February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology by Dalia Buffery

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

February 2014 I Vol 7, No 1 I SPECIAL ISSUE

Payers’ Perspectives in Oncology Including Highlights from ASH 2013*

Novel CAR-T Therapy Topped Decitabine More Cost-Effective than Conventional Induction in the News at ASH 2013 Impressive results in treating subtypes of leukemia, lymphoma By Caroline Helwick

Photo © American Society of Hematology

New Orleans, LA—Excitement was palpable at the 2013 ASH meeting over a novel approach to treating subtypes of leukemia and lymphoma. Although still limited to small pilot studies in small numbers of patients, the findings for engineered T-cells—so-called chimeric antigen receptor (CAR)-T therapy— are very impressive. Patients with very aggressive and refractory disease have had dramatic responses to therapy, achieving complete remissions and no longer demonstrating signs of tumor on computed tomography scans. Some remissions are ongoing for up to 3 years, at this point. “It looks like the disease has disappeared after a single infusion of James N. Kochenderfer, MD

Continued on page 19

Promising Drugs in the Pipeline for Leukemia and Myelodysplastic Syndromes By Wayne Kuznar

he pharmaceutical arsenal for the treatment of patients with leukemias or myelodysplastic syndromes (MDS) currently in the pipeline continues to grow, with some

drugs showing particularly promising results. Updates on many studies for drugs that are currently in development were presented at ASH 2013.

Continued on page 12

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

Older Patients with AML

FDA should consider for this patient population By Wayne Kuznar New Orleans, LA—Decitabine (Dacogen) is more cost-effective than conventional induction therapy for patients aged >60 years with acute myeloid leukemia (AML), according to an economic analysis presented at ASH 2013. The accepted treatments for patients with AML include cytarabine (Cytosar-U) plus daunorubicin, as well as hypomethylating agents such as decitabine. Complete remission rates with either approach are approxi-

Continued on page 7

Hematologists Often Ignore Treatment and Monitoring Recommendations Knowledge gap a major barrier to optimal care By Caroline Helwick New Orleans, LA—Most hematologists and oncologists do not follow evidence-based recommendations for managing acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or B-cell lymphomas, according to new survey results presented at ASH 2013 and compiled by inPractice

Resources, LLC, Reston, VA, a company that de Kevin L. Obholz, PhD velops interactive educational resources for oncologists. Among the deficiencies were that approximately 40% of clinicians were not appropriately monitoring treatment response of patients with CML, Continued on page 6

in th i s i s s u e

Health Economics . . . . . . . . . . . 6 Rituximab infusions costlier when given in the hospital Financial burden of transplants LEUKEMIA. . . . . . . . . . . . . . . . . . 10 Novel anti-CD20 antibodies promising in unfit patients with CLL MULTIPLE MYELOMA. . . . . . . . . 16 Myeloma drug arsenal expanding to new classes

mately 50%, noted the investigators. Furthermore, the 1-year overall survival (OS) rates are approximately 50% with either approach; 30-day mortality is slightly lower in patients receiving decitabine, but decitabine is not approved in the United States by the US Food and Drug Administration (FDA) for the treatment of AML. Given the economic pressures in the US health system, the FDA should consider approving decitabine for patients aged >60 years with newly

LYMPHOMA. . . . . . . . . . . . . . . . . 21 PIK3 inhibitors main focus of pipeline PAYERS’ PERspECTIVE. . . . . . . Increasing emphasis on cost in hematologic cancers

DRUG UPDATE . . . . . . . . . . . . . . Gazyva for chronic lymphocytic leukemia

OTHER HIGHLIGHTS. . . . . . . . . . 24 Ruxolitinib improves survival in high-risk myelofibrosis

CONTINUING EDUCATION. . . . . Biologics for value-based care

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

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

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

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

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

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

FDA Update First Drug Combination Approved for Unresectable or Metastatic Melanoma

The US Food and Drug Administration (FDA) approved the use of da brafenib (Tafinlar; GlaxoSmithKline) plus trametinib (Mekinist; Glaxo SmithKline) as a new combination therapy for the treatment of patients with advanced melanoma that is unresectable or metastatic. The 2 drugs

were individually approved by the FDA in 2013 for melanoma. Each of the 2 drugs blocks molecular signaling in different sites of the same pathway that promotes cancer-cell growth. Dabrafenib was initially approved for patients with melanoma whose tumors express the BRAF V600E mutation. The dabrafenib-trametinib combination is indicated for patients with melanoma who also have the BRAF S:7”

V600E or BRAF V600K mutation. Approximately 50% of skin melanomas have a BRAF mutation. “Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Their development for combination use is based on

Brief Summary Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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Tafinlar Receives Breakthrough Therapy Designation for Lung Cancer

S:10”

INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

the strong understanding of the biological pathways of the disease. This approval illustrates the value of continuing to study drugs in combination for clinical development.” The FDA approval was based on results of a clinical trial of 162 patients with unresectable or metastatic melanoma with the BRAF V600E or BRAF V600K mutation; the majority of the patients were treatment-naïve. They received dabrafenib as a single agent until their disease progressed or their side effects became intolerable, at which point they began using the combination. Overall, 76% of patients receiving the combination had an objective response for an average of 10.5 months compared with 54% of patients receiving dabrafenib alone who had an objective response lasting 5.6 months. Clinical trials are ongoing to determine whether this combination will also result in improved survival. The side effects reported with the combination are similar to those reported with each individual drug. Specifically, the combination was associated with an increase in the incidence and severity of fever. The FDA approved this combination under its accelerated program, and also reviewed it under its priority review. (January 8, 2014)

A few days after the approval of the combination of the 2 melanoma drugs, the FDA approved dabrafenib (Tafinlar) as a breakthrough therapy designation for lung cancer based on interim results from an ongoing phase 2 clinical trial. (January 13, 2014)

Ibrutinib Approved for Chronic Lymphocytic Leukemia

The FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least 1 therapy before. The approval was granted under the FDA’s accelerated approval process to expedite access by patients with CLL to this promising new medication. In November 2013, the FDA granted accelerated approval to ibrutinib for the treatment of patients with mantle-cell lymphoma (MCL), a rare and aggressive type of hematologic cancer; this approval, too, was for patients who had received at least 1 therapy before. “Today’s approval provides an important new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” said Richard Pazdur, MD, DiContinued on page 28

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1 American health & drug benefits NEPA14CDNY2145_PayerAd_Q1_Updte_KING_BS_Asize_r4.indd 1

february 2014

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VOL. 7

NO. 1

Special Issue

The Peer-Reviewed Forum For Evidence in Benefit Design™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Founding Editor-in-Chief Robert E. Henry Engage Healthcare Communications 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

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. Contact Information: For subscription information and edi torial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright.com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VOL. 7

NO. 1

Special Issue

Payers’ Perspectives in Oncology FDA UPDATE Ibrutinib approved for CLL More….. HEALTH ECONOMICS Physicians must consider the financial burden of allogeneic transplants Peripheral T-cell lymphoma linked to high resource use and costs More….. LEUKEMIA Idelalisib improves outcomes in CLL Nilotinib sustains deeper molecular response versus imatinib in Ph+ CML More….. MULTIPLE MYELOMA Myeloma drug arsenal expanding to new classes More…..

PERSONALIZED MEDICINE Genomic sequencing promising for clinical decision-making in hematopoietic cancers More….. LYMPHOMA PI3K inhibitors main focus of lymphoma pipeline More….. PAYERS’ PERspeCTIVE Increasing emphasis on costs in hematologic cancers OTHER HIGHLIGHTS Ruxolitinib improves survival in myelofibrosis More….. DRUG UPDATE Gazyva for chronic lymphocytic leukemia CONTINUING EDUCATION Optimal use of biologics in value-based care

EDITORIAL BOARD Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

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

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director, Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia PHARMACOECONOMICs

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH

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Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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Health Economics

Hematologists Often Ignore Treatment and Monitoring... and 20% of clinicians were inappropriately using cytogenetic testing. While acknowledging that advances in understanding CML, ALL, and B-cell lymphomas, as well as the emergence of new treatments, have increased the complexity of decision-making in patient care, Kevin L. Obholz, PhD, Editorial Director, Clinical Care Options, LLC, Reston, VA, and colleagues noted that “a significant proportion of US hematology/ oncology specialists are not applying optimal care” for these malignancies. The investigators aimed to identify and quantify professional practice gaps and barriers to optimal care for patients treated at academic and community centers. They recruited 250 physicians and interviewed 27 of them for the initial qualitative exploratory phase of the study. The focus was on the personal, contextual, and behavioral factors that influence a provider’s clinical reasoning process in the diagnosis and treatment of patients.

These interviews were analyzed using thematic analysis, and the findings shaped the subsequent quantitative phase of the study. For this,

“Participants did not adequately recognize that early molecular response to TKI therapy is significantly associated with long-term survival outcomes.” —Kevin L. Obholz, PhD, and colleagues 121 physicians completed an online survey of multiple-choice questions, differential rating scales, and case vignettes. A group of expert hematologists provided evidence-based responses for comparison. “A group of 9 core practice gaps were identified through combined

Clinical Practice Guidelines Should Include Patient’s Preferences Clinicians want to provide excellent patient care, without having to appraise every new study in their field, but producing the “authoritative, instructive resource for most clinical scenarios” is not as straightforward as it would seem, according to David A. Garcia, MD, Professor of Medicine, University of Washington School of Medicine, Seattle. At a symposium on quality care and clinical practice guidelines, Dr Garcia emphasized the need to include the preferences of patients, whose lives are impacted by these guidelines. “Our job is to apply evidence and guideline recommendations within the context of individual patient preferences and values, and these can never be predicted or accounted for by people writing the guidelines,” he said. Consider the Patient The best guidelines are based on “strong evidence,” and the proper ingredients of a “strong recommendation” are 2-fold: (1) the inclusion of high-quality evidence that proves the impact on important clinical outcomes, as opposed to surrogate outcomes that may not matter to the patient, and (2) the demonstration that any risks associated with the intervention are clearly outweighed

by the benefits, Dr Garcia said. “These seem obvious, but as physicians, we may not always predict accurately what the patient sees as being worthwhile, in terms of the risks they are willing to accept for the benefits we can offer,” he noted. Future guideline writers need to focus on patient-important (not surrogate) outcomes whenever possible, Dr Garcia suggested, and to be equipped with better knowledge about how patients view the trade-offs associated with treatment options. Dr Garcia suggested the following proposals for guideline developers: • Minimize conflicts of interest but still harness the expertise held by “conflicted” individuals; this can be controlled by limiting the power of those with conflicts of interest • Focus on patient-important outcomes • Consider trade-offs from the patient’s perspective • Maintain transparency regarding the evidence and methods used to create the guideline, as well as any possible conflicts of interest • Provide key recommendations as in synthesis form that can be used at the bedside: a summary, checklist, algorithm—with strength clearly labeled.

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analysis of data from the online surveys and in-depth interviews,” the investigators reported. Treatment Recommendations Often Not Followed The current treatment guidelines recommend the tyrosine kinase inhibitors (TKIs) imatinib (Gleevec), dasa tinib (Sprycel), and nilotinib (Tasigna) as first-line therapy; dasatinib and nilotinib are second-generation TKIs that have shown superior efficacy and safety over imatinib. Experts suggest that dasatinib and nilotinib are preferred over imatinib, because they are superior to imatinib in achieving early responses and major molecular remissions. Only 33% of survey participants agreed with evidence-based expert opinion that early molecular responses to TKIs correlate with long-term clinical outcomes for patients with chronic-phase CML. Similarly, only 38% agreed with expert opinion that

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achieved, but 1 of 5 clinicians order these expensive, invasive procedures as often as every 2 to 6 months. Although PCR should be used every 3 months to monitor response, only 40% of the clinicians agreed with the guidelines and expert opinion on this issue. Similarly, only 22% of the clinicians agreed with expert opinion regarding the timing and frequency of cytogenetic analysis by bone marrow biopsy to assess responses to first-line TKI treatment for chronic-phase CML. Overall, there is overuse of bone marrow cytogenetic analysis by community oncologists, and underuse and inappropriate use of PCR, the survey indicated. In addition, the current guidelines suggest that 3-month response on PCR correlates with outcomes, and that when patients do not achieve a good response by that time point, they should probably be switched to a new drug; however, 40% of the

“There is a clear need for better education of community physicians.…With these relatively rare hematologic diseases, clinicians need expert-led education targeted to them and tools that will help them learn how to make better decisions.” —Kevin L. Obholz, PhD achieving a major molecular response to TKIs substantially decreases the patient’s risk of disease progression. The study showed that the less experienced the clinician, the more likely he or she is to disregard the superiority of the second-generation TKIs in achieving these landmarks. “Notably, study participants did not adequately recognize that early molecular response to TKI therapy is significantly associated with longterm survival outcomes, which could impact clinical decisions for patients with chronic-phase CML,” Dr Obholz and colleagues noted. Ignorance of Monitoring and Switching Recommendations There was also a knowledge gap with regard to the appropriate monitoring of response to TKIs. Quantitative polymerase chain reaction (PCR) on peripheral blood is now the recommended approach, and bone marrow cytogenetics analysis is no longer recommended for monitoring. The guidelines support cytogenetics at 3 months and 12 months if a major molecular response is not

respondents were unsure or would not change therapy at that threshold. A Missed Opportunity to Enroll Patients in Clinical Trials Fewer than 30% of the survey respondents knew the mechanisms of action for agents in phase 2 trials, including inotuzumab ozogamicin (27%), blinatumomab (26%), idelalisib (22%), the recently approved obinutuzumab (Gazyva; 20%), and fostamatinib (18%). Furthermore, when asked to match 9 targeted agents approved for B-cell lymphomas and B-cell ALL to their molecular target, only 20% of the respondents were able to do so. “This potentially represents missed opportunities to enroll eligible patients on clinical trials,” Dr Obholz said. “There is a clear need for better education of community physicians. Those with more experience and those in academic centers are more likely to agree with expert recommendations. With these relatively rare hematologic diseases, clinicians need expert-led education targeted to them and tools that will help them learn how to make better decisions.” n VOL. 7

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Health Economics

Physicians Must Consider the Financial Burden of Allogeneic Transplants Economically vulnerable patients may need financial counseling By Wayne Kuznar New Orleans, LA—Recipients of allogeneic hematopoietic cell transplant are at high risk for financial burden, according to survey-based data collected by Nandita Khera, MD, MPH, a medical oncologist from the Blood and Marrow Transplant Program, Mayo Clinic Arizona, Phoenix, and colleagues. The reasons include prolonged hospital stays, living away from home, high out-of-pocket (OOP) costs, extended duration of work loss for the patient and caregiver, and the occurrence of chronic medical problems, including complications from the transplant. “One of the implications from the study is that, as healthcare providers, we need to be aware of the financial burden of allogeneic transplant, which is an important nonmedical complication of the transplant,” said Dr Khera. To measure the financial toll on patients, Dr Khera and colleagues conducted a cross-sectional survey- based study, with 268 (of 482) eligible patients responding. The team used a 25-item questionnaire to measure

sociodemographic information, as well as OOP expenses and medication copays, financial burden, and impact on medical care. The median age of respondents was 55 years, and 51% of the total respondents were male. The study population was 95% white and 97% nonHispanic, and 51% had unrelated donor transplants, 58% had reducedintensity conditioning regimens, and 49% had acute leukemia. The median follow-up time was 2.3 years. Some 29% of patients reported working full-time or going to school, in contrast to 69% of patients who had reported being a full-time worker or student before the transplant. A total of 31% of patients reported being on medical disability, and 72% had a monthly median household income of >$2000. Of the 255 patients with available financial information, all were insured: 59% had private insurance, 4% Medicaid, 4% miscellaneous, and 33% had Medicare with supplemental coverage. Overall, 73% of patients said that being sick had hurt them financially.

In addition, 33% of patients believed that they did not have enough money to take care of healthcare needs, or

“We need to be aware of the financial burden of allogeneic transplant, which is an important nonmedical complication of the transplant….We also need to be able to offer potential interventions like early and frequent financial counseling or connecting them to appropriate services for health.” —Nandita Khera, MD, MPH that their medicines were too expensive, and 22% reported being unable to pay their medical bills. As a result of their medical bills,

13% of patients reported having had to sell stocks or other investments; 25% had to withdraw money from a retirement account; 9% had to refinance a mortgage, take a second mortgage, or sell their house; and 3% had to declare bankruptcy. The OOP costs for 3 months were >$2000 for 38% of patients and >$5000 for 12% of patients. The median monthly medication copayments were $100 (range, $0-$3000). Of the patients, 19% reported cutting back on or not purchasing their prescription medications, 21% reported not making a physician appointment or having a medical test performed, and 28% deferred the use of a medical service (eg, physical therapy). “We need to recognize the vulnerable patients who are at risk for catastrophic economic outcomes for self and their families. We also need to be able to offer potential interventions like early and frequent financial counseling or connecting them to appropriate services for health,” Dr Khera suggested. n

Decitabine More Cost-Effective than Conventional Induction in Older Patients with... Continued from page 1

effectiveness ratio (ICER). The cytarabine plus daunorubicin regimen consisted of cytarabine 100 mg/m2 continuous infusion for 7 days, and daunorubicin 60 mg/m2 for 3 days. Consolidation therapy Comparing Cost and Efficacy with high-dose cytarabine followed His team compared the direct costs the cytarabine plus daunorubicin regiof decitabine and conventional induc- men. The decitabine dosage used in tion therapy in patients with AML the model was 20 mg/m2 daily as (aged >60 years) using a semi-Mar- a 1-hour infusion for 10 days until kov model compiling survival and remission, and then 5 days every 4 cost data. Derived from the 2012 US weeks until progression. market, the costs of the drugs were The survival probabilities were assumed to be $1637.94 for 50 mg of taken from published literature. Data decitabine, $12.08 for 2 g of cytara- accounted for reinduction therapy bine, and $58.62 for 20 mg/4 mL of with IDA-FLAG (idarubicin, fludar daunorubicin. abine, cytarabine, and granulocyte The hospital costs were evaluated colony-stimulating factor) and consolin a diagnosis-related group system. idation therapy with high-dose cytaThe estimated cost of a direct hospi- rabine (HiDAC). The model assumed tal stay of 1 day was $2104.75, and a maximum of 4 cycles of HiDAC the cost of an infusion clinic visit was and continuing decitabine until loss $524.07. The cost-effectiveness was of benefit. assessed using an incremental cost- At 3 months, the OS rates were diagnosed AML, suggested Nicolas Batty, MD, a hematology/oncology fellow at Roswell Park Cancer Institute, Buffalo, NY, and lead investigator of this analysis.

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98% with decitabine and 63.6% with cytarabine plus daunorubicin, and at

Decitabine was effective and more cost-effective than cytarabine or daunorubicin. Given the economic pressures in the US health system, the FDA should consider approving decitabine for patients aged >60 years with newly diagnosed AML, the investigators suggest. 6 months, the OS rates were 59% and 50.4%, respectively. The survival rate at the end of 12 months was 47% in the

cytarabine plus daunorubicin group and 52.6% in the decitabine group. Life expectancy was 0.16 years long er with decitabine versus with cytarabine plus daunorubicin (0.77 vs 0.61 years), and the quality-adjusted lifeyear (QALY) was 0.46 in the cytarabine plus daunorubicin group and 0.54 in the decitabine group. The expected cost was nearly the same in both groups, with $88,325 for patients receiving cytarabine plus daunorubicin versus $91,312 with decitabine. The ICER per QALY with decitabine was $38,839. Decitabine was the most cost-ef fective therapy. Decitabine was dom inant in the model when the cost of cytarabine plus daunorubicin in creased by 10%, when the cost of decitabine decreased by 10%, and when the time horizon (the period for which the costs and treatment benefits were accounted) was 3 months or 6 months. n

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Health Economics

Significant Hospital Costs Tied to 30-Day Readmissions for Allogeneic Transplants By Wayne Kuznar New Orleans, LA—New research has confirmed that 30-day readmission for reduced-toxicity conditioning allogeneic hematopoietic-cell transplantation (allo-HCT) is linked to greater 100-day posttransplant hospital charges. The finding justifies 30-day readmission as a significant marker of quality of care, said lead investigator Sherri Rauenzahn, MD, a palliative care fellow at West Virginia University in Morgantown, who presented her data at ASH 2013. The criteria that impact 30-day readmission were examined for 91 patients who had reduced-toxicity conditioning allo-HCT with fludar abine (Fludara; total dose, 150-160 mg/m2) and busulfan (Myleran; total dose, 6.4 mg/kg or 12.8 mg/ kg). The researchers also measured the impact of 30-day readmission on mortality and healthcare costs of alloHCT recipients. Of the 91 patients, 35 (38%) required readmission, at a median time of 14 days and a median length of stay of 3 days.

