october 2010, vol. 3, no. 7

The role of intrave n ous (IV) iron asan addition to erythropoiesis-stimulating agents (ESAs) to opti-

mize therapy in patients with anemiafrom cancer or chemotherapy-inducedanemia has been examined in nineprospective, randomized trials,1-9 all ofwhich showed improvement in ESAresponse, time to maximal response,reduction in ESA dose to reach maximalresponse, and improvement in quality-of-life parameters (when mea sured). Theobserved benefit was independent ofbaseline iron parameters, and althoughresponses were greater in iron-depleted

patients, significant benefit was seen inpatients who were iron replete at studyentry. One study, which was powered toshow a difference in red blood cell trans-fusions, found a 36% reduction in thenumber of patients transfused.5 In allthese studies, which represent data onmore than 1200 patients, no significanttoxicity was noted.Despite these data, there remains resist-

ance to the addition of IV iron to the stan-dard treatment paradigm for cancer andchemotherapy-induced anemia. Thisresistance is, in large part, due to misinfor-mation and misinterpretation about the

The Official Newspaper for the

Hem/Onc Pharmacist

BOSTON—New data presented at the50th Interscience Conference on Anti -microbial Agents and Chemo therapy(ICAAC) suggest that standard doses ofantibiotics may not be the right dose forobese individuals and that obese patientsmay need higher doses for some agents.In addition, the researchers said thatmore studies are needed to determinecorrect dosages of drugs for the obese.“Stop using the ideal body weight

equations and its derivative (adjustedbody weight). Consider using lean body

weight–2005 (LBW2005) when esti-mating kidney function in the morbidlyobese subject. Oncology pharmacistsneed to study the role of LBW2005 fordosing cancer chemotherapy agents as apotential surrogate of body surface area.This is important because body surfacearea is not estimated differently for menand women of equal height and weight.LBW2005 gives you estimates by sex,which is important due to known phys-iological differences,” said ManjunathPai, PharmD, an associate professor at

PHARMACY PRACTICE

It May Be Time to Rethink DrugDosing in Your Obese PatientsBy John Schieszer

Continued on page 25Continued on page 20

SUPPORTIVE CARE

Revisiting the Use of IV Iron inPatients with CancerBy Michael Auerbach, MDAuerbach Hematology Oncology Associates, Baltimore, Maryland

Fostering a Dialogue to Improve Patient Care & Outcomes

Submit your cases online today at

www.myelomacases.com

Continued on page 24

Continuing EducationASCO 2010 Update on CML2

Hematologic CancersDasatinib vs Imatinib Study inTreatment-Naïve CML

Dasatinib 100 mg once daily in second-line CP-CMLPage 18

Supportive CareRoutine HBV Screening in CancerImmunosuppressive RecipientsPage 21

Pharmacist/Nurse Model for Delivery ofSupportive CarePage 22

Pharmacy CareersBusiness Management ProgramsPage 25

Oncology Pharmacist Seeks MBA toPrepare for Future of HealthcarePage 28

Inside

©2010 Green Hill Healthcare Communications, LLC

OCTOBER 2010 www.TheOncologyPharmacist.com VOL 3, NO 7

Members of St. Luke’s Mountain States Tumor Institute, from left: DanZuckerman, MD; Alicia Rosales, LMSW; Jill Winschell, RN; and Paul G.Montgomery, MD, FACP.

Reducing Disparities inCancer Care: St. Luke’sMountain States TumorInstitute Embraces NCCCP PillarBy Dawn Lagrosa

St. Luke’s Mountain States Tumor Institute (MSTI) providesadvanced cancer care to patients at clinics in Boise, Fruitland,Meridian, Nampa, and Twin Falls, Idaho. Spanning more than

180 miles across southwestern Idaho, MSTI cares for patients fromrural areas and from metropolitan areas. Because of geographic iso-lation, many people in rural areas present at later stages of disease. Inaddition, large Hispanic populations in the rural counties of the stateare not getting screened for cancers on recommended timelines.“Reduce cancer healthcare disparities” is the first of seven pillars

with which National Cancer Institute Community Cancer CentersProgram (NCCCP) sites are tasked. These inequalities of care includeaccess to cancer screening, treatment, and research. The staff atMSTI hopes to reduce disparities in care for their patients with helpfrom their new contract as a member of the NCCCP.

