AHDB February Vol 5 No 1 Special Issue

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

February 2012 I Vol 5, No 1 I SPECIAL ISSUE

ASH 2011: PAYERS’ PERSPECTIVES AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

Hematologists Are Told to Get Ready for ACOs

Hematologic Pipeline Abundant

A Medical Home May Be a Viable Alternative

T

Many Drugs Show Impressive Results

By Caroline Helwick he hematology drug pipeline is chock full of novel agents that are yielding impressive responses in patients with various tumor types, often with less toxicity than seen with standard agents and, in some cases, overcoming adverse cytogenetic profiles.

By Neil Canavan

Chronic Myeloid Leukemia Ponatinib, an oral third-generation tyrosine kinase inhibitor (TKI), appears capable of overcoming the T315I mutation in chronic myeloid leukemia (CML), a mutation that makes it extremely difficult to treat the tumor. In the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, major cytogenetic response was 47% after treatment with ponatinib, and

65% among patients with the mutation. PACE included 499 patients with CML or with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who were resistant to or intolerant of nilotinib or dasatinib, or who had the T315I mutation. High levels of response were seen in all patient types, including major histologic responses in 74% and major cytologic responses in more than 50% (see article, page 12).

In the 12-month data from the BELA (Bosutinib versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia) trial, which evaluated the TKI bosutinib in 502 treatment-naïve CML patients, the rate of complete response (CR) plus major molecular response was 67% with bosutinib verContinued on page 8

A

ccountable care organizations (ACOs) are the new model of care that has generated a buzz in the industry, but their role in hematology and oncology practices remains unclear. “They’re like unicorns,” said Lawrence A. Solberg, Jr, MD, PhD, of the Mayo Clinic, Jacksonville, FL. “We have an idea of what they’re supposed to look like, we’ve read about them, but I’ve yet to meet a hematologist who’s actually seen one.”

The healthcare reform focuses on

the formation of ACOs as key to transforming the current fee-for-service business model to a model in which provider groups will receive bundled payments, based on measures of the quality and value of care.

Dr Solberg moderated a Practice Forum panel at ASH 2011, titled “How to Prepare Your Practice for ACOs and Other Payment and Health Reforms.”

The Options for Hematologists “The take-home is this,” said panel Continued on page 5

A Large Study Sheds Light on the Cost of Managing NHL

Chronic Myeloid Leukemia: Are We Close to Finding a Cure?

By Neil Canavan

T

he cure for chronic myeloid leukemia (CML) is a topic of intense debate among hematologists these days, not only the possibility of achieving it but what cure actually means.

“What do we mean by ‘cure’?” asked Junia Melo, MD, PhD, Imperial College of Medicine, London, speaking at a CML education session at ASH 2011.

Continued on page 10

IN THIS ISS UE

By Caroline Helwick

A

large, ongoing Canadian study provides an overview of the cost of managing nonHodgkin lymphoma (NHL). “Our study provides total and stage-specific cost estimates for NHL, where attributable costs were 3- to 7-fold higher than those for non-NHL controls, and increased by stage,” said Pierre K. Isogai, BSc, of Sunnybrook Health Sciences Centre in Toronto.

One position is that a cure is the eradication of every leukemic cell from the body; a second perspective holds that what is needed is an “operational cure,” meaning the disappearance of all signs of the disease, so that there is no further impact on the patient’s quality of life.

“The first concept is overly simplistic,” said Dr Melo. “Not only is it difficult to achieve; it’s impossible to

Mr Isogai and colleagues identified 13,336 patients with NHL in the Ontario Cancer Registry (2005-2009) and compared them with 65,668 matched controls from the Institute for Clinical Evaluative Sciences database who were demographically similar and used healthcare resources but did not have cancer.

Resources for the analysis included physician visits, hospitalizations,

HEALTH ECONOMICS . . . . . . . . . . .3 First cost analysis of long-term management of CML Guidelines for molecular testing can reduce costs The cost of myeloproliferative disorders is significant

MULTIPLE MYELOMA . . . . . . . .13 5-Year VISTA analysis confirms survival benefit with bortezomib Pomalidomide a promising new agent

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

OTHER HIGHLIGHTS . . . . . . . . 19 VTE prophylaxis during chemotherapy cost-effective Favorable data for ruxolitinib and a new JAK inhibitor in myelofibrosis

Continued on page 8 ©2012 Engage Healthcare Communications, LLC

LYMPHOMA . . . . . . . . . . . . . . . .18 Obinutuzumab shows promise in relapsed indolent NHL

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a trademark of Incyte Corporation. © 2011, Incyte Corporation. All rights reserved.

RUX-1004C

11/11

Health Economics

First Cost Analysis of Long-Term Management of CML Will Newer TKIs Change the Economic Landscape?

By Neil Canavan

F

ew analyses to date have as

costs asso

sessed the long-term ciated with the management of chronic myeloid leukemia (CML). At

ASH 2011, Shrividya Iyer, PhD, of Pfizer, presented results of a retrospective analysis performed by a group of researchers at Pfizer and the

Eliassen Group that looked at information from the Thomson Reuters MarketScan Commercial Claims and Encounters Database, and the Medicare Supplemental Database.

Medical claims for the years 2002-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) All All Laboratory b Grade 3 Grade 4 Grades Grade 3 Grade 4 Grades Parameter BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk 69.7 9.0 3.9 30.5 1.3 0 Thrombocytopenia myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential 96.1 34.2 11.0 86.8 15.9 3.3 Anemia thrombocythemia myelofibrosis.

18.7 5.2 1.9 4.0 0.7 1.3 Neutropenia CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved.

Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

VOL. 5

NO. 1

SPECIAL ISSUE

2009 were used for 2583 patients with CML who had ≥2 claims associated with a CML diagnosis.

The average annual healthcare utilization costs for a patient with CML were $24,391 for outpatient care, $24,462 for inpatient care, and $15,588 for prescription drugs.

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

The proportion of patients with ≥1 CML-related outpatient, inpatient, or emergency department visit annually were: • 94.9% for outpatient visits (55.1 actual outpatient and office visits combined, per patient-year) • 32.4% for inpatient visits (1.3 average number of actual visits) • 15.1% for emergency department visits (1.6 visits).

The average number of drug prescriptions for the entire CML cohort was 6.7 annually, with the tyrosine kinase inhibitor (TKI) imatinib accounting for 85% of those claims.

The average annual costs for CMLrelated healthcare utilization per patient were: • $24,391 for outpatient care • $24,462 for inpatient care • $15,588 for prescription drugs (CML drugs accounted for 73% of overall prescription costs).

Data for patients with ≥4 years of follow-up indicated an increase in outpatient visits, but with nearly equivalent rates for inpatient and emergency department care; for patients with ≥1 CML-related visit, 98% had an outpatient visit, 31% had inpatient care, and 15% had presented to the emergency department on an annual basis.

This analysis did not address the potential cost and utilization impact of the newer TKIs; improved efficacy and reduced side effects may have a positive impact on overall healthcare utilization and costs in the long-term management of CML, but this remains to be seen. ■

FEBRUARY 2012

www.AHDBonline.com

3

ASH 2011: PAYERS’ PERSPECTIVES

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

In This Issue FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

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

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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4

AMERICAN HEALTH & DRUG BENEFITS

HEALTH ECONOMICS First cost analysis of long-term CML management Guidelines for molecular testing can reduce costs The cost of myeloproliferative disorders is significant More…..

LEUKEMIA Bosutinib shows superior results in CML Novel oral B-cell receptor inhibitor effective in CLL Ponatinib overcomes T315I mutation in CML/ALL More…..

MULTIPLE MYELOMA Pomalidomide a promising new immunomodulator Maintenance strategies in elderly patients Next-generation proteasome inhibitors cause less peripheral neuropathy More…..

LYMPHOMA Maintenance rituximab may be unnecessary in follicular lymphoma Obinutuzumab shows promise in relapsed indolent NHL OTHER HIGHLIGHTS VTE prophylaxis during chemotherapy cost-effective First comparison of catheter-directed thrombosis versus standard care Favorable data for ruxolitinib and a new JAK inhibitor in myelofibrosis More…..

WEB EXCLUSIVE Additional ASH 2011 coverage at www.AHDBonline.com

EDITORIAL BOARD CLINICAL EDITOR

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

F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Sharon, MA ENDOCRINOLOGY RESEARCH

GOVERNMENT EDITOR

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

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA HEALTH INFORMATION TECHNOLOGY

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York EMPLOYERS

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

FEBRUARY 2012

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL HEALTH & VALUE PROMOTION

MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy School of Pharmacy University of Missouri, Kansas City Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and PHARMACY BENEFIT DESIGN Scientific Officer Joel V. Brill, MD Worldwide Clinical Trials Chief Medical Officer, Predictive Faculty, Center for Experimental Health, Phoenix, AZ Pharmacology and Therapeutics, Harvard-MIT Division of Health William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Sciences and Technology Harvard Vanguard Medical Associates Cambridge, MA Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

MANAGED CARE & GOVERNMENT AFFAIRS

Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE), Endo Pharmaceuticals, Chadds Ford, PA

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL

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

SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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Health Economics

Hematologists Are Told to Get Ready... member Neil M. Barth, MD, FACP, Newport Pacific Medical Associates, Newport Beach, CA. “Going forward, to satisfy the needs or the reform legislation, efficiencies must be achieved, delivery systems must be integrated, overall utilization must be reduced, and new payment models must be employed.”

“We have an idea of what [ACOs] are supposed to look like, we’ve read about them, but I’ve yet to meet a hematologist who’s actually seen one.”

—Lawrence A. Solberg, Jr, MD, PhD The goal of the patient-centered model of care is to improve outcomes at a lower cost. To achieve this, Dr Barth sees several options.

Remaining an independent subspecialty provider. The first option is to do nothing: “If you choose to maintain the status quo, be locked into a small practice size, and be fiercely independent, you’re probably going to be eaten alive,” warns Dr Barth.

At least based on his experience in California, the writing is on the wall, Dr Barth said. Not only is there a general decrease in reimbursement, but there is also “narrow network pressure,” whereby providers who have high costs are being dropped by payers and are losing their preferred provider status.

“It started out quietly, but this practice is no longer subtle,” said Dr Barth.

The message is clear: when it comes to cost cutting, an individual cannot compete with a group.

Becoming a subspecialty line consultant. The second option is becoming a consultancy. “This is the extreme makeover for the practicing hematologist,” Dr Barth noted. Under this option, the hematologist identifies strengths and services to be offered to the local healthcare system.

“This will require capitalization on service line knowledge. You have to study and to dissect the service line you would manage,” Dr Barth advised.

Some skills may have to be brought in to round out a consultancy package,

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such as actuaries or an MBA degree.

The third option is clinically integrated groups, including ACOs. “This is a legal structure of individuals or even a corporation of corporations; but however it’s configured, the glue holding it all together is IT [information technology].”

“Integration” means the ability to share medical records, allocate resource utilization, and perform cost accounting. “One of the attractive things about this is, most of my colleagues are fiercely independent,” said Dr Barth. “Doing it this way you do not have to give up financial sovereignty, because you’re not under a common tax ID number.”

This model is outside the ACO structure as proposed, but according to Dr Barth, with the blessing of the Federal Trade Commission, it can be done, and such an entity may engage in collective bargaining.

Joining/creating a clinically integrated ACO. ACOs are integrated groups under a financial umbrella, yet cannot be well defined. “If you’ve seen one, you’ve seen one,” Dr Barth said, “and most of us have not seen any. Frankly, we’re not sure how this is going to play out.”

