JHOP June 2014

JUNE 2014 VOL 4 I NO 2

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

EDITORIAL

OPA’s 10-Year Anniversary Marks Rapid Developments H in Hematology/Oncology Pharmacy Patrick J. Medina, PharmD, BCOP ORIGINAL RESEARCH

A Retrospective Chart Review on the Toxicity of Pegylated Asparaginase in Adult Patients with Acute Lymphoblastic Leukemia Cindy Ippoliti, PharmD; Monank Patel, PharmD REVIEW ARTICLE

Concise Review of Obinutuzumab in the Treatment of Patients with Chronic Lymphocytic Leukemia P eter Tang, PharmD Candidate; Tristan Lindfelt, PharmD, BCPS, BCACP; Robert J. Ignoffo, PharmD, FASHP, FCSHP FDA UPDATE

Recent Cancer Drugs Approved by the FDA FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

WWW.JHOPONLINE.COM

©2014 Green Hill Healthcare Communications, LLC

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40134 February 2014.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

REVIEW ARTICLES

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA Scott Soefje, PharmD, MBA, BCOP Director of Pharmacy University Medical Center Brackenridge Austin, TX

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island, Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Division of Hematology and Medical Oncology Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist The University of Texas M. D. Anderson Cancer Center Houston, TX

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

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Vol 4, No 2

Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

PUBLISHING STAFF

Senior Vice President, Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publishers Russell Hennessy rhennessy@the-lynx-group.com Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon

JUNE 2014

VOLUME 4, NUMBER 2

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY™ THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

TABLE OF CONTENTS EDITORIAL

40 HOPA’s 10-Year Anniversary Marks Rapid Developments in Hematology/Oncology Pharmacy Patrick J. Medina, PharmD, BCOP

Production Manager Lora LaRocca

ORIGINAL RESEARCH

THE LYNX GROUP

42 A Retrospective Chart Review on the Toxicity of Pegylated Asparaginase

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca

in Adult Patients with Acute Lymphoblastic Leukemia Cindy Ippoliti, PharmD; Monank Patel, PharmD

REVIEW ARTICLE 50 Concise Review of Obinutuzumab in the Treatment of Patients with

Chronic Lymphocytic Leukemia Peter Tang, PharmD Candidate; Tristan Lindfelt, PharmD, BCPS, BCACP; Robert J. Ignoffo, PharmD, FASHP, FCSHP

FDA UPDATE 57 Recent Cancer Drugs Approved by the FDA FROM THE LITERATURE 59 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Manager Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan Office Coordinator Robert Sorensen Green Hill Healthcare Communications 1249 South River Road – Ste 202A Cranbury, NJ 08512 Phone: 732-656-7935 • Fax: 732-656-7938

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MISSION STATEMENT The Journal of Hematology Oncology Pharm­acy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright © 2014

by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill 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.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Commun­i­cations, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages.

The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Vol 4, No 2

BD PhaSeal™ Closed System Drug Transfer Device Work safe. Enjoy life.

Protecting Carlos the pharmacist, and Carlos the team mentor.

Pharmacists often tell us how satisfying it is to be such an important part of a patient’s treatment. But, you’re also important to many other people in your life—so please take care of your health, too. Studies connect hazardous drug exposure to serious health risks for pharmacists. We’re helping to change that, by protecting thousands of pharmacists every day from the hazardous drugs they handle. We can’t do what you do, but we can help you do it safely.

Work safe. Enjoy life. bd.com/phaseal

BD, BD Logo and BD PhaSeal are trademarks of Becton, Dickinson and Company. © 2014 BD MSS0523g (04/14)

BD Medical 1 Becton Drive Franklin Lakes, NJ 07417 www.bd.com

EDITORIAL

HOPA’s 10-Year Anniversary Marks Rapid Developments in Hematology/ Oncology Pharmacy Patrick J. Medina, PharmD, BCOP Co-Editor-in-Chief, Journal of Hematology Oncology Pharmacy Associate Professor, Department of Pharmacy, University of Oklahoma College of Pharmacy, Oklahoma City

I

n March of this year, the Hematology/Oncology Pharmacy Association (HOPA) held its annual meeting in New Orleans, LA. What made this meeting special is that it marked the 10-year anniversary of the conference and was highlighted by a special keynote lecture by John Kuhn, one of HOPA’s founding members, and its first president. Starting with approximately 30 founding members, HOPA has grown to more than 2000 members in 2014.

During this rapid expansion of HOPA, we have seen an equally impressive expansion of new agents in hematologic and in solid tumor malignancies. More than 20 new anticancer agents have been approved in the past 10 years, and many drugs (old and new) have received new indications in that same time frame.1 As we have learned more about the pathophysiology of cancer, we have not only been able to better use available agents, but scientists have also been able to develop drugs that target specific malignant processes or specific tumor characteristics.

The individualized, patient-specific chemotherapy approach to care rather than a “one-treatment-fits-all” approach is a paradigm shift in the way we treat our patients and in the way healthcare providers need to constantly update their knowledge base to provide optimal patient care.

The individualized, patient-specific chemotherapy approach to care rather than a “one-treatment-fits-all” approach is a paradigm shift in the way we treat our patients and in the way healthcare providers need to constantly update their knowledge base to provide optimal patient care. This increased knowledge has led to the rapid expansion of new therapeutic agents.

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A small representative example of some breakthroughs in the past 10 years includes: • New agents for rare or difficult-to-treat cancers— such as renal-cell carcinoma, thyroid cancer, and melanoma—that are directed at previously unknown targets, such as the mTOR, RET, and mutated BRAF pathways • Better use of previously approved agents, such as limiting EGFR inhibitors to KRAS wild-type colon cancer • The first new drug for Hodgkin lymphoma in 30 years • New versions of older chemotherapy agents, such as second-generation taxanes and other agents that target mitosis • The rapid expansion of new agents for the treatment of common cancers, such as metastatic prostate and breast cancer.

This is just a short list of the many breakthroughs that have occurred in the past 10 years. With these breakthroughs have come increased challenges and opportunities for oncology pharmacists (as well as other oncology practitioners), including reimbursement challenges and the explosion of oral chemotherapy agents to name a few.

The Journal of Hematology Oncology Pharmacy (JHOP) is dedicated to bringing you such updates and breakthroughs, with the ultimate goal of improving patient outcomes.

In this issue of JHOP, Robert J. Ignoffo, PharmD, FASHP, FCSHP, discusses 2 new articles that illustrate the use of individualized patient tumor characteristics for making treatment decisions. The first study was a phase 1 dose-expansion trial of ceritinib, which was recently approved by the US Food and Drug Administration for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non–small-cell lung cancer (NSCLC) who experience disease progression or intolerance to crizotinib.

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EDITORIAL

The approval of this drug provides patients with this specific mutation another line of therapy for their disease. Patients in the phase 1 trial had an impressive 56% response rate to ceritinib after crizotinib failure, and this response was independent of the type of ALK-resistance mutations identified.2 The second trial Dr Ignoffo discusses is a meta-analysis of chemotherapy or EGFR-directed therapy in patients with wild-type (ie, no positive predictive mutations) EGFR-positive NSCLC.3 Although data have demonstrated that EGFR-targeted therapies have increased response rates in patients with mutations in exon 19 or exon 21, this clinical trial took the opposite approach and evaluated their effect on patients without EGFR mutations.3,4 Not surprising, in this patient population, chemotherapy has superior response rates and superior progression-free survival. These results highlight the need to characterize each patient’s tumor to provide the best care for the patient, not for the general type of cancer, as has been done historically.

These 2 clinical trials provide a glimpse into how the landscape of oncology care has changed in the past 10

years. Treatment is no longer tumor-specific for a cancer such as NSCLC; rather, NSCLC is now characterized by its cell type (eg, adenocarcinoma), ALK-positivity, and EGFR mutational status before making a treatment decision.5 This approach will continue to evolve in the next 10 years and will present healthcare providers many opportunities and challenges in the delivery of optimal care for their patients. n

References

1. US Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm279174.htm. Accessed May 21, 2014.

2. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-smallcell lung cancer. N Engl J Med. 2014;370:1189-1197.

3. Lee JK, Hahn S, Kim DW, et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA. 2014; 311:1430-1437.

4. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): non-small cell lung cancer. Version 3.2014.

January 24, 2014. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 21, 2014.

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ORIGINAL RESEARCH

A Retrospective Chart Review on the Toxicity of Pegylated Asparaginase in Adult Patients with Acute Lymphoblastic Leukemia Cindy Ippoliti, PharmD; Monank Patel, PharmD Background: Historically, complete remission rates seen in adult patients with acute lymphoblastic leukemia (ALL) have been significantly lower than among pediatric patients. Recently, there has been a shift toward more aggressive treatment of adults with ALL, using protocols similar to those used for pediatric patients. This has translated into increased complete remission rates in adults, but the 5-year overall survival rate remains significantly lower in adults (45%) than in pediatric patients (85%). Possible reasons for this disparity include the use of lower doses of chemotherapy (ie, vincristine and corticosteroids) and the omission of highly active agents (eg, asparaginase).

Objective: To determine the tolerability level of asparaginase in adult patients with ALL. Methods: We performed a retrospective chart review of 25 consecutive adult patients with ALL who received treatment at New York-Presbyterian/Weill Cornell Medical Center between April 2006 and October 2010 to investigate the toxicity profile of intravenous pegaspargase used in these patients (at doses of 2000-2500 IU/m2). All patients received standard prophylaxis.

Results: Among the 25 patients included in this study, hepatotoxicity was evident in many of the patients. Overall, 10 (40%) patients had hyperbilirubinemia; of these patients, 3 also had bilirubin levels of >25 mg/dL, which were associated with fatal outcomes in all 3 cases.

Hypertriglyceridemia was observed in 1 patient, with levels reaching >8500 mg/dL, and coinciding with pancreatitis. Hypofibrinogenemia was observed in 36% of the patients in our review. A total of 17 patients in this study died: 3 deaths were related to sepsis, 2 occurred during bone marrow transplant, 2 from multi-organ failure, and the cause of the other 10 deaths, which occurred during follow-up, could not be verified.

J Hematol Oncol Pharm.

Conclusion: The results from our study show that severe toxicities may occur from the 2014;4(2):42-48 administration of pegaspargase, especially in patients aged >50 years. Prognostic factors www.JHOPonline.com Disclosures are at end of text determining which patients will develop significant toxicities are lacking, although dose and age appear to affect the incidence and severity of hepatotoxicity.