CANCER CENTER PROFILE

TOP_October 2010_Web_TOP 10/19/10 12:27 PM Page Cov1

Totect® Kit (dexrazoxane) for injection is for intravenous infusion only. Totect is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

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Demonstrates 98% overall e�cacy based on two biopsy-con�rmed clinical trials1,2 inreducing or avoiding surgical intervention (i.e., surgical debridement, plastic surgery and their related costs), thereby reducing postponement of a patient’s chemotherapy treatments and the avoidance of long-term consequences. Cited in nursing guidelines.3,4 Extravasation management is now a chemotherapy administration safety standard.5

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1 Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane).Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550.2 Totect® package insert.3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009.4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009.5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658.© 2010 Topotarget USA. All rights reserved. TOT0111/7-10Totect and its logo mark are registered trademarks of Topotarget A/SImage is copyright © Photo Researchers, Inc.

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Pharma Chemo Ad 11x14FINAL 4 26 10 indd 1 7/21/10 10:56:51 AM

TOP_October 2010_v6_TOP 10/15/10 2:40 PM Page Cov2

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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Totect is a cytotoxic drug. Vial contents must be mixed and diluted before use. Totect should not be mixed or administered with any other drug during the infusion. Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasa-tion. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the �rst day. The Totect dose should be reduced 50% for patients with creati-nine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the a�ected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.3-5 Direct contact of Totect® with the skin or mucous membranes prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water. Contraindications: None.Warnings and Precautions: Myelosuppression: treatment with Totect is asso-ciated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Use in Pregnancy: Pregnancy Category D. Totect can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions: The most common adverse reactions (≥ 16%) are nausea, pyrexia, injection site pain and vomiting.

Drug Interactions: No drug interactions have been identi�ed. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treat-ment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Speci�c Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and e�ectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Be-cause elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused signi�cant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

TOP_October 2010_v6_TOP 10/15/10 2:40 PM Page 1

EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C.Gammon, BS PharmUniversity ofMassachusetts Memorial HospitalWorcester, MA

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase Cancer CenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDNovant HealthWinston-Salem, NC

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud,PharmD, BCOP,FASHPThe University of TexasM. D. Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina College ofPharmacyColumbia, SC

Steve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Editorial Board

2 OcTOber 2010 I VOL 3, NO 7 www.TheOncologyPharmacist.com

TOP_October 2010_v6_TOP 10/18/10 9:52 AM Page 2

OcTOber 2010 • VOL 3, NO 7

PUBLISHING STAFF

PublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Associate EditorDawn [email protected]

Director, Client ServicesJohn W. [email protected]

Production ManagerStephanie Laudien

Business ManagerBlanche [email protected]

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Circulation [email protected]

Editorial Contact:Telephone: 732-992-1891 Fax: 732-656-7938

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2010 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

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CONTENTS


Hem/Onc Pharmacist

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

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FROM THE EDITOR


GENETICS8 Genetic profiling changing clinical practice in some areas of oncology

DIAGNOSIS8 Undiagnosed cancer clinic helps patients deal with the unknown

CONTINUING EDUCATION12 ASCO 2010 update on chronic myelogenous leukemia: payers’ and providers’

perspectives

HEMATOLOGIC CANCERS18 DASISION: more responses faster with frontline dasatinib in CML in chronic phase

Dasatinib 100 mg once daily is best dose in second-line CP-CML34 New “tip sheets” help NHL patients communicate with the oncology team

SUPPORTIVE CARE21 Routine HBV screening in cancer immunosuppressive recipients finds evidence

of virus in some22 Pharmacist/nurse model for delivery of supportive care improves patient symptoms38 Single-dose IV regimen comparable with 3-day regimen for prevention of CINV

Palonosetron demonstrates benefits over other 5-HT3 receptor antagonists in lungcancer patients