Healthcare reform legislation is still in flux, and ACOs, initially designed with the primary care provider in mind,

Continued from page 1

Dr Sprandio estimates savings of $8.8 million in hospital admissions, $660,000 in emergency department visits, and $12,000 in chemotherapyrelated costs per patient. helps any of these structures come to fruition.” Systems are going to need standardization to store and then share medical records. Evidence-based guidelines must be part of the integration. Algorithms are needed to track performance metrics, and the results will have to be delivered in real time so that providers can compare the results against the agreed-on benchmarks.

The Medical Home Gets Results The definition of a patient-centered medical home (PCMH) varies, but in general the medical home model promotes a team-based approach to patient care through a spectrum of disease states and across various stages of life. Care is led by the patient’s person-

“If you choose to maintain the status quo, be locked into a small practice size, and be fiercely independent, you’re probably going to be eaten alive.”

—Neil M. Barth, MD, FACP

remain to be tailored for the hematologist. The final rules for ACOs were issued in October 2011, and certain changes have been made, including: • The Centers for Medicare & Medicaid Services will annually update ACO patient risk scores • “Meaningful use” for electronic health records is no longer a prerequisite • Start-up funding will be available for physician-group–only ACOs • There is no longer a downside risk in track 1 • The number of quality measures has been reduced from 63 to 33.

Joining a medical foundation. The fourth option for hematologists is joining medical foundations, which are already well integrated and represent the path of least risk and resistance, if available.

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

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

“Applying this model to oncology is what we have been working on for the last several years,” said John D. Sprandio, MD, Chief of Medical Oncology and Hematology at Delaware County Memorial Hospital, Drexel Hill, PA. “Ours was the first in the country to be recognized as a level III patient-centered medical home by the National Committee for Quality Assurance in 2010.”

Dr Sprandio’s PCMH is responsible for coordinating all oncology services.

A primary care provider addresses nononcologic issues, but everyone— surgeons, radiation oncologists, and even hospice staff—is in “intense” communication as part of the overall care unit.

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

oration within the team to assure adherence to treatment guidelines, proactive management of adverse events, palliative care coordination, participation in clinical trials, and active engagement with the patient to develop patient-directed therapeutic goals • The merger of operational and clinical decisions, which include standardization of patient assessments, patient tracking, telephone triage of patients, and patient IT portals (for appointments, etc) • Quality standards, including treating according to guidelines, proactive symptom management, coordinated end-of-life care (shared decision-making), and the creation of high-risk registries • Outcomes can be derived from tools such as the Consumer Assessment of Healthcare Providers and Systems (CAHPS). “We use the CAHPS surveys,” Dr Sprandio said. “It’s a wonderful tool for looking at the actual delivery of care.”

Dr Sprandio shared his experience with the integrated PCMH from 2004 to 2010. “The effects have been substantial in terms of emergency room utilization per patient per year, as well as hospital admissions.” There were 2.6 emergency department visits per patient in 2004, and only 1 visit per patient in 2010; hospital admissions decreased from 1 per patient in 2004 to 6 per patient in 2010.

There was a 23% increase in hospice stays, with 70% of patients in 2010 dying in their own homes. In addition, they had a 40% reduction in the number of admissions in the last 30 days of life and 23% fewer evaluations in the emergency department.

The cost-savings generated by these reductions in utilization were substantial. Dr Sprandio estimates savings of $8.8 million in hospital admissions, $660,000 in emergency department visits, and $12,000 in chemotherapyrelated costs per patient. “Calculated per provider, our hematologists are saving 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 your integration will be done) • Engage payers • Standardize all processes of care • Overall, commit to continuous process improvement.

The panelists conceded that questions regarding the ideal model remain and uncertainty regarding ACOs abounds, especially with regard to hematology/oncology practices. ■

FEBRUARY 2012

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5

Health Economics

Guidelines for Molecular/Cytogenetic Tests Could Eliminate Overordering, Reduce Costs Vanderbilt Hematologists Institute New Standards, Improve Outcomes

By Caroline Helwick

I

nstituting guidelines-based test ordering could lead to more effective, accurate, and complete diagnosis and monitoring of hematolymphoid malignancies, while reducing costs, according to hematopathologists at Vanderbilt University Medical Center, Nashville, who said that tests were frequently overordered by their hematologists.

Molecular and cytogenetic testing is critical in the diagnosis and management of hematologic malignancies, but these can be complex and expensive. No comprehensive guidelines exist for the disease- and patient-specific selection of these tests.

The Hematopathology Diagnostic Management Team explored the hypothesis that there is significant variability in test-ordering patterns, including overordering of unnecessary tests and underordering of necessary tests. They established evidencebased standard operating procedures for molecular and cytogenetic test ordering, which pathologists would apply after a review of the patient’s clinical history and bone marrow morphology. These standards were then compared with current practices at Vanderbilt.

“We found that if we followed the

guidelines in all cases, and eliminated excess testing, we would save our payers $1.25 million a year,” said Adam C. Seegmiller, MD, PhD, a hematopathologist who led this study.

on 804 bone marrow biopsy specimens; this included 769 karyotypes, 1790 fluorescence in situ hybridization assays, and 448 molecular tests.

Comparing how clinicians ordered

“We found that if we followed the guidelines in all cases, and eliminated excess testing, we would save our payers $1.25 million a year.”

—Adam C. Seegmiller, MD, PhD

“Before we instituted this, we found that clinicians had a tendency to overorder tests when doing molecular cytogenetic testing before the bone marrow biopsy was done,” Dr Seegmiller said. “We created a standard operating procedure based on current guidelines, best evidence, and best clinical practice. We decided what tests should be ordered for 6 categories of disease and their stages. It’s a very simple chart.”

They evaluated 3007 ordered tests

(or did not order) tests with this new standard operating procedure showed that: • Only 1927 tests (64%) were concordant with the new guidelines • 1080 tests (36%) were discordant • 307 tests were omitted that would have been recommended by the new guidelines.

“Over one third were tests that the guidelines would not have recommended [ie, overordered], while 307 tests should have been ordered but

were not,” Dr Seegmiller noted.

By stage and clinical scenario, for example, there was 99% concordance between clinicians’ ordering and guidelines for the diagnosis of myeloma, but 0% concordance for testing during follow-up, and 0% posttransplant. For lymphoma, concordance was 81% for diagnosis, 41% for staging, 13% for follow-up, 70% pretransplant, and 32% posttransplant.

“Among discordant tests, only 4% came back positive [ie, detected a mutation], but more than one third of these were redundant. They were positive, but we would have caught these cases elsewhere,” he said. Only 1% of cases were true positives that would have been missed.

“We think we are not only eliminating unnecessary tests, but also increasing the effectiveness of the tests we are using,” Dr Seegmiller added.

“We have now given hematologists the option to turn over all the testing decisions to the hematopathologists, and about 80% of the time our clinicians do that,” he said. Using this new standard, “the hematopathologist makes a decision for testing based on the patient’s clinical history, the appearance of the bone marrow morphology, and the guidelines.” ■

Cost of Treating Myeloproliferative Neoplasms Is Significant

By Neil Canavan

A

new cost analysis of the management of the 3 subtypes of myeloproliferative neoplasms (MPNs)—myelofibrosis, polycythemia vera, and essential thrombocythemia—shows that associated medical and pharmaceutical expenses for patients with these hematologic disorders in patients with cancer are 2 to 6 times that of matched patients without cancer.

Outpatient visits for MPN accounted for more than 50% of the total costs incurred by patients with cancer.

“Some symptomatic treatment options exist, but with the exception of hematopoietic stem-cell transplant, none are curative. And little is known about healthcare costs associated with these diseases,” according to Gregory L. Price, MPH, who presented the data at ASH 2011.

The median survival in these MPN subtypes ranges from months to years for myelofibrosis, and as long

6

as a decade or more for patients with polycythemia vera and essential thrombocythemia.

To perform this cost analysis, data for the years 2005-2008 were extracted from the Thomson Reuters MarketScan database, which includes claims data from more than 100 US payers.

Patients eligible for analysis had to have an MPN diagnosis code for the study period.

Data on matched patients with no cancer (ie, the control group) were selected based on sex, year of birth, geographic region, and insurance type.

Calculated costs were based on total gross payments to the provider.

Total costs were defined as the sum of MPN- and non–MPN-related medical costs, including inpatient, outpatient, and emergency department services and pharmacy. Costs related to pharmacy included chemotherapy (injectable and otherwise) and other prescription supportive care.

AMERICAN HEALTH & DRUG BENEFITS

FEBRUARY 2012

Table Mean Costs for MPNs: Patients with Cancer versus Controls

Costs

Patients Patients with Control with cancer group cancer and MF with MF and PV

Outpatient

$18,395

$3053

$5688

$2541

$8598

$2714

$7803

$1881

$2540

$1474

$2855

$1426

$34,690

$6899

$11,927

$5510

$19,672

$5683

Pharmaceutical Total

Control group with PV

Patients with cancer and ET

Control group with ET

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

A total of 25,145 patients with MPN were included in the analysis.

As expected, all MPN-related costs for the parameters selected exceeded those of noncancer controls. Results for outpatient care cost, pharmaceutical cost, and total cost are highlighted in the Table.

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

was the first drug to be approved by the US Food and Drug Administration for myelofibrosis and related diseases.

New JAK inhibitors are currently in development.

LY2784544, a JAK2 inhibitor, is currently in phase 1 clinical trials. Preliminary data for the current 19 patients enrolled have been presented at the meeting. ■

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Health Economics

Radiologic Surveillance for Early-Stage Hodgkin Lymphoma an Unnecessary Expense?

Most Relapses Identified without Imaging

By Caroline Helwick

P

atients with early-stage nonbulky classic Hodgkin lymphoma (HL) receive intensive radiologic surveillance after treatment, despite a low risk for relapse. A study from Memorial Sloan-Kettering Cancer Center (MSKCC) concluded that routine imaging is unnecessary.

The study evaluated the risk for relapse and value of imaging in a subset of patients who achieved complete remission (by positron-emission tomography [PET]) after 6 cycles of standard chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).

“We asked whether achieving a PET-negative complete remission would obviate the need for radiologic surveillance,” said Sidonie HartridgeLambert, MBBS. “We found that omitting radiologic surveillance would reduce healthcare costs and also radiation exposure, which is important in guarding against second malignancies.”

Dr Hartridge-Lambert said that interim and end-of-therapy PET scanning can provide prognostic information in predicting relapse in HL, but practice and surveillance patterns vary considerably. The pretest

“We found that omitting radiologic surveillance would reduce healthcare costs and also radiation exposure, which is important in guarding against second malignancies.”

—Sidonie Hartridge-Lambert, MBBS

probability for relapse in patients with nonbulky classic HL is low, and the incidence of relapse in early-stage

patients after a negative posttreatment PET is extremely low.

“Research suggests that most relapses are identified without imaging,” she said, “and relapse patterns suggest that imaging may be of limited benefit 2 years after therapy.”

The study included 47 patients who were treated at MSKCC with initial staging by PET and interim and/or posttreatment PET, plus adequate follow-up. All patients achieved complete remission. Interim restaging included 39 PET and 8 computed tomography (CT) scans, identifying 1 positive result. Posttreatment restaging involved 33 PET and 14 CT scans, with 1 positive.

The 2 patients with positive PET scans were biopsy-proven sarcoid.

Two patients relapsed at 7 and 24 months: the first relapse was identified by surveillance scan, the second occurred simultaneously with the resumption of disease symptoms.

The 2 relapsed patients are currently in complete remission after stem-cell transplant.

The other 45 patients had a durable complete remission, of whom 21 had additional unscheduled imaging or work-up during surveillance

for various reasons; 5 patients had further PET scans to confirm complete remission.