“The only variable on multivariate analysis that predicted readmission was an infection during the transplant admission,” said Dr Rauenzahn. “There was no difference [between groups] as far as cause of readmission. Those readmitted within 7 days usually had either a fever or infectious process, but it wasn’t statistically significant.” The caregiver type and the number of caregivers did not influence readmission. After an 18-month median followup for surviving patients, the approximate 2-year overall survival rates were 49% in readmitted patients and 58% in those not readmitted. The 1-year nonrelapse mortality rates were 18% in the patients who were readmitted and 13% in patients who were not readmitted. “Other studies have found that the conditioning regimen used might impact the readmission rate, but we used only a single conditioning regimen to try to eliminate it as one of the confounders,” she said.

“The cost of readmission made a significant difference in the total cost in the 100-day period posttransplant,” Dr Rauenzahn noted. “There was no

“The cost of readmission made a significant difference in the total cost in the 100day period posttransplant. There was no difference in outpatient charges between groups,…it was just the readmission rate.” —Sherri Rauenzahn, MD

difference in outpatient charges between groups,…it was just the re admission rate.” The respective median and mean hospital charges were: • Inpatient: $25,698 and $45,982 for readmitted patients versus $0 and

$24,292, respectively, for patients not readmitted (P <.001) • Outpatient: $43,280 and $47,942 for readmitted patients versus $37,834 and $42,421, respectively, for patients not readmitted (P = .22) • Total: $85,115 and $93,925 for readmitted patients versus $45,083 and $69,142, respectively, for patients not readmitted (P = .002). “In this specific allo-transplant population, a 30-day readmission is an indicator of increased costs,” Dr Rauenzahn pointed out. “What we can do to lessen that readmission rate is going to be challenging, because in the transplant population you already have a fairly good follow-up system, with a lot of attention to detail. Do we keep patients who have an infection during their transplant admission for a few days longer to try to prevent readmissions down the road? Or do we continue to practice the way we currently have and discharge when we think the acute condition has resolved and the [blood] counts have recovered, and see what happens?” n

Peripheral T-Cell Lymphoma Associated with High Clinical Burden, Resource Utilization, and Costs New Orleans, LA—Peripheral T-cell lymphoma (PTCL) is associated with high resource utilization rates and high overall costs, according to a multicenter study presented at ASH 2013. Hospitalizations, in particular, represent a major clinical and economic burden, indicating the need for treatments requiring lower resource utilization with better PTCL management. Michele H. Potashman, PhD, of Millennium Pharmaceuticals, Cambridge, MA, and colleagues, studied 1000 patients with PTCL identified by International Classification of Diseases, Ninth Revision (ICD-9) codes over a period from October 1, 2007, to June 30, 2011. Truven Health Analytics MarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify patients with PTCL. This database comprises medical and pharmaceutical claims for more than 100 million unique patients across the United States. To be included in the study, patients had to have at least 6 months of con-

tinuous enrollment before their index date and 12 months of continuous enrollment after their index date. The mean patient age was 56 years, 58% of the patients were male, and all patients had a high rate of comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39 for the control group).

The average annual costs were $75,934.08 for patients with PTCL compared with $4660.64 for the matched controls, driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). The control group included 5000 randomly selected patients without PTCL, and was considered to represent the average insured patient population.

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Monthly healthcare costs were measured and annualized to provide average annual costs. Healthcare costs included hospitalizations; pharmacy services; office visits; emergency department visits; hospice stays; stem-cell transplant; and other patient-related costs, such as laboratory procedures, blood transfusions, and radiology procedures. The cost estimates were based on net payments received by the providers, and healthcare costs included hospitalizations, pharmacy services, office visits, emergency department visits, and hospice stays. High Annual Costs “On an average annual basis, PTCL patients were hospitalized more often and experienced a longer length of stay compared with matched controls,” noted Dr Potashman. “In addition, PTCL patients had higher utilization of office visits, pharmacy services, emergency room visits, and hospice care.” Overall, the average annual costs were $75,934.08 for patients with

PTCL compared with $4660.64 for the matched controls, driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). A total of 50% of the patients with PTCL compared with 13.8% of the controls had hospitalizations. Emergency department visits were almost twice as frequent in patients with PTCL as in the control group—47% versus 25%, respectively. The mean cost of hospitalization per patient was $24,427 for the patients with PTCL versus $1058 for the controls (P <.001). Some 11.4% of patients with PTCL had stem-cell transplant compared with none of the controls. The mean cost per patient undergoing transplant in the PTCL cohort for a first stem-cell transplant was $126,093.58. The most common diagnoses associated with hospitalization (based on ICD-9 codes) among the patients with PTCL were fever, fatigue, dizziness, dyspnea, chest pain, cough, and other chest symptoms.–—WK n VOL. 7

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Health Economics

Hematologists Urged to Reduce Unnecessary Tests/ Procedures, and Costs to Improve Quality of Care

5 Ways to Reduce Waste The following 5 items named by the task force represent an important step in trimming waste and reducing harm to patients with hematologic malignan-

“Inferior vena cava filters are costly, can cause harm, and do not have a strong evidence base.” —Mark Crowther, MD, MSc

cies and other blood-related conditions. 1. Limit scans in asymptomatic patients after curative-intent treatment for aggressive lymphoma. In this common malignancy, treatment with chemotherapy and radiotherapy carries the expectation of cure, “but the question is how best to monitor these patients,” said Joseph Connors, MD, Clinical Professor of Medical Oncology, University of British Columbia, Vancouver, Canada. “It is intuitively appealing to ‘hover’ over these patients to detect recurrences as soon as possible, but at the end of the day, ‘hovering’ can be counter-productive if the tests themselves are harmful. Use of computed tomography scanning and whole body scanning can be reduced and eliminated a short time after treatment,” Dr Connors said. He noted that unnecessary scans are associated not only with physical harm (ie, radiation exposure) and psychological harm (ie, anxiety), but also with economic harm. Dr Connors estimated that the new recommendation could save the healthcare system in North America $1 billion over 10 years. 2. Avoid the routine use of inferior vena cava filters in patients with acute venous thromboembolism. “Inferior vena cava filters [IVC] are costly, can cause harm, and do not have a strong

evidence base,” said Mark Crowther, MD, MSc, Professor, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. He noted that acute venous thromboembolism (VTE) is the main indication for IVC filters, and some lesser indications may be reasonable, such as some cases of pulmonary embolism (PE). Retrievable filters are recommended over permanent filters, with the removal of the filter when the risk of PE has resolved and/ or when anticoagulation can be safely resumed. Dr Crowther estimated that only 10% of the 250,000 IVC filters inserted annually in the United States are currently being used appropriately. Photo © American Society of Hematology

New Orleans, LA—To improve the quality of care in hematology, and to eliminate waste and reduce costs, the American Society of Hematology (ASH) has embraced the Choosing Wisely initiative of the American Board of Internal Medicine Foundation. The Institute of Medicine estimated that in 2009, some $750 billion was wasted in healthcare, of which $210 billion was spent on unnecessary services across all specialties, according to ASH’s Choosing Wisely Task Force Chair Lisa K. Hicks, MD, MSc, of St Michael’s Hospital and the University of Toronto, Ontario, Canada. “If we could redirect even a fraction of this to real people with real unmet healthcare needs, think of the good that we can do,” Dr Hicks said at a press briefing during the 2013 ASH meeting. “We need to take a step back and decide whether the tests and procedures we order are truly necessary,” Dr Hicks said. “We need a conversation about cost and value.” The task force recommendations focus on unnecessary treatments and testing. The evidence-based recommendations were developed to initiate conversation within the hematologic community about quality of care in hematologic malignancies and other disorders. The dominant principle was to avoid harm, while taking into account evidence, cost, frequency, and scope of practice.

Photo © American Society of Hematology

By Caroline Helwick

“Using more [red blood cell units] generates higher costs and exposes patients to adverse effects.” —Jeffrey L. Carson, MD

3. Do not transfuse more than the minimum number of red blood cell units necessary to relieve symptoms of anemia or to reach a safe hemoglobin range (7-8 g/dL in stable inpatients without heart disease). Clinical trials of red blood cell (RBC) transfusions have demonstrated that liberal transfusion strategies do not improve outcomes compared with the use of less blood (ie, a reduction from 10 g/dL to the range of 7-8 g/dL). “Using more generates higher costs and exposes patients to adverse effects,” said Jeffrey L. Carson, MD, Chief, Division of General Internal Medicine, Robert

Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick. “Avoid the routine use of 2 units of RBC if 1 is sufficient,” Dr Carson recommended. 4. Avoid testing for thrombophilia in adults with VTE in the setting of major transient risk factors, such as surgery, trauma, or prolonged immobility. “Thrombophilia testing is costly and harmful if the duration of anticoagulation is inappropriately prolonged or incorrectly labeled as thrombophilic,” according to John A. Heit, MD, Professor of Medicine, Mayo Clinic, Rochester, MN. This recommendation for testing does not change the approach when this testing is known to be important. 5. Do not administer plasma or prothrombin complex concentrates for the nonemergent reversal of vitamin K antagonists. “Many people are on Coumadin [warfarin] for stroke prevention, and there may be a need to reverse the effect of that drug, as well as a tendency to accomplish this as quickly as possible with plasma or prothrombin complex concentrates. However, there is little evidence that this benefits the patient, and it is adequate to hold the next dose of Coumadin or administer vitamin K instead,” said Robert Weinstein, MD, University of Massachusetts Medical School, Worcester, who added that unnecessary blood products also expose patients to potential harm. “Results of multiple audits suggest that 30% of the 4 million units used each year are given inappropriately. That’s a lot of plasma,” Dr Weinstein noted, estimating that up to 200 unnecessary deaths could be avoided annually. n

Rituximab Infusions Costlier When Given in the Hospital By Wayne Kuznar

retrospective analysis of rituximab infusions presented at the meeting showed that more patients with diffuse large B-cell lymphoma (DLBCL) receive the infusions in the hospital setting, incurring greater costs than those receiving them in the office/clinic. Rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the recommended first-line therapy for DLBCL. Carolina Reyes, PhD, of Genentech, San Francisco, CA, examined differences in treatment patterns, healthcare

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resource use, and costs among patients with DLBCL receiving rituximab plus chemotherapy in the office setting versus the hospital outpatient setting.

Total unadjusted PPPM costs in the hospital cohort were $22,325 compared with $15,541 for the office/clinic cohort. Medical and pharmacy claims from a large, geographically diverse US commercial health plan were used to

identify 491 adults with DLBCL with 2 or more claims for rituximab, 65% of whom received infusions in the office or clinic, and 35% of whom received them in the hospital. The percentage of patients receiving infusions in the hospital increased from 32% in 2007 to 43% in 2011/2012. The mean length of episode of care was not significantly different by the site of service, and the mean number of rituximab infusions was lower (4.92) in the hospital versus the office (6.52), as was the mean number of infusions per month (1.01 vs 1.17, respectively). The total mean costs during the epi-

sode of care, as well as administration costs incurred on days of rituximab infusions, were significantly higher among the hospital cohort compared with the office/clinic cohort. The unadjusted mean infusion-day costs were $12,481 in the hospital cohort versus $5834 in the office/clinic cohort. “Higher infusion-day costs contributed to higher unadjusted mean per patient per month [PPPM] costs among the hospital cohort,” noted Dr Reyes. Total unadjusted PPPM costs in the hospital cohort were $22,325 compared with $15,541 for the office/ clinic cohort. n

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Leukemia

Novel Anti-CD20 Antibodies Show Promising Results in Unfit Patients with Chronic Lymphocytic Leukemia Obinutuzumab potentially practice-changing therapy By Wayne Kuznar New Orleans, LA—The role of antiCD20 antibodies in unfit patients with chronic lymphocytic leukemia (CLL) was discussed in several presentations at ASH 2013. Elderly and unfit patients constitute the majority of patients with CLL, but these groups have limited treatment options. Results of 2 recent studies suggest that anti-CD20 antibodies provide promising alternatives to the current standard in this patient population.

each associated with significantly better PFS than chlorambucil alone. In the updated results presented at the meeting, compared with chlorambucil alone, the risk of disease progression or death was improved by 82% with obinutuzumab (P <.001). The median PFS was 26.7 months with the combination. Rituximab plus chlorambucil produced a 66% reduction in the risk of progression or death, and a 16.3-month median PFS. Overall survival (OS) was also superior with obinutuzumab, with a hazard ratio for death of 0.41 (P = .002).

In November 2013, the US Food and Drug Administration approved obinutuzumab (Gazyva), a novel, glycoengineered, type II CD20 antibody, for use in combination with chlorambucil (Leukeran) for the treatment of patients with previously untreated CLL. Valentin Goede, MD, Hematologist/ Oncologist, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Germany, presented updated results with this drug at the meeting. Obinutuzumab, in combination with chlorambucil, was superior to rituximab (Rituxan) plus chlorambucil in prolonging progression- free survival (PFS) in previously untreated patients with CLL with comorbidities. Treatment with obinutuzumab also led to a significantly higher objective response rate, and more patients treated with obinutuzumab were negative for minimal residual disease (MRD) in the bone marrow and blood, announced Dr Goede. These findings “mean a significant and potentially practice-changing treatment advance for this large patient population,” said Dr Goede. “What we currently know is if we combine obinutuzumab or rituximab with a weaker chemotherapy backbone, obinutuzumab is obviously superior to rituximab, so in this setting I would say that it will substitute for rituximab…at least in the population of elderly patients.” In the CLL11 trial, 781 patients with CLL complicated by comorbidities were randomized to 1 of 3 first-line regimens: chlorambucil alone, chlor ambucil plus rituximab, or chlorambucil plus obinutuzumab. The results from the first stage of CLL11 were reported previously, and showed that obinutuzumab plus chlorambucil and rituximab plus chlorambucil were

Ofatumumab Improves Outcomes, OS, in Elderly Patients

Photo © American Society of Hematology

Obinutuzumab Superior to Rituximab in Unfit Patients

the rituximab arm were MRD negative in blood. After a median follow-up of approximately 19 months, survival still favors obinutuzumab in the head-to-head comparison with rituximab (P = .0849); however, the data for survival remain immature, with fewer than 15% of events included in the analysis, said Dr Goede. More grade ≥3 adverse events (AEs) were reported with obinutuzumab plus chlorambucil than with rituximab plus chlorambucil (70% vs 55%, respectively). Infusion-related reactions (20% vs 4%, respectively) and thrombocytopenia (10% vs 3%, respectively) were more frequent in the obinutuzumab arm.

These findings “mean a significant and potentially practice-changing treatment advance for this large patient population.” —Valentin Goede, MD The second-stage analysis was a head-to-head comparison of the 2 combination regimens. The median PFS with obinutuzumab plus chlor ambucil was 26.7 months versus 15.2 months (P <.001) with rituximab plus chlorambucil, corresponding to a 61% (11.5 months) reduction in risk with the addition of obinutuzumab. Complete responses were achieved in 21% of patients in the obinutuzumab arm versus 7% of patients in the rituximab arm. Each group had a partial response rate of 58%. The overall response rate was 78% with obinutuzumab and 65% with rituximab (P <.001). Some 19.5% of patients in the obinutuzumab arm were MRD negative for bone marrow versus 2.6% of the rituximab group (P <.001). A total of 37.7% of patients in the obinutuzumab arm versus 3.3% of patients in

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When added to chlorambucil (Leukeran), ofatumumab (Arzerra), a second-generation fully humanized mono clonal antibody against the CD20 protein, improves clinical outcomes and is tolerable irrespective of age and fitness in patients with previously untreated CLL who are considered inappropriate for fludarabine (Fludara), according to the results of a phase 3 study. In older patients with CLL who are unfit for the gold standard therapy with fludarabine/cyclophosphamide/ rituximab, chlorambucil, using various dosing schedules, remains a treatment option, said lead investigator Peter Hillmen, MB ChB, PhD, Honorary Consultant Hematologist, St James’s University Hospital, United Kingdom. Ofatumumab has a discrete epitope that targets the small and large extracellular loops of CD20. In vitro, it displays more activity than rituximab through complement and through antibody-dependent cellular cytotoxicities. In the phase 3 COMPLEMENT 1 study, 447 patients with previously untreated CLL who were considered inappropriate for fludarabine-based therapy because of advanced age and/or comorbidities were randomized to chlorambucil or ofatumumab plus chlorambucil until best response. Ofatumumab was given as an intravenous infusion for a maximum of 12 cycles. Chlorambucil was dosed oral-

ly at 10 mg/m2 on days 1 through 7 of each 28-day cycle. Approximately 25% of the patients were aged >75 years. In each group, 87% of patients were aged ≥65 years or had ≥2 comorbidities or a creatinine clearance <70 mL/min, and were thus ineligible for fludarabine, said Dr Hillmen. In each arm, 19% of the patients required a dose reduction of chlorambucil because of neutropenia. After a median follow-up of 28.9 months, PFS was 22.4 months in the arm receiving ofatumumab plus chlorambucil compared with 13.1 months in the arm receiving chlorambucil alone, corresponding to a 43% improvement with ofatumumab (P = .001). OS was significantly superior in the ofatumumab arm versus the chlorambucil alone arm (82% vs 69%, respectively; P <.001), as was the rate of complete response (14% vs 1%, respectively). The median OS was not reached in either arm. Of patients receiving ofatumumab plus chlorambucil, 12% showed no MRD compared with 4% of patients receiving chlorambucil alone. There was a trend toward a shorter time to response with ofatumumab plus chlorambucil versus chlorambucil alone (P = .084). The median duration of response was longer in the ofatumumab plus chlorambucil arm at 22.1 months versus 13.1 months (P <.001) in the chlorambucil alone arm. The time to next treatment was also significantly longer in the patients receiving ofatumumab plus chlorambucil versus in the patients receiving chlorambucil alone (median, 39.8 months vs 24.7 months, respectively; P <.001). More than 80% of the patients completed at least 6 cycles. Combination treatment was well tolerated. The rate of withdrawal as a result of AEs was 13% in each arm. The rate of grade ≥3 AEs was 50% with ofatumumab plus chlorambucil versus 43% with chlorambucil alone. In the ofatumumab plus chlorambucil arm, 10% of patients had grade ≥3 infusion reactions. There was a higher rate of grade ≥3 neutropenia in patients assigned to ofatumumab plus chlor ambucil compared with chlorambucil alone (26% vs 14%, respectively), but this difference did not translate into a higher risk of infection, said Dr Hillmen. n VOL. 7

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NOW APPROVED FOR PREVIOUSLY TREATED MCL

INDICATION - IMBRUVICA™ (ibrutinib) is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - 5% of patients with MCL had ≥ Grade 3 bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies and the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred. At least 25% of patients with MCL had infections ≥ Grade 3, according to NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly. Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2013 © Janssen Biotech, Inc. 2013 11/13

K08BR13037C

Renal Toxicity - Fatal and serious cases of renal failure have occurred. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration.

*Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (7%), Second Primary Malignancies - Other malignancies abdominal pain (5%), atrial fibrillation, diarrhea (5%), (5%) have occurred in patients with MCL who have been fatigue (5%), and skin infections (5%). Treatmenttreated with IMBRUVICA™, including skin cancers (4%) emergent Grade 3 or 4 cytopenias were reported in 41% and other carcinomas (1%). of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). Embryo-Fetal Toxicity - Based on findings in animals, ™ IMBRUVICA can cause fetal harm when administered The most frequent adverse reaction leading to treatment to a pregnant woman. Advise women to avoid becoming discontinuation was subdural hematoma (1.8%). pregnant while taking IMBRUVICA™. If this drug is used Adverse reactions leading to dose reduction occurred in during pregnancy or if the patient becomes pregnant 14% of patients. while taking this drug, the patient should be apprised of DRUG INTERACTIONS the potential hazard to a fetus. CYP3A Inhibitors - Avoid concomitant administration ADVERSE REACTIONS - The most commonly occurring with strong or moderate inhibitors of CYP3A. If a adverse reactions (≥ 20%) in the clinical trial were moderate CYP3A inhibitor must be used, reduce the thrombocytopenia*, diarrhea (51%), neutropenia*, IMBRUVICA™ dose. anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), SPECIAL POPULATIONS - Hepatic Impairment - Avoid vomiting (23%) and decreased appetite (21%). use in patients with baseline hepatic impairment.

Leukemia

B:10.75” T:10.5” S:9.5”

Promising Drugs in the Pipeline for Leukemia and... Chronic Lymphocytic Leukemia Several new, targeted therapies show promise to expand the treatment options for chronic lymphocytic leukemia (CLL) and are more effective and better tolerated than standard chemotherapy. Phase 3 studies of idelalisib dem-

onstrated impressive progression-free survival in previously treated patients with CLL (see article on page 14). An orally bioavailable selective inhibitor of the Bcl-2 protein, known as ABT-199, induced remissions in patients with relapsed or refractory CLL and small lymphocytic lym-

phoma in an early-phase, open-label, dose-escalation trial. Overall, 67 (88%) patients had at least a 50% reduction in the sum product of diameters of nodal masses. The median time to achieve a 50% reduction was 6 weeks (the time of the first computed tomography scan stipulated per protocol).

