evident.

Lenalidomide Extends PFS,

Increases Secondary Cancers

The final results of the phase 3MM-015 trial that investigated thevalue of lenalidomide in elderly,transplant-ineligible patients, medi-an age 71 years, were presented byAntonio Palumbo, MD, University ofTorino, Italy.

“What is really changing in thetreatment paradigm is the concept ofcontinuing treatment, moving from afixed treatment to one incorporat-ing continuous therapy.…Continuoustreatment adds about 10 months ofremission duration in elderly patients.Although no survival advantage hasbeen shown, 3 years of OS projectedat 70% is certainly a good outcome,”said Dr Palumbo.

MM-015 tested 3 treatment regi-mens. Two groups received inductiontherapy consisting of melphalan,

prednisone, and lenalidomide (MPR);half (N = 152) of this group wasplaced on maintenance therapy withlenalidomide (MPR-R), given on days1 to 21 until progression; the otherhalf received no continuous therapy(MPR); the third group (N = 154)received only melphalan and pred-nisone (MP) as induction therapy andno maintenance.

Patient responses were significantlygreater with the 3-drug combination.“For induction, a 3-drug combinationsignificantly increases response rates,so MPR is better than MP when toxic-ity is not a problem,” Dr Palumbosaid. “But maintenance therapy pro-vides the major difference.”

Lenalidomide maintenance signifi-cantly extended progression-free sur-vival (PFS), from 14 months with MPRand 13 months with MP to 31 monthswith MPR-R. “You get a doubling inPFS when you use continuous treat-ment,” he noted.

In a landmark analysis of allpatients, lenalidomide continuoustherapy resulted in a 66% reduction inthe risk of progression (P <.001). Asignificant treatment benefit wasobserved in all subgroups of age,response, and stage. Patients aged ≥75years had slightly lower benefit, prob-ably because more discontinued treat-

ment and frail patients received lessdose intensity.

“The advantage of maintenance ispresent in all patients, independent ofage, grade, prognosis, and so forth,”Dr Palumbo said.

At a median follow-up of 41 months,however, no impact was yet seen onOS, which at 4 years was 59% for MPR-R, 58% for MPR, and 58% for MP aswell. “But don’t forget that the averagesurvival has been around 3 years,” heemphasized. A trend toward a survivalbenefit was observed in the 65- to 75-year-old age-group.

Secondary cancers, although stillrare, were observed in associationwith lenalidomide, especially hemato-logic malignancies. There were 12cases of cancer among patients receiv-ing maintenance lenalidomide, and 10among patients receiving lenalido-mide alone in the induction regimen,compared with only 4 among patientswho received MP only.

Dr Palumbo argued, however, thatthe increased risk of second cancers wasfar outweighed by lenalidomide’s ben-efit in delaying progression. “There is a75% to 80% risk of progression, but lessthan a 5% risk of second primary malig-nancies,” he said. This was echoed bymany specialists at the meeting.

The major toxicities were grade 4neutropenia in 30% of patients andgrade 4 thrombocytopenia in 5% ofpatients. “But as far as maintenance isconcerned, thrombocytopenia andneutropenia rates were very rare.Even in the frail elderly, toxicity isacceptable,” he said.

Bortezomib-Based Maintenance,

Low Toxicity

Bortezomib-based maintenance reg-

imens also represent an attractivestrategy to optimize myeloma treat-ment, reported Maria-Victoria Mateos,MD, PhD, of the Hospital ClinicoUniversitario in Salamanca, Spain, onbehalf of the Spanish Myeloma Group(GEM/Pethema).

In the GEM2005MAS65 trial, 260elderly patients (median age, 71 years)received induction therapy withbortezomib, melphalan, and pred-nisone (VMP) or with bortezomib,thalidomide, and prednisone (VTP),after which 178 received 1 of 2 possiblemaintenance regimens: bortezomibplus thalidomide (VT) or bortezomibplus prednisone (VP).

Maintenance therapy includedbortezomib 1.3 mg/m2 administeredevery 3 months plus thalidomide 50mg/day and prednisone 50 mg every2 days up to 3 years.

The study did not evaluate out-comes in patients who did not receivemaintenance.

Response rates were similar betweenthe regimens: 80% with VMP and 81%with VTP. The current study assessedwhether maintenance therapy wouldupgrade these responses, with a favor-able toxicity profile, and might confer abenefit in terms of PFS and OS.

In the whole population, after amedian of 20 months of maintenance,the rate of complete response (CR)increased from 24% after inductiontherapy to 42% after maintenance.After induction, CR rates were simi-lar between VMP and VTP, butslightly more additional CRs wereachieved in the VT maintenance arm(46% vs 39%).

At 46-month follow-up, medianPFS was slightly higher with VT (39months vs 32 months with VP), andthis was not influenced by the induc-tion regimen. OS has not been reachedwith VT maintenance, with 69% ofpatients being alive at 5 years, and60% alive with VP.