Financial Implications of Surveillance The costs per scan for each patient during the posttreatment surveillance were based on standard, national Medicare reimbursements of $770 per CT and $1181 per PET. Multiplied by the number of scans per patient, and excluding relapses, the cost of follow-up was $181,720 for CT (median, $3850), rising 16% to $210,064 including PET (median, $4620).

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

“Our results, in conjunction with the growing concerns about radiation dose from medical imaging studies, suggest that surveillance imaging in this subset of patients treated with 6 cycles of ABVD alone could be ceased altogether,” she said.

Instead, patients should be closely monitored with history, physical examination, and routine blood work. ■

Graft-versus-Host Disease Often Leads to Posttransplant Readmission, High Costs

G

raft-versus-host disease (GVHD) remains a common complication of hematopoietic stem-cell transplant, but little is known about the rate of hospital admissions and the associated costs. Fiona L. Dignan, MD, of the Royal Marsden Hospital, United Kingdom, presented a study comparing readmission rates and associated costs between patients with GVHD and controls.

The analysis included all patients undergoing allogeneic stem-cell transplant (two thirds for leukemia) at the hospital between 2006 and 2009, and followed for a median of 3.2 years.

Costs were based on hospitalization charges in 2010 currency. Additional drug or procedural costs were not included.

Of 187 patients receiving transplant, 118 (63%) developed GVHD,

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49% of which was grade 4. The only significant difference between patients with and without GVHD was the increased use of alemtuzumab in the non-GVHD group, 71% versus 54%. Of the 118 patients, 38% had biopsy-proven GVHD, 88% required steroid treatment, and 52% were steroid-refractory.

Acute GVHD was present in 44% of patients, chronic GVHD in 19%, and acute and chronic GVHD in 30%.

Seven percent developed GVHD after donor lymphocyte infusion.

Costs and Services Increased 2-fold or More in GVHD Patients Patients developing GVHD had a significantly higher overall hospital readmission rate after transplant, 89% versus 68% for controls, and a higher mean cost of readmission,

€32,217 compared with €15,622, Dr Dignan reported.

“This study shows the high readmission rates and costs associated with the development of GVHD, and highlights the need for new treatment approaches for this condition.”

—Fiona L. Dignan, MD They also had a significantly higher mean total number of readmission days, 42 versus 18, and a higher admission rate to the critical care unit, 34% versus 12%.

For patients with grade 3/4 GVHD,

compared with grade 1/2, differences were also apparent. More severe patients had a higher mean total number of readmission days, 57 versus 37 (P = .054), and a numerically higher readmission rate, 96% versus 88%.

The mean cost of admission for this group was almost double, €44,535 versus €27,001.

“This study shows the high readmission rates and costs associated with the development of GVHD, and highlights the need for new treatment approaches for this condition,” Dr Dignan concluded.

Severe GVHD greatly compromised survival. At 3 years posttransplant, approximately 40% of patients did not develop GVHD, but that proportion dropped to <20% for patients with grade 3/4. Grade 1/2 disease did not diminish survival odds.—CH ■

FEBRUARY 2012

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7

Health Economics

Hematologic Pipeline Abundant... sus 52% with imatinib. The US Food and Drug Administration has accepted a new drug application for bosutinib on January 27, 2012 (see article, page 9).

Other Leukemias Blinatumomab more than doubled the CR rate in adult patients with relapsed or refractory B-precursor ALL compared with standard therapies. Blinatumomab is a BiTE (bispecific T-cell engager) antibody that directs the patient’s cytotoxic T-cells to attack CD19-expressing cancer cells. In a phase 2 study of 25 patients, 68% achieved a CR or a CR with partial hematologic recovery with blinatumomab. Median duration of CR was 7.1 months, and median overall survival (OS) has not been reached (see article, page 12).

PCI-32765, a novel inhibitor of Bcell receptor signaling, this oral drug in early development achieved high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia who were refractory to at least 2 previous treatments, according to updated results of a phase 1b/2 study. This drug represents the first in class of Bruton’s TKIs. In a phase 1b/2 study of 61 patients, response rates approached 50%, depending on dose, and seemed independent of molecular risk features. The 6-month progression-free survival is >90%. Phase 3 trials are planned (see article, page 11).

Updated interim results of a phase 2 monotherapy study of quizartinib (AC220), a new FLT3 inhibitor, suggest that this drug can achieve clinically meaningful responses in patients with both refractory and relapsed FLT3-ITD–positive acute myeloid leukemia (AML). In an exploratory analysis of the 62-patient trial, many patients who were treated with this

drug were able to go on to hematopoietic stem-cell transplant. The composite CR rate reached 46%, with partial responses (PRs) in up to 22%.

Quizartinib is one of the first drugs to induce CRs as a single agent in AML. Multiple Myeloma Data are maturing for carfilzomib, the next-generation proteasome inhibitor, and US Food and Drug Administration approval is expected soon. High response rates and minimal toxicity (including less peripheral neuropathy) were observed when carfilzomib was combined with lenalidomide and low-dose dexamethasone in a phase 2 study of 53 patients. PRs or greater (≥PR) were observed in 94% of patients after 1 cycle, and 53% achieved CR or a stringent CR. Response was not affected by stage or cytogenetics (see article, page 16).

Still in early-phase studies but already generating excitement is the first oral proteasome inhibitor, MLN9708. In a phase 1 study of 56 heavily pretreated patients (46 can be evaluated), 6 achieved ≥PR, 1 patient achieved a minimal response, and 28 patients achieved stable disease, some lasting >16 months. In previously untreated patients, the drug is highly active, according to a phase 1/2 study that showed 9 of 10 patients achieved ≥PR. No peripheral neuropathy grade 3 or higher has been reported with MLN9708. Phase 3 trials will begin next year (see article, page 16).

Monoclonal antibodies are also entering the treatment arena for myeloma. Elotuzumab, the first of these agents, led to very high response rates (82%) and prolonged remissions when combined with lenalidomide in 73 relapsed/refractory patients in a phase 2 study. Median progression-

A Large Study Sheds Light... emergency department visits, drugs, home care, and same-day surgeries.

Costs were inflated to 2009 Canadian dollars ($0.88 US) and were presented as the mean annual cost for all patients and by clinical stage. A public payer’s perspective was used.

The participants’ median age was 68 years, and 55% were male. Geographically, 86% of both groups were from urban areas.

The mean cost difference between the NHL and the control groups represents the mean cost attributable to NHL diagnosis and treatment.

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

8

Continued from page 1

free survival had not been reached by the time of the report, and the responses were highly durable. The drug also appears active even in cytogenetically high-risk patients. Phase 3 trials are ongoing, both in previously untreated patients and in relapsed/refractory patients (see article, page 16).

A novel immunomodulatory drug, pomalidomide, also earned high praise from myeloma experts. In a phase 2 study in 221 relapsed/refractory patients, pomalidomide plus low-dose dexamethasone led to PRs in 34% of patients, and minor responses in 11%. Median OS was nearly 17 months. In treatment-refractory patients, a French phase 2 study of pomalidomide plus low-dose dexamethasone showed similar activity, with median OS of 13 months. Phase 3 trials are currently evaluating pomalidomide in various combinations (see article, page 14).

Two histone deacetylase inhibitors showed activity in patients with relapsed/refractory myeloma. In the global phase 3 VANTAGE trial of 635 patients, vorinostat plus bortezomib significantly prolonged remission compared with bortezomib alone, reducing the risk of progression by 23% (P = .01) and improving response rates from 41% to 56% (P <.001).

In the phase 2 PANORAMA-2 study of 55 treatment-refractory patients, pano­binostat plus bortezomib and dexamethasone produced a clinical benefit rate of 49%. Panobinostat is being combined with a number of different drugs in ongoing studies in myeloma (see article, page 14).

Lymphoma In patients with relapsed indolent non-Hodgkin lymphoma (NHL), a “glycoengineered” humanized antibody against CD20, obinutuzumab

Patients with nonHodgkin lymphoma, $

Control group, $

Difference, $

Ontario Health Insurance Plan

3509

1375

2134

Hospitalization

10,401

1811

8590

Same-day surgery

384

189

195

Drugs

6283

1174

5109

Home care

667

260

407

21,244

4809

16,435

Total

NHL indicates non-Hodgkin lymphoma.

AMERICAN HEALTH & DRUG BENEFITS

FEBRUARY 2012

Myelofibrosis CYT387, a new Janus kinase (JAK) inhibitor, proved capable of keeping patients with myelofibrosis free of transfusion in a phase 1/2 trial of 166 patients. In the study, 54% of the 68 patients who were transfusion-dependent at baseline became transfusionindependent by 12 weeks, with a mean duration of response >6 months. Phase 3 trials for CYT387 are slated to begin soon (see article, page 23). ■

Continued from page 1

Table Mean Annual Costs of Managing Patients with NHL versus Controls Cost category

(GA101) produced comparable outcomes to rituximab in the first headto-head comparison of these drugs, the phase 2 GAUSS trial of 175 patients. Response rates to induction were significantly higher with obinutuzumab than with rituxumab by independent radiology review: 44.6% versus 26.7% (P = .01). The primary end point, however, response according to local investigators, was numerically although not significantly different: 44.6% and 33.3% (P = .08). Median progression-free survival was approximately 17 months in each arm. The study was not designed to show superiority, but to determine if a randomized trial was justified, and trials are now under way comparing the 2 drugs, which are given with chemotherapy (see article, page 18).

In systemic anaplastic large-cell lymphoma, an aggressive subtype of mature T-cell NHL, a multicenter phase 2 study in relapsed/refractory patients found durable clinical remissions and high response rates after treatment with brentuximab­vedotin, an anti-CD30 antibody conjugated to an antimicrotubule agent. Overall response rates were 86%, and CRs were achieved by 56% of patients, with a median duration of response that had not been reached by the time of the analysis.

diagnosis ranged from $9575 for stage I to $26,099 for stage IV. “So, for a typical patient, we spent about $16,000 extra per year,” Mr Isogai noted. “By stage, end of life was the most expensive, costing up to $25,000 versus less than $10,000 for stage I patients.”

Five cost categories were analyzed by the time for reporting at the meeting: health insurance plan, hospitalization, same-day surgery, drug, and home care (Table).

The study is ongoing; the researchers will be analyzing additional data, including cancer clinic visits, other drugs, and radiation therapy. ■

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Health Economics

Is Plerixafor Cost-Effective for Stem-Cell Mobilization?

By Caroline Helwick

T

wo studies presented at ASH 2011 reached different conclusions regarding the costeffectiveness of routine use of the upfront stem-cell mobilizer, plerixafor (Mozobil), before the use of autologous stem-cell transplant.

Reserve Plerixafor for Poor Mobilizers The addition of chemotherapy to granulocyte colony-stimulating factor (G-CSF) for stem-cell mobilization can increase cell yield and improve mobilization outcomes relative to G-CSF alone. A multicenter study investigated the use of mid-dose VP-16 (etoposide) plus G-CSF in patients with lymphoma and whether plerixafor might be incorporated into this chemo-mobilization backbone in a cost-effective way.

Using a predictive modeling approach, plerixafor could be reserved for patients predicted to be “poor mobilizers,” said William Wood, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.

“Poor mobilizers” were defined as patients failing to produce 5 × 106 cells in ≤2 days. The researchers identified certain predictors for poor mobilization.

Of 159 patients in this study:

• 90 (57%) were identified as “good mobilizers” • 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 and 15) accurately predicted good versus poor mobilizers, Dr Wood said.

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

“We estimated that it would not be cost-effective to give plerixafor to all patients, even if 100% of patients subsequently became good mobilizers.”—William Wood, MD plerixafor to all patients, even if 100% of patients subsequently became good mobilizers,” he said.

Instead, by reserving plerixafor for only predicted poor mobilizers at the time of first CD34+ count, the investigators estimated that 64% of these patients would need to become good mobilizers to achieve cost neutrality.