A

cute lymphoblastic leukemia (ALL) is among the most common hematologic malignancies, with an annual incidence of 6020 patients in the United States, of which 2000 to 2500 cases occur in adults.1 Trends have shown an early peak between the ages of 4 and 5 years, with another increase after the age of 50 years.1 With the utilization of pediatric protocols, overall survival in adults has increased from less than 10% to between 30% and 45%.2 The 5-year overall survival rate remains significantly lower in adults (45%) than in pediatric patients (85%). Complete remission

Dr Ippoliti is Clinical Manager, Hematology/Oncology, New York-Presbyterian/Weill Cornell; Dr Patel is PGY-1 Pharmacy Resident, New York-Presbyterian /Weill Cornell, New York.

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rates have also improved to an estimated 85% to 90% for patients with ALL.3 Although significantly lower than in pediatric patients, overall survival and complete remission rates in adults have the potential to increase further with the intensification of chemoregimen dosing, particularly that of nonmyelosuppressive agents, such as asparaginase.4 Asparaginase is a highly effective anticancer drug that has become a cornerstone of combination chemotherapy for pediatric patients with ALL. Asparaginase catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia, causing serum depletion of asparagines in circulation.5 Unlike normal cells, lymphoid cells are unable to synthesize asparagine de novo as a result of their lack of asparagines synthetase, and normally rely on serum asparagine for protein synthesis. Asparagine depletion disrupts

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Intravenous Pegaspargase in Adult Patients with ALL

protein synthesis, causing selective apoptosis of leukemic cells while leaving normal cells unaffected.5 Maximal asparagine depletion is essential for asparaginase efficacy, with higher response rates seen with complete depletion. In 1 study, a total of 85 patients were evaluated to determine the correlation between successful depletion of asparagine and overall survival and disease-free survival (DFS).6 After receiving pegaspargase at a dose of 2000 IU/m2, 22 of the 85 patients did not achieve successful asparagine depletion, and they had significantly inferior overall survival rate (hazard ratio [HR], 2.37; P = .002) and DFS (HR, 2.21; P = .012) compared with the 63 patients who achieved asparagine depletion.6 The results of this study showed a clear benefit of using pegaspargase in a multidrug regimen for patients with ALL when therapeutic asparagine depletion is successful. The reasons for not achieving depletion may be attributable to the formation of asparaginase-neutralizing antibodies or to decreased doses of the drug.

It is important to note that in this study, the dose of pegaspargase was capped at 3750 U, which many of the current treatment protocols do not mandate.6 Despite the effectiveness of asparaginase as an anticancer drug, its use has been associated with several toxicities.5,7 The toxicities of asparaginase fall under 2 main categories: toxicities related to immunologic sensitization to the foreign protein, and those resulting from the inhibition of protein synthesis. The toxicities related to the inhibition of protein synthesis include pancreatitis, hyperglycemia, hepatotoxicity, hypoalbuminemia, and coagulation changes. The coagulopathy results from the decreased synthesis of fibrinogen and plasminogen, as well as decreases in antithrombin III, protein C, and protein S.5,7 These coagulation defects result in either bleeding or, more frequently, thrombotic events. Thrombotic events can range from deep-vein thrombosis to pulmonary embolus and central venous thrombosis.8 Results from a limited number of early studies and clinical practice suggest that adults are more susceptible to asparaginase-associated side effects than children.7 Subsequently, toxicity concerns led to the modification of the treatment regimens for adult patients with ALL to reduce the intensity of asparaginase or to exclude it.7 In contrast to previous studies using pediatric protocols for adult patients,9 the recent data suggest that adults tolerate native asparaginase and pegaspargase in a manner similar to the pediatric population,10 but information regarding pegaspargase toxicity in elderly patients with ALL remains limited and has not been investigated in randomized controlled trials.

The pegylation of native L-asparaginase (Elspar) leads to the diminished immunogenicity of the modified molecule, while retaining the antineoplastic effects of

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the native enzyme.5 The advantages of using the pegylated enzyme have led to the approval of pegaspargase by the US Food and Drug Administration (FDA) for the treatment of patients with ALL who are hypersensitive to native L-asparaginase, and, more recently, for its approval as a component of a multi-agent chemotherapy regimen for the first-line treatment of ALL.11 Pegaspargase has a longer half-life than native enzyme (5.73 days vs 1.28 days).5 Therefore, treatment with pegaspargase results in prolonged asparaginase activity and the subsequent sustained depletion of asparagine.5 The longer half-life of pegaspargase allows for its less frequent administration. Pegaspargase can be administered every 2 weeks, whereas native L-asparaginase has to be administered 2 to 5 times weekly.5

Toxicity concerns led to the modification of the treatment regimens for adult patients with ALL to reduce the intensity of asparaginase or to exclude it. In contrast to previous studies using pediatric protocols for adult patients, the recent data suggest that adults tolerate native asparaginase and pegaspargase in a manner similar to the pediatric population.

A handful of retrospective studies have investigated the toxicities associated with the administration of pegaspargase. According to the prescribing information for pegaspargase, among 112 patients with relapsed ALL, 10% of previously nonhypersensitive patients experienced allergic reactions, as well as 32% of patients with previously noted hypersensitivity to Escherichia coli L-asparaginase.12 Douer and colleagues investigated 51 adults with ALL between the ages of 18 and 57 years who were given 2000 IU/m2 of pegaspargase in a protocol with vincristine, daunorubicin, and prednisone.13 The results showed a 6% incidence of grade 3/4 allergic reactions, a 31% chance of grade 3/4 hyperbilirubinemia, a 63% chance of transaminitis, and a 5% chance of pancreatitis.13 This study has shown that pegylated asparaginase is tolerable in adults.7 Hepatotoxicity is the primary toxicity associated with pegaspargase.8,14,15 Until December 2012, 3 preparations of asparaginase were approved by the FDA and were commercially available: L-asparaginase, pegaspargase, and erwinia asparaginase. The manufacturer of L-asparaginase made a financial decision to discontinue production in late 2012.16 L-asparaginase and pegaspargase are derived from E coli and erwinia asparaginase from Erwinia chrysanthemi. The

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Table 1 P atient Demographics and Dosage Information Characteristic

Patients (N = 25)

Median age, years (range)

49 (21-84)

Sex Male, N

14

Female, N

11

Patients with Ph+ ALL, N

5

Doses of pegaspargase administered, N

38

Median pegaspargase doses per patient, N (range)

1 (1-4)

Pegaspargase doses administered, N 2000 units/m2 IV, N

3

2500 units/m IV, N

35

2

IV indicates intravenous; Ph+ ALL, Philadelphia chromosome– positive acute lymphoblastic leukemia.

Table 2 T reatment Regimens Administered in Our Patients 5 drugs

Cyclophosphamide, vincristine, L-asparaginase, prednisolone, daunorubicin

MOAD

Methotrexate, vincristine, L-asparaginase, dexamethasone

VAD

Vincristine, doxorubicin (adriamycin), dexamethasone

CVAD

VAD with the addition of cyclophosphamide

Table 3 N ormal Reference Ranges of Laboratory Tests Performed Test

Normal range

Aspartate aminotransferase

5-43 U/L

Alanine aminotransferase

5-60 U/L

Total bilirubin

0.2-1.5 mg/dL

Fibrinogen

180-400 mg/dL

Prothrombin time

7-10 sec

Partial thromboplastin time

29-41 sec

Triglycerides

<150 mg/dL

E coli preparations are associated with a higher incidence of hypersensitivity reactions, although the incidence with the pegylated formulation is approximately 3% in asparaginase-naĂŻve patients.12 The withdrawal of native L-asparaginase from the market, coupled with the con-

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venience and reduced toxicity of pegaspargase, have made pegaspargase the upfront treatment for patients with newly diagnosed and relapsed ALL. We performed a retrospective chart review to investigate the tolerability of pegaspargase in adults and in elderly patients with ALL to compare the frequency and severity of toxicities, as seen in previous studies.

The clinical protocol was approved by the Institutional Review Board, and informed consent was obtained from all patients according to the US Department of Health & Human Services guidelines.

Methods Patient Characteristics A total of 25 consecutive adult patients with ALL, ranging in age from 21 to 84 years (median, 49 years) were treated at New York-Presbyterian/Weill Cornell Medical Center between April 2006 and October 2010.

Of these patients, 5 patients had Philadelphia chromosomeâ&#x20AC;&#x201C;positive (Ph+) ALL, a subtype that has been shown to have worse outcomes compared with patients without Ph+ ALL, particularly before the discovery of tyrosine kinase inhibitors.17,18 Patient demographics are outlined in Table 1. Of the total patients, 20 had relapsed disease.

None of these patients had received asparaginase as part of their initial induction. All patients received standard prophylaxis with valacyclovir 500 mg orally daily, fluconazole 400 mg orally daily, and sulfamethoxazole plus trimethoprim 3 times weekly.

Treatment Protocol All patients received pegaspargase at a dose of 2500 units/m2 (except for 2 patients who received 2000 units/ m2), administered intravenously over 1 hour. No doses were capped. Pegaspargase was administered as part of the various protocols that are used for this patient population (Table 2). Of the 25 total patients, 24 received premedication with a corticosteroid as part of the treatment regimen (ie, dexamethasone, or prednisone plus methylprednisolone). The choice of a corticosteroid was based on the regimen used.

Patients were monitored for infusion-related side effects during infusion and for 60 minutes after its completion. Laboratory studies were performed at least 3 times weekly (Table 3) for up to 14 days after an infusion and consisted of a complete blood count, including measures for platelets, prothrombin time, international normalized ratio (INR), fibrinogen levels, direct and indirect bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, and lactate dehydrogenase.

The amylase, lipase, and cholesterol levels were only tested if the patient was symptomatic and pancreatitis

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was suspected. During this period, cryoprecipitate was administered for patients with fibrinogen levels of <100 mg/dL. Data collection included patient demographics, infusion-related events, and laboratory parameters before administration and up to 4 weeks after the last administration of pegaspargase or until the resolution of abnormal events. Disease response, progression-free survival, and overall survival were noted but are not commented on in this report, because of the small number of patients evaluated and the heterogeneity of the population.

Results Toxicity Analysis The treatment-related toxicities are summarized in Table 4. One patient (4%) experienced an infusion-related reaction, which consisted of wheezing and shortness of breath and required supplemental oxygen. This patient was receiving pegaspargase as part of a multidrug regimen, but treatment with dexamethasone had been completed and therefore the patient was not premedicated with the initial dose. Therapy with pegaspargase was discontinued, the patient was treated with 1 mg/kg of methylprednisolone and diphenhydramine, and the symptoms resolved within 60 minutes. The patient was premedicated for the subsequent dose of pegaspargase with methylprednisolone (0.5 mg/kg) and diphenhydramine, and was subsequently rechallenged, without any incident.

A total of 9 (36%) patients had significant decreases in their fibrinogen level (<100 mg/dL), which normalized after receiving 1 or 2 transfusions of cryoprecipitate.

