Journal of Hematology Oncology Pharmacy - December 2011, VOL 1, NO 4 by The Oncology Pharmacist

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DECEMBER 2011

JOURNAL OF

VOL 1 I NO 4

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

CLINICAL CONTROVERSIES Bevacizumab in Metastatic Breast Cancer: Ready for Prime Time?

CON: Katherine Mandock, PharmD, BCPS; Scott A. Soefje, PharmD, BCOP PRO: Val R. Adams, PharmD, BCOP, FCCP REVIEW ARTICLES Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults

Lisa K. Lohr, PharmD, BCOP, BCPS The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous Leukemia

Natalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

From the Literature Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

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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

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

REVIEW ARTICLES Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale New Haven Yale New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT 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 Universityâ&#x20AC;&#x201C;California Mare Island Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine 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

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

John M. Valgus, PharmD, BCOP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

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

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

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December 2011

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Journal of Hematology Oncology Pharmacy

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DECEMBER 2011

VOLUME 1, NUMBER 4 PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TABLE OF CONTENTS

Associate Editors Brett Kaplan Lara J. Lorton

CLINICAL CONTROVERSIES

Bevacizumab in Metastatic Breast Cancer: Ready for Prime Time? CON: Katherine Mandock, PharmD, BCPS; Scott A. Soefje, PharmD, BCOP PRO: Val R. Adams, PharmD, BCOP, FCCP

REVIEW ARTICLES

Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults Lisa K. Lohr, PharmD, BCOP, BCPS The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous Leukemia Natalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

FROM THE LITERATURE

Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889

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

Editorial Assistant Jennifer Brandt 732.992.1536 Directors, Client Services Joe Chanley joe@greenhillhc.com 732.992.1524 Jack Iannaccone jack@greenhillhc.com 732.992.1537 Production Manager Stephanie Laudien Quality Control Director Barbara Marino Business Manager Blanche Marchitto blanche@greenhillhc.com Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

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 highquality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 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™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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 mention 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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CLINICAL CONTROVERSIES

The goal of this section is to feature current clinical controversies by presenting both sides of the problem. Readers are invited to submit articles that present the pro and con of a relevant problem, as featured in the present article.

Bevacizumab in Metastatic Breast Cancer: Ready for Prime Time? CON: By Katherine Mandock, PharmD, BCPS; Scott A. Soefje, PharmD, BCOP PRO: By Val R. Adams, PharmD, BCOP, FCCP

THE CASE AGAINST APPROVAL

ontroversy has developed over the label indications for bevacizumab in metastatic breast cancer (MBC). The US Food and Drug Administration (FDA) had granted accelerated approval for bevacizumab for the treatment of MBC based on clinical trials that demonstrated a progression-free survival (PFS) advantage. This controversy begins when the postapproval trials required with the FDA approval failed to demonstrate an overall survival (OS) advantage in addition to the PFS advantage. Subsequently, the Oncology Drug Advisory Committee (ODAC) recommended, and ultimately the FDA issued its decision, to remove bevacizumab’s current labeled indication for MBC.1 In this debate we take the side that supports the FDA’s final decision to remove that indication. Our position is based on the arguments that reflect the regulatory, efficacy, safety, and economic perspectives. We will demonstrate that this indication does not meet the standard required for labeled indications, that the efficacy for the indication does not show a clinical benefit, that there are serious safety concerns, and that the economic impact is too great to justify the drug’s approval. The FDA Modernization Act of 1997 permitted the FDA to approve the marketing of drugs “upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit.”2 This is exactly what has happened with bevacizumab. However, the FDA’s Guidance for Industry also states,

Dr Mandock is PGY-2 Oncology Resident, Smilow Cancer Hospital at Yale New Haven, and Dr Soefje is Associate Director, Oncology Pharmacy Services, Smilow Cancer Hospital at Yale New Haven, CT, and Section Editor of JHOP; Dr Adams is Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency, Hematology Oncology, University of Kentucky College of Pharmacy, Lexington, and Co-Editor-in-Chief of JHOP.

Journal of Hematology Oncology Pharmacy

“Where an accelerated approval is based upon a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity, postmarketing studies are ordinarily required ‘to verify and describe the drug’s clinical benefit and to resolve remaining uncertainty as to the relation of the surrogate endpoint upon which approval was based to clinical benefit, or the observed clinical benefit to ultimate outcome (57 FR 58942, December 11, 1992).’”3 This is the focus of the regulatory argument. The FDA has not recognized PFS as an end point that will grant approval for first-line indications in oncology. PFS has not translated to OS in any clinical trial in MBC and is, therefore, not considered a surrogate for survival. The burden is then on the drug manufacturer to demonstrate a clinical benefit that meets the criteria for approval, for example, OS, improved quality of life, or another end point that the FDA has recognized. One other such example in oncology is gefitinib, which was approved on a surrogate end point and was then pulled from the market when the primary end point was not met. Bevacizumab has not met the requirements for full approval for an MBC indication; therefore, the FDA’s decision was the correct one. The results of the Eastern Cooperative Oncology Group (ECOG) E2100 trial formed the basis for the FDA’s decision to grant bevacizumab conditional accelerated approval for the first-line treatment of patients with MBC. The ECOG E2100 study demonstrated an almost 2-fold increase in response rate and time to progression, but it failed to show OS benefit when bevacizumab was added to weekly paclitaxel therapy.4,5 Two additional phase 3 trials were designed to validate the results from the E2100 study, while evaluating the use of bevacizumab in combination with other approved chemotherapy in the first-line treatment of MBC.6,7 The AVADO (Avastin and Docetaxel) trial examined the combination of docetaxel and bevacizumab

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Bevacizumab in Metastatic Breast Cancer

administered every 3 weeks6; RIBBON (Regimens in Bevacizumab for Breast Oncology)-1 assessed capecitabine, a taxane-based regimen (docetaxel or nabpaclitaxel) administered every 3 weeks, and an anthracycline-containing regimen administered alone or in combination with bevacizumab.7 As in the case of the E2100 trial, both AVADO and RIBBON-1 failed to demonstrate a significant difference in OS rates. Both trials did demonstrate statistically significant improvements in PFS and in the response rate; however, they failed to confirm the magnitude of the PFS benefit observed in the E2100 trial (Table). Statistical significance does not always correspond to clinical significance, and the clinical impact of adding bevacizumab to a regimen is unconvincing at best, in view of the incremental improvements in PFS observed in the confirmatory trials.6,7 The concern for the clinical benefit of bevacizumab as a first-line agent in MBC is multifactorial but hinges on 3 major issues: (1) the disparity of benefit observed between the E2100 trial and other phase 3 trials, (2) the suitability of PFS as a surrogate end point for OS, and (3) the lack of a clearly defined patient population that is most likely to benefit from the addition of bevacizumab to the treatment regimen. The disparity in the magnitude of improvement in PFS between E2100 and other phase 3 studies is most likely reflective of the choice of chemotherapy. The E2100 trial evaluated bevacizumab in combination with once-weekly paclitaxel therapy. Preclinical evidence suggests an antiangiogenic activity that is associated with weekly paclitaxel therapy, which, when combined with bevacizumab, may have acted synergistically to result in the greater duration of PFS observed in E2100. Therefore, the robust benefit in PFS that was seen with E2100 was most likely derived from fractionating the dose of paclitaxel weekly over 3 weeks rather than from the addition of bevacizumab to the regimen.8 In addition, all 3 studies used PFS as the primary efficacy end point.6-8 As noted earlier, PFS has not been demonstrated as a good surrogate for OS in solid tumors, including MBC.9 Finally, the collective randomized controlled trials have failed to identify a patient population that would derive the greatest potential benefit from the addition of bevacizumab to chemotherapy. Heavily pretreated patients are not likely to experience significant benefits with the addition of bevacizumab, as seen by the shorter PFS among the capecitabine-receiving cohort in RIBBON-1 versus patients who received taxane or anthracycline chemotherapy.7 An earlier trial comparing the efficacy of capecitabine with or without bevacizumab showed no differences in OS or PFS, confirming that bevacizumab is not likely to

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have a significant survival impact in patients with MBC who have received extensive treatment.10 In addition, data from RIBBON-2 suggest that in some chemotherapy cohorts, combinations with bevacizumab may have a negative impact on PFS.11 In a subgroup analysis of second-line agents, the vinorelbine cohort demonstrated shorter PFS and OS compared with the placebo arm. These results must be interpreted with caution, however, because they are based on a small sample size that included a greater percentage of patients with poor prognostic factors.11 In addition to questions regarding its clinical significance, the combination of bevacizumab and chemotherapy raises some serious safety concerns. After convergent safety results from the phase 3 trials, the ATHENA (Avastin Therapy for Advanced Breast Cancer) trial was conducted to further assess the safety of bevacizumab combined with first-line chemotherapy.12 The most frequent grade 3 or more toxicities in ATHENA were neutropenia (5.4%), hypertension (4.4%), thromboembolism (3.2%), proteinuria (1.7%), and bleeding (1.4%), which confirmed the previously established adverse events (AEs) associated with bevacizumab therapy.12

With no evidence of improved survival in phase 3 clinical trials, bevacizumab has failed to meet the conditions set under the current FDA regulatory standards for approval of first-line treatment for MBC, and it is associated with potentially serious AEs. RIBBON-1 demonstrated that hypertension and proteinuria were consistently increased in the bevacizumab arms, regardless of the chemotherapy administered. In addition, the incidence of bleeding and febrile neutropenia was >5% in patients receiving taxane-containing regimens.7 Disconcertingly, it appears that the more serious AEs occur more frequently in the population of patients most likely to benefit from bevacizumabâ&#x20AC;&#x2122;s favorable effects on PFS, namely, patients receiving weekly paclitaxel therapy.7 With no evidence of improved survival in phase 3 clinical trials, bevacizumab has failed to meet the conditions set under the current FDA regulatory standards for approval of first-line treatment for MBC, and it is associated with potentially serious AEs. Until further studies confirm an OS benefit or clinically and statistically significant improvements in PFS in addition to an ideal target population, bevacizumab should not be considered as a first-line agent in combination with chemotherapy for MBC.

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CLINICAL CONTROVERSIES

Table

Results of Randomized Controlled Trials of Chemotherapy with/without Bevacizumab in the Treatment of Metastatic Breast Cancer Chemotherapy without bevacizumab

Study/first- or Chemotherapy PFS HR second-line therapy ± bevacizumab (95% CI)

Chemotherapy with bevacizumab rate

Median Response Median Median Response Median Difference PFS, mo rate, % OS, mo PFS, mo rate, % OS, mo in PFS, mo

ECOG E2100 (2007, 2009) first-linea

Paclitaxel weekly

0.60 (0.51-0.70)

5.9

21.2

25.2

11.8

36.9

26.7

5.9

AVADO (2010) first-lineb

Docetaxel

0.67 (0.54-0.83) 8.1

46.4

31.9

10.0

64.1

30.2

1.9

RIBBON-1 (2011) first-linec

Capecitabine Taxane/ anthracycline

0.69 (0.56-0.84) 5.7 0.64 (0.52-0.80) 8.2/7.9

23.6 37.9

—

8.6 9.2/9.2

35.4 51.3

—

2.9 1.0/1.3

RIBBON-2 (2011) second-lined

Capecitabine Taxane Gemcitabine Vinorelbine

0.73 (0.49-1.08) 0.64 (0.49-0.84) 0.90 (0.61-1.32) 1.42 (0.78-2.59)

35.8 48.7 32.9 26.1

16.4

6.9 8.0 6.0 5.7

15.4 38.3 15.0 52.6

18.0

4.1 5.8 5.5 7.0

2.8 2.2 0.5 –1.3

Median PFS, P <.001; OS, P = .16. Stratified analysis; median PFS, P <.001; OS, P value not significant. c Median PFS, capecitabine cohort, P <.001; median PFS, taxane/anthracycline cohort, P <.001; OS, capecitabine cohort, HR for OS, 0.85 (95% CI, 0.63-1.14), P = .27; OS, taxane/anthracycline cohort, HR for OS, 1.03 (95% CI, 0.77-1.38), P = .83. d Differences in PFS benefit between the taxane, capecitabine, and gemcitabine cohorts were not statistically significant (P = .284); however, differences in PFS between the vinorelbine cohort and the other 3 cohorts were significant (P = .018); OS stratified HR, 0.90 (95% CI, 0.71-1.14); P = .374. AVADO indicates Avastin and Docetaxel; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RIBBON, Regimens in Bevacizumab for Breast Oncology. Sources: References 4-7, 10. b

From an economics perspective, the use of bevacizumab in MBC is not cost-effective. The estimated cost for 1 year of life saved with a course of bevacizumab is $496,000.13 Compared with conventional values between $50,000 and $125,000 for other therapies, this estimated cost of bevacizumab is several times higher. The cost of bevacizumab is approximately $62,000 in the clinical trials.13 The cost of the drug does not seem out of line with the cost of current cancer therapies; however, the benefit—in this case, years of life saved—is so small that the cost-effective amount, which is cost divided by years of life saved, becomes very large and outside the

range that is generally acceptable. In these times of medical economic scarcity, the continued approval of a drug that shows marginal benefit is not in society’s best interest. If asked to pay out of pocket, how many patients would accept bevacizumab, knowing its high cost and the minimal additional life gained? We have demonstrated that bevacizumab has not overcome the regulatory or efficacy hurdles required for approval of a first-line agent for MBC. Combined with the safety concerns and the tremendous associated cost, the FDA’s decision to pull the indication for the drug in the treatment of MBC is acceptable.

THE CASE FOR CONTINUED APPROVAL

ased on the scientific data and the regulatory requests, it is clear that the MBC indication should remain on the label of bevacizumab. The rationale for continued approval is based on the arguments related to the 4 areas cited earlier: regulatory, efficacy, safety, and economic.

Journal of Hematology Oncology Pharmacy

As noted before, the Modernization Act permits the FDA to approve a drug based on a surrogate end point that is reasonably likely to predict clinical benefit.2 This is the way the first-line indication for paclitaxel and bevacizumab for MBC was approved. The pivotal study for the accelerated approval for bevacizumab is the

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ECOG E2100 trial.4 This trial randomized 722 patients to paclitaxel alone or to paclitaxel plus bevacizumab. The trial was designed to measure PFS as the primary end point; it required 546 events (in 685 patients) to detect a 2-month improvement, with a power of 85%. The improvement in PFS was impressive—5.8 months without paclitaxel alone versus 11.3 months for paclitaxel plus bevacizumab—and led to the FDA’s accelerated approval. The secondary end points were also promising, an improved response rate of 37% versus 21% (P <.001), and improved 1-year survival rate of 81% versus 73% (P = .01), respectively.4 As is the case with all accelerated approvals, the FDA requires ≥1 postmarketing studies to confirm or refute the perceived benefit that had led to the accelerated approval.3 Because of the business/financial risk involved with performing large trials that may be rejected by the FDA, the process proceeds with planning meetings that include the FDA, to ensure that the required end points and trial design are clearly defined and deemed acceptable. Accordingly, during a meeting between the manufacturer (Genentech) and the FDA (a type B meeting) on February 2, 2009, the “FDA confirmed that the basis for conversion to full approval will be demonstrated improvement in progression-free survival and evidence that survival is not impaired.”14 This is the key focus of the regulatory argument. With this confirmation, Genentech carried out the RIBBON-1 and the AVADO trials, which were designed to demonstrate (1) a benefit in PFS, and (2) no detriment to OS. The postmarketing studies presented to the FDA included the E2100 (N = 722), RIBBON-1 (N = 1237), and AVADO (N = 736) trials, which totaled >2500 patients randomized and analyzed in these trials.4-7,10 The combined data with 24-month updated data from AVADO showed median 1.9 months and mean 2.5 months of improvement in PFS, which were statistically significant (hazard ratio, 0.67). This clearly meets the first requirement of the FDA.14 The 1-year OS was 77% and 82%, respectively, with a projected median survival of 26.4 and 26.7 months, respectively, with chemotherapy alone or with bevacizumab. Although not superior, this clearly demonstrates that survival was not impaired by treatment with bevacizumab.14 The primary concern of ODAC and of the FDA that led to the removal of the approval stemmed from the survival data (ie, evidence that patients lived longer) and the quality-of-life data.15 This is unfortunate, because the trials were neither designed nor powered to answer the survival question. With the first evaluation of the E2100 study, one can substitute the survival numbers for event rate to see that the study is underpowered to answer the OS question.4,5 The trial’s statistical design