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14.1) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly. Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies: Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers (4%), and other carcinomas (1%). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL receiving the ibrutinib dose of 560 mg per day. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See TableTables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

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Continued from page 1

“Forty-one patients had achieved at least a partial remission at that 6-week scan, indicating that cytoreduction is rapid,” said lead investigator John Seymour, MBBS, PhD, Director, Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia.

IMBRUVICATM (ibrutinib) capsules Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis General disorders and Fatigue Peripheral edema administrative site Pyrexia conditions Asthenia Bruising Skin and subcutaneous tissue Rash Petechiae disorders Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea Cough and mediastinal Epistaxis disorders Metabolism and Decreased appetite nutritional disorders Dehydration Nervous system Dizziness disorders Headache

Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) 57 17 47 29 41 9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

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A total of 89% of patients had at least a 50% reduction in bone marrow infiltrate at the first bone marrow biopsy at week 25, with a median reduction of approximately 95%. The small-molecule inhibitor IPI145, which blocks the activity of the enzyme phosphoinositide-3-kinase

(that is responsible for CLL signaling), was investigated in an earlyphase trial of 193 patients, including 52 patients with CLL that is treatment resistant or has relapsed, and 15 patients with untreated CLL. It is important to note that IPI-145 demonstrated activity in approximately

50% of the enrolled patients who had a mutation in the tumor suppressor gene p53. A 25-mg twice-daily dose of IPI-145 will be further evaluated in a randomized phase 3 clinical trial. A phase 2 clinical trial of otlertuzu mab in combination with bendamustine (Treanda) in patients with relapsed

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, 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 IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists.

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Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2013 K08BR13131B

Issued: November 2013

—Alan S. Gamis, MD, MPH Acute Myeloid Leukemia In a new study, the monoclonal antibody gemtuzumab ozogamicin (Mylotarg)—which had been withdrawn from the market in 2010—when added to standard chemotherapy improved event-free survival without causing excessive toxicity and mortality in children with acute myeloid leukemia. In a phase 3 clinical trial, more than 1000 children (average age, 10 years) received gemtuzumab or a standard treatment regimen, followed by additional chemotherapy for low-risk patients and stem-cell transplants for high-risk patients. Compared with standard regimens, the addition of gemtuzumab was associated with better disease-free survival (55% vs 61%, respectively) and reduced risk of relapse (33% vs 41%, respectively). No significant difference was found between the gemtuzumab and standard treatment groups with respect to overall survival (74% vs 70%, respectively). “The therapy seemed to have a particularly lasting effect among those patients who achieved remission in the course of treatment,” said lead investigator Alan S. Gamis, MD, MPH, Associate Division Director of Oncology, Children’s Mercy Hospitals and Clinics in Kansas City, MO. “Although gemtuzumab was previously removed from the market due to lack of clinical value in earlier trials, this growing body of positive data in populations of critical need may be sufficient to bring it back as a commercial treatment option.” S:13”

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Active ingredient made in China.

“The therapy...[has] a particularly lasting effect among those patients who achieved remission in the course of treatment.”

T:14”

IMBRUVICATM (ibrutinib) capsules

B:14.25”

IMBRUVICATM (ibrutinib) capsules

CLL showed superior response rates compared with bendamustine alone. This randomized trial included 65 patients with relapsed CLL who had received 1 to 3 previous regimens. The overall response rates were 68% (International Workshop on CLL criteria) and 81% (National Cancer Institute Working Group response criteria) in the group receiving otlertuzumab plus bendamustine versus 32% and 64%, respectively, in the patients randomized to bendamustine alone.

Myelodysplastic Syndromes In patients with MDS refractory to hypomethylating agents, treatment Continued on page 14 february 2014

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Leukemia

Idelalisib Improves Outcomes in Heavily Pretreated Patients with CLL New Orleans, LA—A planned interim analysis of the first phase 3 clinical trial shows that idelalisib, a first-in-class selective oral kinase inhibitor, when combined with rituximab (Rituxan), is superior to rituximab alone in progression-free survival (PFS) in patients with heavily pretreated chronic lymphocytic leukemia (CLL). The 24-week data from the randomized, placebo-controlled trial were presented by Richard R. Furman, MD, Richard A. Stratton Assistant Professor in Hematology and Oncology, Weill Cornell Medical College, New York. Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients,” said Dr Furman. Idelalisib was granted Breakthrough Therapy status by the US Food and Drug Administration in 2013. Idelalisib targets the delta isoform of the phosphoinositide-3-kinase enzyme, which is critical for the activation and survival of CLL cells and other lowgrade B-cell lymphomas. It inhibits homing and retention of malignant B-cells in lymphoid tissues, reducing B-cell survival, and restrains proliferation and induces apoptosis in CLL cells. Study Details Overall, 220 adult patients (medi-

Photo © American Society of Hematology

By Wayne Kuznar

Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy.” —Richard R. Furman, MD an age, 71 years) with relapsed CLL who were deemed unfit for further cytotoxic chemotherapy and who had measurable lymphadenopathy that had progressed after the completion of previous therapy, were randomized to a combination of idelalisib twice daily plus rituximab or to placebo twice daily and rituximab continuously until disease progression or death. Patients were eligible for the trial if they had received at least 1 antiCD20 antibody-containing therapy or at least 2 cytotoxic therapies. Patients

had a median of 3 previous therapies before enrollment, with 90% previously treated with rituximab. After 24 weeks, the PFS rate for patients receiving idelalisib plus rituximab was 93% compared with 46% for those receiving rituximab alone (P <.001). The median PFS has not yet been reached in the combination arm, but was 5.5 months in the rituximab plus placebo arm. The patients receiving idelalisib plus rituximab had a significantly better overall response rate (81%) versus patients receiving rituximab alone (13%; P <.001), in addition to a higher lymph-node response rate (93% vs 4%, respectively). The patients who were randomized to idelalisib plus rituximab also had a 72% improvement in overall survival compared with the control group (P = .018). The combination of idelalisib plus rituximab had an acceptable adverse event (AE) profile, said Dr Furman. Grade ≥3 AEs were reported in 56.4% of the patients in the combination arm compared with 47.7% of patients in the rituximab plus placebo arm. The most common AEs included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusion-related reactions. Most study discontinuations were a result of disease progression, although 9 patients in the combination arm and 11 in the control arm discontinued treatment because of AEs.

Promising Safety, Efficacy With several new agents on the horizon for the treatment of CLL, the optimal sequence of therapies will be ripe for exploration. Jennifer R. Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston, said, “That’s going to depend to some extent on

“We believe this treatment could be applicable to all CLL patients, because it eliminates the need for chemotherapy.” —Richard R. Furman, MD emerging patterns of resistance and whether some agents may work better than others based on those emerging patterns of resistance. Certainly, combinations of these agents will be of great interest, and I think that’s what we’ll be evaluating over the next 5 years or so.” Dr Furman said that he sees idel alisib being used beyond the heavily pretreated patient population with CLL. “Given the efficacy and low risk for long-term toxicities demonstrated, we believe this treatment could be applicable to all CLL patients, because it eliminates the need for chemotherapy,” he said. n

Promising Drugs in the Pipeline for Leukemia and... Continued from page 13 with sapacitabine was associated with a 1-year survival rate of up to 38% in a phase 2 clinical study. Sapacitabine is an oral nucleoside analog prodrug that interferes with DNA synthesis by introducing single-strand DNA leading to the arrest of the cell division cycle at the G2 phase. The study included 63 patients with MDS refractory to aza citidine and/or decitabine who were randomized to 1 of 3 dosage arms of sapacitabine. The overall 1-year survival rate was 32%, with greater survival seen in the 2 higher-dosage arms. Of the 63 patients in the study, 23 had stable disease at ≥16 weeks. Oral rigosertib (Estybon) induced responses and transfusion independence in lower-risk patients with MDS in a phase 2 clinical trial presented by Azra Raza, MD, Director, Myelodysplastic Syndrome Center, Columbia University, New York City.

Rigosertib is an inhibitor of the cellular-signaling pathways PI3K and PLK. A combined response rate of 53% (International Working Group criteria) was observed in 36 evaluable patients receiving an intermittent dosing schedule. Overall, transfusion

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independence was observed in 39% of patients who received at least 8 weeks of intermittent rigosertib. In patients with high-risk MDS who were previously treated with hypomethylating agents, a phase 1/2 study of rigosertib demonstrated ei-

ther a reduction in or a stabilization of bone marrow blasts or improvement in peripheral blood counts in 53% of the 19 evaluable patients. The median overall survival of responders was 9.6 months versus 1.7 months in the nonresponders. n

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Leukemia

Nilotinib Sustains Deeper Molecular Response versus Imatinib in Patients with Ph+ CML By Wayne Kuznar New Orleans, LA—Three large randomized phase 3 trials demonstrate the superiority of nilotinib (Tasigna) over imatinib (Gleevec) in achieving molecular response (MR) and complete cytogenetic response (CCyR) across various populations of patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML), including patients who have a suboptimal response to frontline imatinib. LASOR: Frontline Imatinib Failures In patients who fail to achieve a CCyR with frontline imatinib, higher rates of MR are achieved by switching to nilotinib compared with escalating the dose of imatinib to 600 mg daily, reported Jorge E. Cortes, MD, Chair, CML and Acute Myeloid Leukemia sections, M.D. Anderson Cancer Center, Houston, TX. “Patients with suboptimal complete cytogenetic response to imatinib (today classified by ELN [European LeukemiaNet] as warning/failure) represent a significant unmet need in the treatment of CML-CP [chronic phase],” noted Dr Cortes and colleagues. “This important study is the only randomized evaluation of imatinib dose escalation versus switch to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population.” The study included 191 adults with suboptimal CyR to frontline imatinib 400 mg once daily, who were random-

“Patients with suboptimal complete cytogenetic response to imatinib… represent a significant unmet need in the treatment of CML-CP.” —Jorge E. Cortes, MD, and colleagues ized to nilotinib 400 mg twice daily or to imatinib 600 mg once daily. The primary end point, CCyR at 6 months, was observed in 49% and 42.1% of patients in the nilotinib and imatinib arms, respectively, but this difference failed to achieve significance (P = .384). The high rate of crossover from imatinib to nilotinib confounded the results. In the imatinib arm, 15 patients crossed over to nilotinib and 6 achieved CCyR; by contrast, none of the 6 patients who crossed over from the nilotinib arm to imatinib achieved CCyR. The clinical benefit of nilotinib is therefore best evaluated when considering crossover patients as nonresponders, Dr Cortes said. In this type of analysis, 47 (54.7%) patients in the nilotinib arm and 34 (38.6%) in the imatinib arm achieved CCyR at 6 months.

ENESTnd: Newly Diagnosed Disease Updated 5-year data from the openlabel, randomized, multicenter Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) trial support nilotinib as first-line therapy in adults with newly diagnosed Ph+ CML-CP, said Giuseppe Saglio, MD, Director, Department of Molecular Medicine and Targeted Therapy, San Luigi Gonzaga Hospital, University of Turin, Italy. Some 846 patients were randomized to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily. The rates of early and deeper sustained MR, including MR4.5, were higher with nilotinib at either dosage compared with imatinib. At 1 year, the rate of MR4.5 was 6% to 19% greater with nilotinib compared with imatinib; by 5 years, this difference reached 21% to 23%, said Dr Saglio. Furthermore, fewer patients receiving nilotinib progressed to accelerated phase/blast crisis. The estimated rates of patients whose disease did not progress to the accelerated phase or the crisis phase at 5 years were 99.3% and 98.7% in the nilotinib arms (300 mg twice daily and 400 mg twice daily, respectively) versus 95.2% in the imatinib arm. Of the patients treated with ima tinib, 15 had CML-related deaths compared with 10 patients in the

nilotinib arms. The estimated overall survival rates at 5 years were 93.6% and 96% in the nil otinib 300-mg twice-daily and 400-mg twice-daily arms, respectively, compared with 91.6% in the imatinib arm. ENESTcmr: Residual Disease Three-year data from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) trial, an openlabel, randomized phase 3 study, demonstrate that patients with Ph+ CML and detectable BCR-ABL after long-term treatment with imatinib achieved deeper MRs after switching to nilotinib, reported Brian Leber, MD, Associate Professor of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. In ENESTcmr, 207 patients were randomized to nilotinib 400 mg twice daily or to imatinib 400 mg once daily or 600 mg once daily. Of 32 responders in the imatinib arm, 7 achieved MR4.5 after switching to nilotinib. Among patients without documented MR4.5 at baseline, the cumulative incidence of MR4.5 was higher in patients randomized to nilotinib versus imatinib (46.9% vs 33.3%, respectively; P = .045). MR4.5 was achieved faster with a median time to response of 24 months in the nilotinib arm, and was not reached in the imatinib arm (P = .001). By 36 months, no patients in either arm had progressed to AP/BC. n

Call for Papers Hematology/Oncology Theme Issue American Health & Drug Benefits is publishing a Hematology/Oncology Theme Issue in May. Readers are invited to submit manuscripts for this issue, including original research, cost analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends. All articles will undergo the journal’s rigorous peer-review process. ORIGINAL RESEARCH • Clinical research • Best practices in oncology • Case reports/case series • Claims-based analyses • Cost-effectiveness analyses/efficacy comparisons • Data-driven innovation in oncology

• Drug therapy • Health economics research outcomes • Pathways outcomes • Pharmacoeconomics • Survey analyses

REVIEW ARTICLES • Benefit design in hematology/oncology • Disease state overview • Drug therapy/new drug classes • End-of-life issues • Evidence-based comprehensive reviews • Innovation in practice management • Managing toxicities

• Molecular diagnostics • Pathways-based patient care/ guidelines • Quality-of-life issues • Survivorship programs • Targeted therapies • Value-based patient care

Submission Deadline: March 17, 2014 Follow the Information for Authors at www.AHDBonline.com. Submit articles to editorial@engagehc.com or online at www.AHDBonline.com. VOL. 7

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Multiple Myeloma

FIRST Trial Shows Value for Continued Use of Lenalidomide in Transplant-Ineligible Patients with Newly Diagnosed Myeloma By Caroline Helwick to benefit from this approach—he commented, “Overall, we have a new standard of care that is active, convenient, and has excellent tolerability.”

Photo © American Society of Hematology

New Orleans, LA—The value of the continued use of lenalidomide (Rev limid) in patients with newly diagnosed multiple myeloma (MM) was highlighted in a phase 3 clinical trial that was featured in a plenary session during ASH 2013. The Frontline Investigation of Revlimid plus Dexamethasone versus Standard Thalidomide (FIRST) trial was conducted in patients with newly diagnosed MM who were ineligible for stem-cell transplantation and is the largest trial ever conducted in patients with MM. The key finding of FIRST was that lenalidomide given continuously to newly diagnosed, transplant-ineligible patients prolongs progression-free survival (PFS) and overall survival (OS). The hazard ratio (HR) of 0.72 for PFS, the study’s primary end point, was statistically significant, thus establishing continuous lenalidomide “as a new standard of care,” according to Thierry Facon, MD, of the Centre Hospitalier Régional Universitaire de Lille, France. Jesús F. San Miguel, MD, PhD, Head of Hematology, Hospital Universitario de Salamanca, Spain, agreed with

“In the relapse setting, len/low-dose dex has been shown very safe in terms of second malignancies, and this trial confirms it is also safe in the first-line setting.” —Thierry Facon, MD the investigators. “Continuous lenalidomide plus low-dose dexamethasone demonstrates a significant PFS and OS advantage.” While suggesting that some questions remain to be answered—such as the role of alkylators in light of these findings, and the identification of the population most likely

Study Details The study enrolled 1623 patients aged ≥65 years (median age, 73 years) or otherwise ineligible for stem-cell transplant. Unlike many other trials, patients with renal insufficiency were included, making this essentially a “real-life patient population,” Dr Facon noted. The patients were randomized to receive continuous lenalidomide (Rd), to lenalidomide for 72 weeks (Rd18), or to melphalan/prednisone/ thalidomide (MPT) for 72 weeks. Among the study’s main findings are: • Median PFS, the primary end point, was 25.5 months with Rd, 20.7 months with Rd18, and 21.2 months with MPT. The HR for the primary comparison (Rd vs MPT) was 0.72 (P = .006). For Rd versus Rd18, the HR was 0.70 (P = .001) • The 3-year PFS was 42% with Rd, and 23% in the other 2 arms; the 2 lenalidomide arms were equivalent until month 18, then the curves markedly separated

• A consistent benefit was seen across most subgroups • Rd was superior to MPT across all efficacy secondary end points • There were no unexpected toxicities. The interim analysis for OS, with 35% of patients in the intent-to-treat arms having died, was significantly improved with continuous lenalidomide treatment. At 4 years, 59.4% of patients receiving Rd were alive compared with 51.4% of the MPT arm (HR, 0.78; P = .0168) and 55.7% of the Rd18 arm (P = .307). The time to progression and the time to second antimyeloma therapy were also significantly prolonged with Rd (P = .001 for both). The rate of secondary hematologic malignancies was low overall but was actually higher in the MPT arm, with 12 patients (2.2%) developing hematologic malignancies compared with 2 patients (0.4%) in each lenalidomide arm. Solid tumors developed in 2.8% of patients in the MPT and Rd arms, and in 5.4% of patients in the Rd18 arm. “In the relapse setting, len/lowdose dex has been shown very safe in terms of second malignancies, and this trial confirms it is also safe in the first-line setting,” Dr Facon said. n

Lenalidomide Maintenance in Transplant-Eligible Myeloma Population Still Debated New Orleans, LA—The FIRST (Frontline Investigation of Rev limid plus Dexamethasone versus Standard Thalidomide) trial in transplant-ineligible patients demonstrated the benefit of continuous lenalidomide (Revlimid). However, studies in younger, transplant-eligible patients yielded conflicting results, especially in terms of an overall survival (OS) advantage, according to Mayo Clinic investigators, who performed a systematic review and meta-analysis of existing outcomes data—and updated with data presented at ASH 2013—to evaluate the role of maintenance therapy with lenalidomide. They identified 4 randomized controlled trials that met the inclusion criteria—IFM 2005-02, CALGB 100104, MM-015, and RV-MM-PI209—involving 1935 patients who received lenalidomide 10-mg daily, after induction or transplant, and continued until progression. PFS but Not OS Benefit “All 4 studies showed an improvement in PFS [progression-free sur-

vival], with an overall 51% reduction in risk of progression (P <.001),” reported Preet Paul Singh, MD, Division of Hematology, Mayo Clinic, Rochester. “There was modest [but nonsignificant] improvement in OS with lenalidomide maintenance, with 2 studies showing a benefit and 2 not showing one, resulting in a modest 23% reduction in risk.”

“There was modest improvement in OS with lenalidomide maintenance, with 2 studies showing a benefit and 2 not showing one.” —Preet Paul Singh, MD However, the use of lenalidomide maintenance was also associated with a 62% increase in the risk of second primary malignancies (P = .006), a 4.9-fold increased risk of neutropenia (P <.001), a 2.7-fold increase in thrombocytopenia (P <.001), a 2.3-fold increased risk of fatigue (P = .01), and a 3.2-fold increase in venous thromboembolism (P = .02).