Of these patients, 3 had elevations in INR of >1.6, with 1 patient having an INR of >6, which normalized after the administration of cryoprecipitate. Thrombotic events were seen in 2 patients: 1 had pulmonary embolism 1 month after the administration of pegaspargase, and the other patient had deep-vein thrombosis within 1 month of receiving 2 doses of pegaspargase, which were given 2 weeks apart. Both patients received enoxaparin and had no further complications.

A total of 10 (40%) patients had hyperbilirubinemia that could be attributed to pegaspargase (Table 4). For most of the patients, the bilirubin levels normalized within 2 weeks of infusion with no further elevations. In 1 patient, the bilirubin level reached a peak of 25 mg/dL and slowly resolved over a 1-month period; the patient was discharged with a bilirubin level of 5.7 mg/dL. That patient died several months later because of disease progression. In 2 patients, the bilirubin levels reached 29.4 mg/dL and 25.7 mg/dL, and both patients clinically deteriorated and died from multiorgan failure within 1 month of the administration of pegaspargase.

Of the 10 patients with hepatotoxicity, 9 were treated

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Table 4 Adverse Reactions in Patients Receiving Pegylated Asparaginase Patients, N (%) Adverse reaction (N = 25) Infusion-related

1 (4)

Hypertriglyceridemia

1 (4)

Pancreatitis

1 (4)

Hyperbilirubinemia

10 (40)

Hypofibrinogenemia

9 (36)

Elevated INR

3 (12)

INR indicates international normalized ratio.

Table 5 M ortality Data in Patients Receiving Pegylated Asparaginase Patients, N (%) Mortality data/cause (N = 25)a Total deaths

17 (68)

Bone marrow transplant

2 (8)

Sepsis

3 (12)

Multi-organ failure

2 (8)

Total number of patients in this study.

a

for relapsed disease. The contribution of other agents to their condition is difficult to assess. A total of 4 patients were receiving a 5-drug regimen (ie, cyclophosphamide, vincristine, prednisone, asparaginase, and daunorubicin); 4 patients received methotrexate, vincristine, asparaginase, and dexamethasone; and 2 patients received single-agent pegaspargase. Although methotrexate and daunorubicin can cause hepatotoxicity, hepatoxicity from methotrexate or daunorubicin usually manifests as transaminitis.

Of the 10 patients with hepatotoxicity, 9 were treated for relapsed disease.

The contribution of other agents to their condition is difficult to assess.

A single patient presented with severe abdominal pain, and laboratory results revealed a total cholesterol level of 700 mg/dL, triglycerides of 8470 mg/dL, and amylase and lipase levels peaking at 630 mg/dL and 400 mg/dL, respectively. The patient started therapy with oral gemfibrozil 600 mg twice daily, and the patient underwent a single plasmapheresis, with subsequent resolution of the hypertriglyceridemia within 1 week. This patient was not rechallenged with pegaspargase.

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Table 6 H epatotoxicity Data for 10 Patients Receiving Pegylated Asparaginase Age, yrs

Total dose, U (dosage, U/m2)

Doses, N

Baseline total bilirubin, mg/dL (direct); AST, U/L; ALT, U/L

Peak total bilirubin, mg/dL (direct); AST, U/L; ALT, U/L

Patient status

1 (M)

26

4675 (2500)

3

0.9 (0.2); 98; 253

13.2 (7.8); 242; 395

Deceased

2 (M)

36

5125 (2500)

2

0.8 (0.2); 35; 20

4.5 (2.4); 127; 63

Deceased

3 (F)

43

4250 (2500)

2

1.9 (0.7); 101; 270

8.1 (4.3); 80; 80

Deceased

4 (M)

49

5800 (2500)

1

1.7 (0.7); 81; 57

8 (5); 103; 70

Deceased

5 (F)

52

4150 (2500)

2

1.1 (0.2); 18; 22

9.9 (6.3); 139; 146

6 (F)

52

4075 (2500)

3

0.7 (0.1); 36; 40

10.1 (6.1); 112; 306

Deceased

7 (F)

60

4000 (2500)

1

0.4 (0.1); 88; 165

27.8 (10.3); 858; 837

Alive

8 (M)

70

4900 (2500)

1

0.5 (0.1); 36; 33

25.7 (16.4); 220; 369

Deceased

9 (M)

75

4950 (2500)

1

0.6 (0.1); 31; 46

4.3 (2.8); 62; 249

Deceased

10 (M)

84

3960 (2000)

2

0.9 (0.3); 19; 15

29.4 (19.8); 130; 102

Deceased

Patient (sex)

Alive

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.

Patient Outcomes The majority of the patients in this study had relapsed or refractory ALL. Of the 25 patients in this study, 17 (68%) died after the study ended (Table 5). Of the 17 deaths, 2 occurred during bone marrow transplantation, 3 as a result of sepsis, and 2 resulted from multi-organ failure, possibly secondary to hyperbilirubinemia (Table 5).

Their review highlights the significant differences in toxicity between the adult and pediatric populations of patients with ALL; however, the mean age for the adults in their review was 30 years compared with 49 years in our study.

Discussion The increased use of pegylated asparaginase in adults has generated great interest and several review articles, of which the most comprehensive to date is by Stock and colleagues.8,15,19 In 2009, Stock and colleagues assembled a panel of expert physicians to develop specific recommendations for the prevention and management of asparaginase-induced toxicity based on a review of the medical literature and the panel membersâ&#x20AC;&#x2122; experiences.8 Their review highlights the significant differences in toxicity between the adult and pediatric populations of patients with ALL; however, the mean age for the adults in their review was 30 years (range, 14-68 years) compared with 49 years (range, 21-84 years) in our study.

In addition, the dose of pegylated asparaginase in our

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study was 2500 U/m2. Although the dose of an augmented regimen containing cyclophosphamide, vincristine, doxorubicin, and dexamethasone is the same (ie, 2500 U/m2),20 the dose of pegasparaginase recently prescribed by many clinicians is often lower.8 The 2 most common toxicities in the patients in our study were hypofibrinogenemia (36%) and hyperbilirubinemia (40%). In the review by Stock and colleagues, the incidence of hypofibrinogenemia (<60 mg/ dL) was 16%.8 The lower incidence in their study may be explained by the differences in definition, because we used <100 mg/dL. In a study by Beinart and Damon, 93 patients receiving native L-asparaginase at 6000 U/m2 for induction therapy were analyzed for thrombotic events.21 Hypofibrinogenemia was defined as <50 mg/dL, and patients were treated with cryoprecipitate when levels fell to <70 mg/dL. Although previous studies have used <100 mg/dL of fibrinogen as their cut-off, Beinart and Damon hypothesized that patients who had severely reduced fibrinogen levels (ie, <50 mg/dL) also had decreased levels of anticoagulant proteins, thereby being at increased risk for thrombotic events.21 Of the 93 patients in that study, 6 patients experienced a thrombotic event during treatment with L-asparaginase; 3 of them had hypofibrinogenemia. This led the authors to suggest that in patients with ALL receiving asparaginase, fibrinogen levels of <50 mg/dL may be used as a marker for a hypercoagulable state.21 No bleeding episodes were seen in any of our patients, suggesting that hypofibrinogenemia is usually not a fatal adverse event and can be managed with swift res-

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olution. Two thrombotic events occurred among our patients and were managed with enoxaparin, with no further complications. Although the level that should be corrected remains controversial, because the overall incidence of thrombosis appears higher than bleeding in adults,8 we have since adopted the practice of not correcting the fibrinogen level unless the level is <60 mg/ dL or the patient is bleeding.

In our study population, hyperbilirubinemia was the most severe toxicity seen with pegaspargase. Grade 4 hepatotoxicity associated with hyperbilirubinemia, as defined by the National Cancer Institute (ie, >3 times baseline of bilirubin level), was reported in 10 of our patients. Of these, 3 patients had bilirubin levels elevated to approximately 10 mg/dL, which resolved within 1 to 2 weeks. In all, 3 other patients reached bilirubin levels of ≥25 mg/dL: in 1 patient this was resolved gradually over 1 month, and the other 2 died within 1 week of reaching the peak bilirubin levels (Table 6).

The median age of the 10 patients with hepatotoxicity was 52 years (range, 26-84 years) compared with 43.5 years (range, 21-84 years) for patients who did not have hyperbilirubinemia. Of the 6 patients with a bilirubin level of ≥9.9 mg/dL, all but 1 was aged ≥52 years (range, 26-84 years). Both patients who died from multi-organ failure coinciding with hyperbilirubinemia were elderly (ie, aged 70 years and 84 years).

Two cases of severe and persistent hyperbilirubinemia after receiving pegylated asparginase were reported in correspondence by Kim.22 The 81-year-old patient who received 1 dose of 2500 U/m2 had a peak bilirubin level of 19.5 mg/dL.22 The incidence of hyperbilirubinemia we report is higher than the 24% rate reported by Rytting and colleagues in 92 adults; however, the age range in their population was 14 to 71 years.14 This significant difference may reflect the higher proportion of older patients in our study and/or the dose of pegaspargase that we used. Our findings suggest that patients aged >50 years are at an increased risk for severe hepatotoxicity with this medication, which may be fatal in some patients.

Hypertriglyceridemia, as was seen in our sample in 1 patient, occurs infrequently compared with other toxicities; however, when it is present, it may be severe.

Our patient had triglyceride levels in the 8000s mg/ dL. Complications seen with this degree of hypertriglyceridemia include ischemic events resulting from the decreased ability of oxygenated blood to reach vital organs. In this patient, plasmapheresis was administered and, within hours, the patient’s triglyceride level dropped from 8470 mg/dL to 5000 mg/dL. Within 1 more day, the level decreased further to 600 mg/dL, and then gradually to <150 mg/dL within 2 weeks.

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Although the incidence of hypertriglyceridemia was low in our study, the frequency of this adverse event may be higher, because we did not routinely check levels unless the patients were symptomatic. Plasmapheresis has been used for several years as an effective and safe treatment for hypertriglyceridemia, removing an estimated 66% of the triglycerides in the blood within 1 administration and increasing to the removal of 83% of the triglycerides by the second administration.23 This reference patient also experienced symptomatic acute pancreatitis that resolved within the first week.

Hypertriglyceridemia, as was seen in our sample in 1 patient, occurs infrequently compared with other toxicities; however, when it is present, it may be severe. Our patient had triglyceride levels in the 8000s mg/dL. Overall in our study, 17 (68%) patients died—3 deaths were attributed to sepsis, 2 occurred during bone marrow transplantation, 2 resulted from multi-organ failure, and 10 deaths occurred during follow-up from progressing disease. The causes of death could not be ascertained for the 10 patients who died during follow-up. Eligibility criteria, such as age, subtype of disease, time after diagnosis, or even type of treatment regimen, did not exclude any patients from the study.