The researchers are still determin-

ing the cost-effectiveness of adding plerixafor in patients predicted to be poor mobilizers.

Plerixafor Upfront Is Cost-Neutral By contrast, the researchers from Mount Sinai Medical Center, NY, concluded that upfront use of plerixafor does not add a substantial cost burden in the setting of transplant for multiple myeloma.

This prospective study included 50 patients with myeloma who underwent transplant, 25 of whom received plerixafor in combination with G-CSF and 25 received G-CSF alone as an upfront mobilization strategy.

Compared with G-CSF alone, plerixafor mobilizations yielded higher numbers of CD34+ cells/kg, higher numbers of CD34+ cells infused, required fewer G-CSF doses for stemcell collection and for neutrophil recovery, and less apheresis. The plerixafor group had a longer time to neutrophil engraftment; however, this did not translate to longer days of hospitalization posttransplant, said Luis Isola, MD. The plerixafor group required fewer G-CSF doses for mobilization and for neutrophil recovery, and fewer apheresis sessions. Therefore, this group had a lower cost of G-CSF per

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

“Using plerixafor for upfront autologous stem-cell mobilization...does not have a substantial pharmacoeconomic impact.”

—Luis Isola, MD The mean number of plerixafor doses per patient was 1.8, with a $9081 cost per patient.

“Based on our interim data for overall cost analysis, the plerixafor group had similar cost for blood products per patient, overall cost of medications, overall cost of hospitalization, and cost of hospitalization and apheresis combined per patient,” Dr Isola said.

“These data suggest that using plerixafor for upfront autologous stemcell mobilization in patients with multiple myeloma significantly improves success rate of mobilization, decreases the number of apheresis sessions, and does not have a substantial pharmacoeconomic impact.” ■

Leukemia

Bosutinib Shows Superior Results in CML

By Neil Canavan

T

he newest data presented from the BELA (Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia) trial show a superior cumulative complete cytogenetic response rate (CCyR) for bosutinib versus the standard-of-care agent, imatinib, when used as frontline treatment for patients with chronic myeloid leukemia (CML), with 87% and 81% response rates, respectively, at 24 months.

“Given these results, bosutinib may soon offer a new therapeutic option for patients with newly diagnosed chronic-phase CML,” said lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.

The way was not always so clear for bosutinib, the most clinically advanced, investigational second-generation tyrosine kinase inhibitor in the pipeline. The initial report of the pivotal BELA trial was a sensation for the wrong reason; the trial failed to meet its primary end point.

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The reason that the 12-month data (presented in 2010) fell short of expectations was not for the drug’s lack of efficacy, but because of a conflict between the planned intent-totreat (ITT) analysis, and because the trial was conducted in more than 100 locations, where some clinicians failed to proactively manage treatment-related adverse events. This suboptimal care led to an inordinate number of patient discontinuations, thereby driving down the otherwise encouraging treatment response rates. This critical issue has been addressed, and results at 24 months have improved significantly.

BELA Trial at 24 Months The BELA trial was designed to look at the use of bosutinib versus imatinib in 502 patients with treatment-naïve, chronic-phase CML. The study’s primary end point was CCyR at 12 months, with secondary end points including major molecular

response (MMR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. The planned follow-up period for BELA is 8 years.

“Bosutinib may soon offer a new therapeutic option for patients with newly diagnosed chronic-phase CML.” —Jorge E. Cortes, MD At 24 months, the initial ITT analysis for CCyR indicated that the response to both drugs was nearly identical: 79% for bosutinib and 80% for imatinib. However, when patients who discontinued unnecessarily were excluded from the calculation, the cumulative CCyR was 87% for bosutinib versus 81% for imatinib.

Further analysis showed a complete response rate plus MMR of 67% for

bosutinib versus 52% for imatinib, Dr Cortes reported.

Although median PFS and OS have not yet been reached, at 24 months bosutinib has a lower rate of treatment failure: 4% versus 13% for imatinib.

Regarding adverse events, as expected (and now effectively managed), individuals in the bosutinib cohort had more grade 3/4 diarrhea, whereas patients in the imatinib arm had more edema and myalgia.

Hematologic events were more common in the imatinib treatment arm, especially for neutropenia (24% vs 10% for bosutinib).

New Drug Application On January 27, 2011, the US Food and Drug Administration accepted a new drug application for bosutinib for a standard review as a treatment option for patients with previously treated Philadelphia chromosome– positive CML; the drug was submitted for approval in Europe late last year. ■

FEBRUARY 2012

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9

Leukemia

Chronic Myeloid Leukemia... prove.” There is no assay that can ensure that every last leukemic cell present can be detected.

Dr Melo asked if a treatment-free cure is truly that important. “There are 3 things to look at: chronic toxicity with treatment and late-emerging toxicities; cost of continuing treatment; and the threat of lingering, although minimal, disease.”

Toxicities and Cost of Continuing Treatment One recent study has shown that many patients with CML are tired of receiving treatment. When asked to stratify their treatment’s side effects, patients said they “minded very much” fatigue (29%), muscle cramps (30%), pain (30%), and edema (24%).

“We need to consider this when we’re keeping patients on treatment for years at a time,” Dr Melo said.

The cost of years-long treatment is also no small matter. Dr Melo estimates that the cost to treat CML patients using tyrosine kinase inhibitors (TKIs) in the United Kingdom ranges from £18,000 to £32,000 ($27,000-$48,000) annually.

As for the lingering potential for relapse—should a few active leukemic cells survive treatment—what threshold of risk is acceptable? There is no way to say. “So, maybe an operational cure is only a partial success and we should aim higher.”

Treating CML with an allogeneic transplant is defined as curative.

However, as Dr Melo pointed out, although the relapse-free rate with transplant is as high as 70% at 10 years, only 25% of patients are able to find the necessary human leukocyte antigen–matched donor. Furthermore, those who receive a transplant risk developing chronic graft-versushost disease, and, according to very sensitive testing methods, 30% of transplant patients still harbor aberrant BCR-ABL (potentially diseasecausing) transcripts.

Can CML Actually Be Cured?

Accepting the premise that a cure cannot be proved, Dr Melo considered whether cures have been seen in practice. Two clinical trials involved patients who achieved a complete molecular response (CMR) and were allowed to stop treatment with TKIs— the CML8 trial and the STIM (Stop Imatinib) study. Both showed that approximately 40% of patients were able to discontinue treatment and maintain CMR for 5 years.

“This tells us that for some proportion of patients, the TKIs can be safely withdrawn,” Dr Melo said, adding

10

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

In both trials, patients received imatinib. The potential for cure with second-generation TKIs may hold even greater promise (see below). In one study, 64% of patients in CMR who stopped treatment with dasatinib or nilotinib have maintained responses for 10 months of followup. “Although the numbers are very small [N = 33], it is still very encouraging,” Dr Melo said.

Can Cures Be Predicted?

Evidence continues to accrue that some patients can be treatment-free and cured, but predicting who may be cured remains a challenge. A small subset of patients from the STIM trial who successfully stopped treatment (N = 66) displayed a few identifiable commonalities. Significant factors for treatment-free individuals with sus-

Continued from page 1 tained CMR were lower Sokal prognostic scores, imatinib treatment >50 months, and (barely significant for reasons unknown) male sex.

“There are several new agents in development that target the oncogene BCRABL, stop the formation of stem cells, and induce apoptosis in quiescent cells.”

—Junia Melo, MD, PhD

The molecular mechanism of cure is also coming into focus. Citing a recent analysis of data from the IRIS (International Randomized IFN versus STI571) and TIDEL (Trial of Imatinib with Dose Escalation) trials (both with imatinib), Dr Melo favors the idea of a triphasic response to treatment that results in “stem-cell

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

“Can we consolidate CMR with more intense use of TKIs?” asked Dr Melo. Several approaches that are being considered include change of dose, schedule, and adding an immunotherapy. The answer may lie in new drugs that target the stem cells themselves.

“There are several new agents in development that target the oncogene BCR-ABL, stop the formation of stem cells, and induce apoptosis in quiescent cells,” said Dr Melo. But if no method can ensure the detection of no residual, potentially life-threatening CML stem cells, then the reality of achieving a cure will remain a matter of faith and ongoing patient observation. ■

Second-Generation TKIs Have Potential to Cure CML

P

atients with chronic myeloid leukemia (CML) who are in complete molecular remission (CMR) can safely discontinue their treatment with imatinib, according to data from the Stop Imatinib (STIM) and Australasian Leukaemia & Lymphoma Group CML8 clinical trials. As a result, researchers are now asking whether second-generation tyrosine kinase inhibitors (TKIs) can accomplish this at an even higher rate.

Delphine Rea, MD, PhD, of the Hôpital Saint Louis, Paris, presented the initial data from the French CML Study Group that looked at sustained, treatment-free CMR after extended treatment with the secondgeneration TKIs dasatinib or nilotinib, which showed high rates of CMR for up to 24 months after treatment discontinuation.

The results demonstrated that these newer TKIs have superior potency against cancer-causing BCRABL transcripts compared with imatinib, as well as being effective as salvage therapy for patients with CML resistant to or intolerant of imatinib.

STIM Study To perform her study, Dr Rea enrolled adult patients with chronic-

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FEBRUARY 2012

phase or accelerated-phase CML who had been treated with dasatinib or nilotinib for at least 36 months, and had achieved and sustained a CMR for at least 24 months (N = 33). Two patients in the cohort had received treatment with frontline nilotinib; the

“Is cure a total eradication of leukemic cells, or is cure being able to stop therapies without disease relapse?

These are 2 different points.”

—Delphine Rea, MD, PhD

remaining 31 individuals started with imatinib, but were switched to second-generation TKIs as salvage therapy. All active treatment was halted on study entry (N = 33).

The primary end point for the study was stable major molecular response (MMR) at 6 months. Patients are monitored by polymerase chain reaction once a month for the first year, then every 2 to 3 months thereafter. TKIs were reintroduced if MMR is lost.

After second-generation TKI cessa-

tion, 8 patients lost MMR at 2-month median intervals; all 8 regained MMR within 12 months of resuming TKI therapy.

The other 25 patients remained off therapy for a median of 6 months (range, 0-25 months); 15 of the 25 patients have sustained MMR to a median of 13 months. From these initial findings, Dr Rea concluded that second-generation TKIs could be discontinued without jeopardizing short-term outcomes, and that even if patients lost an MMR, they remained sensitive (nonresistant) to such treatment when reintroduced.

What Would a “Cure” Mean to Patients?

“Even defining cure is a real challenge,” said Dr Rea. “Is cure a total eradication of leukemic cells, or is cure being able to stop therapies without disease relapse? These are 2 different points.” This uncertainty has become an issue among patients. “One of the very first questions patients ask is ‘How long is the treatment going to last?’ ‘When am I going to be cured?’ So, from the patient’s perspective, being cured means being able to stop the therapy without disease recurrence,” Dr Rea said. ■

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Leukemia

Novel Oral B-Cell Receptor Inhibitor Very Effective in Chronic Lymphocytic Leukemia Response Rates Increasing Over Time, with Low Toxicities

By Caroline Helwick

A

novel inhibitor of B-cell receptor signaling, PCI-32765, produced high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia (CLL) whose disease was refractory to at least 2 previous treatments, reported Susan O’Brien, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.

“To have agents that are this effective and that are not myelosuppressive is very exciting,” Dr O’Brien said.

“These agents will change the paradigm for the treatment of CLL.” PCI-32765 is the first drug designed to target Bruton’s tyrosine kinase, a protein that is essential for CLL cell survival and proliferation.