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“The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients,” Dr Singh said. Updated IFM 2005-02 Analysis A new analysis of the multiple myeloma (MM) IFM 2005-02 trial presented at the meeting confirmed that len alidomide maintenance prolongs PFS after stem-cell transplantation but does not improve OS. IFM 2005-02 was a randomized, placebo-controlled phase 3 trial that investigated the efficacy of lenalidomide maintenance after transplantation in 614 patients with MM (aged <65 years) who had not progressed after first-line stem-cell transplant. The patients were randomized to main tenance with lenalidomide 10-mg to 15-mg daily or to placebo until disease progression. In the new analysis, the median PFS from randomization was 46 months with lenalidomide and 24 months with placebo (P <.001), but despite the longer 77-month follow-up, the

median OS was still not significantly improved with maintenance lenalidomide, being approximately 80 months in each arm (P = .80). “The discrepancy between PFS and OS was still present,” said Michel Attal, MD, of Toulouse, France. “This is possibly attributed to the shorter survival time after first disease progression in the maintenance arm than is observed in patients receiving placebo.” Dr Attal called attention to the median second PFS, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with a median second PFS of 24 months versus 13 months with lenalidomide (P = .001). Second primary malignancies were also almost twice as high in the lenalidomide arm, and the rates of severe neutropenia were 3 times higher. The meaning of these findings, according to Dr Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years,” after which resistance emerges and creates “a late negative impact of maintenance.”—CH n VOL. 7

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Multiple Myeloma

Myeloma Drug Arsenal Expanding to New Classes By Caroline Helwick New Orleans, LA—Emerging agents for multiple myeloma (MM) are promising as future treatment options. The arsenal now includes many new classes of agents beyond the standard immunomodulatory drugs (IMiDs) and proteasome inhibitors. Here is a look at the key studies presented at ASH 2013. Oral Proteasome Inhibitors In newly diagnosed patients with MM, the oral proteasome inhibitor MLN9708, now known as ixazomib, combined with lenalidomide plus dexamethasone, led to high response rates with extended treatment duration, reported Paul G. Richardson, MD, Clinical Director, Jerome Lipper Center for Multiple Myeloma, Dana- Farber Cancer Institute, Boston. “This is the first all-oral proteasome inhibitor/IMiD combination under investigation in this setting to date, and the data support its feasibility and activity,” Dr Richardson said. The study of treatment-naïve patients included 14 patients in the dosefinding phase 1 trial and 57 patients in the phase 2 study, who received ixazomib 3 mg every 21 days for up to 16 cycles. The objective response rate (ORR) was 94%, and complete responses (CRs) plus very good partial responses (VGPRs) were achieved by 76% of patients. Of the 11 evaluable patients who achieved a stringent CR plus CR, 9 patients had no minimal residual disease. Drug-related serious adverse events (AEs) were seen in 28% of patients; grade 3 drug-related AEs were reported in 58%, and no grade 4 events were reported. In another presentation, Shaji K. Kumar, MD, of the Division of Hematology, Mayo Clinic, Rochester, MN, presented data from a phase 2 trial of ixazomib as a single agent in 69 patients with relapsed MM who had not received bortezomib or received <6 cycles of bortezomib and had a PR or better without progression. For the 32 patients remaining on study, the ORR was 34%. Among the patients, who were followed for 12 months, 77.5% have not progressed and 59% are alive without progression at 12 months. “MLN9708 has single-agent activity, with deep responses seen in some patients. The addition of dexamethasone for lack of response or progression leads to improved response,” Dr Kumar concluded. Another oral proteasome inhibitor, oprozomib, is demonstrating activity. In an ongoing dose-finding study in VOL. 7

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42 relapsed patients, approximately 1 in 4 patients is responding to treatment with oprozomib.

“MLN9708 has single-agent activity, with deep responses seen in some patients. The addition of dexamethasone for lack of response or progression leads to improved response.”

Research Institute, Nashville, TN. The main grade 3 to 4 treatment-related AEs were thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, diarrhea, dyspnea, and hypertension. Frequent dose reductions were required for panobinostat.

Monoclonal Antibodies There is no monoclonal antibody yet approved for MM, but more than 10 candidates are in development. Elotuzumab, which targets CS1, and daratumumab, which targets CD38, are furthest along in development and —Shaji K. Kumar, MD are considered the most promising. Daratumumab received the US Food and Drug Administration BreakHistone Deacetylase Inhibitors through Therapy designation in 2013 The combination of proteasome and for patients with disease that is refrachistone deacetylase (HDAC) inhibitors tory to proteasome inhibitors and is predicted to become a viable treat- IMiDs. In an evaluation of 11 patients ment for patients with MM, attributed who received up to 16 mg of daratum to the dual inhibition of the protea- umab, 8 patients achieved a PR or some and aggresome pathways. better after single-agent treatment (up Dr Richardson presented an up- to 16 mg/kg), including CRs in 3 date of the phase 2 PANORAMA 2 patients, VGPRs in 2 patients, and PRs trial, which evaluated the oral HDAC in 3 patients. Two patients achieved a inhibitor panobinostat paired with minimal response, and 1 had stable bortezomib and dexamethasone in 55 disease; no patients progressed. Corpatients with relapsed, bortezomib- responding to these responses was a refractory disease. marked reduction in M-protein. The ORR was 35%, including VGPRs in 5.5% of patients, with a median response of 6 months. Including “The combination of patients with stable disease, the clini- panobinostat and carfilzomib cal benefit rate was 53%. is feasible and effective in “In this patient population, highrisk cytogenetics did not negatively the relapsed or relapsed/ impact response rates,” said Dr Rich- refractory population.” ardson. In the 14 patients with high—Jesus G. Berdeja, MD risk cytogenetics, the ORR was 42.9%, and the clinical benefit was 71.4%. The median progression-free surThe drug was generally well tolervival (PFS) was 5.4 months, and the ated. Grade ≥3 AEs occurred in 17 median overall survival (OS) was patients, 70% of which were hemato17.5 months, with longer remissions logic; some infusion reactions were among responders. The safety profile observed, primarily bronchospasm, was “manageable.” and typically early in the trial. This Another multicenter phase 2 study was managed well with supportive evaluated panobinostat in combination medications. The maximum tolerated with the proteasome inhibitor carfilzo- dose has not yet been established. mib in 44 patients with relapsed/reSAR650984 is another promising fractory MM. The median PFS was 6.8 monoclonal antibody, although it is months altogether—7.6 months for pa- still in early phase. In a phase 1 study tients with previous bortezomib thera- of SAR650984 as a single agent, the py and 4.8 months in patients refracto- ORR in heavily pretreated patients ry to bortezomib. The 12-month PFS was 25%, with 8% CRs, and 17% PRs. rate was 41%, and the OS rate was 85%; At higher doses, the response rate was the median OS was not yet reached. 31%. The maximum tolerated dose is “The combination of panobinostat still being determined. and carfilzomib is feasible and effective in the relapsed or relapsed/re- Kinesin Spindle Protein Inhibitors fractory population,” said lead invesFilanesib (ARRY-520) is a highly tigator Jesus G. Berdeja, MD, Director selective, targeted kinesin spindle proof Myeloma Research, Sarah Cannon tein (KSP) inhibitor with a mechanism

of action distinct from currently available drugs for MM, such as IMiDs and proteasome inhibitors. Mature data from a phase 2 trial in heavily pretreated patients (median, 6 previous therapies) were reported at the meeting. The response rates with this KSP agent were 16% for single-agent filanesib and 15% among patients whose disease was dual refractory to bortezomib and lenalidomide. In addition, the retrospective use of acute-phase protein alpha-1-acidic gly coprotein (AAG) levels as a biomarker improved response rates and OS. In AAG-low patients, the response rate was 24% with single-agent filanesib, and 19% with filanesib plus dexamethasone in patients with dualrefractory disease; no responses were observed in patients with high AAG levels. The median OS in AAG-low patients was 23.3 months. Also of note, filanesib demonstrated clinical activity in patients previously treated with newer MM agents, including carfilzomib, ixazomib, and/ or pomalidomide, suggesting that filanesib maintains activity in patients who are resistant to multiple standard agents and new myeloma agents. In this population, filanesib had an ORR of 21%, which improved to 33% in an AAG-selected population. The incidence of nonhematologic adverse events was low, including an absence of peripheral neuropathy. Hematologic toxicities were transient, and were managed with supportive measures. “Filanesib has shown clinical activity in relapsed/refractory multiple myeloma patients, both as a single agent, and in separate combination trials with carfilzomib and bortezomib,” said Jatin J. Shah, MD, Assistant Professor, Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX. “These results support advancing filanesib into pivotal trials.” Novel Classes in Early Development Preliminary data were presented for several interesting new classes of anti-MM drugs. Indatuximab ravtansine is a compound that combines a chemotherapeutic drug (ravtansine) with an antibody (indatuximab) that helps deliver the drug to myeloma cells and other cancer cells. When the compound enters a cancer cell, it releases the chemotherapy drug that ultimately kills the cell. The phase 1/2 study included 15 patients with relapsed/refractory disease who had received a median

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Personalized Medicine

Promise of Genomic Sequencing for Clinical Decision-Making in Hematopoietic Cancers By Wayne Kuznar

Genomics and Childhood Leukemias Next-generation DNA sequencing has retrospectively identified new genetic subtypes of leukemia, said James R. Downing, MD, Scientific Director, St Jude Children’s Research Hospital, Memphis, TN. Dr Downing described the Pediatric Cancer Genome Project, a 3-year $65-million project to sequence the complete normal and cancer genomes of 600 children and adolescents with some of the most aggressive and least understood cancers. Over the 3 years, 700 tumors have been sequenced. “I can say today that this has been the most successful project that I have ever been associated with,” said Dr Downing. “For every single pediatric cancer that we looked at, we gained fundamental new insights into the pathogenesis of these diseases, and we gained new prognostic markers and new therapeutic targets.” He described 3 examples of wholegenome sequencing and their clinical implications. The first is the discovery of a fusion gene that is responsible for almost 30% of a rare subtype of pediatric acute myeloid leukemia (AML) called acute megakaryoblastic leukemia (AMKL). It accounts for approximately 4% to 15% of pediatric AML, and is

associated with poor prognosis and a high rate of treatment failure. The fusion product detected by sequenc-

New Orleans, LA—Genomic sequencing and protein analysis are providing new insights into hematologic malignancies, paving the way for treatment advances and personalized medicine. At the Presidential Symposium at ASH 2013, the potential use of genomics in clinical decision-making was explored.

“For every single pediatric cancer that we looked a... We gained new prognostic markers and new therapeutic targets.” —James R. Downing, MD ing 14 cases of pediatric non–Down syndrome AMKL involved 2 genes on chromosome 16—GLIS2 (a protein normally expressed only in renal cells) and CBFA2T3. Half of the patients carried the CBFA2T3-GLIS2 fusion, which enhances the self-renewal of megakaryocyte progenitors. Gene-expression profiling showed that bone morphogenetic protein was markedly upregulated in the cases that expressed the fusion product. Patients with the CBFA2T3-GLIS2 fusion gene had worse overall survival than patients without the CBFA2T3GLIS2 fusion. “From this discovery effort, we have a new prognostic marker; one that I would argue we would

Myeloma Drug Arsenal... Continued from page 17 of 4 previous lines of therapy. Patients received indatuximab ravtansine in combination with lenalidomide and dexamethasone. Among the 9 patients who are currently available for response, the ORR was 78%, with 11% patients achieving CRs, 11% achieving VGPRs, and 55% reaching PRs. The remaining 22% achieved stable disease. ImMucin is a myeloma vaccine being developed in Israel that is based on the protein MUC1, which is found on the surface of cancer cells.

The study presented at the meeting included 15 patients with MM who had received a median of 2 previous lines of therapy, and who had residual or progressive disease after stemcell transplantation. All participants had myeloma cells with the protein MUC1 on the surface. Participants received 6 or 12 biweekly ImMucin injections plus growth factors. Most patients achieved significant reductions in MUC1 levels, and most had stable disease lasting up to 29 months after study completion. n

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probably want to know at diagnosis, so that patients that don’t respond can be funneled into therapeutic protocols that provide a more aggressive treatment approach than the standard AML therapy,” Dr Downing suggested. Two other examples are the discovery of a new high-risk acute lymphoblastic leukemia (ALL) genetic subtype referred to as BCR-ABL1–like ALL, and hypodiploid ALL. Of the patients in the project, 50% were found to have CRLF2 rearrangements, and half of those mutations have activating muta tions in the Janus kinase family. RNA sequencing, whole-genome sequencing, and whole-exome sequencing of 165 pediatric and adult cases of BCRABL1–like ALL revealed unique fusion products that led to activation of the tyrosine kinase. Hypodiploid ALL is a rare aggressive subtype of pediatric ALL. Genetic alterations involving TP53, RB1, and IKZF2 are common in patients with hypodiploid ALL.

“This is a tipping point for recommendation of allogeneic hematopoietic stem-cell transplantation— patients that are intermediate risk-2….We need to know if a mutation is in the founding clone or a subclone.” —Matthew J. Walter, MD Digital Sequencing and Clonality in Myelodysplastic Syndromes Matthew J. Walter, MD, Associate Professor of Medicine, Washington University, St Louis, MO, discussed the use of whole-genome sequencing of patients’ DNA to study mye lodysplastic syndromes (MDS). His group has undertaken a large-scale

sequencing effort to identify gene mutations in MDS, focusing on the transition to secondary AML. “Along the way, we realized that using digital sequencing, we could study clonality,” Dr Walter said. Only 50% of patients with MDS have a cytogenetic abnormality. Using whole-genome sequencing, it was discovered that all patients with MDS carry genetic abnormalities. Digital sequencing has been able to identify additional patients with genetic mutations, “above and beyond cytogenetics,” he noted. Sequencing has found an abnormal karyotype or mutation in up to 90% of patients with MDS, and has identified approximately 20 genes that are consistently mutated in >2% of these patients. There are 6 categories of frequently mutated genes in MDS: TP53, spliceosome genes, epigenetic modifiers, cohesin genes, transcription factor genes, and activated signaling genes. In a gene category, each patient tends not to have more than 1 mutation. These mutations impact prognosis, Dr Walter said. Patients with TP53 mutations tend to have a complex karyotype and deletions on chromosomes 5 and 7, and this group has a poor prognosis. Mutations in 4 other genes—EZH2, ETV6, RUNX1, and ASXL1—have independent prognostic significance for overall survival. Patients categorized as intermediate risk-1 who have a mutation in 1 of these genes have overall survival that is as poor as patients with intermediate risk–2 MDS. “This is a tipping point for recommendation of allogeneic hematopoietic stem-cell transplantation—patients that are intermediate risk-2,” said Dr Walter. Clonal heterogeneity in MDS is common. The clonal evolution model suggests that the progression of MDS to secondary AML is characterized by the persistence of a single founder clone, defined by hundreds of mutations, and the outgrowth of at least 1 new subclone that contains additional mutations. A single population of MDS cells, therefore, undergoes several rounds of mutation, engendering multiple subpopulations that are present in secondary AML. To be useful clinically, “we need to know if a mutation is in the founding clone or a subclone,” said Dr Walter. Without targeting all clones in a tumor, it is unlikely that a durable response can be achieved. n VOL. 7

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Personalized Medicine

Novel CAR-T Therapy Topped the News at ASH...

NCI Study Results in Lymphoma Dr Kochenderfer presented results from the NCI’s study of 15 adult patients with advanced B-cell lymphomas, including 9 patients with chemotherapy-refractory disease (some with up to 10 previous lines of treat-

at a glance ➤ Patients with an aggressive, refractory subtype of leukemia or lymphoma show dramatic responses to engineered T-cells, achieving complete remissions ➤ Engineered T-cells may soon replace bone marrow transplants, and this therapy is less expensive and more widely available ➤ Remissions lasting >3 years have been seen with these T-cells, which continue to kill leukemia cells in the body for months after treatment

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ment). The patients received reducedintensity conditioning, followed by an infusion of their own T-cells that had been CAR-engineered. Of 13 evaluable patients, 12 responded: 5 patients had complete remissions, 6 had partial remissions, and 1 had stable disease.

Photo © American Society of Hematology

these engineered T-cells,” said James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI). The pace of research is rapid, with several pharmaceutical companies now working in partnership with the NCI and the University of Pennsylvania. Other studies are ongoing at M.D. Anderson Cancer Center, Houston, TX. Researchers estimate that the therapy could become available as early as 2016. The approach takes advantage of the fact that the CD19 protein is expressed almost universally on B-cells. The process involves extracting T-cells from the patient, subjecting the cells to CAR cell engineering, and then infusing the engineered T-cells back into the patient. The engineering takes approximately 10 days and alters the T-cell through (1) the addition of a receptor that targets the CD19 antigen on leukemic cells, and (2) the insertion of a viral vector into the cells that triggers the T-cells to expand, proliferate, and seek out and destroy all remaining cancer cells. Michael Kalos, PhD, Adjunct Associate Professor of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, maintained that engineered T-cells are “poised to replace bone marrow transplants with a therapy that is less expensive and is more widely available.”

“It looks like the disease has disappeared after a single infusion of these engineered T-cells….Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable.” —James N. Kochenderfer, MD

“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Dr Kochenderfer said at a press briefing. “We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options…and who are not generally thought to be good candidates for hematopoietic stem-cell transplantation,” he added. Patients with lymphoma are also being treated at M.D. Anderson Cancer Center, with a nonviral gene transfer approach that expresses “second-generation” CD19-specific T-cells. Four patients with non-Hodg kin lymphoma who were treated with a high T-cell dose are in re mission after 3 months, according to Partow Kebriaei, MD, Associate

Professor, Department of Stem Cell Transplantation, M.D. Anderson Can cer Center. Summary of Trial Data from Patients with CLL and ALL Dr Kalos summarized the clinical results to date for adult patients with advanced relapsed or treatmentrefractory chronic lymphocytic leukemia (CLL), and for adult and pediatric patients with treatment-refractory acute lymphocytic leukemia (ALL). In 2 studies, 32 adult patients with CLL have been treated with engineered T-cells, of whom 15 achieved partial responses and 7 achieved complete responses. All of these complete responses are ongoing, Dr Kalos reported. Coinvestigator David L. Porter, MD, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, University of Pennsylvania, added, “We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T-cells.” “We’ve now seen remissions lasting for more than 3 years, and there are clues that the T-cells continue to kill leukemia cells in the body for months after treatment. Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow, and their lymph nodes continued to shrink over time. In some cases, we have seen partial responses convert to complete remissions over several months,” Dr Porter said. Also at the University of Pennsylvania, 22 children with ALL have been treated with engineered T-cells, of whom 19 (86%) achieved a complete response, which is ongoing in 14 patients. A total of 5 adults with ALL have been treated, and all achieved a complete response—4 of which are

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ongoing—some as long as 18 months. “Our results demonstrate the potential of this treatment for patients who truly have no other therapeutic option,” said coinvestigator Stephan A. Grupp, MD, PhD, Director of Translational Research, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia. “In the relatively short time that we’ve observed these patients, we have reason to believe that this treatment could become a viable therapy for their relapsed, treatmentresistant disease.”

“We’ve now seen remissions lasting for more than 3 years, and there are clues that the T-cells continue to kill leukemia cells in the body for months after treatment….We have seen partial responses convert to complete remissions over several months.” —David L. Porter, MD

Toxicity Profile The treatment is not without toxicity. Most patients have developed cytokine release syndrome, which produces high fever, hypotension, respiratory problems, delirium, and other concerning symptoms that usually require a stay in the intensive care unit. However, most patients recover within 2 days and symptoms resolve within 3 weeks. Dr Grupp said that the symptoms associated with delayed cytokine release can be severe but can be managed with the monoclonal antibody tocilizumab, which he called a “game changer” for controlling these toxicities. n

Submit your article to the hematology/oncology theme issue at www.AHDBonline.com Submission deadline: March 17, 2014 february 2014

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NEW FOR 2014

Principles in Value and Market Access

An educational session for product managers, reimbursement specialists, account managers, and marketers focusing on access, reimbursement, proving product value, and international markets. CO-CHAIRS

MAY 6, 2014 Loews Hollywood Hotel Los Angeles, CA

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Gary M. Owens, MD

President Gary Owens Associates

AGENDA 10:45am – 11:00am

Introductions and Opening Remarks Grant Lawless, RPh, MD, FACP; Gary M. Owens, MD

11:00am – 11:40am

Changing Access and Payer Challenges in Oncology - Medicare and Commercial Speaker TBD

11:40am – 12:20pm

Proving the Value for Oncology Therapy Using Comparative Effectiveness Research Dan Malone, PhD, Professor, University of Arizona College of Pharmacy

12:20pm – 1:30pm

Lunch

1:30pm – 2:10pm

Methods and Tools for Optimal Reimbursement Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead

2:10pm – 2:50pm

Impact of Healthcare Reform, Affordable Care Act, and Accountable Care Organizations on the Coverage of Cancer Treatments Speaker TBD

2:50pm – 3:30pm

Impact of New Risk Models on Traditional Pharmaceutical Relationships Ken Schaecher, MD, FACP, CPC, Medical Director, SelectHealth

3:30pm – 4:00pm

Break

4:00pm – 4:40pm

Using Competitive Intelligence to Maintain Coverage and Access Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting

4:40pm – 5:20pm

Panel Discussion - Will improvements in clinical outcomes and efficacy come from new products or a more thoughtful use of existing products using new adaptations? Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE) AVBCC2014May6agenda Ksize_20714

Lymphoma

PI3K Inhibitors Main Focus of Drug Pipeline for Lymphoma By Caroline Helwick

PI3K Dysregulation The selective oral PI3K-delta inhib itor idelalisib produced a high response rate in patients with indolent NHL (iNHL) refractory to rituximab and to an alkylating agent, with responses persisting for 1 year in the average patient, according to mature response data from a phase 2 clinical trial presented at ASH 2013. “Idelalisib may provide meaningful disease control in double-refractory iNHL patients,” said Ajay Gopal, MD, Medical Oncology, University of Washington School of Medicine, Seattle. Bruce D. Cheson, MD, Director of Hematology Research, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, commented, “These are very exciting data, and are potentially practice-changing.” Study 101-09 included 125 previously treated patients who had follicular lymphoma (FL), small lymphocytic lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma/ Waldenström’s macroglobulinemia. Patients received oral idelalisib 150 mg twice daily until disease progression. As of June 2013, approximately 33% of patients remained on treatment and 66% had discontinued treatment. The mean duration of idelalisib treatment was 8.1 months. The overall response rate (ORR) with idelalisib monotherapy was 57%, including complete responses (CRs) in 6% of patients, partial responses (PRs) in 50% of patients, and minor responses in 1%. In addition, 34% of patients had stable disease. Responses were consistent across patient subsets, with the highest responses seen in patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (80%). “Virtually all patients had some degree of tumor reduction,” Dr Gopal pointed out. “A number had proVOL. 7

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longed stable disease, and this is also what I’ve seen in my clinic.” Idelalisib was well tolerated, with the primary adverse event being diarrhea (13% grade ≥3). Neutropenia of grade ≥3 was observed in 27% of patients, but only 5% had neutropenia at baseline. Transaminase elevations were common, with grades 1-2 observed in 35% of patients, grade 3 in 10%, and grade 4 in 2% of patients; these elevations were managed with drug interruption. BAY 80-6946, now known as copanlisib, is administered as a weekly infusion. At the meeting, Martin Dreyling, MD, Department of Medicine, University Hospital Grosshadern, Munich, Germany, reported single-agent activity for weekly infusions of copanlisib in 67 patients with relapsed or refractory lymphoma, some with indolent lymphoma and some with aggressive lymphomas. The preliminary results are encouraging. After a median of 3 cycles, significant activity, including many CRs, was observed. The ORRs were high in patients with FL (40%), chronic lymphocytic leukemia (43%), mantle-cell lymphoma (MCL; 71%), peripheral T-cell lymphoma (50%), and diffuse large B-cell lymphoma (13%).