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stated the need for 546 PFS events in 685 patients to reach the 2-month threshold, with a power of 85%; however, only 483 deaths occurred among the 722 patients, with a projected survival difference of 1.7 months.4 This is close to the unwritten 2-month survival advantage that will reset the standard for diseases such as lung cancer.16,17 One of the reasons it is unfortunate that the E2100 trial was not designed or powered to answer the OS question is that the study was done before the drug’s approval, which minimized the use of second-line bevacizumab. The RIBBON-1 study was designed with 2 cohorts: (1) a capecitabine ± bevacizumab cohort, and (2) a taxane/anthracycline ± bevacizumab cohort.7 The capecitabine cohort required 405 PFS events for 600 patients to detect a 2-month survival difference; again, substituting deaths for PFS events makes it easy to see that the study was underpowered; only 191 deaths

It is clear that the postmarketing studies conducted to facilitate the conversion of the initial accelerated approval to the final regular FDA approval were not designed, powered, or intended to answer the impact on OS. Instead, they were designed, carried out, and proved improved PFS, without deleterious effects on survival. occurred among the 605 patients.7 The crossover factor further confounds the OS data: 85% of the placeboreceiving patients were given ≥1 subsequent chemotherapy regimens, and >50% of those patients received chemotherapy plus bevacizumab.7 Therefore, comparing OS in this study would actually compare the timing (first line vs second line) rather than the true impact of bevacizumab versus no bevacizumab. In the end, it is clear that the postmarketing studies conducted to facilitate the conversion of the initial accelerated approval to the final regular FDA approval were not designed, powered, or intended to answer the impact on OS. Instead, they were designed, carried out, and proved improved PFS, without deleterious effects on survival, which had been the FDA’s agreed upon end point for conversion to regular approval.14 From a regulatory perspective, therefore, bevacizumab clearly should be approved for breast cancer, which would require the FDA to honor its commitment and advice regarding required regulatory end points. The key question in this debate relates to efficacy—Is a 2.5-month improvement in PFS and increased

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CLINICAL CONTROVERSIES

response rate sufficient for the agent to be used (off label) as first-line treatment for MBC? To answer this question in a more objective fashion, we need to consider other precedence in MBC, such as the addition of capecitabine to docetaxel (compared with docetaxel alone). The pivotal study for approval of this combination regimen came from a single study with a combined 511 patients in the 2 arms (255/256).18 The results from this trial are very similar to the data seen with bevacizumab plus chemotherapy: a 58-day increase in PFS, an increase from 22% to 32% in response rate, and a 90-day increased survival. The chemotherapy plus bevacizumab improvements in PFS and response rate are numerically better than these data. Although we do not know the true effect on survival (as discussed above), if we estimate the impact to be approximately 2 months, this would seem to reach the usual survival threshold. Consequently, I would propose that we could compare the efficacy of bevacizumab and chemotherapy to the capecitabine plus docetaxel regimen. Because the utilization of capecitabine and docetaxel varies, this perhaps could be used as a litmus test: if you use docetaxel and capecitabine, then you should consider using bevacizumab plus chemotherapy; if you do not believe that adding capecitabine to docetaxel provides enough benefit to warrant using this combination, you would likely not consider using bevacizumab plus chemotherapy. In summary, I would argue that the threshold for efficacy has been determined by other regimens (primarily by capecitabine added to docetaxel), and that bevacizumab added to chemotherapy appears to provide very similar results and should therefore be available for use in this setting. The other side of efficacy is the toxicity level, or safety, that is required to ensure a net benefit. It is clear that efficacy trumps toxicity; this is most clearly demonstrated with allogeneic hematopoietic stem-cell transplant (SCT) for acute myeloid leukemia (AML).19 However, when the efficacy is more marginal than the results with allogeneic SCT in AML, safety concerns become more importantly and appropriately scrutinized. The pooled data presented to the FDA for bevacizumab clearly show increased overall rates of grade 3 and 4 toxicity with the addition of bevacizumab compared with chemotherapy alone (23% vs 36%, respectively).14 The toxicities in the combination group were known, expected, and consistent with adding bevacizumab to chemotherapy in other settings. The most common safety issues included increased rates of hypertension and proteinuria (approximately 11% increased rate with bevacizumab), as well as an increase in arterial

Journal of Hematology Oncology Pharmacy

thromboembolism and bleeding (approximately 1% higher rate for each).14 Again, it is important to compare this to previous acceptable evidence, such as in the capecitabine and docetaxel regimen in MBC. The pivotal study for capecitabine shows that the combination of these agents led to at least 1 grade 3 toxicity in 76.5% of patients compared with 57.6% of patients with docetaxel alone.18 Although the toxicity level is different between capecitabine and bevacizumab, adding capecitabine to docetaxel increased the percentage of patients who had at least 1 grade 3 AE more than the addition of bevacizumab to chemotherapy (19% vs 13%, respectively). This is an appropriate comparison for toxicity, because as stated above, the efficacy is also similar. In addition, it is important to note that regimens that generate grade 3 and 4 AEs in the range of a 36% rate are common; this reminds us that preventing and managing these toxicities is crucial. Careful monitoring of patients’ blood pressure level and urine for protein, with appropriate intervention, can easily minimize these bevacizumab-induced additional toxicities.14 In summary, the increased toxicity is real and quantifiable; however, it is easy to monitor and manage, and it certainly does not meet a threshold that would restrict the drug from being used on or off label. The last consideration is economics, which arguably is the driving force behind this debate. By removing the approval of bevacizumab for MBC, insurance companies and the Centers for Medicare & Medicare Services have a reason to deny payment for this expensive therapy. The cost of therapy, however, is not under the purview of the FDA’s authority and should not impact approval or disapproval of a drug. In a real-world discussion regarding economics, not paying for bevacizumab for patients with breast cancer because of its high cost would seem unreasonable at many levels. An objective way to evaluate the drug’s cost should consider other uses and benefits of bevacizumab, at similar doses. In the ECOG E3200 trial, patients with colorectal cancer received FOLFOX4 (5-fluorouracil, leucovorin, oxaliplatin) ± bevacizumab with a dose (10 mg/kg every 2 weeks) used in the E2100 breast cancer trial.20 The results of this trial showed that adding bevacizumab to this chemotherapy regimen increased PFS by 2.6 months, response rates by 14%, and OS by 2.1 months.20 Similarly, the ECOG 4599 trial evaluated carboplatin and paclitaxel ± bevacizumab (15 mg/kg every 3 weeks) in patients with advanced-stage non–small-cell lung cancer (NSCLC). The results of this study show that adding bevacizumab to this chemotherapy regimen increased PFS by 1.7 months, increased response rate by 20%, and OS by 2 months.17

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Bevacizumab in Metastatic Breast Cancer

These numbers look very similar to the cumulative results of adding bevacizumab (10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks) to chemotherapy for breast cancer: a PFS increase of 1.9 or 2.5 months (median and mean, respectively), increase in response rate of 11% to 26%, and a projected survival from the E2100 study (as discussed above) of 1.7 months. If one views the above data as similar (as I do), then saying that it is cost-prohibitive could be interpreted as saying that less money should be spent for patients with breast cancer than for those with colorectal or lung cancer. Such a conclusion, I believe, is ethically inappropriate. In summary, although bevacizumab for MBC is expensive, its efficacy, dosing, and, therefore, cost are similar to those seen with the use of this drug in colorectal or lung cancer, which makes this argument defunct. Furthermore, the FDA does not consider cost in its drug approval decisions. Finally, Genentech followed the regulatory process and sought guidance from the FDA to design trials and reach end points required to convert a conditional, accelerated approval to a full, final FDA approval. The cumulative data from these trials (with >2500 patients) demonstrate the achievement of PFS (median, 1.9 months; mean, 2.5 months) and no detrimental effect on survival. Regretfully, the FDA does not have a PFS threshold that the agency would consider approvable. This appears to be a “bait and switch” maneuver; the FDA advised or agreed to a PFS end point, never stating how much was enough, but in the end only voiced concern that there was no evidence to demonstrate a survival advantage. The FDA made a motion to maintain its accelerated approval, while allowing appropriate OS data to be collected; and yet, the FDA decided to remove its initial approval. Based on the E2100 OS data (still inappropriate, but the best we have), the compiled PFS, safety data, and cost, bevacizumab should maintain its original approval, because the data look very similar to existing precedence in MBC (capecitabine added to docetaxel), colorectal cancer (bevacizumab added to FOLFOX4), and NSCLC (bevacizumab added to carboplatin plus paclitaxel). ■ Author Disclosure Statement Dr Mandock and Dr Adams have reported no conflicts of interest. Dr Soefje is on the advisory board of Topotarget.

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References 1. Pollack A. FDA revokes approval of Avastin for use as breast cancer drug. New York Times. November 18, 2011. www.nytimes.com/2011/11/19/business/fda-revokesapproval-of-avastin-as-breast-cancer-drug.html?_r=1&ref=health. Accessed November 20, 2011. 2. US Food and Drug Administration Modernization Act of 1997, S 830, 105th Cong, 1st Sess (1997). www.fda.gov/downloads/RegulatoryInformation/Legislation/ FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/ FDAMA/FullTextofFDAMAlaw/UCM089145.pdf. Accessed November 20, 2011. 3. US Food and Drug Administration. Guidance for industry: fast track drug development programs—designation, development, and application review. Procedural revision 2. January 2006. www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm079736.pdf. Accessed November 20, 2011. 4. Miller K, Wang M, Grawlow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676. 5. Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2009;27:4966-4972. Epub 2009 Aug 31. 6. Miles D, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2010;28:32393247. Epub 2010 May 24. 7. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebocontrolled, phase III trial of chemotherapy with or without bevacizumab for first line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260. Epub 2011 Mar 7. 8. Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-week paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of the Cancer and Leukemia Group B Protocol 9840. J Clin Oncol. 2008;26:1642-1649. 9. Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008;26:1987-1992. 10. Miller KD, Chap LL, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005;23:792-799. 11. Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29:4286-4293. Epub 2011 Oct 11. 12. Smith IE, Pierga JY, Biganzoli L, et al, for the ATHENA Study Group. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol. 2011;22:595-602. Epub 2010 Sep 5. 13. Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res. 2010;16:5972-5980. 14. Horning S. Avastin combined with chemotherapy in HER2-negative first line metastatic breast cancer (MBC). www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM219 979.pdf. Accessed November 30, 2011. 15. National Cancer Institute. FDA approval for bevacizumab: metastatic HER2-negative breast cancer. November 18, 2011. www.cancer.gov/cancertopics/druginfo/fdabevacizumab. Accessed November 30, 2011. 16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): non-small cell lung cancer v.2.2012. Updated 2011. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed November 30, 2011. 17. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542-2550. 18. Xeloda (capecitabine) package insert. Roche Pharmaceuticals; Nutley, NJ; 2011. 19. Bishop MR, Pavletic SZ. Hematopoietic stem cell transplantation (Chapter 32). In: Abeloff MD, Armitage JO, Niederhuber JE, et al, eds. Abeloff’s Clinical Oncology. 4th ed. Philadelphia, PA: Churchill Livingston; 2008:501-512. 20. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539-1544.

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YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

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Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

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Current Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults Lisa K. Lohr, PharmD, BCOP, BCPS

J Hematol Oncol Pharm. 2011;1(4):13-21. www.JHOPonline.com Disclosures are at end of text

Background: Chemotherapy-induced nausea and vomiting (CINV) is a significant complication for patients with cancer. Patients have different risk factors for CINV, and chemotherapy agents differ in their emetogenicity. Despite therapeutic advances, the majority of patients with cancer will experience CINV during their chemotherapy treatment. Objective: To review the current therapies available for the prevention and treatment of CINV in patients with cancer. Discussion: Several important neurotransmitters are involved in the emetic process, and these serve as targets for pharmacologic antiemetics. The serotonin (5-hydroxytryptamine) type-3 (5-HT3) receptor antagonists form the cornerstone of antiemetic regimens for moderately or highly emetogenic chemotherapy, and they have few adverse effects. The four 5-HT3 antagonists currently available for the prevention and treatment of CINV are ondansetron, granisetron, dolasetron, and palonosetron. Dexamethasone is used in conjunction with 5-HT3 antagonists for moderately to highly emetogenic regimens. It has some adverse effects associated with short-term use, although this is seen less than with long-term use. Neurokinin-1 antagonists have a different antiemetic mechanism and are useful when used in combination with a 5-HT3 antagonist and dexamethasone. Other antiemeticsâ&#x20AC;&#x201D;such as dopamine antagonists, olanzapine, or cannabinoidsâ&#x20AC;&#x201D;are useful in some circumstances. Choosing an appropriate antiemetic regimen requires assessment of the emetogenicity of the chemotherapy agents and a consideration of patientrelated risk factors. Conclusion: The care for patients with cancer can be improved by the development of standard antiemetic regimens based on the emetogenicity of particular antineoplastic agents and protocols. Standard regimens should be adjusted based on an individual patientâ&#x20AC;&#x2122;s response to the particular drug regimen.

he impact of chemotherapy-induced nausea and vomiting (CINV) for the patient with cancer cannot be overemphasized. Uncontrolled CINV has been cited as one of the greatest fears among people undergoing cancer treatments.1,2 Advances in antiemetic therapy in the past 20 years have improved patient experiences and outcomes. Despite this, the majority of patients with cancer will experience CINV during their chemotherapy treatments.1,3-6 In particular, nausea is less well controlled than vomiting. Uncontrolled CINV symptoms lead to reduced quality of life, decreased ability for self-care, and low patient morale, as well as to increased healthcare costs.4-7 Preventing and controlling CINV is a vital part of the pharmaceutical care of the Dr Lohr is Oncology Pharmacy Specialist, Oncology Medication Therapy Management, Masonic Cancer Center, University of Minnesota Physicians/Fairview, Minneapolis, MN.

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patient with cancer. This article reviews the current therapies available for the prevention and treatment of CINV.

Neurophysiology CINV represents a wide range of symptoms, from mild, queasy nausea to repetitive vomiting and retching. Acute symptoms can begin within minutes of the administration of chemotherapy, but delayed symptoms can also last for many days afterward. Anticipatory CINV can also occur before chemotherapy administration, as a result of a conditioned response to poor emetic control in previous cycles of chemotherapy. Acute CINV is described as symptoms occurring within the first 24 hours after chemotherapy. Delayed CINV is experienced by patients after the acute phase; these nausea and vomiting symptoms usually peak at about 2 to 3 days after chemotherapy but may last for several days longer.

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In addition to chemotherapy, many other medical conditions can lead to nausea and vomiting in patients with cancer. These include hypercalcemia, gastroparesis, gastrointestinal reflux, brain metastases, infections, and many others. Many medications used by patients with cancer can lead to nausea and vomiting, including antibiotics, antifungals, opiate analgesics, and others. It is important to consider these other causes and treat them appropriately, even though they may coincide with CINV. The symptoms of CINV result from activation of parts of the central nervous system (CNS) and the peripheral nervous system. In the classically described pathway, the toxin exposure is detected by the chemoreceptor trigger zone in the CNS, as well as via the enterochromaffin cells in the gastrointestinal tract. In addition, signals from the cerebral cortex, the limbic system, and the vestibular systems can trigger or accentuate the emetic response. In reaction to these signals, the vomiting center of the CNS activates the emetic response, which includes salivation, contraction of the abdominal muscles, relaxation of the esophageal sphincter, and contraction of the stomach muscles, as well as tachycardia, dizziness, and sweating.

Because most chemotherapy regimens use more than 1 antineoplastic agent given on a single day, it is difficult to predict the emetogenicity of these combination regimens. The transmission of the vomiting signals seen with CINV involves multiple neurotransmitters and receptors. The predominant receptors are the serotonin (5-hydroxytryptamine) type-3 (5-HT3) receptor antagonists, neurokinin-1 (NK1) antagonists, and dopamine receptors. Additional neurotransmitters involved include corticosteroid, endogenous cannabinoids, GABA, acetylcholine, and histamine. The activation or inhibition of these neurotransmitters forms the basis of pharmacologic therapy for CINV. Because multiple neurotransmitters are involved in this process, multiple antiemetic medications are necessary for the maximal prevention and treatment of CINV.