A total of 61 patients with relapsed or refractory CLL received oral PCI-32765 daily (420 mg in previously untreated and 840 mg in previously treated patients) for 28-day cycles or until disease progression. At least 1 poor-risk molecular feature was present in 72% of patients. Median follow-up was 10.2 months for the 420-mg cohort and 6.5 months for the 840-mg cohort.

most adverse events reported being grade 1 or 2. Myelosuppression has not been a problem with this agent, Dr O’Brien said. Phase 3 clinical trials with PCI-32765 are planned.

Jane Winter, MD, Professor of Medicine at Northwestern University Feinberg School of Medicine, Chicago, who moderated the press briefing, commented, “This appears to be a

highly effective new agent, with a new strategy that targets the B-cell receptor.

It has a very low toxicity profile and high efficacy, and it is just the beginning of many new agents in CLL.” ■

“To have agents that are this effective and that are not myelosuppressive is very exciting. These agents will change the paradigm for the treatment of chronic lymphocytic leukemia.”

—Susan O’Brien, MD Response rates were 70% in the 420mg cohort and 44% in the 840-mg group. Nodal partial responses (PRs) were reported in 35% of patients (>50% reduction in aggregate lymph node size), with residual lymphocytosis. Reponses appear to be independent of molecular risk features.

Dr O’Brien noted that response rates have steadily increased over the duration of the study. “At ASCO, we reported a PR rate of 48%. Now we report a response rate of about 70%.

The responses have evolved over time,” she said.

Some 82% of the original patients are still using this treatment; only 8% of patients have progressed so far. The 6-month progression-free survival was 92% in the 420-mg cohort and 90% in the 840-mg cohort.

PCI-32765 is well tolerated, with

Locate the mutation.

Stay one step ahead of CML resistance.

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11

Leukemia

Ponatinib Overcomes Hard-to-Treat T315I Mutation in Patients with CML/ALL

By Neil Canavan

P

reliminary data from the phase 2 PACE (Ponatinib Ph+ALL and CML Evaluation) trial show that ponatinib (Ariad Pharmaceuticals) can overcome the difficult-to-treat T315I mutation in patients with chronic myeloid leukemia (CML). Currently, patients with this genetic mutation have no effective treatment options.

In PACE, the tyrosine kinase inhibitor (TKI) ponatinib achieved a 47% major cytogenetic response (MCyR). For patients with the T315I mutation, ponatinib induced a 65% MCyR. This drug was specifically designed to overcome the T315I mutation.

“Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory/relapsed CML,” said PACE lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.

“Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory/ relapsed CML.” —Jorge E. Cortes, MD This open-label study enrolled 499 patients with CML or with Philadel-

phia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) who had previously been treated with nilotinib or dasatinib, but their disease was resistant or intolerant to those drugs, or they had the T315I mutation.

Patients were stratified into 1 of 6 groups, according to disease, disease phase, and mutation status. All patients were treated with the same dose and schedule. The primary end points were MCyR for chronic-phase (CP)-CML, and major histologic response for accelerated-phase (AP)CML, blast-phase (BP)-CML, or Ph+ALL. After a median follow-up of 5 months, Dr Cortes reported high levels of response being observed in all patient types. Patients with AP-CML achieved a major histologic response of 74%, and MCyRs ranging up to 53%. For patients with the most severe

prognosis, the BP-CML and Ph+ALL cohorts, both groups achieved a major histologic response of 37%, and MCyRs of 34% and 37%, respectively.

A major molecular response rate of 33% was reported in patients with the T315I mutation and those with CPCML/T315I. Treatment-related adverse events were generally mild; the most common serious events were thrombocytopenia and neutropenia.

“Extremely exciting,” said Tim Brümmendorf, MD, of the University Hospital, Aachen, Germany, in response to the ponatinib data. “It is the most promising approach to target the most problematic mutation that we currently see—the T315I mutation.

This mutation confers absolute resistance to all TKIs that we currently have approved in clinical use. So, from what I have seen, it [ponatinib] looks extremely promising.” ■

Investigational Blinatumomab Puts BiTE on Acute Lymphoblastic Leukemia

T

he novel agent blinatumomab more than doubled the complete response (CR) rate in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) compared with standard therapies. If validated, these findings offer significant hope to patients with an otherwise dismal prognosis after having failed to achieve CR with standard treatment.

Blinatumomab is a member of the BiTE (bispecific T-cell engager) drug class, a bispecific monoclonal antibody designed to direct the cytotoxic T-cells of the host’s immune system, via CD3, to attack CD19-expressing cancer cells.

In this open-label, single-arm, doseranging, phase 2 clinical trial, 25 patients with ALL were randomized to 1 of 3 doses of blinatumomab.

Results for all tested doses showed that 17 (68%) of the patients achieved a CR or a CR with partial hematologic recovery with blinatumomab.

For the 12 patients who received the dose selected for further investigation, 9 achieved a CR or partial hematologic recovery. All responders achieved minimal residual disease status, meaning that there were no detectable leukemic cells in their blood or bone marrow.

12

“Blinatumomab as a single agent induced an unprecedented high rate of complete hematological and MRD responses in adult patients with relapsed/refractory B-precursor ALL.” —Max S. Topp, MD Treatment effect with blinatumomab was 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 been reached. This ongoing measure already exceeds median survival times typically seen with combination chemotherapy in ALL. The most common adverse events observed with initial blinatumomab treatment were mild, and were predominantly flulike symptoms of fever and headache.

More serious, but reversible, events included cytokine release syndrome in 2 patients with high tumor burden, and 5 patients with central nervous

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

“Blinatumomab as a single agent induced an unprecedented high rate of complete hematological and minimal residual disease responses in adult patients with relapsed/refractory B-precursor ALL,” said the study’s lead investigator, Max S. Topp, MD, at Wuerzburg University Medical Center, Wuerzburg, Germany, where phase 2 studies are under way.—NC ■

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Multiple Myeloma

VISTA Final Analysis Upholds Survival Benefit of Bortezomib at 5 Years

By Caroline Helwick

T

he final analysis of the phase 3 VISTA trial upheld a persistent and significant survival benefit for bortezomib in patients with previously untreated multiple myeloma.

Of the 655 patients in VISTA, those treated with bortezomib lived an average of 13.3 months longer than those receiving a regimen lacking this agent, VISTA investigator Jesús F. San Miguel, MD, PhD, of the Hospital Clinico Universitario, Salamanca, Spain, reported.

“An overall survival [OS] benefit was seen across multiple prespecified patient subgroups and was maintained after 5 years’ follow-up and despite substantial use of novel agent–based salvage therapies,” said Dr San Miguel.

beyond the incidence of cancer in the general healthy population. Since reports surfaced at ASH last year that lenalidomide seemed to be associated with a higher risk for second malig-

nancies, studies of myeloma therapies all examine this potential risk.

Dr San Miguel said that based on the findings of no excess cancers, he is convinced that the long-term use of

bortezomib is “completely safe.”

5-Year Mortality Risk Reduced by 31% Mortality risk was reduced by 31% Continued on page 15

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REGISTER TODAY at www.regonline.com/avbcc2012 “These findings demonstrate the importance of providing optimal first-line treatment incorporating bortezomib, rather than reserving bortezomib for salvage therapy and using conventional first-line treatment.”

—Jesús F. San Miguel, MD, PhD Data from the initial report of this international phase 3 trial showed that nine 6-week cycles of the bortezomib, melphalan, and prednisone (VMP) regimen were superior to the melphalan and prednisone (MP) regimen in patients with previously untreated multiple myeloma. At 36.7 months of follow-up, a second analysis confirmed a continued OS benefit. The current report was the final updated OS analysis after 5 years of follow-up, which includes data on 95% of the original cohort.

The 5-year follow-up also found no association between bortezomib treatment and the development of second primary cancers, at least above and

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TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

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• 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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13

Multiple Myeloma

Future Directions in Myeloma

By Caroline Helwick

W

ith so many new myeloma drugs of various classes in the pipeline (Table), “myeloma is going to become a chronic illness, with sustained complete responses in a significant fraction of patients,” according to Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

In his presentation about treatment targets and niches, Dr Anderson predicted that the future direction of multiple myeloma management will include: • Development of immune treatments (vaccine and adoptive immunotherapy); these may be very personalized • Development of novel agents aimed at the myeloma cell in the bone marrow microenvironment; these will target cell growth, survival, and drug resistance • Development of rationally based combination therapies, such as bortezomib plus histone deacetylase inhibitors • Utilization of genomics for improved classification; microRNA profiles can already identify clinical subgroups with different survival outcomes • Personalized treatment based on tumor genetics.

Sonja Zweegman, MD, PhD, of VU University Medical Center, Amster-

Table Novel Investigational Agents for Myeloma Agent

Mechanism of action

Carfilzomib,a MLN9708, marizomib

Proteasome inhibitor

Pomalidomidea

Immunomodulatory drug

Daratumumab, elotuzumab,a siltuximab,a cetuximab

Monoclonal antibody

BT062

Immunotoxin

Perifosine,a GSK 2110183 a

With so many new myeloma drugs of various classes in the pipeline, “myeloma is going to become a chronic illness, with sustained complete responses in a significant fraction of patients.”

a

Akt inhibitor

Vorinostat, panobinostat, romidepsin, ACY-1215

Histone 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 inhibitor

a

Currently in phase 3 clinical trials.

—Kenneth C. Anderson, MD

dam, and Erasmus University, Rotterdam, the Netherlands, moderated the session on new agents in myeloma.

She elaborated on the future of personalized treatment for myeloma: “We need many drugs to prolong the life of these patients, and what you will 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 the signaling transduction pathway will respond.

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

ma cells, and a predictive model to help select the most appropriate treatment for a particular patient. That will be the future,” said Dr Zweegman.

Dr Anderson agreed. “With whole genome sequencing coming, and with so many novel agents—including many in phase 3 trials, as we saw discussed at this meeting—I know the future is bright in myeloma.” ■

Pomalidomide a Promising New Immunomodulatory Drug for Multiple Myeloma

E

arly-phase studies of the new immunomodulatory drug pomalidomide drew considerable interest at ASH 2011 and generated enthusiasm from myeloma specialists.

Paul G. Richardson, MD, of DanaFarber Cancer Institute, Boston, who has led trials of pomalidomide, commented, “Over 40% clinical benefit rate and almost 17 months median survival in heavily pretreated patients is fantastic.”

A phase 2 study compared pomalidomide alone versus pomalidomide plus low-dose dexamethasone in 221 patients with relapsed/refractory disease. Patients had received an average of 5 previous lines of therapy, and most of them had progressed with bortezomib or with lenalidomide therapy.

Pomalidomide plus dexamethasone led to a partial response in 34% of patients compared with 13% of patients responding to pomalidomide alone;

14

another 11% of patients had minor responses to the combination regimen.

Median progression-free survival rates were 4.7 months with the combination and 2.7 months with pomalidomide alone, and median overall survival (OS) rates were 16.9 months and 14 months, respectively.

Responses with the combination were observed in 34.5% of patients, and stable disease was present in 48% of patients. Median time to progression was 9.1 months, and median OS was 13.4 months, according to Xavier Leleu, MD, PhD, of Hôpital Claude Huriez, CHRU, Lille, France.

“Over 40% clinical benefit rate and almost 17 months median survival in heavily pretreated patients is fantastic.”

Pomalidomide Plus 2 Drugs and Maintenance Italian investigators combined pomalidomide with 2 other agents, cyclophosphamide and prednisone, followed by maintenance with pomalidomide plus cyclophosphamide in a phase 2 study of 29 relapsed/refractory patients.