“These are very exciting data [for idelalisib], and are potentially practicechanging.” —Bruce D. Cheson, MD

Dr Dreyling called the high response rates in the aggressive lymphomas, such as MCL, “striking.” For example, 1 patient with MCL reported the elimination of symptoms after only 1 week of treatment, and radiologic imaging revealed an almost complete disappearance of a large pleural effusion. “Compared to other compounds... this is a much quicker response than we are used to seeing,” Dr Dreyling noted. Gastrointestinal toxicity was minor and self-limiting, and hematologic toxicity was not a problem, he stated. Metabolic side effects did occur, “but they were manageable with conventional therapy,” he added.

SAR245409 is a potent oral pan- inhibitor of PI3K that also inhibits mTORC1 and mTORC2, another component of the PI3K dysregulated pathway. The multicenter phase 2

Photo © American Society of Hematology

New Orleans, LA—Treatments for non-Hodgkin lymphoma (NHL) may take a new turn with several inhibitors of the PI3 kinase (PI3K) nearing approval. PI3K-delta signaling is critical for B-cell activation, proliferation, and survival, and it is hyperactive in many B-cell malignancies. PI3K-delta inhibition reduces B-cell survival, and as a result of this strong mechanism of action, a number of PI3K inhibitors are being investigated for the treatment of patients with lymphomas.

“Single-agent SAR245409 exhibited clinical activity in patients with relapsed or refractory follicular lymphoma.” —Jennifer R. Brown, MD, PhD

ARD12130 study evaluated the efficacy of SAR245409, given continuously as a single agent, in 28 patients with FL who had received a median of 3 previous regimens. “Single-agent SAR245409 exhibited clinical activity in patients with relapsed or refractory follicular lymphoma,” reported Jennifer R. Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston. In 27 efficacy-evaluable patients, the ORR was 44%, including CRs in

15%. All but 4 patients had a reduction in target lesions, which exceeded 50% in more than 50% of patients. More than 50% of the patients had not progressed at 6 months. The most common adverse event was diarrhea, with grade ≥3 in 2 patients. In addition, 14 patients had rash, with grade ≥3 in 2 patients; 5 patients had hyperglycemia and elevated blood glucose, with grade ≥3 in 2 patients; 4 patients had liver toxic ities, including 2 patients with grade ≥3. Dr Brown noted that transaminitis is relatively common with targeted kinase inhibitors. Targeting the Bcl2 Gene In a departure from PI3K, other investigators are targeting the Bcl2 gene, which plays a role in lymphomagenesis, is involved in chemotherapy resistance, and leads to cell death when disrupted. PNT2258, which is very early in development, is a DNA “interference” molecule (DNAi) that targets the Bcl2 gene. A total of 12 patients with different NHL subtypes and relapsed or refractory disease received PNT2258 intravenously for 5 days every 3 weeks, for 6 cycles. PNT2258 exhibited antitumor effects, and 9 of 11 evaluable patients demonstrated clinical benefit, including CRs in 2 patients and a PR in 1 patient, reported Ayad Al-Katib, MD, FACP, Medical Director, Van Elslander Cancer Center, Grosse Pointe Woods, MI. The patients with FL had 200 to 250 days of progression-free survival, which is ongoing in some patients. The patients tolerated the administration of the drug well and maintained their baseline performance status, Dr Al-Katib said. “We feel that the DNAi strategy warrants further exploration as a cancer therapy,” he noted. n

WEB EXCLUSIVE Additional coverage from ASH 2013 is available online at www.AHDBonline.com • Readmission following stem-cell transplant decreases survival • Genetics providing new insights into signaling pathways and

treatment targets in ALL • Rituximab maintenance and radioimmunotherapy are cost-effective after first-line therapy in follicular lymphoma

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Lymphoma

Surveillance Scanning in Transformed Indolent Lymphoma of Limited Clinical Benefit By Wayne Kuznar New Orleans, LA—In patients with transformed indolent lymphoma (TrIL) who achieve a complete metabolic remission, surveillance scanning with positron emission tomography– computed tomography (PET-CT) is of limited clinical benefit, based on results of a retrospective analysis presented at ASH 2013. The study included 55 patients with TrIL who were managed at a single institution; “all subclinical relapses were low-grade histology and therefore of limited clinical benefit, as such patients rarely merit further therapy based on imaging findings alone,” said lead investigator Chan Y. Cheah, MD, Peter MacCallum Cancer Centre, East Melbourne, Australia. This finding builds on previous evidence that surveillance scans after complete remission (CR) in patients with aggressive lymphoma do not lead

to improved outcomes, Dr Cheah said. Patients were included in the analysis if they reached CR after primary therapy and had subsequent surveillance PET-CT. During the study peri-

“We were unable to find any prognostic factors besides age older than 60 years to isolate a subset of particular patients in whom a surveillance strategy could be focused.” —Chan Y. Cheah, MD od, the treatment protocol called for 6 scans monthly for patients in CR for the first 2 years, followed by an annual scan for 5 years posttreatment if subclinical relapse was detected.

Of 180 surveillance PET-CT scans, 153 were true negatives, 4 false positives, 1 false negative, 7 indeterminate, and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 93%, the sensitivity was 93%, the positive predictive value was 54%, and the negative predictive value was 99%. The high negative predictive value is reassuring, but it comes at a cost of radiation exposure, use of healthcare resources, and unnecessary biopsies, said Dr Cheah. After a median follow-up of 34 months, the actuarial 3-year progression-free survival rate was 77% and overall survival was 88%. Overall, 16 patients had disease relapse: 7 were subclinical and 9 were suspected on the basis of clinical symptoms. Although 5% of the scans

in the first 2 years detected a subclinical relapse, all were shown, clinically or with a biopsy, to be low-grade lymphoma. All diffuse large B-cell lymphoma relapses, in contrast, were accompanied by clinical symptoms. “We were unable to find any prognostic factors besides age older than 60 years to isolate a subset of particular patients in whom a surveillance strategy could be focused,” Dr Cheah said. “When patients relapsed with largecell disease, they typically presented with symptoms first. If they relapsed with indolent disease, they didn’t necessarily have symptoms,” he said. “Picking up patients that didn’t have symptoms didn’t change management,” Dr Cheah said. “If they didn’t have symptoms, they didn’t warrant treatment anyway.” PET-CT should therefore be reserved for the evaluation of suspected relapse only, he advised. n

Rituximab Maintenance Extends Remission in Follicular Lymphoma, but Overall Survival Unaffected By Caroline Helwick New Orleans, LA—Findings from 2 major studies presented at ASH 2013 indicate that the longer the maintenance period, the greater the duration of progression-free survival (PFS) in follicular lymphoma (FL); however, overall survival (OS) was still not improved, even at 6 years of follow-up. Andrew Zelenetz, MD, former Chief of Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York, commented that lacking an OS benefit, he does not believe maintenance is “standard of care” or mandatory. He discusses the data with his patients, and said that approximately 70% of them choose observation (ie, waiting to retreat on progression). “If there is a compelling reason for the patient to delay the time to next treatment, then it makes sense, but that is an individual case-by-case discussion between the doctor and patient,” he suggested. Two Randomized Trials In the randomized phase 3 SAKK 35/03 trial, median PFS doubled when treatment with rituximab was continued to a maximum of 5 years, and this benefit of prolonged maintenance occurred “without increased

undue toxicity,” said Christian J. Taverna, MD, of Kantonsspital in Munsterlingen, Switzerland. This trial was initiated in 2004 to determine if maintenance with rituximab every 2 months for 5 years or until relapse or progression, unacceptable toxicity or death, would be superior to maintenance every 2 months for 4 treatments. A total of 270 patients with untreated, relapsed, stable, or chemotherapy-resistant FL (all grades) were included; all received 4 weekly doses of rituximab. The 165 patients reaching a complete or partial response to this induction regimen were randomly assigned to rituximab as short-term maintenance (4 administrations every 2 months) or to long-term maintenance (every 2 months for a maximum of 5 years). The primary end point was event-free survival. The events included disease progression or relapse, unacceptable toxicity, death from any cause, the initiation of nonprotocol or concomitant steroids or radiotherapy, or secondary malignancy. The event-free survival end point was not met with long-term maintenance rituximab, but Dr Taverna attributed this to the unusual imbalance

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in events before the patients received different therapies. Specifically, more patients in the short-term maintenance arm (3 vs 10) progressed or relapsed during the first 8 months after randomization, when treatments in both arms were the same.

“If there is a compelling reason for the patient to delay the time to next treatment, then it makes sense, but that is an individual case-by-case discussion between the doctor and patient.” —Andrew Zelenetz, MD In an analysis of only patients at risk after 8 months from randomization, however, median event-free survival was significantly prolonged with long er maintenance—7.1 years compared with 2.9 years (P = .004). Furthermore, the secondary end point of PFS was significantly improved with longer maintenance, from 3.5 years in the short-term arm to 7.4 years in the longterm arm (P = .04), but OS and re-

sponse rates were similar. Gilles Andre Salles, MD, PhD, of the Université Claude Bernard in Lyon, France, presented updated 6-year follow-up of the PRIMA study of 2-year rituximab maintenance, showing a 43% reduction in disease progression and a 38% reduction in time to next treatment, but no improvement in OS. PRIMA enrolled 1217 patients treated with various rituximab-based induction, then randomized 1018 patients to observation or to rituximab maintenance. At 3 years, in the initial analysis, PFS rates were 75% for maintenance versus 58% for observation (P <.001). In the updated analysis, with a median follow-up of 6 years, the PFS was 59.2% and 42.7%, respectively (P <.001). At 70 months, subsequent treatment was required by 63.5% versus 51.0%, respectively (P <.001). The OS rates were “excellent,” Dr Salles said, at 88.7% and 87.4%, respectively, but were not superior with maintenance. “Rituximab maintenance did not lead to the selection of more aggressive clones in these patients,” Dr Salles said. Approximately 50% of all deaths were associated with FL progression in each arm. n VOL. 7

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Payers’ Perspective

Increasing Emphasis on Costs in the Management of Patients with Hematologic Cancers Matthew Mitchell, PharmD, MBA Director, Pharmacy Services, SelectHealth, Murray, UT

ematologic cancers continue to gain awareness for payers. This is a result of the number of novel therapies recently approved by the US Food and Drug Administration to treat cancers that have few alternatives, as well as the growing number of expanded indications and use of combination therapies. At the 2013 American Society of Hematology (ASH) meeting, data were presented supporting the clinical value of novel therapies and existing treatments. And just as important was the emphasis on cost-effective tests, treatments, and procedures. Several retrospective analyses evaluated cost-effective treatments through various lines of therapies. One of the more popular takeaways was the list of unnecessary and potentially harmful treatments. Evidence-Based Recommendations Focus on Waste Last year, ASH released specific hematology-related recommendations referred to as “Choosing Wisely” (Hicks LK, et al. Blood. 2013;122:38793883). An ASH task force evaluated suggestions from many committee members and examined systematic reviews to compile a list of management-related recommendations. A total of 5 recommendations were presented at ASH 2013, all targeting the practicing of efficient, cost-conscious medicine by avoiding unnecessary procedures and treatments, including: 1. Do not infuse more than the minimum number of red blood cells necessary to relieve the symptoms of anemia or to return a patient to a safe hemoglobin range 2. Do not test for thrombophilia in adults with venous thromboembolism (VTE) occurring in the setting of major transient risk factors 3. Avoid using inferior vena cava filters routinely in patients with VTE 4. Do not administer plasma or prothrombin complex concentrates for nonemergent reversal of vitamin K antagonists 5. Limit surveillance computed tomography scans in asymptomatic patients after curative intent treatment of aggressive lymphoma. ASH will continue to develop evidence-based guidelines that will likely influence the quality of care; these

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guidelines will be useful for payers in medical technology and in pharmacy and therapeutics assessments.

Data were presented supporting the clinical value of novel therapies and existing treatments. And just as important was the emphasis on cost-effective tests, treatments, and procedures….One of the more popular takeaways was the list of unnecessary and potentially harmful treatments.

Site of Service Affects Cost Identifying the most appropriate site of service is common among payers. Given a choice to cover chemotherapy and supportive care within an office or clinic or in a hospital, the majority of payers will choose the office or clinic as the optimal site, based on cost alone. Carolina Reyes, PhD, evaluated the cost differences by site of service in a retrospective analysis specific to rituximab (Rituxan) infusions. With the use of medical and pharmacy claims, this study examined the use and cost of rituximab infusions in the treatment of diffuse large B-cell lymphoma. Of the 491 patients evaluated, 65% received rituximab in the office and the remaining 35% received infusions in the hospital setting. The follow-up extended through 30 days after the last infusion and included at least 7 months of therapy.

The average number of infusions administered to patients in a hospital was actually less than for patients given infusions in a clinic (4.92 vs 6.52, respectively). Of the patients treated in the clinic, 87% received granulocyte colony-stimulating factor (G-CSF) compared with 77% in patients treated in the hospital. These findings are similar to the rates of patients receiving combination therapy (ie, rituximab plus chemotherapy), which were 93% in the clinic compared with 85% in the hospital. From this, one may assume that with more rituximab infusions, more chemotherapy, and more G-CSF given in the clinic compared with the hospital, the cost would be substantially greater for patients treated in the clinic. However, the average unadjusted daily infusion cost was higher in the hospital than in the clinic setting ($12,481 vs $5834, respectively), and the total per-member per-month costs were also higher for the patients treated in the hospital than those treated in a clinic ($22,325 vs $15,541, respectively). These data emphasize the importance of aligning appropriate contractual arrangements. As more centers adopt accountable care models within oncology through various payer- provider arrangements, site of care will become an even more important cost-containment measure.

Identifying the most appropriate site of service is common among payers. Given a choice to cover chemotherapy and supportive care within an office or clinic or in a hospital, the majority of payers will choose the office or clinic.

Advances in Therapy At the previous meeting, much focus was placed on new treatments and investigational treatments for chronic myelogenous leukemia (CML). There has been a lot of postmarketing activity for second- and

third-generation drugs for CML in the past 12 months. There has also been a lot of emphasis regarding appropriate testing at 3-month intervals, which may influence drug choice. At ASH 2013, one focus area was the pipeline for non-Hodgkin lymphoma (NHL). Several PI3 kinase (PI3K) inhibitors are nearing approval. PI3K inhibition reduces B-cell survival. Phase 2 data have demonstrated a high response rate persisting a year with idelalisib monotherapy in patients with indolent NHL refractory to both an alkylating agent and rituximab. Idelalisib, given orally twice daily, has also demonstrated a strong overall response rate in patients with follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and Waldenström’s macroglobulinemia. The most frequent adverse events with idelalisib monotherapy were diarrhea and transaminase elevations. According to Martin Dreyling, MD, copanlisib may demonstrate the quickest response of the PI3K inhibitors. Copanlisib, given as a weekly infusion, produced significant response rates in patients with follicular lymphoma, chronic lymphocytic leukemia, mantle-cell lymphoma, peripheral T-cell lymphoma, and diffuse large B-cell lymphoma. Common adverse events included gastrointestinal toxicity and metabolic side effects. SAR 245409 is an oral inhibitor of PI3K and mTOR. This agent has demonstrated efficacy as monotherapy in the treatment of relapsed or refractory follicular lymphoma in patients who had received a median of 3 previous regimens. Common adverse events included diarrhea, rash, and liver toxicities. These PI3K inhibitors may bring welcomed treatment options to pa tients with lymphomas. Payers will need to evaluate these new options among themselves, as well as compared with existing options, to determine their true value. In addition to presenting data on new and existing treatments, several cost-efficacy analyses were presented at the 2013 ASH meeting. ASH should also be applauded for its “Choosing Wisely” recommendations, and its continued work to produce evidence-based guidelines. n

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Other Highlights

JAK1/2 Inhibitor Ruxolitinib Improves Survival in High-Risk Myelofibrosis By Wayne Kuznar New Orleans, LA—Long-term analyses of patients with high-risk myelofibrosis show continued efficacy of ruxolitinib in reducing mortality risk compared with conventional therapy. The efficacy of ruxolitinib on outcomes was not affected by the presence of detrimental genetic mutations. Ruxolitinib is an oral inhibitor of the Janus kinase (JAK) 1 and JAK2 tyrosine kinases designed to target overactivation of the JAK/STAT signaling pathway. The data presented at ASH 2013 were updates from 2 studies known as COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment)-I and COMFORT-II, in which patients with intermediate-2 or high-risk primary myelofibrosis, post– polycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis were randomized to ruxolitinib or to control (best available treatment or placebo). In both studies, the patients were allowed to cross over from the con trol arms to ruxolitinib upon protocol-defined progression events, primarily progressive splenomegaly. A 3-year update from COMFORT-I

was provided by Srdan Verstovsek, MD, PhD, Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Some 309 patients were randomized to ruxolitinib or to placebo; doses of ruxolitinib

“The hazard of death for patients originally randomized to placebo decreased as patients crossed over to ruxolitinib.” —Srdan Verstovsek, MD, PhD could be titrated for lack of efficacy or excess toxicity. The patients originally randomized to ruxolitinib had a 31% reduction in mortality risk compared with those receiving placebo (P = .067). Of the 154 patients randomized to placebo, 111 crossed over to ruxolitinib at a median of 41 weeks. “The hazard of death for patients originally randomized to placebo decreased as patients crossed over to ruxolitinib,” said Dr Verstovsek. The suggested risk of death for patients who crossed

over had decreased to approach that for patients originally randomized to ruxolitinib. In COMFORT-II, 219 patients with primary or post–polycythemia vera/ essential thrombocythemia myelofibrosis were randomized in a 2:1 ratio to receive ruxolitinib or best available therapy. Mutations in 12 genes were genotyped at baseline in 166 of the patients (120 randomized to ruxolitinib, 46 randomized to best available therapy). The impact of gene mutations characterizing high molecular risk on the reduction in spleen, development of anemia, and overall survival was assessed. Forty-six (38.3%) patients in the ruxolitinib group and 20 (43.5%) patients in the best available therapy group were classified as high molecular risk. Next-generation sequencing was used for the analysis. Ruxolitinib had a similar survival benefit in patients with and without high-risk mutations. “The negative impact of high molecular risk status on survival is halved by treatment with ruxolitinib compared with best available ther-

apy, and the effect of ruxolitinib is similar in both the high molecular risk and low molecular risk groups,” said Paola Guglielmelli, MD, PhD, of the Department of Experimental and Clinical Medicine, University of Florence, Italy.