Risk Factors The risk for CINV varies among patients who receive chemotherapy. Patient-related risk factors associated with higher rates of CINV include female sex, younger age, poor emetic control in previous chemotherapy cycles, a history of motion sickness or nausea during pregnancy, anxiety and/or depression, and no history of alcohol abuse. The primary determinant of the prevalence of CINV

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is the inherent emetogenicity of the chemotherapy agents administered. The emetogenicity of chemotherapy agents has been classified into 4 categories.7,8 Highly emetogenic agents are those causing CINV in <90% of patients. The largest group is the moderately emetogenic agents, leading to CINV in 30% to 90% of patients. Low emetogenic level chemotherapy results in CINV symptoms in 10% to 30% of patients. Finally, agents with minimal emetogenicity cause CINV symptoms in fewer than 10% of patients.7,8 Table 1 lists the emetogenicity of various chemotherapy agents given by injection. The characteristics of CINV seen with oral chemotherapy agents are different with regard to onset, duration, and severity.8 Most oral chemotherapy agents have minimal to low emetogenicity, but some have moderate to high emetogenicity. Table 2 lists the emetogenic level seen with oral chemotherapy agents. In addition to the emetogenicity, other chemotherapy-related risk factors include high doses, fast infusions, and multiday chemotherapy administration. Multiday chemotherapy regimens are particularly challenging, because the delayed CINV symptoms are overlaid on the latter dayâ&#x20AC;&#x2122;s acute CINV. Because most chemotherapy regimens use more than 1 antineoplastic agent given on a single day, it is difficult to predict the emetogenicity of these combination regimens. It is recommended that the antiemetic regimen be designed to be consistent with the highest emetogenicity associated with the chemotherapy agents given on each day.

The 5-HT3 Antagonists The 5-HT3 receptor antagonists are effective antiemetic agents associated with minimal adverse effects. These agents block serotonin release from the gastrointestinal tract in addition to blocking serotonin receptors in the CNS. When initially approved in the early 1990s, the 5-HT3 antagonists became the first highly active antiemetics that did not have substantial adverse effects. The 4 agents in this classâ&#x20AC;&#x201D;dolasetron, granisetron, ondansetron, and the most recently approved palonosetronâ&#x20AC;&#x201D;are available in a variety of dosage forms in adults (Table 3). The 5-HT3 antagonists are more potent as antiemetic agents than antinausea medications. These agents demonstrate a plateau effect: once enough medication has been given to block the receptors, more medication is not more effective. For patients who can take oral medications, oral therapy is as effective as intravenous (IV) dosing.1,7,9,10 Except for palonosetron, the 5-HT3 antagonists are not more effective than other agents (ie, prochlorperazine, aprepitant, or dexamethasone) for the prevention of delayed CINV.1,9-13

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Current Practice in the Prevention and Treatment of CINV

Table 1 Emetogenic Level Associated with Injectable Chemotherapy Agents Chemotherapy agent

Emetogenic level

Chemotherapy agent

Emetogenic level

Aldesleukin (Proleukin)

Low: ≤12 million U/m2 Moderate: >12 million-15 million U/m2

Gemcitabine (Gemzar)

Low

Idarubicin (Idamycin)

Moderate with high risk of delayed CINV

Ifosfamide (Ifex)

Moderate

Interferon alpha-2b (Intron A)

Low: <10 million U/m2 Moderate: ≥10 million U/m2

Alemtuzumab (Campath)

Minimal

Arsenic Trioxide (Trisenox)

Moderate

Asparaginase (Elspar)

Minimal

Azacitadine (Vidaza)

Moderate

Ipilimumab (Yervoy)

Minimal

Bendamustine (Treanda)

Irinotecan (Camptosar)

Bevacizumab (Avastin)

Moderate Minimal

Moderate, with some risk for delayed CINV

Bleomycin (Blenoxane)

Minimal

Ixabepilone (Ixempra)

Low

Bortezomib (Velcade)

Low

Mechlorethamine (Mustargen)

High

Busulfan (Bulsulfex)

Moderate

Melphalan (Alkeran)

Moderate

Cabazetaxel (Jevtana)

Low

Methotrexate (Trexall)

Carboplatin (Paraplatin)

Moderate, with high risk for delayed CINV

Carmustine (BiCNU)

Moderate: ≤250 mg/m2 High: >250 mg/m2

Minimal: <50 mg/m2 Low: 50-249 mg/m2 Moderate: ≥250 mg/m2, with some risk for delayed CINV

Mitomycin (Mutamycin)

Low

Minimal

Mitoxantrone (Novantrone)

Low

Moderate: <50 mg/m High: ≥50 mg/m2, with high risk for delayed CINV

Nelarabine (Arranon)

Minimal

Ofatumumab (Arzerra)

Minimal

Oxaliplatin (Eloxatin)

Moderate

Cladribine (Leustatin)

Minimal

Paclitaxel (Taxol)

Low

Clofarabine (Clolar)

Moderate

Low

Cyclophosphamide (Cytoxan)

Moderate: ≤1500 mg/m2, with high risk for delayed CINV High: >1500 mg/m2, with high risk for delayed CINV

Paclitaxel Protein Bound (Abraxane) Panitumumab (Vectibix) Pegasparaginase (Oncaspar)

Minimal

Peginterferon alfa-2b (Sylatron)

Minimal

Pemetrexed (Alimta)

Low

Cetuximab (Erbitux) Cisplatin (Platinol)

Minimal

Cytarabine (Ara-C, Cytosar-U)

Minimal: <100 mg/m2 Low: 100-200 mg/m2 Moderate: >200 mg/m2

Pentostatin (Nipent)

Low

Dacarbazine (DTIC)

High

Pralatrexate (Folotyn)

Moderate

Dactinomycin (Cosmegen)

Moderate

Rituximab (Rituxan)

Minimal

Daunorubicin (Cerubidine)

Moderate

Romidepsin (Istodax)

Low

Decitabine (Dacogen)

Minimal

Streptozocin (Zanosar)

High

Docetaxel (Taxotere)

Low

Temozolamide (Temodar)

Moderate

Doxorubicin (Adriamycin)

Moderate, with high risk for delayed CINV

Temsirolimus (Torisel) Teniposide (Vumon)

Minimal Low

Doxorubicin Liposomal (Doxil)

Moderate

Thiotepa (Thiotepa)

Low

Eribulin (Halaven) Epirubicin (Ellence)

Low Moderate, with high risk for delayed CINV

Topotecan (Hycamptin)

Moderate

Trastuzumab (Herceptin)

Minimal

Vinblastine (Velban)

Minimal

Etoposide (VePeSid)

Low

Vincristine (Oncovin)

Minimal

Fludarabine (Fludara)

Minimal

Vinorelbine (Navelbine)

Minimal

Fluorouracil (Adrucil)

Low

CINV indicates chemotherapy-induced nausea and vomiting. Sources: References 7-9, 15.

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Table 2 Emetogenic Level Associated with Oral Chemotherapy Agents Chemotherapy agent Emetogenic level Altretamine (Hexalen)

High

Bexarotene (Targretin)

Low

Busulfan (Myleran)

Minimal: <4 mg Moderate: ≥4 mg

Capecitabine (Xeloda)

Low

Chlorambucil (Leukeran)

Minimal

Cyclophosphamide (Cytoxan)

Low: <100 mg/m2/day Moderate: ≥100 mg/m2/day

Dasatinib (Sprycel)

Minimal

Erlotinib (Tarceva)

Minimal

Etoposide (VePeSid)

Moderate

Everolimus (Afinitor)

Minimal

Fludarabine (Fludara)

Low

Gefitinib (Iressa)

Minimal

Hydroxyurea (Hydrea)

Minimal

Imatinib (Gleevec)

Moderate

Lapatinib (Tykerb)

Low

Lenalidomide (Revlimid)

Minimal

Lomustine (CeeNU)

Moderate

Melphalan (Alkeran)

Minimal

Mercaptopurine (Purinethol)

Minimal

Methotrexate (Trexall)

Minimal

Nilotinib (Tasigna)

Low

Pazopanib (Votrient)

Low

Procarbazine (Matulane)

High

Sorafenib (Nexavar)

Minimal

Sunitinib (Sutent)

Minimal

Temozolamide (Temodar)

Low: ≤75 mg/m2/day Moderate: >75 mg/m2/day

Thalidomide (Thalomid)

Minimal

Thioguanine (Tabloid)

Minimal

Topotecan (Hycamptin)

Low

Tretinoin (Vesanoid)

Low

Vandetanib (Zactima)

Minimal to low

Vorinostat (Zolinza)

Low

Sources: References 7-9, 15.

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The 5-HT3 antagonists are well tolerated and have few adverse effects. The most often reported side effects include headache, constipation, and diarrhea. In addition, prolonged corrected QT (QTc) interval and other cardiac dysrhythmias have been reported, with an incidence of up to approximately 5% (based on Lexicomp and Micromedex information). It is unclear what the true incidence of adverse events is for the different 5HT3 antagonists, because these are likely underreported. The US Food and Drug Administration (FDA) has now warned that IV dolasetron should not be used for the prevention of CINV, because the drug increases the risk for torsades de pointes. The FDA has added warnings to the label of ondansetron against the use of the drug by patients with a long QT syndrome and is recommending electrocardiographic monitoring for patients at high risk for this event—those with electrolyte abnormalities, congestive heart failure, or bradyarrhythmias, and patients using concomitant medications that can increase the QTc interval. For patients without underlying cardiac rhythm disorders or concurrent treatment with other medications that prolong the QTc interval, it is not clear how clinically significant this potential adverse effect is. It is generally accepted that there are no substantial differences in antiemetic efficacy among the 5-HT3 antagonists, except for palonosetron.7,9,10,14,15 With its longer half-life, palonosetron was shown in the original clinical trials to have equivalent or superior effectiveness in the acute and the delayed phases of CINV.7,10,15 These original trials were hampered by including comparator groups that did not reflect the standard of care for highly or moderately emetogenic chemotherapy. Since then, several studies have provided information that further delineates the effects of palonosetron.16-20 When taken in total, current evidence suggests that palonosetron has a small, but real, increase in antiemetic efficacy, especially in the delayed phase.7,16-20 In light of this new evidence, the National Comprehensive Cancer Network (NCCN) guidelines now list palonosetron as the preferred 5-HT3 antagonist for highly and moderately emetogenic chemotherapy.7 The antiemetic guidelines from the Multinational Association of Supportive Care in Cancer (MASCC), as well as the guideline from the American Society of Clinical Oncology (ASCO), identify palonosetron as the preferred 5-HT3 antagonist for moderately emetogenic chemotherapy that is not based on anthracyclinecyclophosphamide regimens.9,15 Palonosetron, however, is substantially more expensive than the alternative agents, and cost-effectiveness should be taken into consideration when choosing among the available 5-HT3 receptor antagonists.

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Current Practice in the Prevention and Treatment of CINV

Table 3 Dosing of Serotonin Type 3 Antagonists in Adults Agent

Dose for acute CINV (on any day of highly/moderately emetogenic chemotherapy)

Dose for delayed CINV

Dolasetron (Anzemet)

Oral: 100 mg

Oral: 100 mg/day

Granisetron (Kytril, oral)

Oral: 2 mg once or 1 mg twice daily IV: 1 mg Topical: 3.1 mg/24 hr (1 patch/7days)

Oral: 1-2 mg/day or 1 mg twice daily Topical: Continuation of patch up to 7 days

Oral: 16-24 mg IV: 8-24 mg IV: 0.25 mg once

Oral: 8 mg twice daily or 16 mg/day

Granisetron (Sancuso, patch) Ondansetron (Zofran) Palonosetron (Aloxi)

None

IV indicates intravenous.

Corticosteroids Corticosteroids, and dexamethasone in particular, have long been used for the prevention and treatment of CINV. Despite the widespread use of corticosteroids, their precise antiemetic mechanism of action is still unclear. The potential mechanisms may include activation of glucocorticoid receptors in the CNS, decreased release of serotonin, inhibition of prostaglandin synthesis in the cerebral cortex, and alteration of cortical input into the emetic center in the CNS.21 Although dexamethasone can be used alone for a chemotherapy regimen with low emetogenicity, it is more often used in conjunction with a 5-HT3 antagonist, with or without an NK1 receptor antagonist, for moderately to highly emetogenic regimens. In these situations, dexamethasone adds about 15% to 20%21 to the complete antiemetic response rate. Dexamethasone is active in the acute and the delayed phases of CINV. The short-term use of dexamethasone in doses used in CINV is usually well tolerated, although the drug is sometimes underutilized, because of concern for its associated adverse effects.21 The most frequently reported adverse effects include insomnia, anxiety, mood changes, increased appetite, mild fluid retention, stomach discomfort, hyperglycemia, and a burning in the rectal/vaginal area when IV doses are infused too rapidly. Hyperglycemia is often seen in patients with preexisting or undiagnosed diabetes. In some patients, the hyperglycemic effect is significant enough to warrant additional glucose monitoring or alterations of antidiabetic medications. The appropriate dexamethasone dose depends on the emetogenicity of the chemotherapy and on whether an NK1 antagonist is coadministered. One group of researchers explored the doseâ&#x20AC;&#x201C;response relationship of dexamethasone in the context of highly emetogenic chemotherapy, showing that the 12-mg and 20-mg doses

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of the drug were associated with a higher complete response rate than the 4-mg and 8-mg doses.22 The investigators also studied different doses and regimens of dexamethasone in moderately emetogenic chemotherapy and found that higher doses were not more effective than a single 8-mg dose.23 These studies have helped shape the current dosing recommendations found in the various guidelines. The dose and schedule of dexamethasone should be modified if a patient will also receive an NK1 antagonist. Aprepitant and fosaprepitant inhibit the cytochrome (CY) P450 3A4â&#x20AC;&#x201C;based metabolism of dexamethasone and result in an approximately 2-fold increase in the area under the curve (AUC) of dexamethasone. Overall, dexamethasone doses are reduced by half if used concurrently with aprepitant. Available CINV guidelines differ slightly in their recommendations for dexamethasone dose.7,9,15 Most guidelines recommend 12 mg to 20 mg of dexamethasone for the acute phase of highly emetogenic chemotherapy and 8 mg to 12 mg for moderately emetogenic chemotherapy. For regimens with a high risk of delayed CINV, oral dexamethasone 8 mg daily or twice daily for 2 to 3 days is recommended, depending on whether an NK1 antagonist is also given.7,9,15 Newer research has explored the question of whether, when administered with palonosetron, a single dose of dexamethasone offers the same efficacy as the typical 3-day dexamethasone regimen.24,25 Two noninferiority studies enrolled patients receiving moderately emetogenic chemotherapy. All 632 patients in the 2 studies combined received IV palonosetron 0.25 mg and IV dexamethasone 8 mg before chemotherapy administration. The patients in the control arms of both studies also received oral dexamethasone on days 2 and 3 (8 mg daily in one study and 4 mg twice daily in the other study).24,25 Both trials showed that the 1-day dexamethasone regimen was noninferior to the 3-day regimen for patients

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receiving moderately emetogenic chemotherapy. However, in one study, the benefit was most apparent in patients receiving chemotherapy other than anthracycline-cyclophosphamide regimens, and in the other study there was a trend toward better nausea control on day 3 with the 3-day dexamethasone regimen.24,25

Neurokinin-1 Antagonists The NK1 antagonists block the action of substance P on the emetic pathways. Aprepitant is the NK1 antagonist administered orally. Fosaprepitant is a prodrug of aprepitant, administered intravenously. Early trials of aprepitant showed that aprepitant administration significantly increased the complete antiemetic response by 12% to 20%, depending on the trial.26 In these trials, aprepitant was administered orally (125 mg before chemotherapy and 80 mg on days 2 and 3), along with a 5-HT3 antagonist and dexamethasone, in patients receiving moderately and highly emetogenic chemotherapy.26