In the 20% of patients with high-risk cytogenetics, neither maintenanceregimen could overcome the poorprognosis. Median PFS was 26months and median OS was 50months, with no differences seenbetween the regimens.

“Toxicity was very low with main-tenance,” Dr Mateos said. VT wasassociated with more peripheral neu-ropathy (9% vs 3%), but in all but 1patient this was worsening, not emer-gent, neuropathy. �

Maintenance Strategies in Elderly Patients with Myeloma Not Eligible for TransplantLenalidomide and Bortezomib Both Prolonged RemissionBy Caroline Helwick

“What is really changing inthe treatment paradigm isthe concept of continuingtreatment, moving from afixed treatment to oneincorporating continuoustherapy.…Continuoustreatment adds about 10months of remission durationin elderly patients.”

—Antonio Palumbo, MD

with the addition of bortezomib tothe treatment regimen, despite thesignificant use of subsequent therapyonce the disease progressed.

Median OS was 56.4 months aftertreatment with VMP versus 43.1months with MP, amounting to anabsolute benefit of 13.3 additionalmonths of life across all subgroups(P = .004). The OS rate at 5 years was46.0% with VMP versus 34.4% withMP, Dr San Miguel said.

Virtually all subgroups benefitedsignificantly from the addition ofbortezomib, including:• Older patients age ≥75 years, who

had a 29% reduction in risk ofdeath

• Patients with International StagingSystem stage III disease, who had a23% risk reduction

• Patients with creatinine clearance<60 mL/min, who had a 30% riskreduction.

Only the small subgroup ofpatients with documented high-riskcytogenetics had no additional bene-fit from bortezomib.

Bortezomib also added 8 addi-tional months to the time before thenext treatment was required, andextended the treatment-free intervalby almost 8 months (P <.001 forboth).

As for the best time to prescribebortezomib to previously untreatedpatients, Dr San Miguel noted thatpatients who received bortezomib asfirst-line treatment had longer OSthan those who received bortezomibor other therapies in subsequenttreatment lines. “These findingsdemonstrate the importance of pro-viding optimal first-line treatmentincorporating bortezomib,” he said,“rather than reserving bortezomibfor salvage therapy and using con-ventional first-line treatment.” �

VISTA Final Analysis... Continued from page 13

Multiple Myeloma


Multiple Myeloma

The first-generation proteasomeinhibitor bortezomib changedthe treatment paradigm of mul-

tiple myeloma. Data are now matur-ing for the next-generation agentcarfilzomib, with US Food and DrugAdministration approval expectedsoon. Several novel agents in this classare also in the pipeline. These second-generation agents appear to be aseffective as bortezomib but less neuro-toxic, according to studies presentedat ASH 2011.

High Response Rates with

Carfilzomib Regimen

High response rates and minimaltoxicity were seen when carfilzomibwas combined with lenalidomide andlow-dose dexamethasone in a phase 2clinical trial presented by AndrzejJakubowiak, MD, of the University ofChicago Medical Center.

“The carfilzomib/lenalidomide/dexamethasone [CRd] regimen is welltolerated and highly active, demon-strating rapid and deep responses innewly diagnosed myeloma,” DrJakubowiak said.

This study included 53 patients whoreceived 8 cycles of CRd and at least 9additional cycles for maintenance. The24 patients who were transplant candi-dates received 4 cycles before theirtransplant and 4 afterward.

Partial responses or better wereobserved in 94% of patients after 1cycle:• 53% achieved complete response

(CR) or stringent complete re -sponse (sCR)

• After 12 treatment cycles, 79%achieved a near-CR, CR, or sCR

• High response rates were not affect-ed by stage or cytogenetics. “These response rates compare

favorably to our best frontline regi-mens, and the study is still early.Responses continue to improve withtime. I think this is going to be one ofthose regimens that will potentiallychange the landscape of what we cando,” Dr Jakubowiak predicted.

First Oral Agent in Early

Development

The first oral proteasome inhibitor,MLN9708, has “similar selectivity andpotency, it dissociates from the protea-some faster, and has greater tissuepenetration compared with bortez -omib,” said Paul G. Richardson, MD,of Dana-Farber Cancer Center, Boston,who has led some of the trials.

“The activity of MLN9708 is dramat-ic,” he said. “Upfront, we are seeing100% response rates, which is amazing;and in the relapsed/refractory setting,where we expect to see nothingbecause patients are so ill, we are see-ing response rates, including somevery good partial responses, and stabledisease. That’s the signal we need inthe advanced disease population.”

Dr Richardson reported the resultsof a phase 1 dose-escalation expan-sion cohort study of 56 patients whoaveraged 3.5 previous therapies; 88%

had previous bortezomib therapy.MLN9708 was given orally twiceweekly in 21-day cycles at a dose of2 mg/m2.