In fact, the treatment regimens in our study were varied, and the patient population was heterogeneous in regard to ALL karyotype, age, and performance status. It should also be noted that most of the patients in our study had relapsed or refractory ALL.

Conclusion In regard to the safety of pegaspargase, the previous literature has shown mixed outcomes, and many authors conclude that pegaspargase toxicity is infrequently severe and is often manageable by supportive care. In our study, 2 deaths were likely attributable to treatment with pegaspargase. Both patients were elderly, had hyperbilirubinemia, and had subsequent sepsis and/ or multi-organ failure. One patient had severe acute pancreatitis and hypertriglyceridemia that was managed and resolved with the use of a single plasmapheresis and gemfibrozil. Hypofibrinogenemia remains a frequent toxicity of pegaspargase that can be well managed with the administration of cryoprecipitate and rarely leads to hemorrhagic events. Hypersensitivity occurred in a single patient and was drastically less frequent than was

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seen in previous studies, likely as a result of the concomitant use of corticosteroids in our study as recommended

by Stock and colleagues.8

Our study findings suggest that patients treated with pegaspargase should be closely monitored for side effects and should be managed according to guidelines from the National Comprehensive Cancer Network and those recommended by Stock and colleagues.

Our study findings suggest that patients treated with pegaspargase should be closely monitored for side effects and should be managed according to guidelines from the National Comprehensive Cancer Network24 and those recommended by Stock and colleagues.8 Dose reduction, especially in the elderly, may be warranted, although controlled trials are needed to confer equal efficacy with lower doses. An awareness of the potential for significant hepatotoxicity, especially in patients aged >50 years, should be noted. n Author Disclosure Statement Dr Ippoliti is on the Speaker’s Bureau of Merck and Sigma Tau Pharmaceuticals; Dr Patel has no conflicts of interest to report.

References

1. American Cancer Society. Leukemia-acute lymphocytic (adults). www.cancer.org/ cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acutelympho cytic-key-statistics. Accessed June 5, 2014.

2. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532-543.

3. Masetti R, Pession A. First-line treatment of acute lymphoblastic leukemia with pegasparaginase. Biologics. 2009;3:359-368.

4. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia.

Hematology Am Soc Hematol Educ Program. 2006:133-141.

5. Avramis VI, Tiwari PN. Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int J Nanomedicine. 2006;1:241-254.

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6. Wetzler M, Sanford BL, Kurtzberg J, et al. Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007;109:4164-4167.

7. Oettgen HF, Stephenson PA, Schwartz MK, et al. Toxicity of E. coli L-asparaginase in man. Cancer. 1970;25:253-278.

8. Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011;52:2237-2253.

9. Ribera J, Oriol A, Morgades M, et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescent and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014; 32:1595-1604.

10. Haiat S, Vekhoff A, Marzac C, et al. Outcome of the treatment of adult acute lymphoblastic leukemia using a pediatric protocol. Haematologica. 2007;92(suppl 1).

Abstract 0029.

11. US Food and Drug Administration. FDA approves pegaspargase (Oncaspar, Enzon Pharmaceuticals, Inc) for the first-line treatment of patients with acute lympho-blastic leukemia. July 24, 2006. www.fda.gov/AboutFDA/CentersOffices OfficeofMedicalProductsandTobacco/CDER/ucm095609.htm. Accessed May 28, 2014.

12. Oncaspar (pegaspargase) injection, for intramuscular or intravenous use [prescribing information]. Gaithersburg, MD: Sigma-Tau Pharmaceuticals; April 2014.

13. Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. J Clin Oncol. 2014;32:905-911.

14. Rytting M, Earl M, Douer D, et al. Toxicities in adults with acute lymphoblastic leukemia (ALL) treated with regimens using pegasparaginase. Blood (ASH Annual Meeting Abstracts). 2008;112. Abstract 1924.

15. Rytting M. Peg-asparaginase for acute lymphoblastic leukemia. Expert Opin Biol Ther. 2010;10:833-839.

16. American Society of Health System Pharmacists. Asparaginase Injection. Updated February 7, 2013. www.ashp.org/menu/DrugShortages/DrugsNoLongerAvailable/ Bulletin.aspx?id=958. Accessed June 5, 2014.

17. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood.

2004;103:4396-4407.

18. Thomas X, Dombret H. Treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49:1246-1254.

19. Earl M. Incidence and management of asparaginase-associated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2009;7:600-606.

20. Faderl S, Thomas DA, O’Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011;11:54-59.

21. Beinart G, Damon L. Thrombosis associated with L-asparaginase therapy and low fibrinogen levels in adult acute lymphoblastic leukemia. Am J Hematol. 2004;77:331-335.

22. Kim S. Two cases of pegylated asparaginase-associated severe and persistent hyperbilirubinemia. Am J Hematol. 2009;84:696.

23. Yeh JH, Chen JH, Chiu HC. Plasmapheresis for hyperlipidemic pancreatitis.

J Clin Apher. 2003;18:181-185.

24. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): acute lymphoblastic leukemia. Version 3.2013.

2014. www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed May 23, 2014.

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Vol 4, No 2

Call for Papers The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession.

Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy management for patients with cancer.

Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo the journal’s blind peer-review process, and acceptance is based on that review.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

COMMENTARIES

LETTERS TO THE EDITOR

SUBMIT YOUR ARTICLE AT

www.JHOPonline.com Manuscripts must follow the Author Guidelines, available online.

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REVIEW ARTICLE

Concise Review of Obinutuzumab in the Treatment of Patients with Chronic Lymphocytic Leukemia Peter Tang, PharmD Candidate; Tristan Lindfelt, PharmD, BCPS, BCACP; Robert J. Ignoffo, PharmD, FASHP, FCSHP Background: Chronic lymphocytic leukemia (CLL) is the second most common leukemia in adults in the United States. The median survival is 10 years and the 5-year overall survival is 82%. The advent of novel active agents may change a treatment strategy based on patient factors, particularly those with early-stage disease and poor prognostic markers.

Obinutuzumab is a second-generation anti-CD20 agent that was developed to improve survival and overcome resistance in B-cell malignancies.

Objective: To review the recent findings of pivotal studies with obinutuzumab compared with other first-line therapies in the treatment of patients with CLL. Discussion: Rituximab, a first-generation anti-CD20 monoclonal antibody, has been shown to improve the overall survival of patients with advanced CLL. Historically, rituximab has been given in combination with chemotherapy or with an alkylating agent as the first-line treatment for patients with CLL. Treatment with rituximab has been shown to produce significant clinical improvement, and, in many cases, long-term survival in patients with CLL. There have been great efforts to develop new biologic therapies similar to rituximab with slight modifications to improve the efficacy and overcome resistance of the CD20 antigen. Obinutuzumab, a humanized, second-generation glycoengineered type II CD20 monoclonal antibody, has been shown to produce greater B-cell depletion and improve progression-free survival compared with rituximab-based regimens. A pivotal clinical trial comparing obinutuzumab plus chlorambucil with other therapies showed an increase in progression-free survival by 15.6 months compared with treatment with chlorambucil alone, and was also significantly better than the combination of rituximab plus chlorambucil (26.7 months vs 15.2 months; P <.001).

Conclusion: Obinutuzumab has been shown to be effective in the treatment of patients with J Hematol Oncol Pharm.

2014;4(2):50-56 CLL and was approved by the US Food and Drug Administration in 2013 for the treatment of naĂŻve patients with CLL, with an orphan drug designation. The National Comprehensive www.JHOPonline.com Disclosures are at end of text Cancer Network guidelines recommend the use of obinutuzumab plus chlorambucil for the first-line treatment of untreated patients with CLL.

I

t is estimated that in 2014 there will be 15,720 new cases of chronic lymphocytic leukemia (CLL) and 4600 deaths from CLL,1 making it the second most common leukemia in adults in the United States.2 The average age at diagnosis is approximately 72 years.1 CLL is a lymphoproliferative disorder that is characterized by progressive accumulation and subsequent overgrowth of functionally incompetent lymphocytes, which ultimately overcrowd and obstruct the normal processes of healthy B-cell lymphocytes. CLL is nearly identical to the indolent small B-cell lymphoma, except that it is

predominately manifested in the bone marrow, whereas B-cell lymphoma is evident more so in the peripheral lymph nodes.3,4 Approximately 25% to 50% of patients with CLL are asymptomatic at the time of diagnosis.5 It is often first detected because of the presence of lymphadenopathy or lymphocytosis.5 The prognosis of CLL is dependent on many factors, including the presence of lymphadenopathy, degree of hepatosplenic involvement, anemia and thrombocytopenia, serum markers (thymidine kinase and β-2 microglobulin), and genetic mutations or cytogenetic abnor-

Mr Tang is PharmD Candidate, Touro University College of Pharmacy, Vallejo, CA; Dr Lindfelt is Assistant Professor of Pharmacy, Touro University College of Pharmacy, Vallejo, CA; Dr Ignoffo is Professor of Pharmacy, Touro University College of Pharmacy, Vallejo, CA, and Clinical Professor Emeritus, University of California, San Francisco.

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malities (eg, deletions of 11q, 13q, and 17p, CD38 and ZAP-70 expression). Patients’ survival times vary considerably, ranging from 2 to 20 years and are dependent on staging and on when treatment is initiated.6,7 The median survival is more than 10 years,6 and the 5-year overall survival is 82%.8 Not all patients with CLL require treatment, because several subsets of patients with this disease may have a normal survival rate.

The clinical features of CLL include the expression of several abnormal B-cell surface antigens, including CD5, CD19, CD20, CD23, and CD52. Both CD20 and CD52 antigens serve as targets for drug therapy.9 Before the recent approval of the monoclonal antibody obinutuzumab, there were 3 other monoclonal antibodies approved for the treatment of CLL, including rituximab, alemtuzumab, and ofatumumab.

Rituximab, a chimeric monoclonal antibody that targets the CD20 antigen on B-cell lymphocytes, is a first-generation anti-CD20 monoclonal antibody that has been shown to improve overall survival in patients with advanced CLL. It was approved by the US Food and Drug Administration (FDA) in 1997 for the treatment of patients with B-cell non-Hodgkin lymphomas, and in 2010 for the treatment of previously treated or untreated patients with CLL.4,10 There have been great efforts to develop new biologic therapies to improve on the efficacy of rituximab and overcome resistance of the CD20 antigen.