“The negative impact of high molecular risk status on survival is halved by treatment with ruxolitinib compared with best available therapy.” —Paola Guglielmelli, MD, PhD In addition, high molecular risk status did not affect the likelihood of obtaining a ≥35% spleen volume reduction nor the risk of developing anemia on treatment. A pooled overall survival analysis of the COMFORT studies showed that the risk of death at 3 years was reduced by 35% in patients initially randomized to ruxolitinib compared with controls (P = .01). n

Hospital Readmission After Stem-Cell Transplant Decreases Survival New Orleans, LA—Infection and fever without a source are the most common causes of readmission after allogeneic hematopoietic stem-cell transplantation (HSCT), and being readmitted within 30 days of discharge is associated with a lower 5-year overall survival (OS) rate, according to Laura Spring, MD, of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston. “A better understanding of the risk factors for readmission in the transplant population will allow for more transitional care and clinical resources to be focused on the highest-risk patients,” said Dr Spring at ASH 2013. The United States spent $17.5 billion on readmissions among Medicare beneficiaries in 2010, she noted. This single-institution, retrospective review included 495 patients receiving myeloablative conditioning (MAC) and 602 patients receiving reduced intensity conditioning (RIC) HSCT at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital. The 30-day readmission rate was examined in addition to the readmission rate at day 100, a traditional assessment point

in transplantation readmission rate. The readmission rate was 26.3% at 30 days and 39.2% at 100 days in the MAC group. In the RIC group, the 30-day readmission rate was 17.4% and the 100-day rate was 30.7%. “In both groups, the most frequent reasons for readmission were documented infection, fever without a source, and graft-versus-host disease,” Dr Spring said. Infection was the reason for readmission in approximately 25%, fever in approximately 19%, and graft-versus-host disease in 15.1% (RIC) and 17.9% (MAC). Readmission Variables A multivariate logistic regression model was used to assess the probability of being readmitted after transplant. Active disease at the time of transplant was a significant risk factor for readmission by day 30 postdischarge (P = .005) and at day 100 (P = .001) in the RIC group. Infection during index admission was a significant risk factor for readmission by day 100 (odds ratio [OR], 1.9; P = .006) in the MAC group. For the RIC group, a mismatched

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The most frequent reasons for readmission were documented infection, fever without a source, and graftversus-host disease….A multivariate analysis confirmed the association between readmission and lower overall survival.” —Laura Spring, MD donor and infection during index admission were significant risk factors for readmission by day 30 after discharge and by day 100. Hispanic/Latino ethnicity was a significant risk factor for readmission at day 100 (OR, 4.6; P = .013) in the MAC group. Non–private insurance was a risk factor at day 30 (OR, 1.8; P = .025) and at day 100 (OR, 1.6; P = .029) in the RIC group. Decreased Survival with Readmission Univariate analysis demonstrated

that being readmitted in either group was associated with decreased survival. In a landmark analysis of patients who survived beyond the studied time points, the 5-year OS for patients readmitted within 30 days of discharge from the index HSCT in the MAC group was 42% compared with 56% among patients not readmitted. Similarly, OS in the RIC group was 26% versus 50%, respectively. The 5-year OS for patients readmitted by day 100 after HSCT was 52% versus 61% of those not readmitted in the MAC group, and 26% versus 57% in the RIC group. “After adjusting for age, donor type, and disease risk index, a multivariate analysis confirmed the association between readmission and lower overall survival,” said Dr Spring. The risk of death at 5 years was 58% higher with 30-day readmission (P = .001) and 32.5% higher with readmission within 100 days (P = .068) in the MAC group. In the RIC group, the risk of death was 68% (P = .002) with 30-day readmission and increased more than 2-fold (P ≤.001) with 100day readmission.—WK n VOL. 7

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Other Highlights

More Transplants Made Possible Through Haploidentical Donors donor for patients with a relative who is a potential haploid donor. The study was a retrospective re view of 273 patients aged 50 to 75 years who received a nonmyeloablative regimen and haploBMT with posttransplant high-dose cyclophosphamide plus drugs for GVHD prophylaxis. This resulted in a low rate of acute GVHD, a low rate of chronic GVHD, a 1-year relapse rate of 37%, and a 6-month nonrelapse mortality rate of 11%. “These results underscore that a reduced-intensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients, up to at least age 75, who require a transplant,” she said.

“These results underscore that a reducedintensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients.” —Yvette L. Kasamon, MD Haploidentical transplant, Dr Cooper said, “shortens the time to finding the donor. We don’t have to pull potential donors from a massive registry. We will often find a donor in the same room as the patient.” Posttransplant Cyclophosphamide Safe and Effective in the Elderly Dr Kasamon and colleagues demonstrated that advanced age need not be a prohibiting factor in haploidentical transplantation. “We found no apparent decrement in overall outcomes in patients aged 60 and older or even 70 to 75 compared to those in their 50s,” Dr Kasamon said. “Since many elderly patients may lack a suitable matched sib donor, the haplo option becomes even more attractive.” She said at a press briefing that, in most cases, Johns Hopkins no long er searches for a matched unrelated

Photo © American Society of Hematology

New Orleans, LA—For the treatment of leukemia and other hematologic malignancies, the pool of donors for hematopoietic stem-cell transplant can be greatly expanded through the use of HLA-haploidentical, or half-matched, donors, according to researchers who reported good outcomes at ASH 2013. With allogeneic bone marrow transplant (BMT), finding a suitable donor can be a challenge. Only 25% of siblings will be an HLA-match, and HLA matches among the pool of unrelated donors are rare. Time is also a factor in coordinating a transplant from an unrelated donor. When a fully HLA-matched donor is not available, transplants of haploidentical hematopoietic stem cells can be effective, the studies presented at ASH suggest. “Almost every patient has at least 1 haploidentical relative, but until recently, haploBMT carried excessive risks,” said Yvette L. Kasamon, MD, Associate Professor of Oncology and Medicine, Johns Hopkins University, one of the pioneering centers for haploidentical transplants. The primary risks include disease recurrence and the development of graft-versus-host disease (GVHD), but the studies reported at ASH found these risks to be minimal. Laurence J. N. Cooper, MD, Associate Director, Center for Cancer Immunology Research, M.D. Anderson Cancer Center, Houston, TX, who moderated the press conference where the studies were described, said these approaches “move the technology forward.”

Photo © American Society of Hematology

By Caroline Helwick

“These results open another avenue, and show that it can actually be advantageous to choose a haploidentical relative.” —Alice Bertaina, MD Improvements in Outcomes Through Graft Manipulation European investigators described a means of making haploidentical transplants safer and more effective through the removal of cells that are most likely to trigger donor cells to attack recipient cells, leading to GVHD, while retaining cells that will be protective.

“We recently developed a new method of graft manipulation based on the physical removal of alpha/beta-positive T-cells and CD19-positive B-cells, which permits us to leave mature natural killer cells and gamma-delta–positive T-cells in the graft, which help prevent relapse and protect against infection,” said Alice Bertaina, MD, of the IRCCS Bambino Gesù Children’s Hospital, Rome, Italy. Their study included 50 children with acute lymphoblastic or acute myeloid leukemia with a parent serving as the haploidentical donor. The donor’s blood was filtered through a column where magnetic microbeads captured and separated the T-cells to be retained from those slated for elimination. Patients underwent a myeloablative regimen, with or without total body irradiation, and received antithymocyte globulin and rituximab. Over 36 months, the cumulative incidence of transplant-related mortality was only 4%, the relapse rate was just 19%, and the leukemia-free survival rate was 77%, rising to 80% in the subset with acute lymphoblastic leukemia. The incidence of acute GVHD was 26%, and no child developed gut or liver acute disease. “Until now, we have searched for unrelated volunteer donors, but it is difficult to propose to the parents that we must wait for this search before we treat,” Dr Bertaina said. “These results open another avenue, and show that it can actually be advantageous to choose a haploidentical relative.” n

New Orleans, LA—An investigational monoclonal antibody may be of benefit in treating patients with multicentric Castleman’s disease, a potentially fatal, incurable disorder with high morbidity believed to be partially mediated by the overproduction of interleukin-6 that results in the dangerous overgrowth of cells in the lymph nodes. The drug, siltuximab, blocks the function of interleukin-6 and ideally ameliorates this uncontrolled cell growth and controls other inflammatory disease symptoms. In a phase 2 study presented at ASH 2013, and featured in a press briefing, investigators randomly assigned VOL. 7

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Photo © American Society of Hematology

Siltuximab: Monoclonal Antibody Relieves Symptoms of Castleman’s Disease “This experimental therapy could become the first globally approved treatment for this incurable disease and could potentially transform how patients are treated in the future.” —Raymond S. Wong, MBChB, MD

70 patients with multicentric Castleman’s disease to siltuximab or to placebo, plus best supportive care. Of the patients treated with siltuximab, 34% achieved a durable tumor and symptom response compared with none of the patients in the placebo arm. At baseline, patients reported fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia (37%), and pruritus (37%). The symptoms completely resolved in 25% of the siltuximab group for a median of 1.3 years, but placebo recipients had no resolution of symptoms. The median time to next treatment was not reached in the

siltuximab arm versus a time of 280 days in the placebo arm. Despite a 2-fold longer duration of treatment with siltuximab, rates of adverse events were similar between the arms, reported Raymond S. Wong, MBChB, MD, a radiation oncologist at the Prince of Wales Hospital, Chinese University of Hong Kong, China. “If siltuximab gains regulatory approval, this experimental therapy could become the first globally approved treatment for this incurable disease and could potentially transform how patients are treated in the future,” Dr Wong predicted. n

february 2014

www.AHDBonline.com

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

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 thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • 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 Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

FDA Update Ibrutinib Approved for Chronic Lymphocytic... Continued from page 4 rector of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process,

which played a vital role in rapidly making this new therapy available to those who need it most.” The approval of ibrutinib for the treatment of patients with CLL was also done under the priority review process of the FDA, based on the demonstration of the drug to have a significant improvement on the safety

or efficacy of patients with this serious condition. Ibrutinib also received an orphan drug designation by the FDA. The new FDA indication for ibrutinib for CLL is based on the results of a clinical trial with 48 previously treated patients with CLL. Patients were diagnosed with CLL an average of 6.7 years before enrolling in the study and

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in 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 teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Adverse All All 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 d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 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 hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

American health & drug benefits

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 normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information].

february 2014

had received 4 previous therapies. Patients received oral ibrutinib until disease progression or unacceptable toxicity. Overall response was seen in nearly 58% of the patients, with a response duration of 5.6 months to 24.2 months during the study. Improvements in survival or disease-related symptoms have not been established. The most common side effects reported with ibrutinib include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper-respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, mouth sores, sinusitis, and dizziness. (February 12, 2014)

Adverse Events Reporting in Oncology Studies Suboptimal

Transparent and comprehensive reporting of adverse events (AEs) in published results of oncology-related clinical trials is crucial for the treatment of patients with cancer. The Consolidated Standards of Reporting Trials (CONSORT) extension group had developed 10 recommendations in 2003 for reporting AEs. A new analysis of 175 publications recently assessed the degree to which the publication of phase 3 trial results in oncology adhered with CONSORT recommendations (Sivendran S, et al. J Clin Oncol. 2014;32:83-89). Based on this analysis, the published reports of AEs is suboptimal and is characterized by significant selectivity of the data. The analysis involved randomized, phase 3 clinical trials in metastatic solid malignancies published between January 2009 and December 2011. Publications were assessed for 14 AEs listed in the CONSORT harms extension statement, using a completeness score of 0 to 14. Data on 96,125 patients were included. The median completeness score was 8. The majority of publications (96%) only reported AEs above a particular threshold rate or severity. Overall, 37% did not specify the criteria used to report AEs, and 88% grouped AEs of varying severity. Only 77% of articles reported absolute numbers of AEs, 75% reported if there were deaths related to AEs, 71% reported whether patients were evaluable for toxicity, and 65% reported reasons for treatment discontinuation. In addition, trials without a specified funding source were associated with significantly lower AE complete reporting scores. This analysis shows substantial selectivity in the reporting of AEs in oncology publications.

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Drug Update

Gazyva for Chronic Lymphocytic Leukemia: First FDA-Approved Breakthrough Therapy in Oncology By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), a monoclonal disorder characterized by progressive accumulation and proliferation of functionally incompetent B-cells, is the most frequently diagnosed leukemia in the United States.1,2 The American Cancer Society has estimated that 4580 Americans will die from CLL in 2013, which represents approximately 19% of all leukemia deaths.2 Because it can have an insidious onset, CLL is often discovered incidentally after blood work is conducted for another reason.3 Between 25% and 50% of patients with CLL are asymptomatic at the time of presentation.3 Patients with CLL are typically receiving treatment when their disease becomes symptomatic or when the signs of rapid disease progression are detected.3 Drug combinations for patients with CLL who warrant treatment include cytotoxic agents, such as the purine nucleoside analog fludarabine (Fludara), and therapeutic antibodies.3,4 Rituximab (Rituxan), a CD20 antibody, is widely used in patients with previously untreated symptomatic CLL and in salvage regimens.4 Other antibodies with clinical activity in CLL include the anti-CD20 antibody ofatumumab (Arzerra) and the anti-CD52 antibody alemtuzumab (Campath).4 Researchers continue to explore multiple novel strategies for the treatment of patients with CLL, including small molecules and newer-generation monoclonal antibodies, such as RG7356 and veltuzumab.5,6 For patients with CLL who are fit enough to tolerate treatment-related toxicities, including bone marrow suppression, modern chemoimmunotherapy combinations have significantly improved clinical outcomes.7 However, none of these regimens is curative, and a significant number of patients with CLL succumb to their disease. The effective management of elderly patients with CLL represents a particular challenge, in part because older patients with multiple comorbidities have been underrepresented in clinical trials of novel agents and drug combinations.7 Because the majority of patients with CLL are older than 65 years at the time of their diagnosis, reimbursement for the treatment of CLL in the United States is typically provided by Medicare.7,8 An analysis of US Medicare data (1999-2007) has demonstrated that the cost burden associated with

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CLL is substantial.9 This study, which was published in 2012, analyzed the total lifetime cost of treatment for more than 7400 patients with CLL compared with matched controls who did not have cancer. The results demonstrated that patients with CLL incurred average treatment costs of more than $87,000 compared with approximately $47,600 for the matched controls, a very significant difference.9

monoclonal antibody directed against CD20.14 On binding to CD20, obinutuzumab mediates B-cell lysis in 3 ways: (1) the engagement of immune effector cells, whose mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, (2) direct activation of intracellular death signaling pathways, and (3) complement cascade activation.14

PFS as assessed by independent review.12 Secondary end points included response rate, complete response rate, duration of response, disease-free survival, OS, minimal residual disease, safety, adverse events, patient-reported outcomes, and symptom burden defined by the European Organisation for Research and Treatment of Cancer questionnaire.15

New Treatment Option for CLL: Obinutuzumab In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (Gazyva; Gen entech) for use in combination with chlorambucil in patients with previously untreated CLL.10 The approval was done under the FDA’s priority review. Obinutuzumab is the first cancer agent with the “breakthrough therapy” designation to receive FDA approval.10,11 The approval of obinutuzumab for the treatment of patients with CLL was based on the demonstration of significant improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial comparing obinutuzumab in combination with chlorambucil versus chlorambucil alone.10,12 The study included 356 patients with previously untreated CD20-positive CLL and coexisting medical conditions or reduced renal function.10,12 In this study, known as CLL11, patients received 1 of 3 treatment regimens: chlorambucil alone for 6 cycles, chlorambucil plus obinutuzumab for 6 cycles, or chlorambucil plus rituximab for 6 cycles.12 All cycles were 28 days.12 Data from the first portion of the CLL11 study—the comparison of obinutuzumab plus chlorambucil and chlorambucil alone—were initially presented at the 2013 American Society of Clinical Oncology annual meeting and served as the basis for the FDA’s approval of the drug.12 In an interview regarding the CLL11 study, lead investigator Valentin Goede, MD, of the German CLL Study Group, Department of Internal Medicine, University Hospital Cologne, Germany, stated, “This [significant PFS] finding suggests an 86% reduction in the risk for a progression, relapse, or death in the obinutuzumab arm.”13

Dosing and Administration For patients with newly diagnosed CLL, the dose of obinutuzumab is 100 mg intravenously on day 1 in cycle 1, 900 mg on day 2, and 1000 mg on days 8 and 15; in cycles 2 to 6, the dose is 1000 mg, administered intravenously every 28 days.14 Premedication before infusion with obinutuzumab is recommended to reduce the risk for infusion-related adverse reactions.14

In the phase 3 obinutuzumab trial, the patient demographics and clinical characteristics were balanced between the treatment arms.12 The patients’ median age was 73 years, 60% were male, and 95% were Caucasian.12,14 Overall, 68% of the patients had a CrCl of <70 mL/min and 76% had multiple comorbidities.14 The median estimated CrCl was 61 mL/min.12 Of the patients who received obinutuzumab plus chlorambucil, 81% received all 6 cycles compared with 67% of patients who received chlorambucil alone.14

Mechanism of Action Obinutuzumab is a humanized

CLL11: Pivotal Phase 3 Clinical Trial In the first portion of the multicenter CLL11 trial, 356 previously untreated patients with CLL were randomly assigned to treatment with obinutuzumab plus chlorambucil or to chlorambucil alone.12 All patients had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) of <70 mL/min.12 The majority of the patients received 1000 mg of obinutuzumab on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg) for 45 patients in the CLL11 trial. Chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of all treatment cycles (1-6).12 The trial’s primary end point was

Patient Population

Efficacy

The phase 3 study demonstrated that obinutuzumab is active and safe in patients with newly diagnosed CLL and comorbidities.12 At the time of data cutoff for primary end-point analysis, patients receiving chlorambucil alone and obinutuzumab plus chlorambucil had been followed for a median of 13.6 and 14.5 months, respectively.12 On assessment by independent reviewers, the median PFS was significantly prolonged for patients receiving obinutuzumab plus chlorambucil compared with patients receiving chlorambucil alone (23 vs 10.9 months, respectively; P <.001).12 This significant difference in median PFS was maintained in a subsequent analysis.