Of the 46 patients evaluable forresponse, 6 achieved partial respons-es or better, including 1 CR. Onepatient achieved a minimal response,and 28 patients experienced stabledisease. Five responders had previ-ously received bortezomib. Diseasestabilization has lasted nearly 16months in many cases, and encourag-ing activity has been seen in bor -

tezomib-resistant patients. The drug activity in previously

untreated patients is even more strik-ing. Jesus G. Berdeja, MD, of SarahCannon Research Institute in Nashville,reported that of 10 treatment-naïvepatients enrolled in a phase 1 and 2study, 9 achieved partial responses orbetter, including 1 CR and 3 very goodpartial responses.

Comparing MLN9708 to carfil-zomib, Dr Richardson said thatalthough carfilzomib is a welcomedagent in myeloma, “you must givecarfilzomib intravenously and weekly2 days in a row, on days 1 and 2, 8 and9, and 15 and 16. It is a great drug, andit is associated with less neurotoxicity,but its delivery is inconvenient for thepatient. MLN9708 has the advantageof being an oral drug that producesvery little neuropathy,” he said in aninterview.

Dr Richardson said that this agenthas “an excellent tolerability profile.”Fatigue, thrombocytopenia, and nauseaare the most common adverse eventsreported, along with skin rash, espe-cially as first-line treatment, “whichpatients find quite manageable.”

No peripheral neuropathy grade ≥3has been reported. Dose reductions asa result of adverse events have beenuncommon.

Phase 1 and 2 clinical trials are eval-uating oral and intravenous formula-tions, using different dosing sched-ules in a variety of tumor types. Phase3 trials will begin next year. �

Next-Generation Proteasome Inhibitors Cause LessPeripheral NeuropathyFirst Oral Agent in the Pipeline Elicits Excitement By Caroline Helwick

“The activity of MLN9708 isdramatic. Upfront, we areseeing 100% response rates,which is amazing; and in therelapsed/refractory setting,where we expect to seenothing because patients areso ill, we are seeing responserates…and stable disease.”

—Paul G. Richardson, MD

Elotuzumab, a humanized IgG1monoclonal antibody, led tovery high response rates and

prolonged remissions in 73 patientswith relapsed multiple myeloma orrefractory to previous treatment in aphase 2 study presented by SagarLonial, MD, of Emory UniversitySchool of Medicine, Atlanta.

Patients who received elotuzumab(10 or 20 mg/kg) in combination withlenalidomide and low-dose dexameth -asone had an 82% overall responserate. Response rates exceeded 90% inpatients who had received 1 previoustherapy and those who received thelower dose.

“We see an 80% to 90% response

rate, and at 14 months, we have notyet hit median PFS [progression-freesurvival],” said Dr Lonial. The PFSrate has ranged from 65% to 75%.

The drug was well tolerated. Withprophylaxis, only 1 grade 3 infusionreaction was documented. Some 12%of patients had complete responsesand 36% had very good partialresponses. “These were durableresponses. Over half the patients arestill on study,” he noted.

In a subset analysis, the combinationshowed encouraging activity—80%response rate—in cytogenetically high-risk patients. “If we can use a drug toovercome high-risk disease, this wouldbe great,” Dr Lonial commented.

Phase 3 trials of 10 mg/kg of elo-tuzumab are ongoing in previouslyuntreated patients and in those withrelapsed/refractory disease.

Sonja Zweegman, MD, PhD, VU Uni -versity Medical Center, Amster dam,and Erasmus University, Rotterdam,the Netherlands, who moderated asession on new agents in myeloma,commented that the use of monoclon-al antibodies is a true advance inmyeloma. “We eagerly await mono-clonal antibody-based therapy inmyeloma. These agents attack theplasma cell in a different way, andthey will certainly be additive to ourarsenal. Encouragingly, what we sawat ASH is that all these new investiga-tional compounds are not only effec-tive, but tolerable. I think elotuzumabhas a lot of potential,” Dr Zweegmanconcluded.—CH �

Monoclonal Antibody Elotuzumab Promising in Multiple Myeloma

“We eagerly awaitmonoclonal antibody-basedtherapy in myeloma. Theseagents attack the plasma cellin a different way, and theywill certainly be additive toour arsenal.”

—Sonja Zweegman, MD, PhD

“Managing patients with myeloma means staying current.”

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Patients with low-burden follic-ular lymphoma (FL) treatedupfront with rituximab can be

managed as well with “watchfulwaiting,” with retreatment on pro-gression, as with extended dosing, ormaintenance therapy, according to arandomized phase 3 study that com-pared the approaches.

“Rituximab retreatment is our rec-ommended strategy if opting for ri -tuximab monotherapy in low-tumor-burden FL,” said Brad Kahl, MD, ofthe University of Wisconsin School ofMedicine and Public Health inMadison, who presented the findingsas a late-breaking abstract.

He referred to the “excellent out-comes, lack of a difference in qualityof life, and fewer doses required withretreatment.”