Alemtuzumab, a humanized monoclonal antibody that targets the CD52 antigen on lymphocytes, was approved in 2001 under the FDA’s accelerated approval process.11 In 2007, the FDA granted approval for alemtuzumab to be used as a first-line single-agent option for patients with CLL.4,11 Ofatumumab, a human monoclonal antibody, targets the CD20 antigen on B-cell lymphocytes and was approved by the FDA in 2009 for the treatment of patients with CLL that is no longer responding to available therapies.4,12 In 2014, ofatumumab was approved in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is inappropriate.13 According to the National Comprehensive Cancer Network (NCCN) guidelines for CLL, the initiation of treatment is based on the Rai clinical staging system.4 This system stages a patient based on a physical exam, which includes a complete blood count, an examination of the lymph nodes, and an examination for the presence of organomegaly.14 Very early stage 0 or 1 disease is usually managed by monitoring the patient’s clinical findings and laboratory tests. Active treatment is usually instituted for later stages of the disease or with the presence of any of several conditions, including disease-related symptoms (fever, night sweats, substantial fatigue), painful spleen,

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50% increase in lymphocytosis, progressive anemia, thrombocytopenia, splenomegaly, or lymphadenopathy.14

Treatment of CLL Traditionally, symptomatic CLL has been treated with one of several drugs, including purine analogs (eg, fludarabine, pentostatin), alkylating agents (eg, chlorambucil, cyclophosphamide, bendamustine), monoclonal antibodies (eg, rituximab, ofatumumab, alemtuzumab), or combinations of these drugs.4 Before the approval of obinutuzumab, the first-line therapy for elderly patients (aged ≥70 years) or frail and without cytogenetic abnormalities, was chlorambucil with or without rituximab. Younger patients aged <70 years received regimens such as fludarabine, cyclophosphamide, and rituximab or bendamustine with or without rituximab.15 Patients with relapsed or refractory disease were treated, retreated, or switched to biologics, such as ofatumumab alone or alemtuzumab with or without rituximab.15 Currently, the preferred first-line therapy for patients aged ≥70 years without cytogenetic abnormalities is obinutuzumab with chlorambucil.4 To guide the selection of all therapy, further testing is required to detect cytogenetic abnormalities.4 These abnormalities are determined through fluorescence in situ hybridization (FISH). Detection of deletions 11q, 13q, or 17p through FISH helps to determine a patient’s prognosis and helps to narrow the therapeutic options.4 Patients with deletion 13q have the most favorable prognosis, with the longest median survival of 133 months.4 Patients with this deletion do not have a specified treatment guideline.4 However, patients who have deletion 11q or 17p have a less favorable prognosis.16 Patients who have deletion 11q have more favorable outcomes when regimens include an alkylating agent.4 Before the approval of obinutuzumab, the first-line therapy for patients with deletion 11q was chlorambucil with or without rituximab.15 The current preferred firstline therapy for patients with deletion 11q is obinutuzumab with chlorambucil.4 Extensive lymphadenopathy and disease progression are associated with deletion 11q, leading to a median survival of 79 months.16,17 Deletion 17p is associated with low response rates; patients with deletion 17p are recommended to participate in clinical trials if there is no standard therapy.4 If therapy is initiated, a choice of obinutuzumab with chlorambucil, high-dose methylprednisolone with rituximab, or alemtuzumab with or without rituximab is preferred as the first-line biologic option.4 In patients with deletion 17p, the median survival time is 32 months.16 Rituximab, given in combination with chemotherapy, can result in significant clinical improvement and, in

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Table 1 C omparing Progression-Free Survival and Response Rates in Patients with CLL Obinutuzumab + chlorambucil

Chlorambucil alone

Rituximab + chlorambucil

Chlorambucil alone

Obinutuzumab + chlorambucil

Rituximab + chlorambucil

Progressionfree survival, mo

26.7

11.1

16.3

11.1

26.7

15.2

Hazard ratio

0.18 (95% CI, 0.13-0.24)

0.44 (95% CI, 0.34-0.57)

0.39 (95% CI, 0.31-0.49)

P <.001

P <.001

P <.001

Treatment arms

Complete response

22.3%

NA

7.3%

NA

20.7%

7%

Partial response

55%

31.4%

58.4%

31.4%

57.7%

58.1%

CI indicates confidence interval; CLL, chronic lymphocytic leukemia; NA, not applicable.

Source: Goede V, et al. N Engl J Med. 2014;370:1101-1110.

many cases, long-term survival.18 Rituximab has played a key role in the treatment of B-cell malignancies. It is a very effective drug in the treatment of CLL; however, resistance is a common problem.19 There have been great efforts to develop biologic therapies similar to rituximab with slight modifications to improve the efficacy and overcome resistance to the CD20 antigen.20 The remainder of this concise review is focused on the clinical use of obinutuzumab, a new medication that attacks CD20, and the clinical studies that have led to the approval of this agent for the treatment of patients with CLL.

Obinutuzumab The Food and Drug Administration Safety and Innovation Act, signed on July 9, 2012, is intended to expedite the development and review of drugs for serious or life-threatening conditions through the request for breakthrough therapy designation.21 Breakthrough therapy–designated drugs must have shown a substantial improvement of outcomes over current therapies.21 Obinutuzumab, a humanized, glycoengineered type II CD20 monoclonal antibody, is the first cancer drug with the breakthrough therapy designation to receive FDA approval.22 On November 1, 2013, the FDA approved obinutuzumab for the treatment of patients with previously untreated CLL. Obinutuzumab was also designated as an orphan drug, because CLL is a rare disease.22 Obinutuzumab Pharmacology Obinutuzumab is an Fc-engineered type II anti-CD20 monoclonal antibody.23 Much like rituximab, obinutuzumab targets the CD20 antigen expressed on B-lymphocytes and activates complement-dependent cytotoxicity.23 Obinutuzumab differs from rituximab by its design; it binds to a different epitope on the CD20 antigen and

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leads to enhanced immune effector functions, especially antibody-dependent cell-mediated cytotoxicity.23 Although type II monoclonal antibodies bind more weakly to complement proteins and have decreased complement-dependent cytotoxicity activity, direct apoptosis is increased.24 The Fc region in antibodies interacts with cell-surface receptors, resulting in activation of the immune system and an increased opsonization, cell lysis, and other processes.24 Obinutuzumab produces greater B-cell depletion compared with rituximab.23 A recent study by Reslan and colleagues showed that obinutuzumab had a significantly greater effect on apoptosis compared with rituximab.25 Furthermore, in preclinical studies, obinutuzumab demonstrated superiority over rituximab in isolated CLL cells.26

Obinutuzumab Pharmacokinetics The elimination of obinutuzumab comprises a linear clearance pathway and a time-dependent nonlinear clearance pathway. The half-life elimination of obinutuzumab is approximately 28.4 days and the volume of distribution is 3.8 L.27 The pharmacokinetics of this drug is not affected by a patient’s age.27 The pharmacokinetics of obinutuzumab was studied in a phase 1 clinical trial.28 A total of 14 days after induction therapy with obinutuzumab, the plasma concentrations of obinutuzumab remained elevated with doses ≥1000 mg. Rapid decline of serum drug concentrations was observed with doses <1000 mg. To maintain saturation of the target (CD20), obinutuzumab doses of at least 1000 mg were required.28 Based on these results, a maintenance dose of 1000 mg was chosen for further clinical studies.

Obinutuzumab Clinical Efficacy Phase 2 Clinical Trials A phase 2 clinical trial investigated the dose-response

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relationship of obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma.29 A total of 40 patients were enrolled in the study: 38 of them had received previous rituximab therapy. In all, 18 patients were randomly assigned to receive an initial dose of obinutuzumab of 400 mg and a maintenance dose of 400 mg, and 22 patients were assigned to receive 1600 mg of obinutuzumab and a maintenance dose of 800 mg. The overall response rate was 55% in the 1600-mg/800-mg treatment arm, with 9% complete responders. In the 400-mg/400-mg treatment arm, the overall response rate was 17%, with no complete responders. The median progression-free survival (PFS) was 11.9 months in the higher-dosed group and 6 months in the lower-dosed group.29 This study showed promising results, but because of the small sample size, the study was not statistically powered to assess the significant differences between the 2 groups.

Most adverse events were infusion-related reactions. No patients withdrew because of adverse events.29 Another phase 2 clinical trial was conducted to determine the clinical efficacy of obinutuzumab in patients with diffuse large B-cell lymphoma or mantle-cell lymphoma who were heavily pretreated.30 A total of 40 patients were enrolled. Of these, 21 patients were randomly assigned to receive an initial dose of 400 mg and a maintenance dose of 400 mg, and 19 patients were randomly assigned to receive an initial dose of 1600 mg and a maintenance dose of 800 mg. The results showed no significant difference in PFS between the 2 treatment arms. Furthermore, the larger dose had a better overall response rate than the flat dose of 400 mg, because the steady-state serum concentration was reached. This study confirmed that a higher dose of obinutuzumab is needed to elicit a response in patients with lymphoma.30

Pivotal Phase 3 Clinical Trial Based on encouraging results from the phase 2 clinical trials, a phase 3, multicenter, international 3-arm protocol was initiated to compare obinutuzumab combined with chlorambucil; rituximab combined with chlorambucil; or chlorambucil monotherapy in treatment-na誰ve patients with CLL and with coexisting conditions.31 This study included 781 patients who were randomized to 3 treatment arms.31 In all 3 treatment arms, chlorambucil was administered orally at a dose of 0.5 mg/kg. The first treatment arm included obinutuzumab, which was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 6, plus chlorambucil, which was administered on days 1 and 15 of cycles 1 through 6. The second treatment arm included rituximab, which was administered intravenously at a dose of 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 through 6,

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Table 2 O binutuzumab plus Chlorambucil Dosing Regimen Cycle (28 days)

Dose of obinutuzumab

1

100 mg IV on day 1

Dose of chlorambucil

900 mg IV on day 2 1000 mg IV on days 8 and 15 2

1000 mg IV every 28 days

3

0.5 mg/kg orally on days 1 and 15 of each cycle

4 5 6 IV indicates intravenous.

Source: Gazyva (obinutuzumab) injection [prescribing information].

South San Francisco, CA: Genentech; November 2013.

plus chlorambucil. The third treatment arm included chlorambucil alone.31 The primary outcome measure for this study was investigator-assessed PFS.31 Treatment lasted for more than 6 months, and the follow-up for disease-progression and safety is for at least 5 years.32 Efficacy results, including the PFS, response rate, and hazard ratio (HR) among the treatment arms are summarized in Table 1.31

The PFS with obinutuzumab plus chlorambucil was also significantly better than the PFS with rituximab plus chlorambucil.