The group consisting of the 5-HT3 antagonists, dexamethasone, and the NK1 antagonists define the most active antiemetic medications, but there is still a need for alternative antiemetics. In general, it is best to consider agents with a different pharmacologic mechanism of action. Aprepitant and fosaprepitant were very well tolerated in these trials, and adverse effects did not differ between the 2 treatment arms.26 Venous irritation has been noted with IV administration, which may require dilution in a larger volume of IV solution. Aprepitant/fosaprepitant is recommended for patients receiving highly emetogenic chemotherapy, as well as those receiving moderately emetogenic chemotherapy associated with a high risk for delayed nausea and vomiting. Aprepitant is metabolized primarily via the CYP3A4 pathway and to a lesser degree via CYP1A2 and CYP2C19 pathways. The activity of aprepitant may be altered when administered with medications that are CYP3A4 inhibitors or inducers. Aprepitant itself is a moderate inhibitor of CYP3A4 and may affect the concentrations of other agents metabolized by this pathway.26,27 The results of clinical trials and clinical observation do not reveal any clinically relevant drug interactions with chemotherapy agents metabolized via the CYP3A4 pathway. One important drug interaction, however, is seen with corticosteroids. Dexamethasone is metabolized via the CYP3A4 pathway, and roughly a 2-fold increase

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in AUC is seen when dexamethasone is administered with aprepitant, although this effect is greater with oral dexamethasone than with IV doses of the drug.26, 27 In addition, aprepitant is an inducer of the CYP2C9 pathway, and it has effects on the elimination of the S-isomer of warfarin, which is metabolized by the CYP2C9 pathway.26, 27 Approximately 5 days after completion of aprepitant therapy a reduction is seen in the S-isomer concentration, with a concurrent decrease in the international normalized ratio (INR). Because aprepitant is used intermittently, the INR value should be monitored closely for 2 weeks after each dose or cycle of aprepitant or fosaprepitant. To enable IV administration of the first dose of an NK1 antagonist before chemotherapy, fosaprepitant was developed as an IV prodrug of aprepitant. A pharmacokinetic analysis showed that a 115-mg IV dose of fosaprepitant is equivalent to that of a 125-mg oral dose of aprepitant.28 Increasing evidence shows that the initial dose of an NK1 antagonist provides most of the antiemetic activity of aprepitant or of fosaprepitant. A recent trial demonstrated the effectiveness of a single 150-mg dose of fosaprepitant in the prevention of CINV.29 In this large study of 2247 patients receiving highly emetogenic chemotherapy, one group received fosaprepitant IV 150 mg before chemotherapy and the other group received the typical aprepitant oral regimen of 125 mg, 80 mg, and 80 mg over 3 days. All patients received ondansetron and dexamethasone, although patients in the fosaprepitant arm received more dexamethasone on days 3 and 4, because of the expectation that the drug interaction would have dissipated. The complete emetic response in the fosaprepitant arm was found to be noninferior to that seen in the aprepitant arm (71.9% vs 72.3%, respectively).29

Other Antiemetics The group consisting of the 5-HT3 antagonists, dexamethasone, and the NK1 antagonists define the most active antiemetic medications, but there is still a need for alternative antiemetics. In general, it is best to consider agents with a different pharmacologic mechanism of action. Dopamine antagonists, such as prochlorperazine or promethazine, are often used for breakthrough CINV symptoms. The butyrophenones (eg, haloperidol, droperidol) are highly active antiemetics but can cause significant sedation and have the potential to prolong the QTc interval. The benzodiazepine lorazepam is frequently used for the treatment of breakthrough nausea and vomiting. Exactly how lorazepam acts as an antiemetic is unclear, but it likely affects the limbic or cortical input into the vomiting center. Its additional activity in reducing anx-

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Table 4 Prevention and Treatment of CINV Based on NCCN Guidelines ANTIEMETIC OPTIONS Emetic risk associated Acute phase with IV/oral chemotherapy 5-HT3 antagonist

Acute phase NK1 antagonist

Acute phase steroid

Dolasetron PO or Granisetron PO, IV, or transdermal or Ondansetron PO or IV or Palonosetron IV (preferred)

Aprepitant PO 125 mg or Fosaprepitant IV 115 mg on day 1

Dexamethasone PO Aprepitant PO or IV 12 mg on day 1 80 mg on days 2-3 plus dexamethasone PO 8 mg on days 2-4

Fosaprepitant IV 150 mg on day 1

Dexamethasone PO or IV 12 mg on day 1

Moderate emetic risk

Dolasetron PO or Granisetron PO, IV, or topical or Ondansetron PO or IV or Palonosetron IV (preferred)

± Aprepitant POa 125 mg or Fosaprepitant IVa 115 mg on day 1

Dexamethasone PO 5-HT3 antagonist Consider addition or IV 12 mg on day 1 (dolasetron, of lorazepam and/or granisetron, or H2 blocker or PPI ondansetron) on days 2-3 or Dexamethasone PO 8 mg on days 2-3 or Aprepitant PO 80 mg on days 2-3 (if NK1 antagonist used on day 1)

Low emetic risk

Dexamethasone PO or IV 12 mg/day or Metoclopramide PO or IV 10-40 mg/day (then every 4-5 hrs PRN) or Prochlorperazine PO or IV 10 mg/day (then every 4-5 hrs PRN)

None

Consider addition of lorazepam and/or H2 blocker or PPI

Minimal emetic risk

No routine prophylaxis

None

Consider addition of lorazepam and/or H2 blocker or PPI

None

Consider addition of lorazepam and/or H2 blocker or PPI

Delayed phase

Adjunct therapies

IV chemotherapy High emetic risk

Consider addition of lorazepam and/or H2 blocker or PPI

Dexamethasone Consider addition PO 8 mg on day 2, of lorazepam and/or then 8 mg twice H2 blocker or PPI daily on days 3-4

Oral chemotherapy High-to-moderate emetic risk

Granisetron PO daily or Ondansetron PO daily

None

Low-to-minimal emetic risk

Only if patient experiences CINV: Metoclopramide PO 10-40 mg/day (then every 4-6 hrs PRN) or Prochlorperazine PO 10 mg/day (then every 4-6 hrs PRN) or Haloperidol PO 1-2 mg every 4-6 hrs PRN

Treatment of breakthrough CINV

Dexamethsone PO or IV 12 mg/day or Dolasetron PO 100 mg/day or Dronabinol PO 5-10 mg every 3-6 hrs or Granisetron PO 1-2 mg/day or 1 mg twice daily, or IV 1 mg/day or Haloperidol PO or IV 0.5-2.0 mg every 4-6 hrs or Lorazepam PO or IV 0.5-2 mg every 4-6 hrs or Metoclopramide PO or IV 10-40 mg every 4-6 hrs or Olanzapine PO 2.5-5.0 mg twice daily or Ondansetron PO or IV 16 mg/day or Prochlorperazine PR 25 mg every 12 hrs, or PO or IV 10 mg every 4-6 hrs or Promethazine PO or IV 12.5-25.0 mg every 4 hrs or Scopolamine patch every 72 hrs

NCCN, National Comprehensive Cancer Network; PO, oral; PPI, proton pump inhibitor. a Aprepitant should be added for select patients receiving certain chemotherapies of moderate emetic risk (eg, carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate).

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Antiemesis V.1.2012. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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iety is an added benefit. When low-to-moderate doses (ie, 0.5-1.0 mg) are used, excessive sedation is not usually a problem. Cannabinoids can be useful adjunctive treatments for CINV in selected patients. Dronabinol, and more recently nabilone, are orally available cannabinoid agents. These medications have substantial adverse effects, such as sedation, dysphoria or euphoria, and dry mouth, as well as other CNS adverse effects. These agents are usually reserved for patients who have an inadequate response to other antiemetics and who can tolerate the associated adverse effects.

The prevention of acute CINV in patients receiving highly emetogenic chemotherapy should include a 5-HT3 antagonist and dexamethasone, along with an NK1 antagonist is recommended. Olanzapine was originally developed as an atypical antipsychotic medication but was found to have antiemetic activity thought to be caused by its inhibitory activity at various serotonin and dopamine receptors. After early experience with olanzapine in the treatment of nausea and vomiting in hospice patients, noncontrolled studies of olanzapine have shown the drugâ&#x20AC;&#x2122;s activity in conjunction with 5-HT3 antagonists and dexamethasone in CINV. A recent comparison study showed that a group of patients receiving olanzapine (along with a 5-HT3 antagonist and dexamethasone) had a substantially improved complete emetic response rate compared with patients who did not receive olanzapine.30 The most frequently reported adverse effects with olanzapine include drowsiness, dry mouth, and dizziness. Olanzapine is also highly active in relieving breakthrough CINV symptoms in patients with highly refractory symptoms and is perhaps most often used in this situation.31,32 Gabapentin also has been studied in the prevention of nausea and vomiting. Early research with this agent began after the drugâ&#x20AC;&#x2122;s antiemetic action was noticed in patients with breast cancer who were receiving the drug to help relieve hot flashes. After showing activity in the prevention of CINV in noncontrolled trials, gabapentin was studied in a randomized, double-blind fashion in 8 patients.33 The gabapentin dose in the experimental arm was titrated upward 5 days before chemotherapy began and continued until 5 days after chemotherapy. Patients in both arms received standard therapy with ondansetron and dexamethasone. Significantly more patients had complete antiemetic response in the treatment arm than in

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the control arm, and the gabapentin therapy was well tolerated.33 More research will help to define the role of gabapentin in the prevention of CINV.

Treatment Regimen Recommendations Consensus and evidence-based guidelines and recommendations have been published from 3 major professional oncology groups. The guideline from ASCO was updated in 2011.9 Recommendations from the MASCC and the European Society of Medical Oncology were updated and published in 2011.15 The guidelines from the NCCN are revised and electronically published frequently, often multiple times annually, as new information becomes available.7 Although there are some differences between the guidelines, they largely agree on the basic framework of recommended antiemetic treatment of CINV.7,9,15 The prevention of acute CINV in patients receiving highly emetogenic chemotherapy should include a 5-HT3 antagonist and dexamethasone, along with an NK1 antagonist. For the prevention of delayed CINV in those receiving highly emetogenic chemotherapy, dexamethasone and an NK1 antagonist (if the IV 150-mg fosaprepitant dose is not used) is recommended.7,9,15 For cases with moderately emetogenic chemotherapy, patients should receive a 5-HT3 antagonist and dexamethasone, with or without an NK1 antagonist, in the acute phase. Options for the delayed phase include prophylaxis with a 5-HT3 antagonist, dexamethasone, or an NK1 antagonist plus dexamethasone.7,9,15 Patients receiving low emetogenic chemotherapy can be given a single dose of dexamethasone, a dopamine antagonist, or a 5-HT3 antagonist. Patients who are receiving minimally emetogenic chemotherapy generally do not require any preventive antiemetic. Patients receiving oral chemotherapy associated with a high or moderate emetic potential should be given an antiemetic medication before each dose of the oral chemotherapy.7,9,15 Those receiving oral chemotherapy with a low to minimal emetic potential, as-needed antiemetics should be sufficient. Recommendations from the more frequently updated NCCN guidelines are shown in Table 4. Many patients have breakthrough CINV symptoms. Patients receiving moderately to highly emetogenic chemotherapy should be sent home with 1 to 2 medications to use for breakthrough symptoms, if they occur. The best choice of antiemetic medications would include agents from a different class with a different mechanism of action than those of the antiemetics given for prophylaxis. Patients should be encouraged to take their as-needed antiemetics at the beginning of a nausea episode,

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before the symptoms get worse. Patients should be made aware that many medications used for breakthrough CINV can cause more sedation than other agents. If refractory CINV symptoms continue, the additional agents should be administered on a scheduled basis, and the patient should be evaluated for the need for IV hydration or for electrolyte supplementation. In addition, the antiemetic effectiveness should be evaluated before the next cycle of chemotherapy, and potential modifications should be considered. These may include scheduling active as-needed medications, upgrading the antiemetic regimen to a regimen with greater emetogenic level, or adding olanzapine or a cannabinoid medication. Patients who develop anticipatory nausea and vomiting may receive lorazepam the night before and the morning of the chemotherapy regimen, before they arrive at the treatment center. They may also be offered behavioral interventions, such as relaxation techniques or hypnosis.

Conclusion Because of the multiple neurotransmitters and organs involved in the emetic response, multiple antiemetics, with different mechanisms of action are needed to prevent and treat CINV. By matching the antiemetic regimen to the emetogenic level of the chemotherapy regimen, patients can be offered the optimal preventive regimens. Pharmacists are uniquely positioned to ensure that patients receive the appropriate CINV prevention and treatment, to manage adverse effects, and to improve patient outcomes. ■ Author Disclosure Statement Dr Lohr has reported no conflicts of interest.

References 1. Panesar K. Strategies for managing chemotherapy-induced nausea and vomiting. US Pharmacist. 2011;36(oncology suppl):12-15. 2. Trigg ME, Higa GM. Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice. J Oncol Pharm Practice. 2010;16:233-244. Epub 2010 Jan 19. 3. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol. 2011;22:30-38. Epub 2010 Oct 14. 4. Kris MG. Why do we need another antiemetic? Just ask. J Clin Oncol. 2003;21:4077-4080. Epub 2003 Oct 14. 5. Roscoe JA, Morrow GR, Hickok JT, et al. Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage. 2000;20:113-121. 6. Haiderali A, Menditto L, Good M, et al. Impact on daily functioning and indirect/direct costs associated with chemotherapy-induced nausea and vomiting (CINV) in a US population. Support Care Cancer. 2011;19:843-851. Epub 2010 Jun 9. 7. National Comprehensive Care Network. NCCN clinical practice guidelines in oncology. Antiemesis. V1.2012. July 20, 2011. www.nccn.org/professionals/physi cian_gls/pdf/antiemesis.pdf. Accessed November 14, 2011. 8. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—state of the art. Support Care Cancer. 2011;19(suppl 1):S43-S47. Epub 2010 Oct 24. 9. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:41894198. Epub 2011 Sep 26.

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10. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. 11. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systemic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol. 2005;23:1289-1294. 12. Huang JQ, Zheng GF, Deuson R, et al. Do 5-hydroxytryptamine3 receptor antagonists (5-HT3) improve the antiemetic effect of dexamethasone for preventing delayed chemotherapy-induced nausea and vomiting (CINV)? A meta-analysis of randomized controlled trials. J Clin Oncol. 2004;22(14 suppl):Abstract 6037. 13. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine receptor antagonists versus prochlorperazine for control for delayed nausea caused by doxorubicin: a URCC CCOP randomized controlled trial. Lancet Oncol. 2005;6:765-772. 14. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database of Systemic Reviews 2010. Issue 1. Article No: CD006272. Published online January 20, 2010. http://summaries. cochrane.org/CD006272/serotonin-receptor-antagonists-to-prevent-nausea-andvomiting-after-chemotherapy. Accessed November 14, 2011. 15. Multinational Association of Supportive Care in Cancer. MASCC/ESMO antiemetic guideline 2011. April 2011. http://data.memberclicks.com/site/mascc/ MASCC_Guidelines_English_2011.pdf. Accessed November 14, 2011. 16. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for the prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomized, comparative phase III trial. Lancet Oncol. 2009;10:115-124. Epub 2009 Jan 8. 17. Botrel TE, Clark OAC, Clark L, et al. Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systemic review and meta-analysis. Support Care Cancer. 2011;19:823-832. Epub 2010 May 22. 18. Mattiuzzi GN, Cortes JE, Blamble DA, et al. Daily palonosetron is superior to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemia. Cancer. 2010;116:5659-5666. 19. Yu Z, Liu W, Wang L, et al. The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial. Support Care Cancer. 2009;17:99-102. Epub 2008 Sep 30. 20. Likun Z, Xiang J, Yi B, et al. A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults. Oncologist. 2011;16:207-216. Epub 2011 Jan 31. 21. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy and tolerability analysis. Ann Oncol. 2007;18:233240. Epub 2006 Nov 15. 22. The Italian Group for Antiemetic Research. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. J Clin Oncol. 1998;16:2937-2942. 23. The Italian Group for Antiemetic Research. Randomized, double-blind, dosefinding study of dexamethasone in preventing acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide. J Clin Oncol. 2004;22:725-729. 24. Celio L, Frustaci S, Denaro A, et al. Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial. Support Care Cancer. 2011;19:1217-1225. Epub 2010 Jun 25. 25. Aapro M, Fabi A, Nolè F, et al. Double-blind, randomized, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy. Ann Oncol. 2010;21:1083-1088. 26. Curran MP, Robinson DM. Aprepitant: a review of its use in the prevention of nausea and vomiting. Drugs. 2009;69:1853-1878. 27. Aapro MS, Walko CM. Aprepitant: drug-drug interactions in perspective. Ann Oncol. 2010;21:2316-2323. Epub 2010 May 20. 28. Lasseter KC, Gambale J, Jin B, et al. Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol. 2007;47:834-840. Epub 2007 May 24. 29. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol. 2011;29:1495-1501. Epub 2011 Mar 7. 30. Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of chemotherapy induced nausea and vomiting. J Exper Clin Can Res. 2009;28:131-137. 31. Jackson WC, Taverneir L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med. 2003;6:251-255. 32. Srivastava M, Brito-Dellan N, Davis MP, et al. Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. J Pain Symptom Manage. 2003;25:578-582. 33. Cruz FM, Cubero DIG, Taranto P, et al. Gabapentin for the prevention of chemotherapy-induced nausea and vomiting: a pilot study. Support Care Cancer. Epub 2011 April 5.