Patients in the maintenance armreceived 15.8 doses of rituxumabcompared with only 4.5 in the retreat-ment arm. The number of dosesranged from 5 to 31 in the mainte-nance arm and from 4 to 16 in theretreatment arm.

“Treat without Breaking the Bank”

Andrew Zelenetz, MD, Chief of theLymphoma Service at Memorial Sloan-Kettering Cancer Center, New York,said these findings have great clinicaland economic implications, based onthe vast amount of rituximab thatcould be spared with the retreatmentapproach. “We are in an era when,without question, we have to figureout how to give effective high-quality

care, without breaking the bank.Retreatment may give us the same ben-efit at a much, much lower cost.”

“Some people in the field say thatmaintenance is unequivocally thestandard of care. I happen not to sharethat opinion,” Dr Zelenetz added.

The Eastern Cooperative OncologyTrials group conducted the RESORT(Rituximab Extended Schedule orRetreatment Trial) study to comparemaintenance rituximab with retreat-ment on progression. The studyincluded 545 untreated patients withstage III or IV indolent non-Hodgkinlymphoma and low tumor burden,including 384 with FL histology whoformed the basis of this analysis.

After median follow-up of 3.8 years,there was no difference in the primaryend point of time to treatment failure:3.9 years with maintenance rituximaband 3.6 years with retreatment, DrKahl said. “Both strategies appear todelay time to chemotherapy com-pared with historical controls.”

Treatment failures occurred in 69patients in the maintenance arm and

65 in the retreatment arm. Time to firstchemotherapy treatment was longerin the maintenance arm, with 95% ofpatients remaining chemotherapy-free compared with 86% in the retreat-ment arm (P = .03).

There were no appreciable differ-ences in toxicity or in the develop-ment of second cancers between thearms. More patients withdrew fromthe maintenance arm—26 versus 16 inthe retreatment arm.

“We also wondered if there mightbe a psychological benefit to beingmaintained in remission, but at 1-year postrandomization we found nodifference in quality of life,” Dr Kahlreported.

“Rituximab retreatment was aseffective as maintenance rituximab fortime to treatment failure. Andalthough maintenance was superiorto retreatment for time to cytotoxictherapy, this came at a cost of 3.5 timesmore rituximab,” Dr Kahl concluded.“There was also no benefit in terms ofbetter quality of life or less anxiety at12 months with maintenance.” �

Maintenance Rituximab May Be Unnecessary in FLRetreatment Recommended as Preferred, Cost-Effective StrategyBy Caroline Helwick

“Rituximab retreatment wasas effective as maintenancerituximab for time totreatment failure. Andalthough maintenance wassuperior to retreatment fortime to cytotoxic therapy,this came at a cost of 3.5times more rituximab.”

—Brad Kahl, MD

For more than 10 years, rituximabhas held a unique place in thetreatment of a range of B-cell

lymphomas. But a new “glycoengi-neered” humanized monoclonal anti-body is entering the treatment arena,and data presented at ASH 2011 setthe stage for phase 3 testing againstthe long-term standard of care.

In patients with relapsed indolentnon-Hodgkin lymphoma (NHL),the CD20 inhibitor obinutuzumab(GA101) produced outcomes compa-rable to rituximab in the first head-to-head comparison of these drugs,Canadian investigators reported.

In the phase 2 GAUSS trial, induc-tion therapy with obinutuzumab ledto a higher overall response rate thaninduction with rituximab, accordingto an independent radiology review:44.6% versus 26.7% (P = .01), includ-ing complete responses of 12.2% and5.3%, respectively.

However, the primary end point—response rates according to localinvestigators—was not significantlydifferent: 44.6% and 33.3% (P = .08),respectively, reported Laurie H. Sehn,MD, MPH, of the University of BritishColumbia, Vancouver.

Median progression-free survivalwas also similar between the armsat 17.3 months, with progressionobserved in 39.2% of obinutuzumab-treated patients and 34.7% of ritux-imab-treated patients.

According to Dr Sehn, the GAUSStrial was “not really designed to defi-nitely answer if one agent is better. Itis an attempt to get some comparisonsand to determine if a randomized con-trolled trial is justifiable. The resultsimply a trend in benefit.”

In this open-label study, 175patients (149 with follicular lym-phoma and 26 with nonfollicularindolent NHL) were randomized toreceive 4 weekly infusions with obin-utuzumab or with rituximab. Onaverage, patients had received 2 pre-vious regimens, all with rituximab.Patients without evidence of diseaseprogression after induction continuedthe regimen for up to 2 years.

Obinutuzumab was tolerable, butmore infusion-related reactions werereported with it than with rituximab(74% vs 51%, respectively), including11% and 6%, respectively, that weregrade 3 or 4.

Additional data were presented

from other phase 2 studies of patientswith relapsed/refractory indolentNHL showing encouraging activityfor obinutuzumab as a single agentand in combination with fludarabineand cyclophosphamide or CHOP(cyclophosphamide, doxorubicin, vin-cristine, and prednisone). Responseswere seen in patients with NHLrefractory to rituximab.