The group of patients (N = 238) receiving obinutuzumab plus chlorambucil achieved a median PFS of 26.7 months compared with 11.1 months with chlorambucil alone (N = 118; P <.001), for an increase of 15.6 months with obinutuzumab plus chlorambucil.31 The overall response rate was 77.3% for the combination therapy group and 31.4% for the chlorambucil-alone group.31 In addition, the HR for progression or death between therapy with obinutuzumab plus chlorambucil compared with chlorambucil alone is 0.18, which translates to an 82% risk reduction in patients who are receiving obinutuzumab plus chlorambucil versus chlorambucil alone.27 The PFS with obinutuzumab plus chlorambucil was also significantly better than the PFS with rituximab plus chlorambucil (26.7 months vs 15.2 months, respectively; P <.001).31 In addition, the overall survival with obinutuzumab plus chlorambucil compared with chlorambucil

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Table 3 A dverse Events of Grade ≥3, Safety Populationa Obinutuzumab–chlorambucil vs chlorambucil alone

Rituximab–chlorambucil vs chlorambucil alone

Obinutuzumab–chlorambucil vs rituximab–chlorambucil

Obinutuzumab– chlorambucil, N (%) (N = 241)

Chlorambucil alone, N (%) (N = 116)

Rituximab– chlorambucil, N (%) (N = 225)

Chlorambucil alone, N (%) (N = 116)

Obinutuzumab– chlorambucil, N (%) (N = 336)

Rituximab– chlorambucil, N (%) (N = 321)

Any event

175 (73)

58 (50)

125 (56)

58 (50)

235 (70)

177 (55)

Infusionrelated reactions

51 (21)

—

9 (4)

—

67 (20)

12 (4)

Neutropenia

84 (35)

18 (16)

60 (27)

18 (16)

111 (33)

91 (28)

Anemia

11 (5)

5 (4)

10 (4)

5 (4)

14 (4)

12 (4)

Thrombocytopenia

27 (11)

5 (4)

8 (4)

5 (4)

35 (10)

10 (3)

Leukopenia

13 (5)

0

3 (1)

0

15 (4)

3 (1)

Infections

27 (11)

16 (14)

30 (13)

16 (14)

40 (12)

44 (14)

Pneumonia

8 (3)

4 (3)

11 (5)

4 (3)

13 (4)

17 (5)

F ebrile neutropenia

4 (2)

5 (4)

4 (2)

5 (4)

8 (2)

4 (1)

Event

The safety population included all patients who received at least one dose of study medication. Shown are adverse events of grade 3, 4, or 5 with an incidence of 3% or higher in any treatment group, irrespective of whether the event was considered related or unrelated to treatment by the investigators. a

From Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Table 4 A dverse Events Grade Severity Grade 1

Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated

Grade 2

Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living

Grade 3

Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living

Grade 4

Life-threatening consequences; urgent intervention indicated

Source: National Cancer Institute. NCI guidelines for investigators: adverse event reporting requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs. February 29, 2012. http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/aeguidelines.pdf.

alone was significantly better, with a HR of 0.41 (95% confidence interval [CI], 0.23-0.74; P = .002). There was no significant difference between the overall survival with obinutuzumab plus chlorambucil and rituximab plus chlorambucil (HR, 0.66; 95% CI, 0.41-1.06; P = .08]).31

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This pivotal trial led to the FDA approval of obinutuzumab plus chlorambucil for the treatment of patients with CLL.22

Dosing The prescribing product information describes the recommended dosing regimen for obinutuzumab plus chlorambucil for the treatment of patients with previously untreated CLL (Table 2).27 Safety Infusion-Related Reactions Studies performed in non-Hodgkin lymphoma and B-cell malignancies suggest that obinutuzumab is welltolerated.27,33 The primary adverse events reported with obinutuzumab, which is administered intravenously, have been infusion-related reactions. The adverse events reported in the phase 3 trial are listed in Table 3.31 Infusion-related reactions reported include hypotension, pyrexia, nausea, vomiting, chills, asthenia, flushing, headache, and larynx irritation. Most reactions were observed during the first infusion. No patients discontinued the treatment because of toxicities. Infusionrelated reactions resolved after slowing or interrupting the infusion. Adverse events that required hospitalization

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Table 5 Premedication Associated with Obinutuzumab Day of obinutuzumab treatment cycle

Patients requiring medications

Premedication

Administration

Cycle 1 Day 1 Day 2

All

Intravenous glucocorticoid

At least 1 hr before obinutuzumab infusion

Acetaminophen Antihistamine

Cycle 1 Day 8 Day 15

All

Acetaminophen

Patients with a previous infusion-related reaction

Antihistamine

Cycles 2-6 Day 1

Patients with a grade 3 reaction to previous infusion or with a lymphocyte count >25 × 109/L before next treatment

Intravenous glucocorticoid

At least 30 min before obinutuzumab infusion

At least 1 hr before obinutuzumab infusion

Source: Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech; November 2013.

included anemia, neutropenia, thrombocytopenia, and tumor lysis.33 Although a humanized antibody, obinutuzumab produced a substantial number of infusion-related reactions in phase 1 and phase 2 trials: 55% to 83% of infusion-related reactions were grade 1 or 2, and 8% to 18% of infusion-related reactions were grades 3 or 4.34 Furthermore, in the phase 3 study by Goede and colleagues, infusion-related reactions were more common in the obinutuzumab-plus-chlorambucil group than in the chlorambucil-alone group.31 Reactions may be related to many factors, including drug concentration, pH of the solution, infusion rate of the drug, or diluents.27 For patients who develop infusion-related reactions rated grade 1 or grade 2, a reduced infusion rate or interruption is recommended to manage symptoms.27 For grade 3 reactions, an interruption in therapy is recommended. Patients who develop a grade 4 reaction are recommended to discontinue immediately and permanently.27 The degrees of severity of adverse events are defined in Table 4.35 Premedication is often required before the administration of monoclonal antibodies to reduce the risk of infusion-related reactions.27 Premedication includes antihistamines, glucocorticoids, and acetaminophen.

The premedication regimen for obinutuzumab infusion is listed in Table 5.27

Boxed Warnings Obinutuzumab contains a boxed warning with 2 warnings, which include hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML).

Screening for HBV before treatment is required.27 Patients with high levels of hepatitis B may be monitored with serial measurements of hepatitis B viral load

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and treated if the viral load increases. If treatment is started in patients with HBV infection, prophylactic antiviral therapy is recommended. Patients with prophylactic treatment need to be monitored for hepatitis B viral load monthly during, and every 3 months after, treatment. The NCCN panel recommended that prophylactic treatment is to be maintained for up to 12 months after treatment with obinutuzumab ends.4,27 The diagnosis of PML should be considered in any patient presenting with new onset or changes to preexisting neurologic indicators. In patients who develop PML, obinutuzumab therapy should be discontinued.

Use in Specific Populations Obinutuzumab is classified as pregnancy category C. There are no adequate and well-controlled studies of obinutuzumab in pregnant women. Animal studies have shown that there were no teratogenic effects. Pediatric use has not been established because CLL is typically a disease of the elderly. For geriatric use, there were no significant differences in efficacy between patients aged ≥75 years and patients aged <75 years. In patients who have renal or hepatic impairment, no dosage adjustments have been studied or provided in the manufacturer’s labeling.27 Cost Considerations The average wholesale price of obinutuzumab 1000 mg in a 40-mL intravenous solution is estimated to be $6192.36 A full course of obinutuzumab therapy is 8000 mg, which would amount to approximately $49,536 (depending on the purchase by an institution).

Place in Therapy In the phase 3 trial that led to its approval, obinutuzumab in combination with chlorambucil demonstrated a

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significant increase in PFS benefit, overall response rate, and complete response rate compared with chlorambucil alone.31 Based on this evidence, the FDA fast tracked it through the review process for the treatment of patients with CLL. The current NCCN guidelines for CLL include obinutuzumab plus chlorambucil as the preferred initial treatment for patients with CLL without 11q or 17p deletions and as the preferred initial treatment for patients with 11q deletion. For patients with deletion 17p, obinutuzumab plus chlorambucil is a first-line therapy choice.5

Conclusion Obinutuzumab, an Fc-engineered type II anti-CD20 monoclonal antibody, has been shown to be effective in the treatment of patients with CLL, and is the first cancer drug with a breakthrough therapy designation to receive FDA approval. Obinutuzumab in combination with chlorambucil is now the preferred first-line regimen for patients aged ≥70 years with CLL that requires pharmacotherapy. It is also the preferred first-line regimen for any patient with CLL and deletion 11q. n Author Disclosure Statement Mr Tang, Dr Lindfelt, and Dr Ignoffo have no conflicts of interest to report.

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19. Tsai PC, Hernandez-Ilizaliturri FJ, Bangia N, Olejniczak SH, Czuczman MS. Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2012;18:1039-1050.

20. Jaglowski SM, Alinari L, Lapalombella R, Muthusamy N, Byrd JC. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood. 2010; 116:3705-3714.

21. US Food and Drug Administration. Regulatory information: frequently asked questions: breakthrough therapies. Updated May 22, 2014. www.fda.gov/regula toryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamend mentstothefdcact/fdasia/ucm341027.htm. Accessed May 29, 2014.

22. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. Updated November 1, 2013. www.fda.gov/ newsevents/newsroom/pressannouncements/ucm373209.htm. Accessed May 27, 2014.

23. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115: 4393-4402.

24. Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by antiCD20 monoclonal antibodies. Mol Immunol. 2007;44:3823-3837.

25. Reslan L, Dalle S, Herveau S, et al. Apoptotic induction by anti-CD20 antibodies in chronic lymphocytic leukemia: comparison of rituximab and obinutuzumab.

Leuk Lymphoma. 2014;55:188-190.

26. Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the antiCD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2011;152:295-306.

27. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech; November 2013.

28. Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20positive B-cell malignancies. Blood. 2012;119:5118-5125.

29. Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31:2920-2926.

30. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31:2912-2919.

31. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110.

32. CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1a). Trial NCT01010061. http://clinicaltrials.gov/show/NCT01010061. Accessed June 5, 2014.

33. Salles G, Morschhauser F, Lamy T, et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012;119:5126-5132.

34. Mancheril BG, Aubrey Waddell J, Solimando DA Jr. Drug monographs: afatinib and obinutuzumab. Hosp Pharm. 2014;49:237-241.

35. National Cancer Institute. NCI guidelines for investigators: adverse event reporting requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs. February 29, 2012. http://ctep.cancer.gov/protocolDevelopment/electronic_appli cations/docs/aeguidelines.pdf. Accessed May 19, 2014.

36. Lexi-Drugs Online. Obinutuzumab. Hudson, OH: Lexi-Comp, Inc. http://0-online. lexi.com.library.touro.edu/lco/action/doc/retrieve/docidpatch_f/4801839?hl= 700830. Accessed February 6, 2014.