After a median of 4 cycles, partial response or better was observed in 81% of the patients with refractory disease and in 55.5% of the patients who relapsed. Very good partial response or better was seen in 27% and 28% of

—Paul G. Richardson, MD Similar findings emerged from the French phase 2 IFM 2009-02 study of pomalidomide plus low-dose dexamethasone in 84 patients with disease refractory to both lenalidomide and bortezomib.

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FEBRUARY 2012

patients, respectively, and complete responses were documented in 9% and 5.5% of patients, respectively, according to Antonio Palumbo, MD, of the University of Torino in Italy, for the Italian Multiple Myeloma Network.

Dr Palumbo also suggested that using a combination with “a good risk-benefit ratio, where there is not much toxicity,” and continuing the 3 drugs as maintenance therapy, “may help explain the higher proportion of responses” in this study.

Pomalidomide was generally well tolerated in all studies. The most common grade 3 or 4 toxicities were neutropenia, anemia, pneumonia, thrombocytopenia, and fatigue. More unusual grade 3 or 4 nonhematologic toxicities include rash and central neurologic toxicity in <10% of patients. Phase 3 trials are currently evaluating pomalidomide in various drug combinations.—CH ■

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Multiple Myeloma

Maintenance Strategies in Elderly Patients with Myeloma Not Eligible for Transplant Lenalidomide and Bortezomib Both Prolonged Remission

By Caroline Helwick

T

he value of continuous, or maintenance, therapy in patients newly diagnosed with multiple myeloma who are not eligible for stem-cell transplant (such as the elderly) is still debated. Studies presented at ASH 2011 showed that maintenance therapy can delay disease progression, although an overall survival (OS) advantage is not yet evident.

Lenalidomide Extends PFS, Increases Secondary Cancers The final results of the phase 3 MM-015 trial that investigated the value of lenalidomide in elderly, transplant-ineligible patients, median age 71 years, were presented by Antonio Palumbo, MD, University of Torino, Italy.

“What is really changing in the treatment paradigm is the concept of continuing treatment, moving from a fixed treatment to one incorporating continuous therapy.…Continuous treatment adds about 10 months of remission duration in elderly patients.

Although no survival advantage has been shown, 3 years of OS projected at 70% is certainly a good outcome,” said Dr Palumbo.

MM-015 tested 3 treatment regimens. Two groups received induction therapy consisting of melphalan,

prednisone, and lenalidomide (MPR); half (N = 152) of this group was placed on maintenance therapy with lenalidomide (MPR-R), given on days 1 to 21 until progression; the other half received no continuous therapy (MPR); the third group (N = 154) received only melphalan and prednisone (MP) as induction therapy and no maintenance.

Patient responses were significantly greater with the 3-drug combination.

“For induction, a 3-drug combination significantly increases response rates, so MPR is better than MP when toxicity is not a problem,” Dr Palumbo said. “But maintenance therapy provides the major difference.”

Lenalidomide maintenance significantly extended progression-free survival (PFS), from 14 months with MPR and 13 months with MP to 31 months with MPR-R. “You get a doubling in PFS when you use continuous treatment,” he noted.

In a landmark analysis of all patients, lenalidomide continuous therapy resulted in a 66% reduction in the risk of progression (P <.001). A significant treatment benefit was observed in all subgroups of age, response, and stage. Patients aged ≥75 years had slightly lower benefit, probably because more discontinued treat-

VISTA Final Analysis... Continued from page 13 with the addition of bortezomib to the treatment regimen, despite the significant use of subsequent therapy once the disease progressed.

Median OS was 56.4 months after treatment with VMP versus 43.1 months with MP, amounting to an absolute benefit of 13.3 additional months of life across all subgroups (P = .004). The OS rate at 5 years was 46.0% with VMP versus 34.4% with MP, Dr San Miguel said.

Virtually all subgroups benefited significantly from the addition of bortezomib, including: • Older patients age ≥75 years, who had a 29% reduction in risk of death • Patients with International Staging System stage III disease, who had a 23% risk reduction • Patients with creatinine clearance <60 mL/min, who had a 30% risk reduction.

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Only the small subgroup of patients with documented high-risk cytogenetics had no additional benefit from bortezomib.

Bortezomib also added 8 additional months to the time before the next treatment was required, and extended the treatment-free interval by almost 8 months (P <.001 for both).

As for the best time to prescribe bortezomib to previously untreated patients, Dr San Miguel noted that patients who received bortezomib as first-line treatment had longer OS than those who received bortezomib or other therapies in subsequent treatment lines. “These findings demonstrate the importance of providing optimal first-line treatment incorporating bortezomib,” he said, “rather than reserving bortezomib for salvage therapy and using conventional first-line treatment.” ■

ment and frail patients received less dose intensity.

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

“What is really changing in the treatment paradigm is the concept of continuing treatment, moving from a fixed treatment to one incorporating continuous therapy.…Continuous treatment adds about 10 months of remission duration in elderly patients.”

—Antonio Palumbo, MD At a median follow-up of 41 months, however, no impact was yet seen on OS, which at 4 years was 59% for MPRR, 58% for MPR, and 58% for MP as well. “But don’t forget that the average survival has been around 3 years,” he emphasized. A trend toward a survival benefit was observed in the 65- to 75year-old age-group.

Secondary cancers, although still rare, were observed in association with lenalidomide, especially hematologic malignancies. There were 12 cases of cancer among patients receiving maintenance lenalidomide, and 10 among patients receiving lenalidomide alone in the induction regimen, compared with only 4 among patients who received MP only.

Dr Palumbo argued, however, that the increased risk of second cancers was far outweighed by lenalidomide’s benefit in delaying progression. “There is a 75% to 80% risk of progression, but less than a 5% risk of second primary malignancies,” he said. This was echoed by many specialists at the meeting.

The major toxicities were grade 4 neutropenia in 30% of patients and grade 4 thrombocytopenia in 5% of patients. “But as far as maintenance is concerned, thrombocytopenia and neutropenia rates were very rare.

Even in the frail elderly, toxicity is acceptable,” he said.

Bortezomib-Based Maintenance, Low Toxicity Bortezomib-based maintenance reg-

imens also represent an attractive strategy to optimize myeloma treatment, reported Maria-Victoria Mateos, MD, PhD, of the Hospital Clinico Universitario in Salamanca, Spain, on behalf of the Spanish Myeloma Group (GEM/Pethema).

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

Maintenance therapy included bortezomib 1.3 mg/m2 administered every 3 months plus thalidomide 50 mg/day and prednisone 50 mg every 2 days up to 3 years.

The study did not evaluate outcomes in patients who did not receive maintenance.

Response rates were similar between the regimens: 80% with VMP and 81% with VTP. The current study assessed whether maintenance therapy would upgrade these responses, with a favorable toxicity profile, and might confer a benefit in terms of PFS and OS. In the whole population, after a median of 20 months of maintenance, the rate of complete response (CR) increased from 24% after induction therapy to 42% after maintenance.

After induction, CR rates were similar between VMP and VTP, but slightly more additional CRs were achieved in the VT maintenance arm (46% vs 39%).

At 46-month follow-up, median PFS was slightly higher with VT (39 months vs 32 months with VP), and this was not influenced by the induction regimen. OS has not been reached with VT maintenance, with 69% of patients being alive at 5 years, and 60% alive with VP. In the 20% of patients with highrisk cytogenetics, neither maintenance regimen could overcome the poor prognosis. Median PFS was 26 months and median OS was 50 months, with no differences seen between the regimens.

“Toxicity was very low with maintenance,” Dr Mateos said. VT was associated with more peripheral neuropathy (9% vs 3%), but in all but 1 patient this was worsening, not emergent, neuropathy. ■

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15

Multiple Myeloma

Next-Generation Proteasome Inhibitors Cause Less Peripheral Neuropathy First Oral Agent in the Pipeline Elicits Excitement

By Caroline Helwick

T

he first-generation proteasome inhibitor bortezomib changed the treatment paradigm of multiple myeloma. Data are now maturing for the next-generation agent carfilzomib, with US Food and Drug Administration approval expected soon. Several novel agents in this class are also in the pipeline. These secondgeneration agents appear to be as effective as bortezomib but less neurotoxic, according to studies presented at ASH 2011.

High Response Rates with Carfilzomib Regimen High response rates and minimal toxicity were seen when carfilzomib was combined with lenalidomide and low-dose dexamethasone in a phase 2 clinical trial presented by Andrzej Jakubowiak, MD, of the University of Chicago Medical Center.

“The carfilzomib/lenalidomide/ dexamethasone [CRd] regimen is well tolerated and highly active, demonstrating rapid and deep responses in newly diagnosed myeloma,” Dr Jakubowiak said.

This study included 53 patients who received 8 cycles of CRd and at least 9 additional cycles for maintenance. The 24 patients who were transplant candidates received 4 cycles before their transplant and 4 afterward.

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

(CR) or stringent complete response (sCR) • After 12 treatment cycles, 79% achieved a near-CR, CR, or sCR • High response rates were not affected by stage or cytogenetics.

“These response rates compare favorably to our best frontline regimens, and the study is still early.

Responses continue to improve with time. I think this is going to be one of those regimens that will potentially change the landscape of what we can do,” Dr Jakubowiak predicted.

First Oral Agent in Early Development The first oral proteasome inhibitor, MLN9708, has “similar selectivity and potency, it dissociates from the proteasome faster, and has greater tissue penetration compared with bortezomib,” said Paul G. Richardson, MD, of Dana-Farber Cancer Center, Boston, who has led some of the trials.

“The activity of MLN9708 is dramatic,” he said. “Upfront, we are seeing 100% response rates, which is amazing; and in the relapsed/refractory setting, where we expect to see nothing because patients are so ill, we are seeing response rates, including some very good partial responses, and stable disease. That’s the signal we need in the advanced disease population.”

Dr Richardson reported the results of a phase 1 dose-escalation expansion cohort study of 56 patients who averaged 3.5 previous therapies; 88%

“The activity of MLN9708 is dramatic. Upfront, we are seeing 100% response rates, which is amazing; and in the relapsed/refractory setting, where we expect to see nothing because patients are so ill, we are seeing response rates…and stable disease.”

—Paul G. Richardson, MD had previous bortezomib therapy.

MLN9708 was given orally twice weekly in 21-day cycles at a dose of 2 mg/m2.

Of the 46 patients evaluable for response, 6 achieved partial responses or better, including 1 CR. One patient achieved a minimal response, and 28 patients experienced stable disease. Five responders had previously received bortezomib. Disease stabilization has lasted nearly 16 months in many cases, and encouraging activity has been seen in bor -

tezomib-resistant patients.

The drug activity in previously untreated patients is even more striking. Jesus G. Berdeja, MD, of Sarah Cannon Research Institute in Nashville, reported that of 10 treatment-naïve patients enrolled in a phase 1 and 2 study, 9 achieved partial responses or better, including 1 CR and 3 very good partial responses.

Comparing MLN9708 to carfilzomib, Dr Richardson said that although carfilzomib is a welcomed agent in myeloma, “you must give carfilzomib intravenously and weekly 2 days in a row, on days 1 and 2, 8 and 9, and 15 and 16. It is a great drug, and it is associated with less neurotoxicity, but its delivery is inconvenient for the patient. MLN9708 has the advantage of being an oral drug that produces very little neuropathy,” he said in an interview.

Dr Richardson said that this agent has “an excellent tolerability profile.”

Fatigue, thrombocytopenia, and nausea are the most common adverse events reported, along with skin rash, especially as first-line treatment, “which patients find quite manageable.”

No peripheral neuropathy grade ≥3 has been reported. Dose reductions as a result of adverse events have been uncommon.