At a press briefing, Dr Sehn saidthat “Unlike rituximab or other anti-CD20 agents in development, GA101is a type 2 (humanized) monoclonalantibody. In preclinical testing, it hasbeen shown to have a greater abilityto directly cause cell death and toinduce a greater immune-type reac-tion against the tumor. What isrequired now is to move this into tri-als to see if this translates into benefitsfor patients.”

Jane Winter, MD, of NorthwesternUniversity Feinberg School of Med -icine, Chicago, moderated the pressbriefing. She commented, “This studyshows how our new technologies areproviding us with tools that are betterthan we have had before. Dr Sehnshowed the benefit of bioengineeringan antibody, which is different fromserendipitously finding one that iseffective.”

With the improved response ratesand favorable toxicity profile, Dr Sehnand her colleagues concluded that,“phase 3 trials to truly test its efficacyare warranted.” Studies are now com-paring obinutuzumab plus CHOP, orother regimens with rituximab plusCHOP.—CH �

Obinutuzumab Could Give Rituximab a Run for Its Moneyin Relapsed Indolent NHL

Lymphoma

“Unlikerituximab orother anti-CD20agents indevelopment,

GA101 is a type 2 (humanized)monoclonal antibody. Inpreclinical testing, it hasbeen shown to have agreater ability to directlycause cell death and toinduce a greater immune-typereaction against the tumor.”

—Laurie H. Sehn, MD, MPH


Ever since Dolly, the first clonedsheep, made the global head-lines, scientists, clinicians, busi-

nesspersons, and no small army ofscience fiction writers have beenimagining the technology’s potential.However, the technical and ethicalcomplexities of the task abound.

Now it appears that one very criti-cal application of cloning technologymay be realized by thinking small, asin the in vitro production of humanplatelets, according to Naoya Taka -yama, MD, PhD, of the Center for iPSCell Research and Application atKyoto University in Japan.

Dr Takayama and colleagues arepioneering a technique that avoids atleast the ethical issues related to theuse of embryonic stem cells by usingpluripotent adult stem cells, which

can come from any living person.“This work is preliminary, but thepromise it holds is wonderful,” com-mented Peter D. Emanuel, MD, of theUniversity of Arkansas for MedicalSciences, Little Rock, and Liaison,Chair, Committee on Communicationsfor ASH 2011.

The technique described by DrTakayama employed human-inducedpluripotent stem cells (hiPSCs),specifically, an immortalized mega -karyocyte progenitor cell line derivedfrom hiPSCs, which is the bone mar-row cell type responsible for produc-ing thrombocytes (platelets). Themegakaryocytes were induced tomake platelets through temporalmanipulation of the activation of theregulator gene, c-MYC, and associat-ed downstream factors, INK4A and

ARF. The resultant cell line subse-quently showed proplatelet formation

leading to the release of functionalCD41a+/CD42b+ platelets.

The compatibility of the cloned cellswas validated by the transfusion ofplatelets into immunodeficient mice.

The platelets were accepted, and theyexhibited normal circulation 24 hoursafter their transfusion.

Dr Takayama concluded, “Throughgene manipulation one could poten-tially provide a stable supply ofplatelets at a predefined quality andquantity for transfusion therapy.”

“Platelet supplies for transfusionsare always in short supply,” said DrEmanuel. “The shelf life is short, anddonors are less willing to donatebecause it takes more time than wholeblood. So, if we could mass-producethem in the laboratory, it would be amajor step forward.”

Dr Emanuel further pointed outthat not only would patients benefit,but a ready-made platelet supplycould dramatically reduce the associ-ated costs. �

Ready-Made Platelets? A Boon for Patients If It WorksBy Neil Canavan

Venous thromboembolism (VTE)is a common cause of seriousmorbidity and mortality, and

patients with cancer are at particularrisk. “VTE has a substantial burdenon the current US medical system. Itspreventable costs and indirect costsfrom premature deaths are substan-tial,” said Alex C. Spyropoulos, MD,of McMaster University, Hamilton,Canada.

Dr Spyropoulos and colleaguesdeveloped a decision tree and costmodel to estimate the national health-care costs for pulmonary embolism(PE), total hospital-acquired PE, andtotal preventable PE. The modeldemonstrated annual savings of $4.6billion to $14.3 billion in the basemodel, and as high as $12.8 billion to$42.2 billion when adjusted to 2011 USdollars in the sensitivity analysis.

The authors concluded that “appro-priate type, dose, and duration of pro-phylaxis is cost-effective.”

VTE Prophylaxis Is Cost-Effective

Other investigators from theUniversity of Pittsburgh agreed thatVTE prophylaxis is cost-effective. Asbackground, they noted that despiteevidence that low-molecular-weightheparin (LMWH) has antitumoreffects and improves short-term sur-vival, the cost-effectiveness of anticoagulation in ambulatory cancerpatients is unknown.