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FDA UPDATE

Recent Cancer Drugs Approved by the FDA

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his section provides information on recent drug approvals by the US Food and Drug Administration (FDA) to provide oncology/hematology pharmacists up-to-date information on new therapies and new combination therapies reaching the market, or expanded indications for older drugs already on the market, that can improve the management of

Zykadia Approved for Metastatic, ALK-Positive Lung Cancer The FDA approved ceritinib (Zykadia; Novartis) for the treatment of patients with metastatic, anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) on April 29, 2014. Ceritinib is an ALK tyrosine kinase inhibitor (TKI) that blocks proteins that promote cancer-cell growth. The drug is approved for the treatment of patients with late-stage NSCLC who were previously treated with crizotinib, the first and only other ALK TKI approved by the FDA for this indication.

The FDA had granted ceritinib a breakthrough therapy and an orphan drug designation, as well as a priority review based on preliminary clinical results provided by the manufacturer that demonstrated the drug’s safety and efficacy, indicating that ceritinib offered a substantial improvement over currently available therapies for this specific indication.

The FDA approved ceritinib under its accelerated approval process 4 months ahead of the scheduled final review date to expedite access to this drug for a patient population facing a life-threatening condition and very few available treatment options.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The safety and efficacy of ceritinib were established in a clinical trial with 163 patients with metastatic, ALK-positive NSCLC. In the trial, all patients received ceritinib therapy; approximately 50% of the patients had their tumor shrink with this therapy, and this lasted an average of approximately 7 months.

Reported side effects were mainly gastrointestinal, such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities included increased liver

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patients with a variety of cancers, including solid tumors and hematologic malignancies. The following news briefs are intended to help pharmacists keep up with new information related to cancer management. This section also infrequently provides updates on significant decisions by the FDA related to drugs in the pipeline. enzymes and pancreatic enzymes, as well as increased glucose levels.

FDA Approves Ofatumumab for Patients with Chronic Lymphocytic Leukemia On April 17, 2014, the FDA approved ofatumumab (Arzerra Injection, GlaxoSmithKline) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate.

The approval was based on the results of a multicenter, randomized, open-label trial comparing ofatumumab in combination with chlorambucil with chlorambucil alone. The 447 patients included in the study were deemed ineligible for fludarabine-based therapy because of advanced age or comorbidities. Overall, 72% of patients had ≥2 comorbidities, and 48% had a creatinine clearance of <70 mL/min.

Infusion of intravenous (IV) ofatumumab was administered as 300 mg in cycle 1 on day 1, followed by 1000 mg on day 8 (first arm), or 1000 mg administered on day 1 of all subsequent 28-day cycles (second arm). In both arms, chlorambucil was administered at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Before each infusion of IV ofatumumab, patients received premedication with acetaminophen, an antihistamine, and a glucocorticoid.

The primary end point of the trial was progressionfree survival (PFS) as assessed by a blinded independent review committee. The median PFS was 22.4 months (95% confidence interval [CI], 19-25.2) in patients receiving ofatumumab plus chlorambucil compared with 13.1 months (95% CI, 10.6-13.8) in patients receiving chlorambucil alone (hazard ratio, 0.57; 95% CI, 0.450.72; P <.001).

The most common adverse reactions (≥5%) reported with ofatumumab plus chlorambucil were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia,

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and upper abdominal pain. Overall, 67% of the patients who received ofatumumab had ≥1 symptoms of infusion reaction. In addition, 10% of patients had a grade ≥3 infusion reaction.

The recommended regimen for ofatumumab in patients with previously untreated CLL is 300 mg on day 1, followed by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of the subsequent 28-day cycles, for a minimum of 3 cycles and a maximum of 12 cycles.

Ramucirumab First FDA-Approved Drug for Advanced Stomach Cancer after Chemotherapy On April 21, 2014, the FDA approved ramucirumab (Cyramza; Eli Lilly) for the treatment of patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, which mostly affects older adults.

Ramucirumab is an angiogenesis inhibitor that blocks the blood supply to tumors and is intended to be used in patients with unresectable cancer or with metastatic stomach cancer after receiving chemotherapy with a fluoropyrimidine- or a platinum-containing agent. This is the first FDA-approved therapy for patients with stomach cancer who have already received chemotherapy.

“Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies,” said Dr Pazdur.

“Cyramza is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.”

Ramucirumab was approved under the FDA’s priority review program, and was also granted an orphan drug status, because it is intended to treat rare conditions.

The safety and efficacy of ramucirumab were demonstrated in a clinical trial of 355 patients with unresectable or metastatic stomach or gastroesophageal junction cancer. Patients were randomized to ramucirumab (66%) or to placebo (34%). The main end point was overall survival (OS). The median OS was 5.2 months with ramucirumab compared with 3.8 months with placebo (P <.001).

Ramucirumab also improved PFS compared with placebo.

Results from a second clinical trial that evaluated the

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Palonosetron Receives New Indication for the Prevention of CINV in Pediatric Patients On May 28, 2014, the FDA approved a new indication for palonosetron HCl (Aloxi; Eisai) injection for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial or repeated courses of emetogenic chemotherapy in children aged 1 month to <17 years. This is the first FDA approval of a therapy for the prevention of acute CINV in patients aged 1 month to 6 months. The age of peak cancer incidence among children occurs within the first year of life, so this approval offers an important option to children, and especially infants, undergoing chemotherapy.

The FDA approval was based on 1 randomized, double-blind, noninferiority pivotal trial comparing palonosetron with ondansetron in pediatric patients. The primary end point was complete response (CR), defined as no vomiting, retching, or antiemesis rescue medication required within the first 24 hours after chemotherapy.

CR was achieved in 59.4% of the patients using palonosetron compared with 58.6% of patients receiving ondansetron.

The trial also showed that pediatric patients required a higher dose of palonosetron based on weight than that required by adults; however, the safety profile of the drug in pediatric patients was consistent with its safety profile in adults.

Adverse events were comparable across both arms; the most frequently reported adverse event with palonosetron was headache.

Palonosetron is already approved for the prevention of CINV in adults aged ≥17 years. n

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efficacy of ramucirumab plus paclitaxel versus paclitaxel alone also showed an OS improvement with the addition of ramucirumab.

Common adverse events reported with ramucirumab in clinical trials include diarrhea and high blood pressure.

The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered as an IV infusion over 60 minutes until disease progression or unacceptable toxicity.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

nA LK- Positive

Non–Small-Cell Lung Cancer Responds to Ceritinib Treatment

BACKGROUND: Non–small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib. Despite initial responses to crizotinib, resistance ultimately occurs. In preclinical studies, ceritinib, a novel, oral adenosine triphosphate–competitive inhibitor of the ALK tyrosine kinase, has shown greater antitumor potency than crizotinib.

METHODS: This phase 1 clinical trial consisted of 2 dose-finding phases and included 130 patients. In the dose-escalation phase, 59 patients with tumors harboring ALK mutations were treated with ceritinib at doses of 50 mg to 750 mg once daily in 21-day cycles. In an expansion phase, 71 patients were treated at the maximum tolerated dose of 750 mg daily. Among the 130 patients enrolled, 122 had advanced NSCLC and had previously received cytotoxic chemotherapy. Of the 122 patients with advanced NSCLC, 68% had previously received crizotinib.

RESULTS: Among the 114 patients with NSCLC who received ≥400 mg of ceritinib daily, the overall response rate was 58%, which included 1 (1%) confirmed complete response and 65 (57%) partial responses. The overall response rate was 56% among 80 patients previously receiving crizotinib, and 62% among the 34 crizotinib-naïve patients. Among 114 patients receiving ≥400 mg daily, the median progression-free survival was 7 months, which was similar at 6.9 months in the crizotinib relapse group and was 10.4 months in crizotinib-naïve patients.

The most common adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and elevated alanine aminotransferase (ALT; 35%) levels.

The most common grade 3 or 4 drug-related adverse events were increased ALT levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%), and increased lipid lipase levels (7%), all of which were reversible on discontinuation of treatment. Of 130 patients, 66 (51%) required at least 1 dose reduction. In 8 of the 130 patients (6%), ceritinib was permanently discontinued as a result of an adverse event. Of 81 patients receiving the 750-mg dose, 50 (62%) required at

least 1 dose reduction; in 32 patients in the latter group, the reduction occurred in cycle 3 or later. No treatmentrelated deaths occurred.

In this phase 1 study, ceritinib produced a highly active response rate in patients with advanced ALKrearranged NSCLC, including patients with previous crizotinib treatment and irrespective of the presence of ALK-resistance mutations. Because ceritinib induced substantial and durable responses in a majority of cases, this new agent may be an alternative treatment for patients with ALK-rearranged NSCLC who no longer respond to crizotinib.

Source: Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALKrearranged non–small-cell lung cancer. N Engl J Med. 2014;370: 1189-1197.

COMMENTARY BY ROBERT J. IGNOFFO

It was astonishing to this reviewer when a phase 1 study of a new ALK inhibitor, ceritinib, was published in one of the highest impact factor journals in the United States, the New England Journal of Medicine.

However, it was the impressive results reported in the group of patients with highly resistant disease, many of whom had received previous treatment with standard crizotinib therapy, that led to the publication of this study. A surprisingly high response rate and improvement in progression-free survival (PFS) rates were observed in the dose-finding and the expansion phase of the study. Ceritinib was equally effective—approximately 60% response rate and median PFS of 7 to 10 months—in patients with resistant and nonresistant ALK-positive NSCLC. These outcomes are substantially better than that seen in patients who had relapsed after crizotinib therapy and then received other agents—approximately 10% response rate. The toxicity profile of ceritinib is similar to that of other epidermal growth factor receptor inhibitors and includes diarrhea, nausea, vomiting, and fatigue, which were dose-limiting, with doses of >600 mg daily. Ceritinib is a definite advance in the treatment of ALK-positive NSCLC and should be studied further to determine if it can be moved into second-line therapy, and even first-line therapy.

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R ituximab Active in Nodular Lymphocyte– Predominant Hodgkin Lymphoma

BACKGROUND: Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare type of Hodgkin lymphoma that represents approximately 5% of all cases.

Unlike classic Hodgkin lymphoma, the malignant cells of NLPHL universally express CD20. Rituximab, an anti-CD20 monoclonal antibody, has therefore been evaluated as a treatment option for this patient population. Previous preliminary results of a phase 2 clinical trial using single-agent rituximab in patients with NLPHL showed that the overall response rate was 100%, but the estimated median freedom from progression was less than 1 year. These are the mature results of the phase 2 trial of rituximab induction, with and without maintenance rituximab, in patients with NLPHL. METHODS: In this new study, researchers modified the study protocol of rituximab induction with and without maintenance rituximab in patients with NLPHL to evaluate patient response rate at 2 years.