Phase 1 and 2 clinical trials are evaluating oral and intravenous formulations, using different dosing schedules in a variety of tumor types. Phase 3 trials will begin next year. ■

Monoclonal Antibody Elotuzumab Promising in Multiple Myeloma

E

lotuzumab, a humanized IgG1 monoclonal antibody, led to very high response rates and prolonged remissions in 73 patients with relapsed multiple myeloma or refractory to previous treatment in a phase 2 study presented by Sagar Lonial, MD, of Emory University School of Medicine, Atlanta.

Patients who received elotuzumab (10 or 20 mg/kg) in combination with lenalidomide and low-dose dexamethasone had an 82% overall response rate. Response rates exceeded 90% in patients who had received 1 previous therapy and those who received the lower dose.

“We see an 80% to 90% response

16

“We eagerly await monoclonal antibody-based therapy in myeloma. These agents attack the plasma cell in a different way, and they will certainly be additive to our arsenal.”

—Sonja Zweegman, MD, PhD

rate, and at 14 months, we have not yet hit median PFS [progression-free survival],” said Dr Lonial. The PFS rate has ranged from 65% to 75%.

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The drug was well tolerated. With prophylaxis, only 1 grade 3 infusion reaction was documented. Some 12% of patients had complete responses and 36% had very good partial responses. “These were durable responses. Over half the patients are still on study,” he noted.

In a subset analysis, the combination showed encouraging activity—80% response rate—in cytogenetically highrisk patients. “If we can use a drug to overcome high-risk disease, this would be great,” Dr Lonial commented.

Phase 3 trials of 10 mg/kg of elotuzumab are ongoing in previously untreated patients and in those with relapsed/refractory disease.

Sonja Zweegman, MD, PhD, VU University Medical Center, Amsterdam, and Erasmus University, Rotterdam, the Netherlands, who moderated a session on new agents in myeloma, commented that the use of monoclonal antibodies is a true advance in myeloma. “We eagerly await monoclonal antibody-based therapy in myeloma. These agents attack the plasma cell in a different way, and they will certainly be additive to our arsenal. Encouragingly, what we saw at ASH is that all these new investigational compounds are not only effective, but tolerable. I think elotuzumab has a lot of potential,” Dr Zweegman concluded.—CH ■

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“Managing patients with myeloma means staying current.”

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

7

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Lymphoma

Maintenance Rituximab May Be Unnecessary in FL Retreatment Recommended as Preferred, Cost-Effective Strategy

By Caroline Helwick

P

atients with low-burden follicular lymphoma (FL) treated upfront with rituximab can be managed as well with “watchful waiting,” with retreatment on progression, as with extended dosing, or maintenance therapy, according to a randomized phase 3 study that compared the approaches.

“Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in low-tumorburden FL,” said Brad Kahl, MD, of the University of Wisconsin School of Medicine and Public Health in Madison, who presented the findings as a late-breaking abstract.

He referred to the “excellent outcomes, lack of a difference in quality of life, and fewer doses required with retreatment.”

Patients in the maintenance arm received 15.8 doses of rituxumab compared with only 4.5 in the retreatment arm. The number of doses ranged from 5 to 31 in the maintenance arm and from 4 to 16 in the retreatment arm.

“Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure. And although maintenance was superior to retreatment for time to cytotoxic therapy, this came at a cost of 3.5 times more rituximab.”

—Brad Kahl, MD

“Treat without Breaking the Bank” Andrew Zelenetz, MD, Chief of the Lymphoma Service at Memorial SloanKettering Cancer Center, New York, said these findings have great clinical and economic implications, based on the vast amount of rituximab that could be spared with the retreatment approach. “We are in an era when, without question, we have to figure out how to give effective high-quality

care, without breaking the bank.

Retreatment may give us the same benefit at a much, much lower cost.”

“Some people in the field say that maintenance is unequivocally the standard of care. I happen not to share that opinion,” Dr Zelenetz added.

The Eastern Cooperative Oncology Trials group conducted the RESORT (Rituximab Extended Schedule or Retreatment Trial) study to compare maintenance rituximab with retreatment on progression. The study included 545 untreated patients with stage III or IV indolent non-Hodgkin lymphoma and low tumor burden, including 384 with FL histology who formed the basis of this analysis.

After median follow-up of 3.8 years, there was no difference in the primary end point of time to treatment failure: 3.9 years with maintenance rituximab and 3.6 years with retreatment, Dr Kahl said. “Both strategies appear to delay time to chemotherapy compared with historical controls.”

Treatment failures occurred in 69 patients in the maintenance arm and

65 in the retreatment arm. Time to first chemotherapy treatment was longer in the maintenance arm, with 95% of patients remaining chemotherapyfree compared with 86% in the retreatment arm (P = .03).

There were no appreciable differences in toxicity or in the development of second cancers between the arms. More patients withdrew from the maintenance arm—26 versus 16 in the retreatment arm.

“We also wondered if there might be a psychological benefit to being maintained in remission, but at 1year postrandomization we found no difference in quality of life,” Dr Kahl reported.

“Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure. And although maintenance was superior to retreatment for time to cytotoxic therapy, this came at a cost of 3.5 times more rituximab,” Dr Kahl concluded.

“There was also no benefit in terms of better quality of life or less anxiety at 12 months with maintenance.” ■

Obinutuzumab Could Give Rituximab a Run for Its Money in Relapsed Indolent NHL

F

or more than 10 years, rituximab has held a unique place in the treatment of a range of B-cell lymphomas. But a new “glycoengineered” humanized monoclonal antibody is entering the treatment arena, and data presented at ASH 2011 set the stage for phase 3 testing against the long-term standard of care.

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

In the phase 2 GAUSS trial, induction therapy with obinutuzumab led to a higher overall response rate than induction with rituximab, according to an independent radiology review: 44.6% versus 26.7% (P = .01), including complete responses of 12.2% and 5.3%, respectively.

However, the primary end point— response rates according to local investigators—was not significantly different: 44.6% and 33.3% (P = .08), respectively, reported Laurie H. Sehn, MD, MPH, of the University of British Columbia, Vancouver.

18

Median progression-free survival was also similar between the arms at 17.3 months, with progression observed in 39.2% of obinutuzumabtreated patients and 34.7% of rituximab-treated patients.

According to Dr Sehn, the GAUSS trial was “not really designed to definitely answer if one agent is better. It is an attempt to get some comparisons and to determine if a randomized controlled trial is justifiable. The results imply a trend in benefit.”

In this open-label study, 175 patients (149 with follicular lymphoma and 26 with nonfollicular indolent NHL) were randomized to receive 4 weekly infusions with obinutuzumab or with rituximab. On average, patients had received 2 previous regimens, all with rituximab.

Patients without evidence of disease progression after induction continued the regimen for up to 2 years.

Obinutuzumab was tolerable, but more infusion-related reactions were reported with it than with rituximab (74% vs 51%, respectively), including 11% and 6%, respectively, that were grade 3 or 4.

Additional data were presented

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FEBRUARY 2012

“Unlike rituximab or other anti-CD20 agents in development, GA101 is a type 2 (humanized) monoclonal antibody. In preclinical testing, it has been shown to have a greater ability to directly cause cell death and to induce a greater immune-type reaction against the tumor.”

—Laurie H. Sehn, MD, MPH from other phase 2 studies of patients with relapsed/refractory indolent NHL showing encouraging activity for obinutuzumab as a single agent and in combination with fludarabine and cyclophosphamide or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Responses were seen in patients with NHL refractory to rituximab.

At a press briefing, Dr Sehn said that “Unlike rituximab or other antiCD20 agents in development, GA101 is a type 2 (humanized) monoclonal antibody. In preclinical testing, it has been shown to have a greater ability to directly cause cell death and to induce a greater immune-type reaction against the tumor. What is required now is to move this into trials to see if this translates into benefits for patients.”

Jane Winter, MD, of Northwestern University Feinberg School of Medicine, Chicago, moderated the press briefing. She commented, “This study shows how our new technologies are providing us with tools that are better than we have had before. Dr Sehn showed the benefit of bioengineering an antibody, which is different from serendipitously finding one that is effective.”

With the improved response rates and favorable toxicity profile, Dr Sehn and her colleagues concluded that, “phase 3 trials to truly test its efficacy are warranted.” Studies are now comparing obinutuzumab plus CHOP, or other regimens with rituximab plus CHOP.—CH ■

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Other Highlights

Ready-Made Platelets? A Boon for Patients If It Works

By Neil Canavan

E

ver since Dolly, the first cloned sheep, made the global headlines, scientists, clinicians, businesspersons, and no small army of science fiction writers have been imagining the technology’s potential.

However, the technical and ethical complexities of the task abound.

Now it appears that one very critical application of cloning technology may be realized by thinking small, as in the in vitro production of human platelets, according to Naoya Takayama, MD, PhD, of the Center for iPS Cell Research and Application at Kyoto University in Japan.

Dr Takayama and colleagues are pioneering a technique that avoids at least the ethical issues related to the use of embryonic stem cells by using pluripotent adult stem cells, which

can come from any living person.

“This work is preliminary, but the promise it holds is wonderful,” commented Peter D. Emanuel, MD, of the University of Arkansas for Medical Sciences, Little Rock, and Liaison, Chair, Committee on Communications for ASH 2011.

The technique described by Dr Takayama employed human-induced pluripotent stem cells (hiPSCs), specifically, an immortalized megakaryocyte progenitor cell line derived from hiPSCs, which is the bone marrow cell type responsible for producing thrombocytes (platelets). The megakaryocytes were induced to make platelets through temporal manipulation of the activation of the regulator gene, c-MYC, and associated downstream factors, INK4A and

ARF. The resultant cell line subsequently showed proplatelet formation

“Through gene manipulation one could potentially provide a stable supply of platelets at a predefined quality and quantity for transfusion therapy.”

—Naoya Takayama, MD, PhD

leading to the release of functional CD41a+/CD42b+ platelets.

The compatibility of the cloned cells was validated by the transfusion of platelets into immunodeficient mice.

The platelets were accepted, and they exhibited normal circulation 24 hours after their transfusion.

Dr Takayama concluded, “Through gene manipulation one could potentially provide a stable supply of platelets at a predefined quality and quantity for transfusion therapy.”

“Platelet supplies for transfusions are always in short supply,” said Dr Emanuel. “The shelf life is short, and donors are less willing to donate because it takes more time than whole blood. So, if we could mass-produce them in the laboratory, it would be a major step forward.”

Dr Emanuel further pointed out that not only would patients benefit, but a ready-made platelet supply could dramatically reduce the associated costs. ■

VTE Prophylaxis during Chemotherapy Cost-Effective Venous Thromboembolism a Common, Costly Adverse Event

By Caroline Helwick

V

enous thromboembolism (VTE) is a common cause of serious morbidity and mortality, and patients with cancer are at particular risk. “VTE has a substantial burden on the current US medical system. Its preventable costs and indirect costs from premature deaths are substantial,” said Alex C. Spyropoulos, MD, of McMaster University, Hamilton, Canada.

Dr Spyropoulos and colleagues developed a decision tree and cost model to estimate the national healthcare costs for pulmonary embolism (PE), total hospital-acquired PE, and total preventable PE. The model demonstrated annual savings of $4.6 billion to $14.3 billion in the base model, and as high as $12.8 billion to $42.2 billion when adjusted to 2011 US dollars in the sensitivity analysis.

The authors concluded that “appropriate type, dose, and duration of prophylaxis is cost-effective.”

VTE Prophylaxis Is Cost-Effective Other investigators from the University of Pittsburgh agreed that VTE prophylaxis is cost-effective. As background, they noted that despite evidence that low-molecular-weight heparin (LMWH) has antitumor effects and improves short-term survival, the cost-effectiveness of anticoagulation in ambulatory cancer patients is unknown.

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“Prophylactic anticoagulation appears to be cost-effective in ambulatory cancer patients during the first 4 months of chemotherapy.”