Allyson Pishko, BS, and colleaguesconstructed a Markov model to eval-uate prophylactic anticoagulationwith enoxaparin in such patientswith no previous VTE during 4months of chemotherapy. The modelused data from a 2011 CochraneReview of 9 randomized controlledstudies of cancer patients with noindication for anticoagulation pro-phylaxis. The researchers measuredmedical costs, effectiveness (mea-sured by mortality reduction), quali-ty-adjusted life-years (QALYs), andincremental cost-effectiveness ratio(ICER) over a 24-month period.Enoxaparin 40 mg/day was estimat-ed to cost $1132 per month.

The cost of treating a major bleed-ing event was $5317 and the cost of a

minor bleeding, $73. Death was calcu-lated at $5000. Compared with noLMWH, 4 months of primary prophy-laxis with enoxaparin was associatedwith a relative mortality risk of 0.92over 24 months, at a gain of 0.0484QALY, for an ICER of $76,922 perQALY gained. The relative risk fordeep-vein thrombosis was 0.55.

“This is well within the accepted$100,000/QALY threshold,” Ms Pishkosaid. However, if the ICER increasesto >$100,000 per QALY, it may nolonger be considered cost-effective.

“Prophylactic anticoagulation ap -pears to be cost-effective in ambula-tory cancer patients during the first 4months of chemotherapy. If the sug-gested mortality benefit is confirmedby additional randomized controlled

studies, administering anticoagula-tion to ambulatory cancer patientsduring high-risk chemotherapy treat-ments should be considered,” sheconcluded.

Electronic Reminder Enhances

VTE Prophylaxis

The use of an electronic “smartorder set” to remind physiciansabout VTE risk boosted the use ofVTE prophylaxis within JohnsHopkins Hospital. The interventionalso dramatically reduced the rate ofsymptomatic VTEs, reported AmerM. Zeidan, MD, of Johns HopkinsUniversity.

A review of patient records showedthat risk-appropriate prescribing ratesrose from 68% to 86% when the smartorder set was added to the institu-tion’s decision support (P <.001). Therate of VTE episodes within 90 days ofadmission fell from 2.5% to 0.7% (P =.002) as a result of VTEs that occurredpostdischarge; the rates of majorbleeding did not increase with the useof VTE prophylaxis.

This intervention was developedafter an internal review showed thatVTE prophylaxis was not being pre-scribed for many patients deemed eli-gible by national guidelines. “Ourresults support the use of a mandatedrisk-adaptive strategy for considera-tion of VTE prophylaxis for every hos-pitalized patient,” Dr Zeidan said. �

VTE Prophylaxis during Chemotherapy Cost-Effective Venous Thromboembolism a Common, Costly Adverse EventBy Caroline Helwick

“Through gene manipulationone could potentially providea stable supply of plateletsat a predefined quality andquantity for transfusiontherapy.”

—Naoya Takayama, MD, PhD

“Prophylacticanticoagulationappears to be cost-effective inambulatory cancerpatients during thefirst 4 months ofchemotherapy.”

—Allyson Pishko, BS

Other Highlights

New Data: 5-Year Median Follow-up

I

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

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

50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com

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

‡VELCADE (Vc) in combination with MP.

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

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New Data: 5-Year Median Follow-up

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MP (n=338)

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IMPORTANT SAFETY INFORMATIONVELCADE Warnings and Precautions ▼ Women should avoid becoming pregnant while being treated

with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

▼ Peripheral neuropathy, including severe cases, may occur—manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

▼ Patients with risk factors for, or existing heart disease, should be closely monitored

▼ Acute diffuse infiltrative pulmonary disease has been reported

▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement

▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Adverse Reactions Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page.

Median overall survival:

56.4 vs 43.1 months HR=0.695 (95% CI, 0.57-0.85); P<0.05

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

Kaplan-Meier estimate.

1 9:27 AM

Hematopoietic cell transplant(HCT) cures many hemato-logic malignancies, but recip-

ients remain at high risk for chronicmedical and psychological conditions,according to the first-ever study ofthese long-term outcomes.

“It is important to realize that once atransplant is over, it is not really over,”said Stephanie J. Lee, MD, MPH,University of Washington School ofMedicine, Seattle, who commented onthe findings at a press briefing.

The study showed that the burden

of long-term physical and emotionalmorbidity experienced by survivors≥10 years posttransplant can be sub-stantial and often results in high uti-lization of specialized healthcareresources.

Can-Lan Sun, PhD, of the City of

Hope Comprehensive Cancer Center,Duarte, CA, who presented theresults, said that high-intensity thera-peutic exposures, as well as prolongedimmunosuppression regimens, canincrease the risk for long-term compli-cations after HCT, and these problemsonly accelerate over time.

There is a need for special clinicsthat would follow these patientsaggressively, detect complicationsearly, and reduce the associated mor-bidity, Dr Sun said.