The study included 39 patients with previously treated or with newly diagnosed NLPHL. The initial protocol included 23 patients (ie, rituximab group) who received rituximab 375 mg/m2 administered once weekly for 4 weeks. The protocol was amended after this patient cohort had enrolled to include 16 patients (ie, rituximab plus maintenance group) who received maintenance dosing with rituximab 375 mg/m2 administered in 4 once-weekly doses at 6-month intervals for 2 years. For patients with previously untreated disease, the median age at treatment was 38 years, and the median time from diagnosis to treatment induction was 4 months. The median time from original diagnosis of NLPHL to study entry in patients experiencing relapse was 12.7 years, and the median age at treatment was 44 years. The primary end point was progression-free survival (PFS), and the secondary end points were complete response and overall response rate.

RESULTS: After 4 weekly treatments, the overall response rate was 100%, with 67% of patients achieving complete response and 33% achieving partial response. No difference in the overall response rate was observed in previously treated patients versus treatment-naïve patients.

At a median follow-up of 9.8 years in the rituximab group, the PFS was 3 years. At the median follow-up of 5 years in the rituximab plus maintenance group, the PFS was 5.6 years. The median overall survival was not reached in either group. The estimated 5-year PFS and overall survival rates for patients in the rituximab group compared with patients in the rituximab plus maintenance group were 39.1% and 95.7% versus 58.9% and 85.7%, respectively.

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Treatment-related adverse events were minimal in both groups, and no grade 3 or 4 toxicities were observed. A total of 23 patients experienced relapse, and 9 of these patients had evidence of transformation to aggressive B-cell lymphoma.

The researchers concluded that rituximab is well-tolerated and is an active single agent in patients with NLPHL who had received no previous treatment and in patients with relapsed disease. Although the responses are not durable in the majority of the patients, a substantial minority experience remission lasting more than 5 years.

Because single-agent rituximab is not curative for NLPHL, it should be primarily considered in patients in the relapsed setting. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of repeated biopsy and longer-term follow-up.

Source: Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte– predominant Hodgkin lymphoma. J Clin Oncol. 2014;32:912-918.

COMMENTARY BY ROBERT J. IGNOFFO

NLPHL is an indolent form of Hodgkin lymphoma, with an 8-year survival rate of 94% in patients with stage III disease and 41% in patients with stage IV disease. Before the advent of rituximab, most patients were treated with the standard chemotherapy regimen of mechlorethamine, vincristine, procarbazine, and prednisone, or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Today, the guidelines from the National Comprehensive Cancer Network (NCCN) recommend rituximab as first-line therapy. Relapse occurs in approximately 25% of patients, who often respond again to rituximab. The NCCN recommends that rituximab may be added to standard ABVD; cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, and prednisone. The current study was developed to assess whether maintenance rituximab will improve outcomes in patients with newly diagnosed or relapsed NLPHL, and this strategy can prevent the transformation to aggressive non-Hodgkin lymphoma.

The results of this study show that although rituximab does not cure NLPHL, induction plus maintenance rituximab improves disease-free survival by almost 3 years versus rituximab induction alone. Unfortunately, 9 of 23 patients progressed to an aggressive non-Hodgkin lymphoma, 6 of whom received rituximab maintenance. Of note, the median overall survival had not been reached; even for progressing patients, the median overall survival was 52 months, reflecting an indolent disease.

Rituximab is an acceptable therapy for treating patients

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with newly diagnosed or relapsed NLPHL. Further follow-up is needed to determine if maintenance therapy with rituximab with improve overall survival in this group of patients.

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D ovitinib Active, but Not Superior to Sorafenib, in Patients with Metastatic Renal Cancer

BACKGROUND: Therapies targeting vascular endothelial growth factor (VEGF) and mTOR signaling pathways are standard first-line and second-line treatment options for patients with metastatic renal cell carcinoma. However, an unmet medical need exists for patients who had previously received VEGF-targeted and mTOR inhibitor therapies. Fibroblast growth factor pathway activation may be a mechanism of escape from VEGF-targeted therapies. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor that inhibits VEGF, fibroblast growth factor receptors, and platelet-derived growth factor receptors. Therefore, researchers sought to compare dovitinib versus sorafenib as third-line targeted therapies in this patient population.

METHODS: The Global Oncologic Learnings for Dovitinib trial was a multicenter, open-label, randomized, phase 3 trial that included 570 patients with metastatic renal cell carcinoma with clear cell or a component of clear cell histology, and who had received 1 previous VEGF-targeted therapy (eg, sunitinib or bevacizumab) and 1 previous mTOR inhibitor (eg, everolimus or temsirolimus). Patients were randomly assigned in a 1:1 ratio to receive dovitinib 500 mg orally according to a 5-dayson and 2-days-off schedule (N = 284), or to sorafenib 400 mg twice daily (N = 286). Randomization was stratified by risk group and by region. Patient characteristics were well-balanced between both groups. The primary end point was progression-free survival (PFS) on masked central review. Efficacy was assessed in all patients who were randomly assigned, and safety was assessed in patients who received at least 1 dose of the study drug.

RESULTS: The findings showed no difference in PFS between the 2 treatment groups. The median follow-up was 11.3 months. The median PFS times were 3.7 months in the dovitinib group and 3.6 months in the sorafenib group (hazard ratio [HR], 0.86; P = .063). No subgroup had a clinically significant PFS benefit with dovitinib versus sorafenib treatment in analysis by patient demographics and disease characteristics. The median PFS times according to favorable-, intermediate-, and poor-risk Memorial Sloan Kettering Cancer Center status were 5.5 months versus 3.7 months, 3.7 months

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versus 3.7 months, and 3.6 months versus 2.1 months, respectively. Partial response was noted in 4% of the patients in each group. In the dovitinib and sorafenib groups, the median overall survival times were 11.1 months and 11 months, respectively (HR, 0.96).

Common grade 3 and 4 adverse events included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), and anemia (5%) in the dovitinib group; and hypertension (17%), fatigue (8%), dyspnea (7%), palmar-plantar erythrodysesthesia (6%), and anemia (6%) in the sorafenib group. The most common serious adverse event in the dovitinib and sorafenib groups was dyspnea (6% and 5%, respectively).

Adverse events led to dose change or interruption in 51% of the patients receiving dovitinib and in 49% of the patients receiving sorafenib.

Although dovitinib showed activity in this setting, the researchers concluded that dovitinib and sorafenib had similar efficacies when used as third-line targeted treatments for metastatic renal cell carcinoma. The 11month median overall survival highlights the need for study and identification of novel agents in this setting.

Source: Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:286-296.

COMMENTARY BY ROBERT J. IGNOFFO

Dovitinib is not inferior to sorafenib for the treatment of advanced metastatic renal cancer. In comparative studies of a new drug that demonstrate noninferiority, one may look at other outcomes, particularly adverse effects, to determine if the new drug will be a useful treatment. In this study, dovitinib was generally associated with more adverse effects than sorafenib. It produced more diarrhea, nausea, vomiting, and leukopenia, whereas sorafenib caused more hand-foot syndrome.

Therefore, dovitinib offers an active alternative drug for treating metastatic renal-cell carcinoma and may be substituted for sorafenib in patients who find some of its adverse effects intolerable.

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C omparing Chemotherapy and EGFR Kinase Inhibitors for Patients with Advanced NSCLC and Wild-Type EGFR

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients with advanced nonâ&#x20AC;&#x201C;small-

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cell lung cancer (NSCLC) who have tested positive for EGFR mutations, because of better outcomes than conventional chemotherapy. However, it is unclear if EGFR TKIs are as efficacious as chemotherapy in patients without EGFR mutations (known as EGFR wild-type), which account for the majority of patients with advanced NSCLC. METHODS: This systematic review and meta-analysis of randomized controlled trials was conducted to determine the association between the first-generation EGFR TKI treatments (erlotinib and gefitinib) versus chemotherapy and survival in patients with advanced NSCLC harboring wild-type EGFR. Using PubMed, EMBASE, the Cochrane Database, and meeting abstracts of the American Society of Clinical Oncology and the European Society for Medical Oncology, researchers identified 11 randomized controlled trials, with 1605 patients with wild-type EGFR (811 patients in the TKI group, and 794 patients in the chemotherapy group). In all, 4 trials were performed in the first-line setting, 4 in second-line, and 3 in second-line or later settings. All 11 trials used TKIs in their standard dosing and schedule (erlotinib 150 mg daily, gefitinib 250 mg daily). The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate and overall survival.

RESULTS: In this pooled analysis, chemotherapy was associated with longer PFS compared with EGFR TKI in patients with wild-type tumors (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.1-1.81). In a subgroup analysis of 4 trials using more sensitive platforms, conventional chemotherapy demonstrated a longer PFS compared with TKI (HR, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy improvement in PFS was also significant in 6 second-line or later trials (HR, 1.34; 95% CI, 1.09-1.65). The higher objective response rate (including complete and partial responses) of chemotherapy also supported the longer PFS in patients with wild-type EGFR tumors compared with TKI therapy (16.8% vs 7.2%, respectively). However, the overall survival did not differ between the groups.

The researchers acknowledged that the apparent discrepancy between the PFS/objective response rate and

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EGFR mutations are a predictive marker for EGFR TKIs in patients with NSCLC. First-generation EGFR TKIs are considered a first-line therapy in patients with EGFR-mutated NSCLC. However, the majority of patients with NSCLC have no EGFR mutations (ie, wildtype disease). Thus, this large meta-analysis was undertaken to determine if first-generation EGFR TKIs have a therapeutic role compared with conventional chemotherapy. The bottom line is that conventional doublet chemotherapy in EGFR wild-type NSCLC produces a significantly higher response rate and a longer progression-free disease than EGFR TKIs. However, there was no difference in overall survival. Of note, in this study toxicities were not assessed. This study had limitations as a result of a possible unbalanced randomization of patients with EGFR wild-type disease. In addition, the impact of treatment crossover could not be assessed, because overall outcomes were reported only for the combined wild-type and mutated groups. This commentator believes that performing a large randomized trial of first-generation EGFR TKIs in patients with EGFR wildtype NSCLC would not be fruitful and would be a very expensive endeavor. It is suggested that investigators wait until more effective TKIs for patients with EGFR wild-type NSCLC become available.

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GLOBAL BIOMARKERS CONSORTIUM

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Source: Lee J-K, Hahn S, Kim D-W, et al. Epidermal growth factor tyrosine kinase inhibitors vs conventional chemotherapy in non– small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA. 2014;311:1430-1437.

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overall survival can be explained by the large crossover rates of the included trials. Therefore, they note, the findings suggest that in patients with wild-type EGFR tumors, conventional chemotherapy could be the preferred treatment option over EGFR TKI. The investigators cautioned that this recommendation cannot be conclusive, because overall comparisons were based on randomization. Toxicity outcomes were also not assessed.

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Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

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