Table 1 Phase 3 Clinical Trial CLL11: Efficacy Results Obinutuzumab plus Chlorambucil chlorambucil (N = 238) (N = 118)

Efficacy end point PFS Median PFS, months

Hazard ratio Stratified log-rank test P value

11.1

0.16 (95% CI, 0.11-0.24) <.001

Response rate Overall, % Complete, %

75.9 27.8

32.1 0.9

Median duration of response, mo

15.2

3.5

CI indicates confidence interval; PFS, progression-free survival. Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013.

february 2014

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Drug Update Table 2 P hase 3 Clinical Trial CLL11: Adverse Reactions in ≥5% of Patients and ≥2% More in the Obinutuzumab-Treated Arm Obinutuzumab plus chlorambucil (N = 240) Chlorambucil (N = 116) Adverse reactions All grades, % Grade 3-4,a % All grades, % Grade 3-4,a % Injury, poisoning, and procedural complications Infusion-related reactions

Neutropenia

Thrombocytopenia

Anemia

Leukopenia

Blood and lymphatic system disorders

General disorders and administration-site conditions Pyrexia Respiratory, thoracic, and mediastinal disorders Cough

No grade 5 adverse reactions have been observed with a difference of ≥2% between the treatment arms. b Clinically significant events. Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013. a

After a median observation time of 23 months, the median PFS for patients receiving obinutuzumab plus chlorambucil was 23 months compared with 11.1 months in patients receiving chlorambucil alone (P <.001).14 The PFS and overall response findings from the CLL11 study are summarized in Table 1.14

Safety

Of the 240 patients included in the phase 3 trial, approximately 194 (81%) received all 6 cycles (28 days each) of obinutuzumab-based therapy.14 Among the patients who received obinutuzumab, the most common adverse reactions (incidence, ≥10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder (Table 2).14 Infusion reactions were noted in 69% of patients undergoing their first infusion of obinutuzumab.14 Severe (grade 3 or 4) infusion reactions were observed in 21% of patients receiving obinutuzumab, and 8% of patients discontinued therapy.14 The incidence of infusion reactions was significantly lower with subsequent infusions—3% with the second 1000mg dose of obinutuzumab, and less than 1% thereafter. No severe infusion reactions were reported after the first 1000-mg infusion.14 After this initial experience with infusion reactions in the CLL11 trial, study protocol modifications were made to require premedication with a corticosteroid, an antihistamine, and acetaminophen.14 The first dose of obinutuzumab was also divided into 2 infusions—100 mg on day 1 and 900 mg on day 2. Among the 45 patients for whom these measures were implemented, 21 (47%) had an

infusion reaction with the first 1000 mg of obinutuzumab. Less than 2% of patients experienced an infusion reaction with subsequent doses of obinutuzumab.14 HBV infection reactivation. Hepatitis B virus (HBV) reactivation can occur in patients treated with anti-CD20 antibodies, including obinutuzumab. Reactivation of HBV replication is often followed by hepatitis, manifesting as an increase in transaminase levels and, in severe cases, increases in bilirubin level, liver failure, and death.14 In some recipients of obinutuzumab, the reactivation of the HBV resulted in fulminant hepatitis, hepatic failure, and death. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive, as well as in patients who are HBsAg negative but are anti–hepatitis B core antibody (HBc) positive. Reactivation was also observed in patients who appeared to have resolved HBV infection (ie, HBsAg negative, antiHBc positive, and hepatitis B surface antibody positive).14 Warnings and Precautions Boxed warning. The approval of obinutuzumab includes a boxed warning regarding HBV infection reactivation and progressive multifocal leukoencephalopathy (PML).10 Clinicians should advise patients of these warnings, and should assess patients for HBV and reactivation risk.10 All patients receiving obinutuzumab should be screened for HBV infection by measuring HBsAg and anti-HBc before treatment initiation. Patients who show evidence of HBV infection should consult with physicians experienced in HBV infection to discuss the potential use of HBV antiviral therapy.14

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february 2014

In patients who develop reactivation of the HBV while receiving obinutuzumab, obinutuzumab and any concomitant chemotherapy should be discontinued immediately. Appropriate treatment should be instituted. In patients whose HBV reactivation resolves, resumption of obinutuzumab can be discussed with physicians who are experienced in managing patients with HBV infection. There are insufficient data regarding the safety of resuming obinutuzumab in patients who develop reactivation of the HBV.14 Progressive multifocal leukoencephalopathy. JC virus infection resulting in PML, a potentially fatal condition, was observed in patients receiving obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset neurologic manifestations or with changes to preexisting neurologic manifestations. If PML is diagnosed, therapy with obinutuzumab should be discontinued.14 Consider the discontinuation or reduction of concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.14 Infusion reactions. Obinutuzumab can cause severe and life-threatening infusion reactions during initial and subsequent infusions. Symptoms include hypotension, tachycardia, dyspnea, and respiratory symptoms. Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills.14 Patients should receive premedication with acetaminophen, an antihistamine, and a glucocorticoid. Patients should be closely monitored during the entire infusion; reactions within 24 hours of receiving obinutuzumab have occurred. If infusion reactions occur, institute medical management with

glucocorticoids, epinephrine, bronchodilators, and/or oxygen as needed.14 Table 3 summarizes the recommendations for managing infusion reactions associated with obinutuzumab.14 Because patients with preexisting cardiac or pulmonary conditions may be at greater risk for experiencing more severe infusion reactions, they should be monitored more frequently throughout the obinutuzumab infusion and the postinfusion time frame.14 Hypotension may occur as part of the obinutuzumab infusion reaction. Consider withholding antihypertensive treatments for 12 hours before the obinutuzumab infusion, during the infusion, and for the first hour after administration until blood pressure is stable. For patients who are at increased risk of hypertensive crisis, the benefits and risks of withholding their hypertensive medication should be deliberated.14 Tumor lysis syndrome. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia secondary to tumor lysis syndrome (TLS) can occur 12 to 24 hours after the first infusion of obinutuzumab. Because patients with high tumor burden and/or high circulating lymphocyte count (>25 × 109/L) are at greater risk for TLS, appropriate prophylaxis with antihyperuricemics (eg, allopurinol) and hydration should begin 12 to 24 hours before the infusion.14 Infection. Serious bacterial, fungal, and new or reactivated viral infections can occur during and after obinutuzumab therapy. Obinutuzumab should not be given to patients with active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection while taking obinutuzumab.14 Neutropenia. Neutropenia associated with obinutuzumab can occur more than 28 days after the completion of treatment and can last more than 28 days. Patients with grade 3 or 4 neutropenia while taking obinutuzu mab should be monitored frequently until resolution. Any symptoms or signs of infection should be addressed immediately. Patients with neutropenia should receive antimicrobial prophylaxis during the treatment and may consider antiviral and antifungal prophylaxis.14 Thrombocytopenia. In the CLL11 trial, 12% of patients receiving obinutuzumab plus chlorambucil had grade 3 or 4 thrombocytopenia. In 5% of patients, obinutuzumab caused an acute thrombocytopenia within 24 hours after infusion. Platelet counts should be monitored frequently in patients with grade 3 or 4 thrombocytopenia until resolution. Platelet transfusions may be required.14 VOL. 7

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Drug Update resulted in serious adverse events in geriatric patients. Among 240 treatment-naïve patients who received obinutuzumab in combination with chlorambucil, 82% were aged ≥65 years and 45% were aged ≥75 years. Of those aged ≥75 years, 45% had serious adverse events and 5% died. Among those aged ≥65 years, adverse event rates were similar in the active treatment and the comparator arms. The efficacy rates were not significantly different among patients of different ages.14

ecommended Management of Adverse Reactions to Obinutuzumab Table 3 R Infusion, by Severity (Grade) Recommendations Infusion reaction severity Grade 4 reaction (life-threatening): • Stop the obinutuzumab infusion and permanently discontinue obinutuzumab includes, but not limited to, anaphylaxis, acute life-threatening therapy respiratory symptoms, or other • Manage symptoms life-threatening infusion reaction Grade 3 (severe)

• Interrupt obinutuzumab infusion • Manage symptoms • On resolution of symptoms, consider restarting obinutuzumab infusion at no more than 50% of the previous rate (used at the time that the infusion reaction occurred) • If no further infusion reaction symptoms occur, infusion rate escalation may be resumed at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling) • Permanently discontinue treatment if the patient has a grade 3 infusion-related symptom on rechallenge

Grade 1 or 2 infusion reactions (mild to moderate)

• Interrupt obinutuzumab therapy or reduce the rate of the infusion • Manage symptoms • On resolution of symptoms, continue or resume infusion • If no further infusion reaction symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling)

Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013.

Immunization. Immunization with live virus vaccines is not recommended until the completion of obinutuzumab treatment and B-cell recovery.14 Special Populations Obinutuzumab has not been specifically studied in pregnant or nursing women. Women of childbearing

age should use effective contraceptive when receiving this medication and for the 12 months after treatment.14 Nursing women should be carefully evaluated for the benefits of obinutuzumab for the woman versus potential risk for the infant.14 The combination of obinutuzumab and combination chlorambucil has

Conclusion Obinutuzumab is the first cancer drug with a designated breakthrough therapy to receive FDA approval. This third-generation anti-CD20 monoclonal antibody, which was approved for the initial treatment of patients with CLL in combination with chlorambucil, has demonstrated improved efficacy with manageable side effects compared with chlorambucil alone.11,16 For patients with CLL and coexisting medical conditions and/or reduced renal function, obinutuzumab plus chlorambucil represents an effective alternative to purine analog-based therapy and to the use of chlorambucil alone. Obinutuzumab may also confer clinical benefit in other cancers that express CD20. Clinical studies are under way to evaluate the use of obinutuzumab combined with cytotoxic agents in indolent and aggressive subtypes of non-Hodgkin lymphoma (NHL), including follicular NHL, diffuse large B-cell lymphoma, and mantle-cell lymphoma.17 n References

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocyt-

ic leukemia. N Engl J Med. 2005; 352:804-815. 2. American Cancer Society. Cancer facts and figures 2013. 2013. www.cancer.org/acs/groups/content/@ epidemiologysurveilance/documents/document/ acspc-036845.pdf. Accessed November 27, 2013. 3. Mir MA, Liu D, Patel SC, Rasool HJ. Chronic lymphocytic leukemia. Medscape. Updated November 11, 2013. http://emedicine.medscape.com/article/199313overview. Accessed November 27, 2013. 4. Jaglowski SM, Alinari L, Lapalombella R, et al. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood. 2010;116:3705-3714. 5. Zhang S, Wu CC, Fecteau JF, et al. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci U S A. 2013;110:6127-6132. 6. OBR. OBR Pipeline Online: chronic lymphocytic leukemia (CLL). http://obr oncology.com/pipeline_ online.php. Accessed November 29, 2013. 7. Stephens DM, Byrd JC. Ask the hematologists. Hematologist. 2012;9:4-5. 8. American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Revised November 14, 2013. www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chroniclymphocytic-key-statistics. Accessed November 28, 2013. 9. Lafeuille MH, Vekeman F, Wang ST, et al. Lifetime costs to Medicare of providing care to patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1146-1154. 10. US Food and Drug Administration. Drugs: Gazyva (obinituzumab). Updated November 1, 2013. www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm373263.htm. Accessed November 29, 2013. 11. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm373209.htm. Accessed November 29, 2013. 12. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31(15 suppl). Abstract 7004. 13. McCall B. Obinutuzumab active in elderly chronic lymphocytic leukemia. Medscape Medical News. June 21, 2013. www.medscape.com/viewarticle/806700. Accessed November 29, 2013. 14. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; November 2013. 15. ClinicalTrials.gov. CLL11: A Study of RO5072759 (GA101) with Chlorambucil in Patients with Previously Untreated Chronic Lymphocytic Leukemia. http:// clinicaltrials.gov/ct2/show/NCT01010061?term= obinutuzumab&rank=12. Accessed November 29, 2013. 16. Ingram I. FDA approves obinutuzumab (Gazyva) for chronic lymphocytic leukemia. Cancer Network. November 1, 2013. www.cancernetwork.com/news/fdaapproves-obinutuzumab-gazyva-chronic-lymphocyticleukemia. Accessed November 29, 2013. 17. ClinicalTrials.gov. Obinutuzumab. Search results. http://clinicaltrials.gov/ct2/results?term=obinutu zumab &Search=Search. Accessed November 29, 2013.

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Government and Employers An educational session for policymakers and employers focusing on healthcare reform, benefit design, insurance, and coverage trends. Co-Chairs

May 7, 2014 Loews Hollywood Hotel Los angeles, Ca

aGEnda

Jayson Slotnik, JD, MPH

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

F. Randy Vogenberg, PhD, RPh

Principal Institute for Integrated Healthcare

8:30am – 8:40am

Introductions and Opening Remarks Jayson Slotnik, JD, MPH; F. Randy Vogenberg, PhD, RPh

8:40am – 9:25am

Session 1: Investor Community Views on Healthcare Market Winners and Losers Michael E. Meyers, MPH, Managing Director, Head of Investment Banking, T.R. Winston & Company

9:25am – 10:10am

Session 2: Insurance Innovation on Reinsurance and Benefit Design Trends Matthew Palmgren, PharmD, President, Healthcare Solutions in Int’Ovation Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC

10:10am – 10:15am

Break

10:15am – 11:00am

Session 3: Private Exchanges: Why Different from Public Exchange Trends for Oncology Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions

11:00am – 11:40am

Session 4: Diagnostics: Recent FDA and CMS Policies Impacting Access to Diagnostic and Oncology Drugs John Ridge, Senior Director, Managed Care and Reimbursement, Exact Sciences Timothy J. Thompson, Chief Executive Officer, Intervention Insights

11:40am – 12:00pm

Session 5: What’s Next with Healthcare Reform – Fixes or More Related to Oncology? Denise Pierce, President and CEO, DK Pierce & Associates Jayson Slotnik, JD, MPH, Vice President of Reimbursement Strategy & Innovation, United BioSource Corporation F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare

12:00pm – 12:15pm

Break

12:15pm – 1:15pm

Lunch/Product Theater

1:15pm – 1:30pm

Break

1:30pm – 2:15pm

Session 6: Employer Onsite Clinic Trends from Wellness into Infusion and Emergent Care Larry Boress, President & CEO, Midwest Business Group on Health; Executive Director, National Association of Worksite Health Centers

2:15pm – 3:45pm

Meet the Experts Roundtables Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE)

3:45pm – 4:15pm

Poster Presentations

4:15pm – 5:00pm

Poster and Session Discussant

5:00pm – 7:00pm

Cocktail Reception in the Exhibit Hall

AVBCC2014May7agenda Ksize_20714

NeW foR 2014

Personalized Medicine and Payers An educational session for payers focusing on cost efficiency, value, outcomes, and impacts on treatment of personalized medicine. Co-ChAirs

May 8, 2014 Loews Hollywood Hotel Los angeles, Ca

AgendA 7:00am – 8:30am 8:30am – 8:40am 8:40am – 9:20am

9:20am – 10:00am

10:00am – 10:40am

10:40am – 11:20am

11:20am – 12:00pm

12:00pm – 12:15pm 12:15pm – 1:15pm 1:15pm – 2:45pm

2:45pm – 3:00pm 3:00pm – 4:00pm 4:00pm – 5:00pm 5:00pm – 7:00pm

Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Special Session: Value-Based Strategies for Patients with Multiple Myeloma Supported by funding from Millennium: The Takeda Oncology Company Introductions and Opening Remarks Michael A. Kolodziej, MD; Grant Lawless, RPh, MD, FACP Session 1: Personalized Medicine and Value Peter Bach, MD, MAPP, Memorial Sloan-Kettering Cancer Center Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna Session 2: Measuring the Value of Prognostic and Predictive Outcomes Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine Macey Johnson, Vice President of Managed Care and Reimbursement, BioTheranostics Session 3: Utilizing Big Data to ID Phenotypes and Predictive Outcomes Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint George W. Sledge, MD, FASCO, Chief of Oncology, Stanford University Department of Medicine Session 4: Value Paradigm in Drug Development Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Kevin Knopf, MD, MPH, California Pacific Medical Center Christiane Langer, MD, Lead Medical Director for CRC, GU, and GBM, Genentech Panel Discussion - How will personalized medicine impact future treatment and use existing therapy? Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint Break Lunch/Product Theater Meet the Experts Roundtables Al Benson, MD, Professor of Medicine and Oncology, Northwestern University Medical School Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Break Poster Presentations Poster and Session Discussant Cocktail Reception in the Exhibit Hall AVBCC2014May8agenda Ksize_20714

Continuing Education

Optimal Use of Biologics in Delivering Value-Based Care: Challenges for Managed Care Pharmacy Faculty Douglas Burgoyne, PharmD

John Fox, MD, MHA

President VRx Pharmacy Services, LLC Salt Lake City, UT

Senior Medical Director Vice President of Medical Affairs Priority Health Associate Professor of Medicine Michigan State University College of Human Medicine Grand Rapids, MI

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by an educational grant from Genentech/ Biogen Idec. Target Audience This activity was developed for managed care pharmacists and professionals who are involved in the care of patients with cancer or autoimmune disorders, and who manage insurance designs. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-028-H01-P.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CPE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Sabeeha Muneer, PhD, Medical Writer, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational use of any products/devices. Patricia Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.

Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the current trends in the use of biologic therapies in oncology, rheumatology, inflammatory bowel disease, and multiple sclerosis • Discuss the challenges facing all stakeholders in optimizing value in the use of biologic therapies • Analyze issues around cost, quality, and access to care in the use of biologic therapies • Formulate biologic treatment options that maximize value by improving clinical outcomes and reducing disease burden on patients, families, and the healthcare system

Faculty Disclosures Douglas Burgoyne, PharmD, has received consulting fees from Biogen Idec, Eli Lilly, Novo Nordisk, and Purdue. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices. John Fox, MD, MHA, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices. Jeffrey D. Dunn, PharmD, MBA, has received honorarium from AbbVie, Biogen Idec, and Janssen. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Jeffrey D. Dunn, PharmD, MBA Senior Vice President VRx Pharmacy Services, LLC Salt Lake City, UT

Disclaimer The information provided in this CPE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CPE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13031E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1 hour Date of initial release: February 11, 2014 Valid for CPE credit through: February 11, 2015.

To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

Supported by an educational grant from Genentech/Biogen Idec.

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

American health & drug benefits

february 2014

VOL. 7

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Special Issue

Continuing Education

he advent of biologic therapies has revolutionized the management of patients with cancer and autoimmune diseases across the therapeutic spectrum. These advances reflect improved understanding of the pathobiology of different malignancies and immunologically mediated disorders, and identification of rational targets for therapeutic development. Current projections, however, indicate that spending related to specialty drugs, including biologic agents, will reach astronomical levels by the year 2018—amounting to an increase per member per year (PMPY) from $290 in 2012 to $845 PMPY in 2018 (Figure).1 Although the clinical drug pipeline historically has been dominated by biologic agents directed toward cancer-relevant antigens, a majority of biologic therapies are increasingly being developed for noncancerous indications, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). Consistent with this trend, inflammatory diseases, such as RA and MS, show the highest PMPY spending of specialty drugs (23.3% and 18.0%, respectively), followed by oncology at 14.3%.2 The concept of Triple Aim, which was first proposed in 2008, defines the simultaneous improvement of population health, patient experience of care, and per-capita cost reduction as the 3 dimensions needed to achieve optimal outcomes.3 Outcome measures for achieving these lofty goals have since been developed by the Institute for Healthcare Improvement, and they serve as the central tenet for public and private health organizations.4 As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal. A live symposium was held on October 16, 2013, during meetings of the Academy of Managed Care Pharmacy, to educate managed care pharmacists, who are uniquely positioned to evaluate the value of biologic therapies, on recent treatment advances and practice management strategies. This review provides a synthesis of the proceedings of this meeting, including current trends in personalized biologic therapy–based management approaches in oncology and chronic inflammatory diseases, and cost-effective strategies for improving overall outcomes from the perspective of managed care pharmacists.

Review of Current and Emerging Biologic Agents for the Treatment of Cancer and Autoimmune Diseases Biologics in Oncology According to the most recent estimates from the Centers for Disease Control and Prevention, cancer is the second leading cause of death in the United States, Figure Exponential Growth of Specialty Drug Spending Traditional

surpassed only by cardiovascular diseases.5 Historically, standard treatment modalities in oncology have included a combination of surgery, radiation, and/or chemotherapy. Immunotherapy with biologic agents, however, is now considered an integral and indispensable component of the treatment arsenal for many different types of cancer.6,7 Cancer immunotherapy strategies are aimed at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms, and include monoclonal antibodies (mAbs), cytokines and growth factors, and vaccines.6,7 Indeed, the oncology arena has witnessed an unprecedented upswing in the use of biologic therapies. Currently, the US Food and Drug Administration (FDA) lists more than 50 medications with accompanying pharmacogenomic biomarkers that have been approved for clinical use.8 In many cancer types, antibody-based treatment has dramatically improved disease response while reducing the major concomitant toxicities typically associated with the use of chemotherapy. In the field of oncology, mAbs include the anti–human epidermal growth factor receptor 2 (HER2) mAb trastuzumab for breast cancer, the anti-CD20

As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal. mAb rituximab for non-Hodgkin’s lymphoma, the anti–vascular endothelial growth factor (VEGF) mAb bevacizumab for several different cancer types, the anti–epidermal growth factor receptor (EGFR) mAb panitumumab for colon cancer, and the anti-EGFR mAb cetuximab for colorectal cancer and head and neck cancer.9 These mAbs directly target the cancer antigen, resulting in blockade of growth factor–mediated signaling and inhibition of angiogenesis, which regulate key processes involved in cancer growth and progression. Other types of biologic immunotherapy used in oncology include cytokines such as interleukin (IL)-2 and interferon (IFN)-alpha for various forms of cancer, and vaccines9 such as Bacillus Calmette-Guérin for the treatment of bladder cancer. In addition, biologic agents are used as supportive care in oncology, for the mitigation of treatment-related side effects. These treatments include the use of such hematopoietic growth factors as granulocyte colony-stimulating factor following cytotoxic chemotherapy, in order to promote neutrophil production and thus reduce the risk for infection.9

Biologics for Autoimmune Diseases Multiple sclerosis MS is a chronic autoimmune disease that is defined by the progressive destruction of axonal myelin sheaths in the central nervous system.10,11 The symptoms associated with MS are interrelated, having a major impact on quality of life

Specialty

$1800 $1600 $1400

Table 1 Biologics Currently Approved for the Treatment of Multiple Sclerosis

$1200 $612

$1000 $800

$348

$290

$722

$845

$514

$425

$600 $400

$665

$675

$694

$722

$751

$789

$836

$200 $0

2012

2013

2014

2015

2016

2017

2018

VOL. 7

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Generic name

Mechanism of action

Approval date

Interferon beta-1b

Immunomodulator

1993

Interferon beta-1a

Immunomodulator

1996

Glatiramer acetate

Immunomodulator

1996

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2006

Fingolimod

Immunomodulator

2010

Teriflunomide

Immunomodulator

2012

Dimethyl fumarate

Immunomodulator

2013

Source: Reference 12.

february 2014

www.AHDBonline.com

Continuing Education

Table 2 Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Name of agent

Mechanism of action

Approval date

Infliximab

Anti–TNF-α

1998

Etanercept

Anti–TNF-α

1998

Anakinra

IL-1 receptor

2001

Adalimumab

Anti–TNF-α

2002

Abatacept

CD28

2005

Rituximab

CD20

2006

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2009

Tocilizumab

IL-6 receptor

2010

IL indicates interleukin; TNF, tumor necrosis factor. Sources: References 18, 19.