—Allyson Pishko, BS

Allyson Pishko, BS, and colleagues constructed a Markov model to evaluate prophylactic anticoagulation with enoxaparin in such patients with no previous VTE during 4 months of chemotherapy. The model used data from a 2011 Cochrane Review of 9 randomized controlled studies of cancer patients with no indication for anticoagulation prophylaxis. The researchers measured medical costs, effectiveness (measured by mortality reduction), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over a 24-month period.

Enoxaparin 40 mg/day was estimated to cost $1132 per month.

The cost of treating a major bleeding event was $5317 and the cost of a

minor bleeding, $73. Death was calculated at $5000. Compared with no LMWH, 4 months of primary prophylaxis with enoxaparin was associated with a relative mortality risk of 0.92 over 24 months, at a gain of 0.0484 QALY, for an ICER of $76,922 per QALY gained. The relative risk for deep-vein thrombosis was 0.55.

“This is well within the accepted $100,000/QALY threshold,” Ms Pishko said. However, if the ICER increases to >$100,000 per QALY, it may no longer be considered cost-effective.

“Prophylactic anticoagulation appears to be cost-effective in ambulatory cancer patients during the first 4 months of chemotherapy. If the suggested mortality benefit is confirmed by additional randomized controlled

studies, administering anticoagulation to ambulatory cancer patients during high-risk chemotherapy treatments should be considered,” she concluded.

Electronic Reminder Enhances VTE Prophylaxis The use of an electronic “smart order set” to remind physicians about VTE risk boosted the use of VTE prophylaxis within Johns Hopkins Hospital. The intervention also dramatically reduced the rate of symptomatic VTEs, reported Amer M. Zeidan, MD, of Johns Hopkins University.

A review of patient records showed that risk-appropriate prescribing rates rose from 68% to 86% when the smart order set was added to the institution’s decision support (P <.001). The rate of VTE episodes within 90 days of admission fell from 2.5% to 0.7% (P = .002) as a result of VTEs that occurred postdischarge; the rates of major bleeding did not increase with the use of VTE prophylaxis.

This intervention was developed after an internal review showed that VTE prophylaxis was not being prescribed for many patients deemed eligible by national guidelines. “Our results support the use of a mandated risk-adaptive strategy for consideration of VTE prophylaxis for every hospitalized patient,” Dr Zeidan said. ■

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19

New Data: 5-Year Median Follow-up

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

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

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

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

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

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

‡

VELCADE (Vc) in combination with MP.

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

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

Median overall survival:

80

56.4 vs 43.1 months

Patients Surviving (%)

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

VELCADE+MP (n=344)

10

MP (n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

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

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

Other Highlights

High Morbidity Burden Borne Years Later by Survivors of Transplant Severe or Life-Threatening Problems Found in 40% of Cases

By Caroline Helwick

H

ematopoietic cell transplant (HCT) cures many hematologic malignancies, but recipients remain at high risk for chronic medical and psychological conditions, according to the first-ever study of these long-term outcomes.

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

The study showed that the burden

of long-term physical and emotional morbidity experienced by survivors ≥10 years posttransplant can be substantial and often results in high utilization of specialized healthcare resources.

Can-Lan Sun, PhD, of the City of

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

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

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

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

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy:: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

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

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

Cardiac Disorders:: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS):: There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

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

Thrombocytopenia/Neutropenia:: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

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

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

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

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

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.

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

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

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

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

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

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

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

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

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

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

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

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AMERICAN HEALTH & DRUG BENEFITS

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Hope Comprehensive Cancer Center, Duarte, CA, who presented the results, said that high-intensity therapeutic exposures, as well as prolonged immunosuppression regimens, can increase the risk for long-term complications after HCT, and these problems only accelerate over time.

There is a need for special clinics that would follow these patients aggressively, detect complications early, and reduce the associated morbidity, Dr Sun said.

She and her colleagues evaluated the risk for chronic medical and psychological conditions in 366 individuals who had received HCT at least 10 years earlier, along with 309 of their siblings, who served as controls.

A severity score was assigned for each medical condition, and the Brief Symptom Inventory was used to describe adverse psychological conditions. The investigators also accessed health records.

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

—Stephanie J. Lee, MD, MPH Long-Term Complications The most often reported severe or life-threatening chronic health conditions included myocardial infarction, stroke, blindness, diabetes, musculoskeletal problems, and subsequent malignancies. The 15-year cumulative incidence of any chronic health condition was 71%, and for severe life-threatening conditions or death was 40%.

Compared with age- and sexmatched siblings, HCT survivors had a 5.6 times increased risk for a severe/life-threatening condition. The cumulative incidence of these problems did not differ by type or HCT. Anxiety and depression scores were comparable between survivors and their siblings, but somatic distress was more common among transplant recipients. Survivors were 2.7 times more likely to report somatic distress.

In addition, female sex, low household income, and poor self-rated health status were associated with even higher risks for somatic distress.

The vast majority (90%) of HCT survivors reported having health insurance coverage, which the investigators noted was “fortunate,” considering their need for ongoing specialized care. ■

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Other Highlights

DVT Prophylaxis: First Comparison of CatheterDirected Thrombolysis versus Standard Care

By Neil Canavan

I

n the first comparative trial of its kind, the Catheter-Directed Venous Thrombolysis (CaVenT) study determined that treating a clot directly with the recombinant, antithrombotic agent alteplase reduced the frequency of postthrombotic syndrome (PTS) and improved long-term outcome in patients with proximal deep-vein thrombosis (DVT) compared with standard anticoagulation methods.

PTS can greatly affect a patient’s quality of life: 1 in 4 patients with DVT will experience PTS, despite having been treated according to current clinical guidelines.

To offset the risk of PTS, alteplase has been used in this setting. “This interventional therapy is expensive,”

said CaVenT lead investigator Tone Rønnaug Enden, MD, PhD, of Oslo University Hospital in Norway. “It is also associated with life-threatening bleeding. However, it has become standard care in some centers, despite a complete lack of evidence from randomized, controlled trials.”

This multicenter investigation enrolled 209 adults who had experienced an objectively verified DVT within 21 days of study entry and who met other entry criteria. Patients were randomized to standard treatment (ie, control group) with heparin/warfarin anticoagulation for 6 months, in addition to the use of elastic compression stockings for 24 months, or to standard treatment plus

Genetic Profiles Linked to Hematologic Outcomes

By Caroline Helwick

H

ematologic malignancies are characterized by genetic subtypes with varying prognoses. Analysis of these subtypes is beginning to make a difference in the clinic.

“Researchers are finding that genetic determinants are important causes of treatment failure,” said Kathryn Roberts, MD, who presented the findings from St. Jude Children’s Research Hospital in Memphis.

“But it is currently not possible to increase the dose or intensity of current therapies because of toxicity,” Dr Roberts said.

The findings support the screening of all patients newly diagnosed with acute lymphocytic leukemia (ALL) for the presence of high-risk subtypes. Identifying these patients should help characterize the genetic abnormalities that underlie a unique subtype of high-risk B-cell ALL and also help select candidates for targeted therapies.

Dr Roberts and her colleagues have identified a unique subtype of BCR-ABL–negative, high-risk B-cell ALL, with a deletion or mutation of IKZF1, which confers a poor outcome. They refer to this new subtype as “Ph [Philadelphia chromosome]like ALL.” Up to 15% of pediatric ALL cases can be classified as Phlike, and previous trials have shown that the outcome of these cases can be improved when tyrosine kinase inhibitors such as imatinib are

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added to chemotherapy regimens.

“This study represents potential changes in care,” said Martin S. Tallman, MD, Chief of Leukemia Services, Memorial Sloan-Kettering Cancer Center, New York, who moderated a press briefing. “This study provides further evidence that we can target specific leukemias with directed therapy, rather than just continue to give relatively indiscriminate chemotherapy.”

For Lymphoma, Genetic Risk Score Predicts Outcome In patients with diffuse large B-cell lymphoma (DLBCL), a genetic risk score based on the expression of a small number of genes was able to predict clinical outcomes related to specific treatments, investigators from the Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group reported.

Using tissue from 183 DLBCL patients in the ECOG E4494 phase 3 trial, researchers were able to construct a 5-gene predictor model that identified outcomes of patients treated with CHOP (cyclophosphamide/ doxorubicin/vincristine/prednisolone) and a 6-gene model that was predictive in patients treated with R-CHOP (CHOP plus rituximab). High-versuslow genetic risk scores significantly predicted clinical outcomes at a median follow-up of 9.4 years, reported Jane Winter, MD, of the Lymphoma Committee, ECOG, Chicago, IL. ■

catheter-directed thrombolysis (CDT) with alteplase for up to 96 hours, but not exceeding 20 mg/day.

“This is a minimally invasive percutaneous technique performed with local anesthesia,” said Dr Enden.

End points included measures of outcome for patient-rated criteria of pain, cramps, heaviness, pruritus, and clinician-rated criteria of edema, skin induration, hyperpigmentation, venous ectasia, and ultrasound examination.

At 24-month follow-up, 37 (41.1%) patients in the CDT group had PTS compared with 55 (55.6%) patients in the control group, an absolute risk reduction of 14.4%.

Regarding adverse events, 20 bleeding complications were reported—3 were classified as major and 5 as clinically relevant. The majority of bleeds were related to the puncture site, and no bleeding related to CDT led to a permanently reduced outcome.

Dr Enden concluded that the addi-

“This interventional therapy is expensive. It is also associated with lifethreatening bleeding.

However, it has become standard care in some centers, despite a complete lack of evidence.”

—Tone Rønnaug Enden, MD, PhD tion of CDT to standard treatment improved long-term outcomes and should be considered for patients with iliofemoral DVT when there is no contraindicating risk of bleeding. “These results should be taken into account when guidelines are revised.” ■

Favorable Data for Ruxolitinib and for a New JAK Inhibitor in Myelofibrosis

R

uxolitinib is the first Janus kinase (JAK) inhibitor that was approved last year for the treatment of myelofibrosis. Data presented at ASH 2011 from the randomized pivotal COMFORT I trial of 309 patients with myelofibrosis showed a significant survival advantage with ruxolitinib compared with placebo: 24 patients in the placebo arm died during the study or during the extended follow-up compared with 13 ruxolitinib-treated patients, representing a 50% risk reduction with ruxolitinib.

In a post-hoc analysis of COMFORT II, which compared ruxolitinib with best available therapy in 219 patients, improvements in healthrelated quality of life were significantly greater in those receiving ruxolitinib. The greatest differences were reported in improvements in appetite loss, dyspnea, fatigue, insomnia, and pain.

“Myelofibrosis is a life-shortening disease, with symptoms that significantly compromise patients’ everyday lives,” said investigator Claire Harrison, MD, of Guy’s Hospital, London. “As a result, therapies that

address the severe burden of myelofibrosis are urgently needed.”

CYT387 Promising in Anemia Responding to this urgent need, the new JAK inhibitor, CYT387, is currently furthest along in development for myelofibrosis, demonstrating promising results.

The critical issue of this disease is anemia, according to Mark Kowalski, MD, PhD, Chief Medical Officer of YM BioSciences, the drug’s manufacturer. “Progressive anemia is a hallmark of this disease, with the consequence that many patients require frequent blood transfusions,” said Dr Kowalski. In addition, anemia is an indicator of poor life expectancy in this patient population.

In ongoing analyses of the phase 1/2 CYT387 dose-ranging trial in 166 patients with myelofibrosis, 54% of the 68 patients who were transfusiondependent at baseline became transfusion-independent by 12 weeks. In addition, 65% of patients receiving 300 mg daily became transfusion-free. The mean duration of response exceeded 6 months. Phase 3 trials for CYT387 are slated to begin soon.—NC ■

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