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D e M di n Follow-u FFollow-up ll upp N New w Data: ear Media 55-Y 5-Year YYear Median

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

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

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

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

‡

VELCADE (Vc) in combination with MP.

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

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

Median overall survival: survival:

556.4 6 .4 vs 443.1 3..1 m months onths

PPatients atients Sur Surviving viving (%)

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

VELC ADE+MP (n=344) VELCADE+MP

MP ((n=338) n=338)

0 0

Kaplan-Meier estimate.

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

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

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

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Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

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

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

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

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous Leukemia Natalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

J Hematol Oncol Pharm. 2011;1(4):25-32. www.JHOPonline.com Disclosures are at end of text

Background: Before 2001, therapy for chronic myelogenous leukemia (CML) was mainly limited to hydroxyurea, interferon (IFN)-alpha, and allogeneic stem-cell transplant (SCT). Additional therapies, including busulfan, hydroxyurea, cytarabine, and splenic radiation, were used; however, they had limited efficacy in CML. Objective: To review the advances in the pharmacotherapy of chronic-phase CML (CML-CP) and highlight the clinical data regarding the use of dasatinib and nilotinib in patients with newly diagnosed CML-CP. Discussion: Only allogeneic SCT provides the potential for long-term, disease-free survival in CML-CP, but suitable donors are lacking for many patients, and the associated toxicity is formidable. Imatinib mesylate was initially shown to have superior activity in achieving hematologic and cytogenetic responses relative to IFN-based therapy in patients with IFN-alpha–refractory disease and, later, in newly diagnosed patients with CML-CP. In recently published phase 3 randomized trials that compared nilotinib and dasatinib with imatinib in patients with newly diagnosed CMLCP, significantly improved rates of molecular response and cytogenetic remission were seen at 18 months of follow-up with dasatinib and 24 months of follow-up with nilotinib. On the basis of these trials, dasatinib and nilotinib received US Food and Drug Administration approval in 2010 for the treatment of newly diagnosed adults with Philadelphia chromosome–positive CML-CP. Conclusion: The post-imatinib era for first-line treatment of CML is emerging, but long-term data are needed to confirm the optimal therapy for newly diagnosed disease. Because of the relatively immature data in first-line therapy with second-generation tyrosine kinase inhibitors, it remains to be seen whether an increase in response rates will translate into longer progression-free survival, and whether the toxicities associated with nilotinib and dasatinib will decrease over time.

hronic myelogenous leukemia (CML) is a hematologic malignancy initiated by a translocation event that results in the fusion of the breakpoint cluster region (BCR) of chromosome 22 with the Abelson leukemia oncogene (ABL) tyrosine kinase on chromosome 9 in bone marrow stem cells. This chromosomal abnormality is known as the Philadelphia (Ph) chromosome.1,2 The dysregulation of ABL kinase activity transforms the stem cell, resulting in the production of undifferentiated blasts as opposed to normally differentiated white blood cells. Left untreated, CML progresses

Dr Greisl is Oncology Clinical Pharmacist, Department of Pharmacy, and Dr Fausel is Clinical Director, Oncology Pharmacy Services, Indiana University Simon Cancer Center, Indianapolis.

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through an indolent chronic phase to a lethal phase of blast crisis within 3 to 5 years.1 Before the advent of tyrosine kinase inhibitor (TKI) therapy, median survival for patients who had progressed to advanced disease—the accelerated phase— ranged from 6 to 39 months.3,4 For patients in blast crisis, survival was from 2 to 8 months.5,6 Historically, conventional cytotoxic agents such as busulfan and hydroxyurea were used to control peripheral blood counts but did not prevent the progression of disease.1,7 Therapy would become less effective after 3 to 5 years of treatment, after which the disease would transform to accelerated phase or blast crisis. Interferon (IFN)-alpha was the first therapy that was demonstrated to increase overall survival (OS) in CML, and survival was marginally increased with the addition of low-dose cytarabine.8

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REVIEW ARTICLE

A transformative discovery in cancer therapeutics was the characterization of the adenosine triphosphate (ATP) binding site on the BCR-ABL tyrosine kinase, and its role in imatinib-mediated inhibition of that kinase.9 Imatinib, a BCR-ABL TKI, became standard first-line therapy when it was shown to be superior to IFN-alpha plus cytarabine therapy.10 However, mutations in the BCR-ABL tyrosine kinase binding site induce imatinib resistance in some patients, necessitating active second-line therapy, which led to the development and the US Food and Drug Administration (FDA) approval of 2 second-generation TKIsâ&#x20AC;&#x201D;dasatinib and nilotinib. As discussed below, these 2 agents have been shown to achieve cytogenetic remissions and molecular responses in patients with CML who are intolerant of or whose disease is refractory to imatinib. This review discusses the advances in the pharmacotherapy of chronic-phase CML (CML-CP) and highlights the clinical data regarding the use of dasatinib and nilotinib in patients with newly diagnosed disease.

Because of age limitations, the limited availability of appropriately matched donors, and the toxicities associated with treatment, only 30% of patients with CML meet the eligibility criteria for allogeneic SCT, precluding its widespread use. The Pre-Imatinib Era Busulfan was a frontline treatment for CML when in 1963 a clinical trial demonstrated its superiority over 6mercaptopurine therapy during an era when the goal of therapy for patients with CML was limited to normalization of the white blood cell count.11 Hydroxyurea, originally synthesized almost a century earlier, was found to have antileukemic effects in mice and was subsequently investigated as a therapy for CML.12 Metabolic experiments in that study suggested that hydroxyurea inhibited DNA synthesis, thereby blocking the proliferation of transformed blasts. Additional clinical studies demonstrated that hydroxyurea improved survival in patients with CML by extending the length of the chronic phase.13,14 As recently as 1993, the median survival for a patient with CML-CP taking hydroxyurea as a frontline medication was approximately 5 years.14 Busulfan and hydroxyurea have minimal potential to induce cytogenetic response and do not alter the disease course of CML.13,14 In the 1980s, IFN-alpha, a nonspecific, immune-modulating agent, advanced into clinical trials for the treat-

Journal of Hematology Oncology Pharmacy

ment of patients with CML. In randomized clinical trials, IFN-alpha demonstrated efficacy by its ability to induce at least partial hematologic responses in 55% to 86% of patients, at least minor cytogenetic responses of 10% to 52%,8,15-18 a 12% to 20% absolute improvement in the 5year survival rate, and an increase in median OS of 1 to 2 years over previous therapies.19 IFN-alpha has a considerable toxicity profile that includes flulike symptoms along with arthralgia and myalgia and depression.8,20 A study comparing therapy with IFN-alpha monotherapy and IFN-alpha plus cytarabine in patients with recently (â&#x2030;¤6 months) diagnosed CML-CP showed that the 3-year OS increased from 79.1% among patients receiving IFN-alpha alone to 85.7% among those receiving IFN-alpha plus cytarabine.8 In addition, combination therapy increased the percentage of patients who achieved a major cytogenetic response (MCyR) from 24% to 41%.8 Allogeneic stem-cell transplant (SCT) is the only proved option for achieving cure in CML. After a 3- to 5-year follow-up, disease-free survival of patients with good prognostic factors undergoing transplant from human leukocyte antigen (HLA)-matched related donors can be as high as 78%; it ranges from 46% in patients aged >40 years to 61% in patients aged <30 years, for HLA-matched unrelated donors.21,22 Because of age limitations, the limited availability of appropriately matched donors, and the toxicities associated with treatment, only 30% of patients with CML meet the eligibility criteria for allogeneic SCT, precluding its widespread use.23-26 Furthermore, in addition to long-term complications, such as infections and secondary malignancies, late relapses have been seen as long as 14 years or more after transplant.27-29

The Imatinib Era The introduction of imatinib, a multikinase inhibitor with high specificity for the inhibition of BCR-ABL activity, revolutionized the treatment of CML.30 Imatinib was developed from a small-molecule library in a screening for inhibitors of protein tyrosine kinases.31 Imatinib competes with ATP for binding to the BCR-ABL tyrosine kinase in a region known as the phosphate-binding loop (P-loop).9 The interaction of imatinib with the BCR-ABL tyrosine kinase is conformationally sensitive; only the closed conformation of the P-loop serves as a binding site. Cell-culture studies confirmed that imatinib inhibited the growth of CML blasts in vitro.31 Imatinib was studied in a phase 1 dose-escalation trial that examined 83 patients with CML-CP in whom IFN-alpha therapy had failed.32 Patients were succes-

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sively assigned to dosing groups ranging from 25 mg to 1000 mg daily. All doses were well tolerated, and the most common adverse events (AEs) reported were nausea, myalgia, edema, and diarrhea.32 Of the 54 patients who received a dose of 300 mg or more, 98% achieved complete hematologic response, 54% achieved cytogenic response, and 13% achieved complete cytogenic response (CCyR).32 In a second analysis of this study, patients with CML who had progressed to blast crisis also responded to imatinib, but to a lesser extent.33 A total of 38 patients with CML were in myeloid blast crisis and 20 patients either had Ph-positive (Ph+) acute lymphoblastic leukemia (ALL) or were in lymphoid blast crisis. Although 21 of the 38 patients (55%) in myeloid blast crisis responded with a decrease in blasts in the marrow, only 4 (19%) of them achieved complete hematologic response. Although 70% of the patients with ALL/lymphoid blast crisis responded to imatinib, the disease subsequently relapsed in virtually all the responders.33 In a phase 2 study, 454 patients with CML-CP in whom IFN-alpha therapy had failed were treated with oral imatinib 400 mg once daily.34 Complete hematologic response was achieved by 95% of the patients and MCyR was achieved by 60% of patients. After a mean follow-up of 18 months, 89% of the patients remained in chronic phase and 95% were still alive. Intolerable AEs led to imatinib discontinuation in only 2.1% of the patients. The most common AEs consisted of superficial edema, nausea, and muscle cramps.34 In the IRIS (International Randomized Study of Interferon Versus STI571) study, a phase 3, open-label, randomized, controlled trial, imatinib was compared directly with IFN-alpha plus cytarabine as frontline treatment for newly diagnosed CML.10 A total of 553 patients received 400 mg imatinib daily; the IFN-alpha plus cytarabine group (N = 553) received gradually escalating doses of IFN-alpha, up to 5 million U/m2 of body surface area daily. When the maximum tolerated dose was reached, subcutaneous low-dose cytarabine was added to the regimen for 10 days monthly.10 The study design allowed patient crossover from IFNalpha plus cytarabine to imatinib if patients showed no response to treatment, lost response, or had an AE; a majority of the patients (57.5%) crossed over to the imatinib group, and more than one third (43%) who crossed over did so because of intolerance of IFN-alpha.10 The analyzed results did not account for outcomes in patients who crossed over to alternative therapies. The imatinib arm demonstrated greater complete hematologic response (95.3% vs 55.5%, respectively; P <.001), MCyR (85.2% vs 22.1%; P <.001), and CCyR (73.8% vs 8.5%; P <.001) compared with the IFN-alpha plus

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cytarabine arm. At 12 months, progression-free survival (PFS) was 96.6% for the imatinib group and 79.9% for the IFN-alpha group (P <.001).10 The 5-year follow-up demonstrated an increase in CCyR to 82% and OS of 89%.35 Only 6% of the patients randomized to imatinib progressed to accelerated-phase or blastphase CML, and these progression events occurred primarily within the first 2 to 3 years of treatment.35 Two important analyses performed in the 5-year follow-up of the IRIS study demonstrated the association of response at 12 months with long-term disease outcomes. In the first analysis, 97% of 350 patients who achieved CCyR by 12 months of imatinib treatment had not progressed to accelerated-phase or blast-phase CML during the 5-year follow-up.35 Of the 139 patients who achieved CCyR and a major molecular response (MMR)â&#x20AC;&#x201D;defined as â&#x2030;Ľ3-log reduction in BCR-ABL transcriptsâ&#x20AC;&#x201D;at 12 months, 100% remained free of progression to accelerated phase or blast phase at 5 years. AEs decreased over time, and their general profile did not change.35

Some patients develop resistance to imatinib primarily in response to the emergence of cells containing BCR-ABL mutations unresponsive to imatinib. Most of these mutations occur in the kinase domain of the fusion protein. The results at 8-year follow-up were presented in 2009.36 The estimated event-free survival (81%) and OS (85% when all causes are considered, 93% considering only CML-related deaths) continue to remain high and stable. No new toxicities were identified, and only 1 patient had disease progression.36 Some patients develop resistance to imatinib primarily in response to the emergence of cells containing BCR-ABL mutations unresponsive to imatinib. Most of these mutations occur in the kinase domain of the fusion protein.37 In addition, for some patients, the AEs are not tolerable and preclude the use of imatinib.

The Post-Imatinib Era The second-generation TKIs dasatinib and nilotinib were initially studied as treatment alternatives for patients with imatinib-resistant or -intolerant CML. Dasatinib and nilotinib are capable of inhibiting most BCR-ABL mutations, with the exception of the T315I mutation, which is resistant to all currently available TKIs.38,39 The safety and efficacy of nilotinib and dasatinib were first established in the second-line setting in patients with imatinib-resistant or -intolerant CML.

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REVIEW ARTICLE

Table 1 Nilotinib versus Imatinib: Treatment Discontinuation and Adverse Events in the ENESTnd Study

Median dose, mg/day (range)

Nilotinib 300 mg bid (N = 282)

Nilotinib 400 mg bid (N = 281)

Imatinib 400 mg/day (N = 283)

592 (543-600)

779 (581-800)

400 (389-400)

46 (16) 13 (28) 33 (72)

51 (18) 26 (51) 25 (49)

59 (21) 21 (35.6) 38 (64.4)

Median duration of treatment, mo Discontinuation, N (%) Adverse events leading to discontinuation, N (%) Other reason for discontinuation, N (%)

ENESTnd, indicates Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients. Source: Reference 48.