She and her colleagues evaluatedthe risk for chronic medical and psy-chological conditions in 366 individ-uals who had received HCT at least10 years earlier, along with 309 oftheir siblings, who served as controls.A severity score was assigned foreach medical condition, and the BriefSymptom Inventory was used todescribe adverse psychological condi-tions. The investigators also accessedhealth records.

Long-Term Complications

The most often reported severe orlife-threatening chronic health condi-tions included myocardial infarction,stroke, blindness, diabetes, muscu-loskeletal problems, and subsequentmalignancies. The 15-year cumulativeincidence of any chronic health condi-tion was 71%, and for severe life-threat-ening conditions or death was 40%.

Compared with age- and sex-matched siblings, HCT survivors hada 5.6 times increased risk for asevere/life-threatening condition. Thecumulative incidence of these prob-lems did not differ by type or HCT.

Anxiety and depression scores werecomparable between survivors andtheir siblings, but somatic distress wasmore common among transplantrecipients. Survivors were 2.7 timesmore likely to report somatic distress.In addition, female sex, low house-hold income, and poor self-ratedhealth status were associated witheven higher risks for somatic distress.

The vast majority (90%) of HCTsurvivors reported having healthinsurance coverage, which the investi-gators noted was “fortunate,” consid-ering their need for ongoing special-ized care. �


VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139Copyright © 2011, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

INDICATIONS:

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

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastictherapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. :However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatmentwith VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These:events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of :decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown :etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial,the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients:receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and :vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid andelectrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that:follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the:complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant :medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients:with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becomingpregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesisat a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA:

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

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo);(each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combinationwith melphalan/prednisone is consistent with the known safety profiles of both VELCADE andmelphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%),nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%),constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%),pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%),asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain(14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension(12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%),arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, hadno effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greaterthan 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and mshould be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposureof bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are :excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. :

Geriatric Use: No overall differences in safety or effectiveness were observed between patients : ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of :renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renalinsufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and :severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic :patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

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

V-11-0264 12/11

Other Highlights

High Morbidity Burden Borne Years Later by Survivors of TransplantSevere or Life-Threatening Problems Found in 40% of CasesBy Caroline Helwick

“It is important to realize that once a transplant is over, it is not really over.”

—Stephanie J. Lee, MD, MPH


In the first comparative trial of itskind, the Catheter-Directed VenousThrombolysis (CaVenT) study

determined that treating a clot directlywith the recombinant, antithromboticagent alteplase reduced the frequencyof postthrombotic syndrome (PTS) andimproved long-term outcome inpatients with proximal deep-veinthrombosis (DVT) compared withstandard anticoagulation methods.

PTS can greatly affect a patient’squality of life: 1 in 4 patients withDVT will experience PTS, despite hav-ing been treated according to currentclinical guidelines.

To offset the risk of PTS, alteplasehas been used in this setting. “Thisinterventional therapy is expensive,”

said CaVenT lead investigator ToneRønnaug Enden, MD, PhD, of OsloUniversity Hospital in Norway. “It isalso associated with life-threateningbleeding. However, it has becomestandard care in some centers, despitea complete lack of evidence from ran-domized, controlled trials.”

This multicenter investigationenrolled 209 adults who had experi-enced an objectively verified DVTwithin 21 days of study entry andwho met other entry criteria. Patientswere randomized to standard treat-ment (ie, control group) withheparin/warfarin anticoagulation for6 months, in addition to the use ofelastic compression stockings for 24months, or to standard treatment plus

catheter-directed thrombolysis (CDT)with alteplase for up to 96 hours, butnot exceeding 20 mg/day.

“This is a minimally invasive percu-taneous technique performed withlocal anesthesia,” said Dr Enden.

End points included measures ofoutcome for patient-rated criteria ofpain, cramps, heaviness, pruritus,and clinician-rated criteria of edema,skin induration, hyperpigmentation,venous ectasia, and ultrasoundexamination.

At 24-month follow-up, 37 (41.1%)patients in the CDT group had PTScompared with 55 (55.6%) patients inthe control group, an absolute riskreduction of 14.4%.

Regarding adverse events, 20 bleed-ing complications were reported—3were classified as major and 5 as clin-ically relevant. The majority of bleedswere related to the puncture site, andno bleeding related to CDT led to apermanently reduced outcome.

Dr Enden concluded that the addi-

tion of CDT to standard treatmentimproved long-term outcomes andshould be considered for patients withiliofemoral DVT when there is no con-traindicating risk of bleeding. “Theseresults should be taken into accountwhen guidelines are revised.” �

DVT Prophylaxis: First Comparison of Catheter-Directed Thrombolysis versus Standard CareBy Neil Canavan

Other Highlights

Genetic Profiles Linked toHematologic OutcomesBy Caroline Helwick

Hematologic malignancies arecharacterized by geneticsubtypes with varying prog-

noses. Analysis of these subtypes isbeginning to make a difference inthe clinic.