Table 3 Expanding Therapeutic Pipeline for Inflammatory Bowel Disease Name of agent

Mechanism of action

Approval date

Adalimumab

Anti–TNF-α

2007

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2008

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2013

Tofacitinib

JAK inhibitor

2012

Vedolizumab

Adhesion molecule blocker (anti-integrin α-4/β-7)

In FDA review

PF-00547659

Mucosal adhesion blocker

In clinical testing

GSK-1605786

Oral chemokine antagonist

In clinical testing

Ustekinumab

Cytokine blocker

In clinical testing

FDA indicates US Food and Drug Administration; JAK, Janus kinase; TNF, tumor necrosis factor. Source: Reference 25.

(QOL) and carrying a considerable economic burden.11 The current treatment armamentarium for MS includes IFN beta-1a, IFN beta-1b, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, and dimethyl fumarate— all of which are able to reduce relapse rates and the accumulated disability scores in patients with relapsing-remitting MS (RRMS) (Table 1).12 The overwhelming majority of these treatments, however, have been unable to prevent disease progression or demonstrate curative potential. Therefore, several novel therapies, including alemtuzumab, daclizumab, laquinimod, and neuroprotective agents, are currently under investigation for the treatment of MS.13 In the near future, biosimilars, generics, and novel formulations of current agents (eg, low-dose and generic fingolimod, glatiramer acetate injections 3 times weekly, and first-line intravenous natalizumab) should be available in the biologic MS space, which is expected to have a favorable impact on the treatment paradigm, as well as on the cost of therapy.14 Rheumatoid arthritis RA is a chronic, debilitating, systemic autoimmune disorder that is often characterized by swollen joints, pain, and decreased functional mobility.15,16 Little is understood about the many extraarticular manifestations of RA, including cardio-

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vascular disease, infections, depression, and gastrointestinal ulcers.16 Consequently, RA frequently leads to an increased risk for premature mortality, hospitalization, work disability, increased medical costs, and poor QOL.16 Historically, RA has been managed primarily with corticosteroids and nonsteroidal anti-inflammatory agents, followed by the use of conventional, nonbiologic disease-modifying antirheumatic drugs (DMARDs). These agents have been able to prevent or delay erosive changes that lead to disability, have demonstrated efficacy in reducing synovitis and systemic inflammation, and have improved functionality.16 Recently, the use of biologic agents has significantly altered the natural history of the disease. The latest RA treatment guidelines from the European League Against Rheumatism advocate that the key to optimizing patient outcomes is early diagnosis and early aggressive therapy with optimal doses of conventional DMARDs and, if active disease persists, early introduction of biologic agents.17 Biologic approaches include such tumor necrosis factor (TNF) alpha inhibitors as etanercept, infliximab, adalimumab, golimumab, and certolizumab; the anti–IL-6 agent tocilizumab; the anti–CD20-directed mAb rituximab; the small-molecule Janus kinase (JAK) 1/3 inhibitor tofacitinib; and the antiCTLA-4 fusion protein abatacept (Table 2).18,19 These agents all have demonstrated efficacy in limiting both symptomatic manifestations and radiographic progression of disease.18,19 Inflammatory bowel disease IBD broadly refers to conditions that are believed to be the result of immune dysregulation, impaired mucosal integrity, enteric bacterial dysbiosis, and genetic susceptibility factors.20 These debilitating diseases are characterized by intestinal inflammation, and are associated with such symptoms as persistent diarrhea, cramping abdominal pain, fever, rectal bleeding, loss of appetite, and weight loss.21-23 The 2 most common types of IBD are Crohn’s disease and ulcerative colitis.23-25 The expanding pipeline of drugs for IBD include the anti–TNF-alpha agents adalimumab and golimumab; the adhesion molecule blockers natalizumab, vedolizumab, and certolizumab; the mucosal adhesion blocker PF-00547659; the oral chemokine antagonist GSK-1605786; the JAK inhibitor tofacitinib; and the cytokine blocker ustekinumab (Table 3).25 Increased understanding of the pathogenesis of IBD has identified several other biologic targets for the disorder, including growth factors such as platelet-activating factor and transforming growth factor beta; inflammatory cytokines such as IL-1; immunoregulatory cytokines such as IL-2, IL-4, and IL-12; and chemokines such as intercellular adhesion molecule-1, all of which might further expand the biologic armamentarium for IBD.26

Personalized Management Approaches with Biologic Agents Our expanding knowledge regarding the role of genetic and molecular drivers of disease pathogenesis heralds an era of molecular disease classification and personalized treatment strategies. In basic terms, personalized medicine refers to tailoring treatment to address patient- and disease-related characteristics that are unique to each individual. At the core of practicing personalized medicine is the identification and validation of biomarkers that may be useful for diagnostic purposes, along with the prediction of disease course, prognosis, treatment response, and risk for adverse events associated with a particular therapy. Personalized Medicine in Oncology The use of trastuzumab in breast cancer serves as a prototype for the successful application of personalized medicine.27 Trastuzumab, first approved in 1998 for the treatment of patients with HER2-positive breast cancer, relied on a molecular diagnostic test to identify individuals who overexpress HER2 and would therefore benefit from trastuzumab therapy.27 Prior to the approval of trastuzumab, patients with HER2-positive disease were resigned to a particularly poor prognosis.28 In addition to trastuzumab, several other HER2-targeted therapies are now available for this patient population, including pertuzumab, trastuzumab-DM1, and lapatinib, all with proven efficacy in significantly improving outcomes in both early and metastatic HER2-positive breast cancer settings.28 In a subset of lung adenocarcinomas, the identification of driver mutations in the EGFR gene is associated with response to the tyrosine kinase inhibitor (TKI) erlotinib, leading to the successful application of genetic profiling and rational use of targeted therapies directed toward these common mutations.29 Similarly, recent data demonstrate that response to the anti-EGFR mAb cetuximab in EGFRVOL. 7

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expressing tumors in metastatic colorectal carcinoma is predicted not by EGFR expression, but rather by KRAS mutation status.30 In a non–small-cell lung cancer subset, the presence of mutations in the anaplastic lymphoma kinase (ALK) receptor has provided the opportunity for successful use of the ALK/Met TKI crizotinib in these patients.31 Therefore, current National Comprehensive Cancer Network (NCCN) guidelines recommend the first-line use of erlotinib and crizotinib in patients with EGFR and ALK mutations, respectively, and doublet chemotherapy or cisplatin plus pemetrexed in those without mutations.31 Unfortunately, acquired resistance to TKI therapy is a clinical challenge; a clearer understanding of drug-resistance mechanisms is critical to developing more effective personalized therapeutics. Along the same line, activating mutations in BRAF, such as V600E and V600K, have been identified in metastatic melanoma. The selective BRAF V600E inhibitor vemurafenib has been FDA approved in this patient subset, and is associated with improved outcomes with respect to overall survival, progression-free survival, and clinical response rates.32 In patients with colorectal cancer, the same BRAF V600E mutation is also present in 5% to 15% of all tumors and in up to 80% of tumors with high microsatellite instability, and is associated with a poor prognosis.33 Unexpectedly, patients with colorectal cancer who harbor BRAF V600E mutations and are treated with vemurafenib exhibit suboptimal responses, highlighting the importance of disease-specific studies.33 These conflicting data emphasize the heterogeneous biology and pathogenesis underlying different malignancies, and caution against extrapolating results among different cancer types. Although whole-genome sequencing is an attractive prospect in oncology, contradictory data, such as with the BRAF V600E mutation, undermine its universal applicability. Moreover, considerable intratumor heterogeneity exists, rendering biomarker assessment challenging. Gerlinger and colleagues found significant mutational microheterogeneity and corresponding protein expression, with discrepancies detected in different regions of the same tumor, and among molecular profiles of primary and metastatic lesions.34 Despite such limitations, however, it is clear that identification of genetic or molecular tumor abnormality profiles in oncology will allow more rational use of targeted agents and biologic therapies, leading to improved health outcomes, improved patient experience, better use of resources, and reduced costs through avoidance of ineffective therapies.

Personalized Medicine in Chronic Inflammatory Diseases Unlike in oncology, personalized management approaches are still in their infancy in chronic inflammatory diseases, with few biomarkers having made their way into clinical practice. Increasing evidence, however, suggests that this will be the way in which inflammatory or immunologically mediated diseases will be treated in the future.

Emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNF-alpha agent. MS is a highly heterogeneous disorder with diverse etiology, pathologic features, clinical course, disease severity, and response to therapy, which presents obvious challenges when making treatment decisions.35 Treatment selection for MS has been largely empirical and not guided by validated molecular or genetic biomarkers. Existing treatments for RRMS have demonstrated limited efficacy, with disease activity persisting in the majority of patients despite therapy. Treatment response has been based on preventing clinical relapses and progression of disability, and monitoring for new lesions on magnetic resonance imaging after 1 year of treatment.36 Established predictive biomarkers include neutralizing antibodies against such immunotherapies as IFN-beta and natalizumab.37 Detection of pathologic immune responses, primarily antibody responses, against putative autoantigens has also shown some promise in predicting patient response.35 VOL. 7

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In RA, several matrices have been developed to predict the risk for rapid radiologic progression following treatment with either DMARD monotherapy or combination therapy.38 Predictive biomarkers have also been identified for response to biologic agents and for their successful discontinuation upon achievement of treatment goals. Moreover, emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNFalpha agent.39 In IBD, genomic assessments have identified approximately 100 loci whose gene products function as key transcription factors or are involved in several critical pathways, such as the IL-23 pathway, and in modulating functions that affect IBD pathogenesis, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense.40 Such profiles also reveal association patterns that are similar between Crohn’s disease and ulcerative colitis, such as those involving Th17 pathways, indicating significant overlap in pathophysiology, as well as distinct disease-specific pathways (eg, NOD2 and autophagy in Crohn’s disease; major histocompatibility complex and epithelial barrier genes in ulcerative colitis).41,42

Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.” Despite these promising new avenues of research, only clinical markers of treatment response are being applied at the current time. Other tools, however, such as disease activity measures, are being used to assess remission and state of disease activity in patients with MS, RA, and IBD.43-46 In RA, the Simplified Disease Activity Index is a validated composite score of the tender joint count, swollen joint count, patient global assessment, physician global assessment, and C-reactive protein (CRP) level, which is associated with the highest sensitivity and specificity for treatment decisions.43,44 In spite of its limitations, the Kurtzke Expanded Disability Status Scale, which combines disability and neurologic impairment, remains the most widely used activity score in MS.45 Similar indices are available for patients with IBD, such as the Crohn’s Disease Activity Index and the HarveyBradshaw Index, as well as such surrogate markers as CRP and fecal calprotectin.46 Their reliability and sensitivity remain questionable, however. Taken together, these data suggest that a combination of clinical markers, response biomarkers, and disease activity or disability indices holds great promise for the use of personalized medicine in patients with chronic inflammatory diseases.

Cost-Effective Strategies for Improving Overall Outcomes from the Managed Care Perspective: Meeting the Challenges and Barriers to the Use of Biologic Agents Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.”2,47 Given that the “pursuit of the Triple Aim is an exercise in balance,”3 it is imperative that the clinical utility and “value” of biologic agents be balanced, and that appropriate utilization occurs—that is, the biologic is used in the right patient with the right disease at the right time. In this regard, numerous examples abound in clinical practice in which significantly less expensive, nonbiologic therapy can be used to obtain good clinical outcomes prior to the use of biologic agents.48 For example, a recent 2-year, randomized, double-blind study demonstrated that initial methotrexate monotherapy with the option to step up to combination therapy is associated with similar outcomes to the use of immediate combination therapy in patients with early, poor-prognosis RA.48 Managed care pharmacy, in particular, plays a key role in incorporating diagnosis, cost, and treatment information with pharmacy data. These efforts also february 2014

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Table 4 Clinical Pathways in Oncology Clinical pathways: Are an evidence-based approach to care Use the framework of tumor-specific guidelines Specify which interventions are performed and in what sequence Are intended to reduce practice variation, improve outcomes, and reduce costs Are typically developed by an individual provider team or national organization Source: References 50, 51.

improve appropriate utilization and optimal leveraging of pharmacy resources, thereby affecting benefit design, implementing management approaches for diseases that can be treated with biologic agents, and ensuring cost-effectiveness. From a managed care perspective, cost-effectiveness of an intervention equates with “value” in terms of efficacy and cost. A survey by The Zitter Group showed that most stakeholders are concerned about the inappropriate utilization of specialty drugs in oncology and consider waste reduction to be a primary cost-control strategy. The participants in this survey differed significantly, however, with respect to their estimation of the percentage of excess cost that could be eliminated from cancer treatment without negatively impacting overall outcomes.49 Payers were of the opinion that there was a 22.7% wastage in oncology, whereas oncologists and practice managers believed the wastage to be approximately 18% and 15.9%, respectively.49 Excessive end-of-life care, inappropriate drug use, and unwarranted diagnostic testing were considered to be key contributors to excess costs by payers and by oncologists.49 The costs of biologic agents and waste drive many of the value-based control mechanisms currently in place. Potential solutions, such as comparative effectiveness research (CER) and drug benefit designs, have been implemented by many managed care organizations.50 An important value initiative has been the recent efforts to define limited clinical pathways or evidence-based algorithms that describe the treatment selection, sequence, and timing of biologic therapies, and typically drive formulary decisions (Table 4).50,51

When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care. In oncology, clinical pathways typically use tumor-specific guidelines from the NCCN and the American Society of Clinical Oncology, which are systematically developed, evidence-based best practices. The primary purposes of clinical pathways are to ensure proper utilization, reduce practice variation or standardize care, improve outcomes, and reduce cost variation. Preferred pathway options are often developed by individual teams or national organizations in collaboration with participating physicians. Oncologists may receive incentives to achieve a certain level of pathway compliance, whereas potential manufacturer rebates received for use of specific drugs in the preferred pathways can further lower net costs to payers.51 Additional data related to clinical pathways are warranted to substantiate improved outcomes and cost-savings, not only for oncology, but for inflammatory diseases as well. In addition, a patient-focused, value-based benefit design has been developed that offers plan-based incentives, such as reduction or elimination of patient cost-sharing, to encourage patients to use preferred treatment pathways and fol-

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low healthy behaviors, in order to improve health outcomes and control costs.52 Alternatively, patients may be penalized with increased cost-sharing for services that are not associated with clinical benefit or that have marginal benefit improvements with significant price increases. In inflammatory diseases, optimization of the use of specialty pharmaceuticals in a cost-effective manner is of primary interest. Several cost-containment management strategies for biologic agents are being implemented, including pharmacy prior authorization, clinical care management, 30-day supply limits, preferred products and formulary, pharmacy step therapies, cost-sharing tiers, restricted medical benefit coverage and closed pharmacy benefits, and tracking outcomes.53 Moreover, improving medication adherence in these chronic diseases is a major priority; increased out-of-pocket costs and adverse effects associated with biologic agents can limit patient adherence and result in reduced drug efficacy.54 Essentially, health plans want to realize the clinical benefits of their financial investment in biologics. When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care.55 Rising healthcare costs and the introduction of novel, efficacious, and expensive biologic therapies have led to renewed emphasis on comparing the relative merits of one intervention versus competing interventions, particularly in the absence of head-to-head comparison data, in order to bridge knowledge gaps and drive informed clinical decisions and outcomes. Such efforts are known as CER, which is defined as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care.”56 CER consolidates evidence from multiple sources, including prospective observational studies and peer-reviewed, published, retrospective analyses of healthcare data, such as medical or pharmacy claims, electronic health records, registries, and systematic literature reviews or meta-analyses.

Conclusion Biologic agents have become the mainstay of treatment for several disease states, including several cancer types, MS, RA, and IBD, and are the cornerstone of personalized medicine in these disorders. In the face of ongoing innovation, rising utilization, and increased costs, important considerations related to cost, value, patient access, and clinical utility are warranted. Cost-effectiveness may be optimized by implementation of value-based initiatives, including the use of CER and clinical pathways to inform treatment decisions for payers and physicians. Moreover, managed care pharmacists play a critical role in managing the use of biologics and in improving healthcare outcomes in their plan members. In this context, managed care pharmacists find themselves in the unique position of evaluating the clinical utility of biologic agents, affecting benefit design, optimizing current standards of personalized care, and helping providers and patients achieve optimal clinical outcomes. ◆ Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article. References

1. Artemetrx. Specialty drug trend across the pharmacy and medical benefit. 2013. www.artemetrx. com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed December 17, 2013. 2. CVS/Caremark. Insights 2011. http://info.cvscaremark.com/files/reports/Insights2011.pdf. Accessed December 19, 2013. 3. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood). 2008;27(3):759-769. 4. Stiefel M, Nolan K. A Guide to Measuring the Triple Aim: Population Health, Experience of Care, and Per Capita Cost. IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2012. www.IHI.org. Accessed December 18, 2013. 5. Hoyert DL, Xu J. Deaths: preliminary data for 2011. National Vital Statistics Reports. 2012; 61(6). www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed December 18, 2013. 6. Schuster M, Nechansky A, Kircheis R. Cancer immunotherapy. Biotechnol J. 2006;1(2):138-147. 7. Huber CH, Wölfel T. Immunotherapy of cancer: from vision to standard clinical practice. J Cancer Res Clin Oncol. 2004;130(7):367-374. 8. US Food and Drug Administration. www.fda.gov/drugs/scienceresearch/researchareas/pharma cogenetics/ucm083378.htm. Accessed January 10, 2014. 9. Boyle RM. The use of biologics in cancer therapy. US Pharm. 2010;35(3)(Oncology suppl):4-7. www.uspharmacist.com/content/s/115/c/19768/. Accessed December 18, 2013.

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38. van den Broek M, Visser K, Allaart CF, Huizinga TW. Personalized medicine: predicting responses to therapy in patients with RA. Curr Opin Pharmacol. 2013;13(3):463-469. 39. Edwards CK III, Green JS, Volk H-D, et al. Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone. Front Immunol. 2012;3:366. 40. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastro enterology. 2011;140(6):1704-1712. 41. Parkes M. The genetics universe of Crohn’s disease and ulcerative colitis. Dig Dis. 2012;30(suppl 1):78-81. 42. Gerich ME, McGovern DP. Towards personalized care in IBD. Nat Rev Gastroenterol Hepatol. 2013 Dec 17 [Epub ahead of print]. 43. Anderson JK, Zimmerman L, Caplan L, Michaud K. Measures of rheumatoid arthritis disease activity: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Activity Score with 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data (RAPID), Rheumatoid Arthritis Disease Activity Index (RADAI) and Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based Disease Activity Score With ESR (PDAS1) and Patient-Based Disease Activity Score Without ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S14-S36. 44. Bentley MJ, Reed GW. Simplified composite disease activity measures in rheumatoid arthritis: should they be used in standard care? Clin Exp Rheumatol. 2008;26(2):358-366. 45. Kurtzke JF. Disability rating scales in multiple sclerosis. Ann N Y Acad Sci. 1984;436:347-360. 46. Burri E, Beglinger C, Lehmann FS. Monitoring of therapy for inflammatory bowel disease. Digestion. 2012;86(suppl 1):1-5. 47. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69. 48. O’Dell JR, Curtis JR, Mikuls TR, et al; TEAR Trial Investigators. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65(8):1985-1994. 49. The Zitter Group. The Managed Care Oncology Index. Summer 2011. Data on file at The Zitter Group. 50. Holcombe D. Oncology management programs for payers and physicians: evaluating current models and diagnosing successful strategies for payers and physicians. J Oncol Pract. 2011;7(3 suppl):e46s-e49s. 51. Danielson E, Demartino J, Mullen JA. Managed care & medical oncology: the focus is on value. J Natl Compr Canc Netw. 2010;8(suppl 7):S28-S37. 52. Fendrick AM, Smith DG, Chernew ME. Applying value-based insurance design to low-value health services. Health Aff (Millwood). 2010;29(11):2017-2021. 53. Greenapple R. Trends in biologic therapies for rheumatoid arthritis: results from a survey of payers and providers. Am Health Drug Benefits. 2012;5(2):83-92. www.reimbursementintelligence. com/wp-content/uploads/2012/05/Trends-in-Biologic-Therapies-for-Rheumatoid-Arthritis-Resultsfrom-a-Survey-of-Payers-and-Providers.pdf. Accesssed January 23, 2014. 54. Goldberg EL, DeKoven M, Schabert VF, Coyle K. Patient medication adherence: the forgotten aspect of biologics. Biotechnol Healthc. 2009;6(2):39-42. 55. Brixner DI, Oderda G. It is important to distinguish CER from patient-centered outcomes research. Introduction. J Manag Care Pharm. 2012;18(4 suppl A):S3-S4. 56. Institute of Medicine of the National Academies. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: The National Academies Press; 2009. www.iom.edu/~/ media/Files/Report%20Files/2009/ComparativeEffectivenessResearchPriorities/CER%20 report%20brief%2008-13-09.ashx. Accessed January 23, 2013.

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