Nilotinib Nilotinib (originally known as AMN107) was rationally designed through close examination of the crystal structure of the imatinib/BCR-ABL tyrosine kinase complex.40 Nilotinib binds to the closed-loop structure of the BCR-ABL tyrosine kinase. However, additional interaction sites between the BCR-ABL tyrosine kinase and nilotinib allow the drug to bind with a much greater affinity than imatinib. The potency of nilotinib for inhibition of the wild-type BCRABL is 20 to 40 times greater than that of imatinib, and its potency for inhibition of many BCR-ABL mutations is much greater than that of imatinib.41 Although nilotinib binds to the BCR-ABL tyrosine kinase with high affinity, its binding to other tyrosine kinases is largely reduced and is generally not significant at clinical doses.42 Nilotinib’s greater selectivity versus imatinib is seen in its higher affinity for the BCR-ABL tyrosine kinase, its similar inhibition of platelet-derived growth factor and c-KIT receptor tyrosine kinases, and its lack of activity against a wide range of other protein kinases, including the C-Src oncogene.40 The efficacy and safety of nilotinib were initially reported in an open-label, phase 2 study of patients with imatinib-resistant or -intolerant CML-CP.43 At 6 months of follow-up, 48% of the patients achieved MCyR and 31% achieved CCyR. The estimated 1-year OS was 95%: nilotinib was well tolerated in these patients. In response to these positive data, nilotinib received FDA approval in 2007 for second-line treatment of CML-CP. At 24 months of follow-up, 46% of patients achieved CCyR with nilotinib therapy, 56% of whom achieved an MMR.44 The estimated PFS rate was 64%, and OS was 87% at 24 months, with no changes in the safety profile.44 The efficacy and safety of nilotinib in the frontline setting were evaluated in a phase 2 trial of 51 patients with newly diagnosed CML-CP.45 By 3 months, 90% of the patients achieved CCyR; by 6 months, that per-

Journal of Hematology Oncology Pharmacy

centage increased to 96%. At 12 months, 81% of the patients achieved an MMR. The estimated event-free survival at 24 months was 90%; transformation-free survival was 98%.45 The most common AEs were increased liver transaminase activity or bilirubin levels, skin rash, fatigue, hyperglycemia, neutropenia, anemia, and thrombocytopenia.45 Most AEs were grade 1 or 2. Grade 3 and 4 AEs included elevation of bilirubin, lipase, or amylase levels. Cardiac events were rare; 2 patients developed hypertension, and 2 developed a prolonged corrected QT (QTc) interval; none of these AEs was grade 3 or 4.45 A second phase 2 trial was conducted by the GIMEMA (Gruppo Italiano Malattie e Matologiche dell’Adulto) CML Working Party to investigate nilotinib as a first-line therapy in 73 patients with newly diagnosed CML.46 All patients achieved complete hematologic response within 3 months. By 6 months, 96% achieved CCyR, and by 12 months 85% achieved an MMR. AEs were similar to those observed in the previous trial.45,46 A recent 3-year analysis demonstrated the durability of nilotinib responses in patients with newly diagnosed CML, without any new safety concerns.47 Nilotinib has been compared with imatinib in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) trial, a phase 3 open-label study (Table 1).48 A total of 846 patients with newly diagnosed CML-CP were randomized in a 1:1:1 ratio into 3 arms: nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily (the control arm). The primary end point was MMR at 12 months.48 At data cutoff, the MMR rates for the 300-mg and 400-mg nilotinib arms were 57% and 54%, respectively, compared with 30% in the imatinib arm.48 The median time to MMR, as estimated by a Kaplan-Meier analysis, was shorter for the 300-mg nilotinib (8.6 months) and 400-mg nilotinib (11.0 months) groups

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compared with the imatinib arm (median not yet reached).48 Complete molecular response (defined as <0.0032% of baseline transcripts on the International Standard) at the data cutoff was 13% and 12%, respectively, for the nilotinib 300-mg and 400-mg arms and 4% for the imatinib arm.48 CCyR rates by 12 months were significantly greater in the 2 nilotinib arms compared with the imatinib arm (80% with nilotinib 300 mg and 78% with 400 mg vs 65% with imatinib; P <.001 for both comparisons).48 Progression to accelerated-phase or blast-phase CML occurred in 11 patients (4%) receiving imatinib compared with 3 patients (<1%) receiving nilotinib (2 in the 300-mg arm and 1 in the 400-mg arm).48 Although no patient who attained an MMR had progressed, 3 patients receiving imatinib who had achieved CCyR progressed. Nilotinib was superior to imatinib in terms of the time to progression (P = .01 for the 300-mg group and P = .004 for the 400-mg group compared with the imatinib-treated group).48 Overall, grade 3 or 4 nonhematologic AEs were uncommon. The incidence of nausea, diarrhea, vomiting, muscle spasm, and edema were higher in the imatinib arm, whereas rash, headache, pruritus, and elevated liver enzymes were higher in the nilotinib arms.48 No patient had a QTc longer than 500 milliseconds or a decreased left-ventricular ejection fraction. Grade 3 or 4 hematologic abnormalities occurred within the first 2 months of therapy for both treatments.48 Recently, results of a 24-month analysis were presented, demonstrating that the responses observed with nilotinib were durable; no new safety concerns emerged with longer follow-up.49 In mid-2010, this trial led to the approval of nilotinib for the treatment of newly diagnosed CML-CP in treatment-na誰ve patients.

Dasatinib Dasatinib (originally known as BMS-354825) was identified through a screening of a small-molecule library for inhibitors of the C-Src kinase.50 The affinity of dasatinib for the BCR-ABL fusion gene is 325-fold higher than that of imatinib.42 Dasatinib can bind to open and closed conformations of the BCR-ABL tyrosine kinase as well as to most BCR-ABL mutations. In addition, dasatinib has inhibitory activity against the C-Src kinase, c-KIT, and the platelet-derived growth factor receptors.42,50 The efficacy and safety of dasatinib were demonstrated in a phase 2 study involving patients with imatinib-resistant or -intolerant CML-CP.51 At 8 months of treatment, 90% of the patients achieved complete hematologic response, 52% achieved an MCyR, and the PFS rate was 92%. Dasatinib was well tolerated, and there was no cross-

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intolerance with imatinib.51 Follow-up at 15 months indicated 91% of patients achieved complete hematologic response and 59% maintained or attained MCyR; PFS was 90%, and OS was 96%.52 A recently published phase 2 study established the safety and efficacy of dasatinib in the frontline setting.53 A total of 62 patients were randomized to receive 100 mg once daily or 50 mg twice daily until either disease progression or an unacceptable AE occurred. The primary end point was an MMR in <40% of the treatment group within 12 months (the average response rate for imatinib).53 Efficacy was similar for the 2 dosages. At 3 months, 82% of the patients achieved a CCyR, and 24% achieved an MMR. By 12 months, 98% of the patients achieved CCyR and 71% achieved an MMR. Complete molecular response was achieved by 7% of the patients; however, this was lost by 30 months.53

A recently published phase 2 study established the safety and efficacy of dasatinib in the frontline setting. At 3 months, 82% of the patients achieved a CCyR, and 24% achieved an MMR. By 12 months, 98% of the patients achieved CCyR and 71% achieved an MMR. Muscle and joint pain, fatigue, rash, headache, and diarrhea were the most common nonhematologic AEs. Grade 3 and 4 nonhematologic AEs consisted of fatigue (6%), joint and muscle pain (6%), peripheral neuropathy (5%), dyspnea (5%), and memory impairment (5%). Pleural effusion occurred in 13% of the patients; 2% of these events were grade 3 in severity. Hematologic toxicities included neutropenia (63%), anemia (81%), and thrombocytopenia (69%).53 The DASISION (Dasatinib versus Imatinib Study in Treatment-Na誰ve CML Patients) trial examined frontline treatment with dasatinib in comparison with imatinib.54 A total of 519 patients with newly diagnosed CML-CP were randomized to 1 of 2 arms: dasatinib 100 mg daily or imatinib 400 mg daily. The primary end point was a confirmed CCyR by 12 months. Confirmation required 2 measures of CCyR, at least 28 days apart.54 Of the patients receiving dasatinib, 77% achieved confirmed CCyR versus 66% of imatinibtreated patients (P = .007). The rate of MMR, a secondary end point, was 46% versus 28%, respectively, at 12 months of follow-up (P <.001).54

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Table 2 Dasatinib versus Imatinib: Treatment Discontinuation and Adverse Events in the DASISION Study Dasatinib 100 mg Imatinib 400 mg once daily once daily (N = 258) (N = 258) Median dose, mg/day 99 (21-136) (range)

400 (125-657)

Median duration of treatment, mo Discontinuation, N (%)

14.0

14.3

40 (15.5)

48 (18.6)

Reason for discontinuation Drug-related AEs, 13 (5.0) N (%)

11 (4.3)

Hematologic AEs, N (%)

4 (1.6)

8 (3.1)

Treatment failure, N (%)

6 (2.3)

10 (3.9)

No CHR or CyR by 6 mo, N (%) ± SD

2 (0.8)

4 (1.6)

PCyR at 12 mo, N (%) No CCyR at 18 mo, N (%) AE unrelated to drug, N (%) Withdrew consent, N (%)

3 (1.2)

6 (2.3)

1 (0.4)

3 (1.2)

1 (0.4)

2 (0.8)

3 (1.2)

Became pregnant, N (%) Did not adhere to therapy, N (%) Lost to follow-up, N (%) Request to discontinue, N (%) Other reason, N (%)

2 (0.8)

3 (1.2)

2 (0.8)

1 (0.4)

3 (1.2)

AEs indicate adverse events; CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; DASISION, Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients; PCyR, partial cytogenetic response. Source: Reference 54.

An examination of the subpopulation of patients in each arm who had achieved CCyR showed a greater MMR rate with dasatinib than with imatinib (54% vs 39%, respectively; P = .002).54 Progression to accelerated phase or blast phase occurred in 5 patients (1.9%) in the dasatinib arm and in 9 patients (3.5%) in the imatinib

Journal of Hematology Oncology Pharmacy

arm. At 12 months, the estimated rates of PFS were indistinguishable for the 2 groups (96% vs 97%, respectively). The OS was 97% for the dasatinib arm and 99% for the imatinib arm.54 AEs for the 2 treatment groups were primarily grade 1 and 2; however, the pattern of specific AEs was distinct for the 2 treatments. Nausea, vomiting, muscle inflammation, rash, and fluid retention occurred more frequently in the imatinib group.54 Pleural effusion, headache, and cytopenias were more frequent in the dasatinib group. Gastrointestinal or other bleeding events occurred in 5% of patients in the dasatinib and imatinib arms. One patient in each group had a QTc interval longer than 500 milliseconds.54 The recently reported 18-month DASISION results showed that cytogenetic and molecular responses remained higher in the dasatinib arm than in the imatinib arm and were associated with no new safety concerns (Table 2).55 Since 2006, dasatinib has been available for the treatment of imatinib-resistant or -intolerant CML-CP, CML in blast phase, or CML in accelerated phase. In October 2010, dasatinib received FDA approval for the treatment of newly diagnosed CML-CP. The 2011 National Comprehensive Cancer Network guidelines recommend the use of imatinib, nilotinib, or dasatinib as treatment options for patients with newly diagnosed CML-CP.56 Perhaps the most important differentiator between the 2 second-generation TKIs dasatinib and nilotinib is their safety profile. Compared with imatinib, nilotinib showed a relative increase in rash, headache, and pruritus, whereas dasatinib showed a relative increase in pleural effusion, headache, and cytopenia (Table 3).

Future Therapies Aurora kinase inhibitors, such as VX-68057 and PHA-739358,58 inhibit the BCR-ABL T315I mutation, as well as other mutations. The investigational agent bosutinib has been evaluated in a phase 2 trial of 288 patients with CML-CP who had been previously treated with imatinib.59 After a median of 24.2 months of follow-up, 53% achieved an MCyR—the primary end point of the trial—and 41% achieved CCyR. Of the patients who achieved CCyR, 64% attained an MMR. The drug was well tolerated, and the most frequently reported AE was gastrointestinal toxicity. Notably, bosutinib is not active against BCR-ABL mutations with the T315I mutation.59 AP24534 (ponatinib)—a second investigational drug that has activity in inhibiting BCR-ABL T315I—is being studied in a phase 2 trial of 320 patients with CML-CP, CML in accelerated phase, or CML in blast phase and Ph+ ALL.60 The study will include patients

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The Evolution of Tyrosine Kinase Inhibitor Therapy

Table 3 Oral Dosages, Interactions, and Adverse Reactions of Tyrosine Kinase Inhibitors Imatinib Dasatinib Nilotinib Chronic-phase CML dose 400 mg/day 100 mg/day 300 mg bid Accelerated-phase or 600 mg/day or 140 mg/day 400 mg bid blast-crisis CML dose 400 mg bid Metabolism

CYP3A4 substrate/inhibitor

CYP3A4 substrate

CYP3A4 substrate CYP 2C8, 2C9, 2D6 and 3A4 inhibitor

Food intake with drug

With food

With/without food

Without food

Adverse drug reactions

Generalized edema Periorbital edema Headache Rash Nausea/vomiting Myelosuppression

Edema Headache Rash Nausea/vomiting Myelosuppression QTc prolongation Pleural effusion

Edema Headache Rash Nausea/vomiting Myelosuppression QTc prolongation

CY indicates cytochrome; CML, chronic myeloid leukemia; QTc, corrected QT.

with CML or ALL resistant to or intolerant of nilotinib or dasatinib or who have the T315I mutation. As these newer agents accumulate additional clinical experience, the prospect for additional treatment options for patients with CML refractory to first-line treatment will be expanded.

Conclusions The improvement in outcomes with imatinib therapy has ushered in a new era of CML management and provided the impetus for the further development of targeted therapies for cancer. The improved efficacy of nilotinib and dasatinib in achieving MMR and CCyR with early follow-up suggests a potential change in the first-line treatment of CML. There are no prospective head-tohead studies comparing the efficacy and safety of dasatinib and nilotinib in either the first-line or second-line treatment settings, making a direct comparison infeasible. The post-imatinib era for first-line treatment of CML is emerging, but long-term follow-up is needed to confirm the optimal therapy for newly diagnosed CML. Because of the relatively immature data in frontline therapy with second-generation TKIs, it is unknown whether an increase in the rates of CCyR and MMR translate into improvement in long-term freedom from disease progression and whether the toxicities associated with nilotinib and dasatinib will decrease over time, as was observed in the IRIS study with imatinib. Careful analysis is necessary to elucidate the potential resistance profiles that may emerge for dasatinib and nilotinib. The emergence of second-generation TKIs for first-line treatment of CML has raised the question of what the optimal treatment standard is for second-line therapy. The impact of TKI therapy on the role of allogeneic SCT is

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still being investigated. It is not yet known whether the administration of TKIs after allogeneic SCT will improve long-term disease control or treat relapsed Ph+ disease; however, work in this area is ongoing.61,62 ■

Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Robert Scheinman, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their medical editorial assistance. Author Disclosure Statement Dr Fausel is on the Speaker’s Bureau of Millennium Pharmaceuticals. Dr Greisl has reported no conflicts of interest.

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REVIEW ARTICLE

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Clin Pharmacol Ther. 2010;87:543-552. Epub 2010 Mar 17. 31. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566. 32. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037. 33. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042. 34. Kantarjian H, Sawyers C, Hochhaus A, et al, for the International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652. 35. Druker BJ, Guilhot F, O’Brien SG, et al, for the IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417. 36. Deininger M, O’Brien SG, Guilhot F, et al. International Randomized Study of Interferon vs STI571 (IRIS) 8-year follow-up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:Abstract 1126. 37. Tauchi T, Ohyashiki K. Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk Res. 2004;28(suppl 1):S39-S45.

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38. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542-2551. 39. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401. 40. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141. 41. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11:4941-4947. 42. Giles FJ, O’Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698-1707. Epub 2009 May 28. 43. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540-3546. Epub 2007 Aug 22. 44. Kantarjian HM, Giles FJ, Bhalla KN, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: clinical response, safety, and long-term outcomes. Blood. 2009;114:Abstract 1129. 45. Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392-397. Epub 2009 Dec 14. 46. Rosti G, Palandri F, Castagnetti F, et al, for the GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009;114:4933-4938. Epub 2009 Oct 12. 47. Rosti G, Castagnetti F, Gugliotta G, et al. Excellent outcomes at 3 years with nilotinib 800 mg daily in early chronic phase, Ph+ chronic myeloid leukemia (CML): results of a phase 2 GIMEMA CML WP clinical trial. Blood. 2010;116:Abstract 359. 48. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. Epub 2010 Jun 5. 49. Hughes TP, Hochhaus A, Saglio G, et al. ENESTnd update: continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2010;116:Abstract 207. 50. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658-6661. 51. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309. Epub 2006 Nov 30. 52. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206. Epub 2008 Apr 10. 53. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398-404. Epub 2009 Dec 14. 54. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:22602270. Epub 2010 Jun 5. 55. Shah N, Kantarjian H, Hochhaus A, et al. Dasatinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the DASISION trial: 18-month follow-up. Blood. 2010;116:Abstract 206. 56. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 2.2012. www.nccn.org/profession als/physician_gls/pdf/cml.pdf. Accessed October 30, 2011. 57. Bebbington D, Binch H, Charrier JD, et al. The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg Med Chem Lett. 2009;19:3586-3592. Epub 2009 May 3. 58. Gontarewicz A, Brümmendorf TH. Danusertib (formerly PHA-739358)—a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor. Recent Results Cancer Res. 2010;184:199-214. 59. Cortes JE, Kantarjian HG, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SK-606) in chronic-phase Philadelphia chromosome positive chronic myeloid leukemia with resistance or intolerance to imatinib. Blood. 2011;118:4567-4576. Epub 2011 Aug 24. 60. Ariad Pharmaceuticals. ARIAD announces initiation of ponatinib (AP24534) pivotal trial in drug-resistant or intolerant chronic myeloid leukemia [press release]. September 13, 2010. http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irolnewsArticle&ID=1470049&highlight. Accessed October 30, 2011. 61. Wright MP, Shepherd JD, Barnett MJ, et al. Response to tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia relapsing in chronic and advanced phase following allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2010;16:639-646. Epub 2010 Feb 4. 62. Nishiwaki S, Miyamura K, Kato C, et al. Impact of post-transplant imatinib administration on Philadelphia chromosome-positive acute lymphoblastic leukaemia. Anticancer Res. 2010;30:2415-2418.