“Researchers are finding thatgenetic determinants are importantcauses of treatment failure,” saidKathryn Roberts, MD, who presentedthe findings from St. Jude Children’sResearch Hospital in Memphis.

“But it is currently not possible toincrease the dose or intensity of cur-rent therapies because of toxicity,” DrRoberts said.

The findings support the screen-ing of all patients newly diagnosedwith acute lymphocytic leukemia(ALL) for the presence of high-risksubtypes. Identifying these patientsshould help characterize the geneticabnormalities that underlie a uniquesubtype of high-risk B-cell ALL andalso help select candidates for target-ed therapies.

Dr Roberts and her colleagueshave identified a unique subtype ofBCR-ABL–negative, high-risk B-cellALL, with a deletion or mutation ofIKZF1, which confers a poor out-come. They refer to this new subtypeas “Ph [Philadelphia chromosome]-like ALL.” Up to 15% of pediatricALL cases can be classified as Ph-like, and previous trials have shownthat the outcome of these cases canbe improved when tyrosine kinaseinhibitors such as imatinib are

added to chemotherapy regimens. “This study represents potential

changes in care,” said Martin S.Tallman, MD, Chief of LeukemiaServices, Memorial Sloan-KetteringCancer Center, New York, who mod-erated a press briefing. “This studyprovides further evidence that wecan target specific leukemias withdirected therapy, rather than justcontinue to give relatively indiscrim-inate chemotherapy.”

For Lymphoma, Genetic Risk

Score Predicts Outcome

In patients with diffuse large B-celllymphoma (DLBCL), a genetic riskscore based on the expression of asmall number of genes was able topredict clinical outcomes related tospecific treatments, investigators fromthe Eastern Cooperative OncologyGroup (ECOG) and Southwest Oncol -ogy Group reported.

Using tissue from 183 DLBCLpatients in the ECOG E4494 phase 3trial, researchers were able to con-struct a 5-gene predictor model thatidentified outcomes of patients treat-ed with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisolone)and a 6-gene model that was predic-tive in patients treated with R-CHOP(CHOP plus rituximab). High-versus-low genetic risk scores significantlypredicted clinical outcomes at a medi-an follow-up of 9.4 years, reportedJane Winter, MD, of the LymphomaCommittee, ECOG, Chicago, IL. �

“This interventional therapyis expensive. It is alsoassociated with life-threatening bleeding.However, it has becomestandard care in somecenters, despite a completelack of evidence.”—Tone Rønnaug Enden, MD, PhD

Ruxolitinib is the first Januskinase (JAK) inhibitor thatwas approved last year for the

treatment of myelofibrosis. Data pre-sented at ASH 2011 from the ran-domized pivotal COMFORT I trialof 309 patients with myelofibrosisshowed a significant survival advan-tage with ruxolitinib compared withplacebo: 24 patients in the placeboarm died during the study or duringthe extended follow-up comparedwith 13 ruxolitinib-treated patients,representing a 50% risk reductionwith ruxolitinib.

In a post-hoc analysis of COM-FORT II, which compared ruxolitinibwith best available therapy in 219patients, improvements in health-related quality of life were signifi-cantly greater in those receiving rux-olitinib. The greatest differenceswere reported in improvements inappetite loss, dyspnea, fatigue,insomnia, and pain.

“Myelofibrosis is a life-shorteningdisease, with symptoms that signifi-cantly compromise patients’ every-day lives,” said investigator ClaireHarrison, MD, of Guy’s Hospital,London. “As a result, therapies that

address the severe burden of myelo -fibrosis are urgently needed.”

CYT387 Promising in Anemia

Responding to this urgent need, thenew JAK inhibitor, CYT387, is current-ly furthest along in development formyelofibrosis, demonstrating promis-ing results.

The critical issue of this disease isanemia, according to Mark Kowalski,MD, PhD, Chief Medical Officer ofYM BioSciences, the drug’s manufac-turer. “Progressive anemia is a hall-mark of this disease, with the conse-quence that many patients requirefrequent blood transfusions,” said DrKowalski. In addition, anemia is anindicator of poor life expectancy inthis patient population.

In ongoing analyses of the phase1/2 CYT387 dose-ranging trial in 166patients with myelofibrosis, 54% of the68 patients who were transfusion-dependent at baseline became transfu-sion-independent by 12 weeks. Inaddition, 65% of patients receiving 300mg daily became transfusion-free. Themean duration of response exceeded 6months. Phase 3 trials for CYT387 areslated to begin soon.—NC �

Favorable Data for Ruxolitiniband for a New JAK Inhibitorin Myelofibrosis

©2011 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

goal

One goal: discovering and delivering breakthrough medicines to combat cancer.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in

oncology worldwide — with more than 17 compounds in development for a broad range of solid and

hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease

pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition,

apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a

dramatic impact on cancer therapeutics over the next decade.

AHDB February Vol 5 No 1 Special Issue

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