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BD Welcomes BD PhaSeal®

BD is pleased to announce the addition of BD PhaSeal, a unique evidence-based closed-system drug transfer device (CSTD) for safe handling of hazardous drugs, to its family of BD Medical products. At BD, healthcare worker safety has always been an important focus. The addition of BD PhaSeal will help provide an enhanced suite of safety products to its customers. For more information about BD PhaSeal, call 1-866-487-9250 or visit www.phaseal.com.

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8-Reviewers Thankyou_Cover 12/19/11 11:28 AM Page 34

2011 PEER REVIEW

THANK YOU JHOP PEER REVIEWERS The Editors of the Journal of Hematology Oncology Pharmacy wish to extend a heartfelt Thank You to all those who participated in the peer-review process during 2011. Your diligence and careful comments go a long way to ensure the continued high quality of articles published in the journal.

Brian G. Cochran, PharmD, BCOP

Jennifer LaFollette, PharmD, BCOP

Michael B. Crockerham, MS, PharmD

Gary C. Lee, PharmD

Tina Gegeckas, RPh, BCOP

Lisa K. Lohr, PharmD, BCOP, BCPS

Rebecca Greene, PharmD

Kate Mandock, PharmD

Cyrine-Elaine Haidar, PharmD

Patrick J. Medina, PharmD, BCOP

R. Donald Harvey, PharmD, BCPS, BCOP, FCCP

Cindy L. Oâ&#x20AC;&#x2122;Bryant, PharmD, BCOP, FCCP

Nancy Heideman, PharmD

Joanna Maudlin Pangilinan, PharmD

Jon D. Herrington, PharmD

Scott Soefje, PharmD, BCOP

Lew Iacovelli, PharmD

Steven Stricker, PharmD

Robert J. Ignoffo, PharmD, FASHP, FCSHP

Timothy G. Tyler, PharmD, FCSHP

Anthony Jarkowski, III, PharmD

John M. Valgus, PharmD, BCOP

Kellie L. Jones, PharmD

Susan K. Woelich, PharmD

Sara S. Kim, BSPharm

Daisy Yang, PharmD, BCOP

Susannah E. Koontz, PharmD

Gary Y. Yee, PharmD, FCCP, BCOP

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drug

shortages

genetic testing

medicine and

personalized

Emergence of

Increased need for

Patient Financial

Assistance

Co-payments shift from dollars to thousands

channel

Emerging clinical standards and pathways

Keeping patients in community versus in-patient care

Supply

Cutbacks in Government programs

with REMS regulatory processes

Compliance and Adherence to therapy and protocols

of FDA reach

Higher drug oversight and Prior Authorization processes

Growing billing and collection risks Expansion 500% increase in drug inventory carrying costs

Reduction in drug margins

Oncology providers face a multitude of disruptive changes...

Complex insurance verification

Additional staff burdens

What to do?

REACT TO CHANGE SEEK PROVEN SOLUTIONS Pharmacy / 877.662.6633

Fax / 877.662.6355

Website / OncoMed.net

7-From theLit_Cover 12/19/11 1:18 PM Page 36

FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University—California, Mare Island Vallejo, CA

■ A Phase 3 Trial Comparing Axitinib and Sorafenib in Advanced Renal-Cell Cancer Background: More than 170,000 people are diagnosed annually with renal carcinoma, resulting in 72,000 deaths and a 30% relapse rate. Many patients are resistant to existing chemotherapy and cytokine treatments. However, the treatment of advanced renal-cell cancers has been changing through the use of drugs that inhibit angiogenesis by targeting the vascular endothelial growth factor receptors. This is the first phase 3 clinical trial to compare the effectiveness of 2 second-generation antiangiogenic agents—axitinib and sorafenib—in the treatment of metastatic renal-cell cancer. Design: This multicenter, randomized, unmasked, phase 3 clinical trial included 723 patients aged ≥18 years from 175 sites, hospitals, and outpatient clinics in 22 countries who had been diagnosed with renal-cell carcinoma that had progressed despite first-line therapy with sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. From September 2008 to July 2010, patients were randomized to axitinib 5 mg initially, increased to 7 mg and then to 10 mg, twice daily (N = 361) or to sorafenib 400 mg twice daily (N = 362). Patients were randomized according to previous treatment type and Eastern Cooperative Oncology Group (ECOG) performance score. The primary end point was progression-free survival (PFS), assessed by a masked, independent radiology review of the intention-to-treat (ITT) population. Secondary end points were overall survival (OS), objective response rate, response duration, and time to deterioration. Summary: The median PFS was significantly (42%) longer with axitinib than with sorafenib (6.7 months vs 4.7 months, respectively; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.81; 1-sided P <.001). In patients who previously received cytokines, the median PFS was 12.1 months with axitinib and 6.5 months with sorafenib (HR, 0.46; 95% CI, 0.32-0.68; P <.001), and among those who had received sunitinib, the median PFS was 4.8 months and 3.4 months (HR, 0.74; 95% CI, 0.57-0.96; P = .011). The objective response rate was 19% with axitinib and 9% with sorafenib (P = .001), and

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the median duration of response was 11 months and 10.6 months, respectively. Treatment discontinuation from toxic effects was observed in 14 (4%) of the 359 patients who received axitinib and 29 (8%) of the 355 patients who received sorafenib. The most common adverse events reported were diarrhea, hypertension, and fatigue in the axitinib group and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib group. Takeaway: This new agent, axitinib, appears to be a very good second-line agent in the treatment of advanced renal-cell cancer. It appears to be as safe as sorafenib, with a better objective response rate and a longer PFS. The maker of axitinib received a unanimous vote by the US Food and Drug Administration (FDA) advisory committee favoring the use of this drug for patients with advanced renal-cell cancer who have failed first-line systemic therapy. The FDA will be reviewing the product in this setting early in 2012. Rini BI, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal-cell cancer. Lancet. 2011;378:1931-1939. Epub 2011 Nov 4.

■ Letrozole More Effective than Tamoxifen for LongTerm Mortality Reduction in Postmenopausal Women with Breast Cancer Background: Postmenopausal women with hormone receptor–positive early invasive breast cancer are often managed with an aromatase inhibitor, such as letrozole. The aim of the Breast International Group (BIG) 1-98 study was to compare tamoxifen and letrozole as monotherapies and as sequential treatments. Because of the long-term risk of recurrence and death in this patient population, an extended, 8.1-year median follow-up was conducted to assess patient outcomes after the treatment regimens ended in 2008. Design: Currently in its twelfth year, BIG 1-98 is an international, randomized, phase 3, double-blind clinical trial with 8010 postmenopausal women (median age, 61 years) from 148 hospitals in 27 countries who tested positive for estrogen-receptor or progesterone-

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FROM THE LITERATURE

receptor cancer. Women who had evidence of metastatic disease and previous or concurrent cancer other than adequately treated noninvasive breast cancer, cervical cancer, or carcinoma of the skin were excluded. Patients were randomized to monotherapy with either letrozole 2.5 mg orally once daily or tamoxifen 20 mg orally once daily for 5 years. They then were randomized to 1 of 4 groups: monotherapy with tamoxifen or letrozole for 5 years, sequential therapy with letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. After a significant disease-free survival benefit with letrozole reported in 2005, the study protocol was amended to allow a crossover from tamoxifen to letrozole. The final treatment phase ended in 2008. Efficacy comparisons were based on ITT analyses and on inverse probability of censoring weighted Cox models, which addressed the potential bias introduced from the selective crossover from tamoxifen to letrozole. The primary study end point was disease-free survival. Secondary end points included OS, distant recurrencefree interval (DRFI), and invasive breast cancer–free interval (BCFI). Summary: After a median follow-up period of 8.1 years, 2074 patients showed disease-free survival compared with 1569 patients showing disease-free survival by the protocol-specified update in 2009. The additional 505 events (a 32% increase) occurred between 2003 and 2011, in the latter phases of the study. In addition, 5936 (74%) of the patients were reported to be alive and without a disease-free survival event at their most recent follow-up. At a median follow-up of 8.7 years, letrozole monotherapy was associated with significantly better disease-free survival compared with tamoxifen therapy (HR, 0.82; 95% CI, 0.74-0.92; P = .002), OS (HR, 0.79; 95% CI, 0.69-0.90; P = .006), DRFI (HR, 0.79; 95% CI, 0.68-0.92; P = .003), and BCFI (HR, 0.80; 95% CI, 0.700.92; P = .002). Takeaway: In early-stage hormone-responsive breast cancer, 5 years of letrozole monotherapy reduced both recurrence (HR, 0.79) and mortality (HR, 0.82) when compared with 5 years of tamoxifen monotherapy. Sequential treatment with letrozole for 2 years, followed by 3 years of tamoxifen therapy or vice versa, was not different from letrozole monotherapy in patients with BCFI or DRFI. With more than 8 years of follow-up, this study confirms that letrozole is more effective than tamoxifen in the management of early-stage postmenopausal breast cancer. Regan MM, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer. Lancet Oncol. 2011;12:1101-1108.

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■ Bortezomib plus Rituximab Superior to Rituximab Alone in Relapsed Follicular Lymphoma Background: Bortezomib and rituximab have demonstrated additive activity in preclinical models of lymphoma. Both are active and usually well tolerated in patients with follicular lymphoma (FL) and marginal zone lymphoma. A phase 3 study compared the efficacy and safety of rituximab alone and in combination with bortezomib in patients who were rituximab-naive or rituximab-sensitive and aged 18 years or older with relapsed grade 1 or 2 disease. Design: This unmasked, open-label, phase 3 trial included 676 rituximab-naïve and rituximab-sensitive patients with relapsed grade 1 or 2 FL from 164 centers in 29 countries across Europe, the Americas, and Asia from April 2006 to August 2008. All patients had an ECOG performance score of 0 to 2, no active central nervous system lymphoma, and adequate hematologic, renal, and hepatic functions. Patients were excluded if they had grade 2 or higher peripheral neuropathy or neuropathic pain; clinical evidence of transformation to aggressive lymphoma; or treatment with antineoplastics, investigational therapy, or radiation therapy within 3 weeks of enrollment, nitrosoureas within 6 weeks, radioimmunoconjugates or toxin immunoconjugates within 10 weeks, stem-cell transplantation within 6 months, or bortezomib at any time before randomization. Eligible patients were randomized to receive five 35-day cycles of intravenous (IV) infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 2 through 5, either alone (N = 340) or in combination with bortezomib 1.6 mg/m2 (N = 336), which was administered by IV injection on days 1, 8, 15, and 22 in all treatment cycles. Randomization was stratified by FL international prognostic index (FLIPI) score, previous use of rituximab, time since last therapy, and region. The primary end point was PFS, analyzed in the ITT population. Secondary end points included time to progression, time to next treatment, and OS. Summary: After a median follow-up of 34 months, the median PFS was 11.0 months (95% CI, 9.1-12.0) in the rituximab group and 12.8 months (95% CI, 11.515.0) in the bortezomib plus rituximab group (HR, 0.82; 95% CI, 0.68-0.99; P = .039). The estimated 2year PFS rates were 23.5% and 31.2%, respectively. In a subgroup analysis, bortezomib plus rituximab was associated with a longer PFS in patients with high-risk features, including high FLIPI score (P = .013) and high tumor burden (P = .019). PFS was also significantly longer in patients aged ≤65 years (P = .005) but not in older patients (P = .353). The combination therapy was also associated with a longer PFS than ritux-

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FROM THE LITERATURE

imab alone in patients who received previous lines of therapy, but the differences were not significant. Among patients who had received any previous rituximab therapy, the median PFS was 9.2 months in the rituximab group versus 11.4 months in the bortezomib plus rituximab group (HR, 0.93; 95% CI, 0.70-1.24; P = .609). In a post-hoc multivariate analysis for independent prognostic factors for PFS, treatment with bortezomib plus rituximab, time since last antilymphoma treatment >1 year, female sex, absence of tumor burden, and stage I or II disease were associated with a longer PFS. Most patients in both groups who did not receive the 5-cycle median (range, 1-5) of treatment discontinued early in response to disease progression. The rate of adverse events was higher with bortezomib plus rituximab (95%) than with rituximab alone (78%). The most common grade 3 or higher adverse events were neutropenia, infection, diarrhea, herpes zoster, nausea or vomiting, and thrombocytopenia. Drug-related adverse events leading to death occurred in 3 (1%) patients who received bortezomib plus rituximab but in none of those who received rituximab alone. Takeaway: This study shows that bortezomib combined with rituximab improved PFS in relapsed or refractory FL. The greatest benefit for the combination was observed in patients aged <65 years and in those with poor prognostic factors. Significant improvements were also noted in response rates, durability of response, and time to next treatment for the combination. Bortezomib plus rituximab produced a higher rate of adverse events, including grade 3 toxicities such as diarrhea, neutropenia, and infections. This is the first phase 3 study to show the benefits of rituximab alone or in combination in relapsed or refractory FL. Coiffier B, et al. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma. Lancet Oncol. 2011;12:773-784. Epub 2011 Jul 1.

■ Second-Generation TKIs Produce Faster Response than Imatinib in Newly Diagnosed CML Background: The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib have a proven efficacy in the treatment of chronic myeloid leukemia (CML) in patients resistant to or intolerant of imatinib. However, it is unknown whether the European LeukemiaNet (ELN) response definitions (ie, “optimal,” “suboptimal,” and “failure”) that were based on imatinib treatment as front-line therapy are

Journal of Hematology Oncology Pharmacy

relevant to the second-generation TKIs, because most patients who receive these more potent drugs achieve early complete cytogenetic response (CCyR). Design: In 2 simultaneous phase 2 trials, 167 patients with newly diagnosed CML in the chronic phase were randomized to nilotinib 400 mg twice daily (N = 81) or to dasatinib 100 mg once daily (N = 86). At 3, 6, 12, and 18 months of therapy, the incidence of optimal, suboptimal, and failure responses (determined according to ELN guidelines) was assessed in patients who were still receiving therapy and had demonstrated a hematologic, cytogenetic, and/or molecular response. Also evaluated at these time points was event-free survival, defined by the period from the start of treatment to the loss of complete hematologic response, the loss of CCyR or major cytogenetic response, the discontinuation of therapy because of toxicity or lack of efficacy, the progression of CML to accelerated or blastic phases, or death. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log-rank test. Summary: Overall, 155 patients (93%) achieved a CCyR after a median follow-up period of 33 months, including 146 (87%) who achieved a major molecular response (MMR) and 46 (28%) who achieved complete molecular response (CMR). At 3 months, all 160 evaluable patients demonstrated optimal response (ie, complete hematologic response). By 18 months, 99 (84%) of 118 evaluable patients achieved an optimal response. At months 6, 12, and 18, the rates of suboptimal response (ie, less than MMR) were 2%, 1%, and 12%, respectively. The failure response was not demonstrated until month 18, when it occurred in 5 (4%) patients. At each time point, disease-free survival did not differ significantly between patients who achieved CCyR without an MMR or CMR and those who achieved CCyR with an MMR or CMR. These results confirm that second-generation TKIs used in the frontline setting are highly efficacious, with the majority of responses occurring within the first 3 months of therapy. In contrast, imatinib therapy produces CCyR rates that peak around 12 to 18 months. Since the majority of patients (99%) achieved an optimal response within 3 months, the ELN definitions of response are not applicable in patients being treated with second-generation TKIs. Takeaway: This study shows that the second-generation TKIs produce CCyRs after 3 months of treatment, a much faster rate than with imatinib (ie, 12-18 months for maximum response). Furthermore, this study shows that the standard response criteria established by the ELN are not appropriate for use with these second-

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generation agents. The authors also propose that for patients receiving nilotinib or dasatinib, achieving a CCyR by 3 months is considered an optimal response, and that a partial cytogenetic response is suboptimal. Jabbour E, et al. Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia. J Clin Oncol. 2011;29:4260-4266.

■ High-Risk Myelodysplastic Syndrome Outcomes after Azacitidine Treatment Failure Background: Treatment with azacitidine is the current standard of care for high-risk myelodysplastic syndrome (MDS), despite frequent primary or secondary treatment failure in many patients. The absence of data on outcomes after treatment failure limits the development of clinical trials and the interpretation of their data. An analysis of 4 clinical trial data sets aimed to describe those outcomes. Design: Outcomes data from 435 patients with highrisk MDS or acute myeloid leukemia (AML) with 20% to 30% blasts who demonstrated treatment failure after receiving azacitidine therapy between 2000 and 2009 were compiled from 4 clinical trial cohorts: the Johns Hopkins University J9950 and J0443 trials; the AZ001 trial; and the French azacitidine compassionate use program database. Therapy was administered for 8 weeks in the J9950, J0443, and AZ001 trials and for 12 weeks in the French azacitidine compassionate use program. Patients in all cohorts continued their azacitidine regimen until their disease progressed or intolerance to therapy led them to discontinue it. OS rates were estimated using the Kaplan-Meier method, and prognostic factors of OS were determined from univariate analyses. Summary: A total of 302 (74%) patients received therapy for MDS, and 133 (26%) received therapy for AML. The median follow-up after azacitidine failure was 15 months. The median OS was 5.6 months, and the 1-year and 2-year survival probability was 28.9% and 15.3%, respectively. Factors correlated with a

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shorter OS included increasing age (P = .002), male sex (P = .04), high-risk cytogenetics (P = .002), higher bone marrow blast count before azacitidine treatment (P = .04), and the absence of previous hematologic response to azacitidine (P = .007). In addition, among initial responders to azacitidine, high-risk cytogenetics were associated with a shorter OS after treatment failure (P = .03). Post-failure treatment data were available for 270 patients. Among this group, the prognosis was worst for patients who received unknown salvage (OS, 3.6 months) or best supportive care (OS, 4.1 months) but was best for those who received investigational agents (overall response rate [ORR], 11%; OS, 13.2 months) or allogeneic stem-cell transplantation (ORR, 68%; OS, 19.5 months). Poor outcomes were also observed in patients who received low-dose chemotherapy (ORR, 0%; OS, 7.3 months) or intensive AMLlike chemotherapy (ORR, 14%; OS, 8.9 months). Takeaway: This study shows that there is no standard second-line chemotherapy treatment for high-risk MDS after azacitidine failure. Best supportive care or cytotoxic chemotherapy (ie, hydroxyurea, mercaptopurine, low-dose cytarabine, low-dose melphalan, or intense AML-like chemotherapy) were not of any substantial benefit to these patients. A variety of investigational agents—DNA methyltransferase enzyme inhibitors alone or in combination with histone deacetylase inhibitors, thalidomide-derivative (ie, lenalidomide or thalidomide), treatments for patients in clinical trials evaluating nonregistered drugs (including immunotherapy, bryostatin, triapine, farnesyl transferase inhibitors, and mammalian target of rapamycin inhibitors)—produced better OS than best supportive care or cytotoxic chemotherapy. The best outcomes were observed in patients receiving allogeneic bone marrow transplant. The authors suggest that the results of this study can be used as a basis for comparing new agents to be used in palliative care in future trials. ■ Prébet T, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322-3327.

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Help stop CINV before it starts, with a regimen including EMEND, a 5-HT3 antagonist, and a corticosteroid

Have you included EMEND from Cycle 1?

These highly and moderately emetogenic chemotherapy regimens increase the risk of CINV. Breast Cancer1,2 AC (doxorubicin + cyclophosphamide) TAC (docetaxel + doxorubicin + cyclophosphamide) TC (docetaxel + cyclophosphamide) CMF (cyclophosphamide + methotrexate + fluorouracil) TCH (docetaxel + carboplatin + trastuzumab)

Lymphoma1,5 ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) ± rituximab CVP (cyclophosphamide + vincristine + prednisone)

Lung Cancer1,3 Carbo-Tax (carboplatin + paclitaxel) Cisplatin + vinorelbine Cisplatin + gemcitabine Cisplatin + pemetrexed

Colorectal Cancer1,6,7 FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil) CapeOX (capecitabine + oxaliplatin) Irinotecan Cisplatin-based regimens

Head and Neck Cancer1,4 Cisplatin-based regimens Carboplatin-based regimens

Ovarian Cancer1,8 Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin) Cisplatin

EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.

Selected Important Safety Information EM EN D should b e used with caution in patient s re ceiving concomitant medications, including chemotherapy a g e nt s , t hat are pr imar il y m et a b o lize d t hro ugh C Y P3A 4 . I nhib i t i o n of C Y P3A 4 by EM EN D co ul d re sul t in e l e vate d plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CY P3A 4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND 125 mg / 80 mg was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND 125 mg / 8 0 mg did not influence the pharmacokinetic s of docetaxel or vinorelbine. Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. The efficacy of hormonal contraceptives may be reduced during coadministration with EMEND and for 28 days after the last

dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND. Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle. Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10%, in patients receiving highly emetogenic chemotherapy were asthenia /fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%). In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy in patients receiving moderately emetogenic chemotherapy were alopecia (12.4% EMEN D vs 11.9% standard therapy) , dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia ( 5. 8 % v s 5.6%) , as thenia ( 4.7% v s 4.6%) , and s tomatitis (3.1% vs 2.7%). In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2.2-fold; therefore, the dexamethasone dose administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. See PRECAUTIONS, Drug Interactions, in the Prescribing Information for EMEND for additional information on dosage adjustment for methylprednisolone when coadministered with EMEND. Please read the Brief Summary of the Prescribing Information for EMEND on the following pages.

References : 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: antiemesis—V.1.2011. www.nccn.org/professionals/physician_gls/ f_guidelines.asp. Accessed January 5, 2011. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer—V.2.2011. www.nccn.org/ professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: head and neck cancers—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Hodgkin lymphoma—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer—V.2.2011. www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed January 5, 2011. 8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. CINV=chemotherapy-induced nausea and vomiting.

An antiemetic regimen including

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Brief Summary of the Prescribing Information for

INDICATIONS AND USAGE Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV): EMEND, in combination with other antiemetic agents, is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin; and CAPSULES for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative nausea and vomiting. Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration is not recommended. CONTRAINDICATIONS EMEND is contraindicated in patients who are hypersensitive to any component of the product. EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of EMEND with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions]. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients. Chronic Continuous Use: Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS The overall safety of aprepitant was evaluated in approximately 5300 individuals. 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. Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone. In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, 3.1 Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1 Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 Hemic and lymphatic system: neutropenia: 3.1, 2.9 Metabolism and nutrition: anorexia: 10.1, 9.5 Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 Respiratory system: hiccups: 10.8, 5.6 In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies. Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy. In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy (n=846), respectively: Blood and lymphatic system disorders: neutropenia: 5.8, 5.6 Metabolism and nutrition disorders: anorexia: 6.2, 7.2 Psychiatric disorders: insomnia: 2.6, 3.7 Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9

EMEND® (aprepitant) capsules General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar in the 2 treatment groups. Highly and Moderately Emetogenic Chemotherapy: The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen in either HEC or MEC studies: Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection Neoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinoma Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia Psychiatric disorders: anxiety disorder, confusion, depression Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor Eye disorders: conjunctivitis Cardiac disorders: myocardial infarction, palpitations, tachycardia Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia Renal and urinary disorders: dysuria, renal insufficiency Reproductive system and breast disorders: pelvic pain General disorders and administrative site conditions: edema, malaise, pain, rigors Investigations: weight loss Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. Laboratory Adverse Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Proteinuria: 6.8, 5.3 ALT increased: 6.0, 4.3 Blood urea nitrogen increased: 4.7, 3.5 Serum creatinine increased: 3.7, 4.3 AST increased: 3.0, 1.3 The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse-experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively: Infections and infestations: urinary tract infection: 2.3, 3.2 Blood and lymphatic system disorders: anemia: 3.0, 4.3 Psychiatric disorders: insomnia: 2.1, 3.3 Nervous system disorders: headache: 5.0, 6.5 Cardiac disorders: bradycardia: 4.4, 3.9 Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2 Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4 General disorders and general administration site conditions: pyrexia: 5.9, 10.6 The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: Infections and infestations: postoperative infection Metabolism and nutrition disorders: hypokalemia, hypovolemia Nervous system disorders: dizziness, hypoesthesia, syncope Vascular disorders: hematoma Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia Skin and subcutaneous tissue disorders: urticaria General disorders and administrative site conditions: hypothermia, pain Investigations: blood pressure decreased Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: Nervous system disorders: dysarthria, sensory disturbance Eye disorders: miosis, visual acuity reduced Respiratory, thoracic, and mediastinal disorders: wheezing Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant. Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). Other Studies: In addition, 2 serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: 1 case of constipation, and 1 case of subileus.

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EMEND® (aprepitant) capsules Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy-induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. Chemotherapeutic agents: [see Warnings and Precautions] Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce the metabolism of S(–) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as international normalized ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND. Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important. In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/ day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (eg, elderly patients) and degree of

monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy-induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/ day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/ day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND. Additional Interactions: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC 0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC 0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND in pediatric patients have not been established. Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in SpragueDawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC 0–24hr ) of 0.7 to 1.6 times the human exposure (AUC 0–24hr =19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/ kg/day doses in male mice. Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test. Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed. Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia. Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction. EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND. For detailed information, please read the Prescribing Information. Rx only

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

EDITING—Routine editorial changes are made on all articles to conform to house style, following the AMA Manual of Style, 10th ed.1 The edited manuscript is sent to the corresponding author for a final review and for any outstanding editorial queries. Time from submission to publication is generally 4 to 7 months, but could be longer, depending on the peer-review and revision processes.

GENERAL INFORMATION—Manuscripts submitted to JHOP must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP.

AUTHORSHIP/COPYRIGHT—Authors listed on the manuscript should only include those who have made a direct contribution to the content of the article, in accordance with the authorship criteria provided by the International Committee of Medical Journal Editors (ICMJE).2 Credit for authorship is based on a substantial contribution to (1) conception and design, or data analysis/interpretation, (2) drafting or revising the article critically for intellectual content, and (3) approval of the final version to be published. These 3 criteria must all be met.2 Those who have contributed to the article but do not meet these authorship criteria should be acknowledged at the end of the article.

The editors invite readers to submit articles on a variety of points of view and approaches to meet the mission of the journal. Articles will be divided into 4 main categories, including (1) original research, to provide an outlet for translational and practice-based research, including case reports and case series; (2) review articles that focus on drug and disease state as well as on basic science regarding the complex molecular biology of cancer with a pharmacy focus; (3) clinical controversies that discuss common clinical issues for which treatment is unclear, or “point, counterpoint” and “how I treat” type of articles; (4) practical issues in pharmacy management that will focus on realworld issues involving logistics, economics, and other practice-related topics. PEER REVIEW—All articles undergo an initial internal review for topic appropriateness and manuscript format. Manuscripts that are not submitted according to the guidelines in this document will be returned to the author. All manuscripts are subject to a strict, blinded peer review (by 2-3 reviewers), and acceptance is determined by the section editor based on that review. Reviewers look for accuracy of the information and data presented, as well as relevance to the objectives of JHOP. All authors’ identifying information is removed from the article for the purpose of the peer review, but any study funding information is provided to reviewers. Authors are notified as soon as possible regarding the initial decision of acceptance or rejection of the article. The majority of articles that are accepted for publication, however, will require revisions and resubmission.

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Provide authors’ highest academic degree and professional affiliations. Also provide the name, address, telephone number, e-mail, and fax number of the corresponding author. The corresponding author is responsible for securing signatures for all forms from all authors. All authors are required to sign an Authorship/Copyright Transfer Form, assigning all copyrights for the manuscript to Green Hill Healthcare Communications, LLC, publisher of JHOP. For an article to be considered for publication, authors must adhere to the manuscript format described in this document and follow the general ICMJE guidelines.2 DISCLOSURE STATEMENTS—All authors must disclose any relationship that could be viewed as a potential conflict of interest, based on ICMJE guidelines,2 including any financial interests, direct or indirect, and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript. Each author must sign the Financial Disclosure Form in accordance with the ICMJE guidelines.2 JHOP discloses all information regarding employment, consultancies, stock ownership, honoraria, grants, or other financial sources with potential conflict of interest

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in relation to a manuscript, or if authors discuss any products or services with such commercial interest. Any information regarding funding, grants, or other financial compensation must be listed on the title page of the manuscript. All published articles will include disclosure statements listing any relationships with real or potential conflict of interest for all authors and for the manuscript/research. PERMISSIONS—Authors must secure written permission to reuse or adapt any graphic elements (table, figure) from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. Authors are responsible for acknowledging all information that has been published previously. MANUSCRIPT FORMAT—Manuscripts that do not adhere to the format described in this document will be returned to the author. Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author. List all funding sources for the study/article. Abstract: Articles must include an abstract (200-300 words) that describes the main objectives of the article, why this article is important, and what it adds to the literature. The abstract must be divided into these categories: Background, Objective, Methods (and Study Design, if relevant), Results, and Conclusion. An abstract for an article that does not represent research findings should include the following categories to suggest why the article is important and what its main objective is: Background, Objective, Discussion, Conclusion. Text: The entire text must be provided as a doublespaced Word file and all pages numbered consecutively. Cite any graphic elements (tables, figures, algorithms, appendix) consecutively in the text, but place actual tables/figures at the end of the article, after the references. Limit the length of the text to 3500 words (excluding references, tables, and figures). Conclusion: The conclusion is not a summary of the article. Rather, it should add something new to the

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article, a point of view or comments related to the rationale for the article and what the article adds to the literature. Tables and figures: Cite all figures, tables, algorithms, and other graphics in the text, but place the graphic elements at the end of the article, after the references. Type all tables and all figure heads and captions in the Word document. Figures and other images (excluding tables) must also be provided as individual graphic files, saved at high resolution (300 dpi), as jpg or pdf file. Attach an individual file for each image. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact JHOP@greenhillhc.com. References: Use most up-to-date, post-1990, primary sources only, cited consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Avoid automatic numbering or footnote/endnote features. Try to limit the number of references to 35. Use citation format according to the AMA Manual of Style.1 Examples: 1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news? pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

HOW TO SUBMIT MANUSCRIPTS—Articles that do not follow the guidelines described in this document will not be considered for publication. Save the manuscript as a Word file and attach individual files for each image or figure. Save images (figures) individually as an image file (jpg or pdf). Submit the entire manuscript and a cover letter stating the objectives of the article to JHOP@greenhill hc.com. For assistance call 732-992-1536. REPRINTS—Reprints may be ordered for a nominal fee by contacting JHOP@greenhillhc.com. 1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007. 2. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated April 2010. www.icmje.org/urm_full.pdf. Accessed June 1, 2010.

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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 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 a 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

Manuscripts should follow the Author Guidelines on pages 44-45 and available at www.JHOPonline.com. For more information, call 732-992-1536.

Journal of Hematology Oncology Pharmacy

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection, For intravenous infusion only. Initial U.S. Approval: 1996

• • • •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinumbased therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

–––––––––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS –––––––––––––––––––––––––––––––––––––––––––––– • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) –––––––––––––––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS –––––––––––––––––––––––––––––––––––––––––– • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ––––––––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS ––––––––––––––––––––––––––––––––––––––––––––––– Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA

Reference EN-2761

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Single Vial

Docetaxel Injection (10 mg/mL concentration) • Larger 160 mg Multiple Dose Vial • More convenient 80 mg Multiple Dose Vial • Requires NO dilution with a diluent prior to adding to the infusion solution

Clarity of glass

Barrier sheath

Exclusive Onco-Tain™ packaging for safe handling1

PVC reinforced bottom

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 • Severe fluid retention may occur despite dexamethasone

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

Indications and Usage

Safety Information

Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC

1. Data on file at Hospira P11-3247-8.125x10.875-Apr., 11

only

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See brief Prescribing Information on reverse side.