PHARMACY CAREERS23 Business management programs help clinicians improve healthcare delivery28 Experienced oncology pharmacist seeks MBA to better prepare for future of

healthcare

BREAST CANCER23 Meta-analysis of bevacizumab trials in breast cancer show longer PFS28 Combination of agents shows promise in MBC

SKIN CANCER36 High responses in melanoma for wool dye/ocular stain Rose Bengal

DEPARTMENTS10 News Notes26 Personal Finance30 Oncology Drug Codes34 International News41 Meetings

Asurvey just released showsthat more than 40% ofUS adults will forego a flu

vaccine this year and 33% do notplan to get their children vacci-nated. Somewhat surprisingly, thesurvey, by the National Foundationfor Infectious Diseases, found thatawareness of the vaccine’s effective-ness does not increase acceptance. In cancer care, use of intravenous

(IV) iron in patients receiving anerythropoiesis-stimulating agentfor anemia has met with resist-

ance despite evidence of its safety and efficacy. DrMichael Auerbach explains reasons for this lack ofacceptance and discusses new agents, which may lead towider use of IV iron.Another topic that has generated much discussion is

appropriate dosing for the obese. The report in this issuefrom the Interscience Conference on AntimicrobialAgents and Chemotherapy suggests a new approach tothis problem.

In addition to clinical issues, many pharmacists haveadministrative responsibilities, which has led some toseek management training to complement their clinicalknowledge and experience. Several schools of businessare now offering programs specifically geared for stu-dents with an interest in healthcare. In an interview,Scott Soefje of the University of Texas Health ScienceCenter discusses his own decision to enroll in a master’sof business administration program after many years asa pharmacist and teacher. Additionally, he notes thatresidents at his institution attend monthly manage-ment training sessions to increase the administrativecapabilities. This trend in pharmacy education maycontinue, especially in oncology pharmacy, where apharmacist often administratively handles reimburse-ment of drug.As the demand for oncology services grow, pharmacists

will assume increasing responsibilities for patient care andeducation, for helping their institutions function efficient-ly, and for training the new generation of pharmacists. Abroad education encompassing many aspects of pharmacypractice will be needed to prepare students and residentsto fulfill these multifaceted roles.�

Patrick Medina,PharmD, BCOPEditor-in-Chief

Erratum: In the article in the August issueon cabazitaxel for prostate cancer, thedosage was incorrectly stated as “threetimes weekly.” It should read “every 3weeks,” as indicated in the package insert.

TOP_October 2010_Web_TOP 10/19/10 12:27 PM Page 4

Undiagnosed Cancer Clinic Helps Patients Deal with the UnknownBy John Schieszer

Ateam of oncology clinicians inNew York has now started whatthey call “The Undiagnosed

Cancer Clinic.” The clinic waslaunched more than 1 year ago, and ithas become an important new resourcefor primary care providers and theirpatients in cases where cancer is sus-pected but a clear diagnosis is not indi-cated by symptom presentation and/ordiagnostic tests.In many respects, the clinic is

something that is long overdue andmay start a new trend in oncology.The Undiagnosed Cancer Clinic hasbeen set up by a team of oncologyexperts at Roswell Park Cancer

Institute, Buffalo, New York, to helpimprove the efficiency of diagnosisand care of cancer for people living inand around western New York.However, because of its success, otherclinics like this may sprout up aroundthe United States.“It’s about efficiency and decreased

wait times for these patients and theirfamilies, and the ability to drill down to what the issue is,” said MartinMahoney, MD, PhD, who helps runthe clinic. In many of the patients presenting

at this clinic, cancer is suspected or anabnormality has been found on a radi-ogram or computed tomography scan

that is consistent with cancer, but fur-ther testing and a biopsy is needed toconfirm what type of cancer it is. The

clinic’s multidisciplinary team of spe-cialists can obtain a biopsy using the

most appropriate method, make adiagnosis, and refer the patient forcare with one of the disease-siteexperts at Roswell Park CancerInstitute. Mahoney pointed out oftenvaluable time can be lost as careproviders try to determine what to donext, and which type of biopsy may bethe least invasive and yield rapidresults. In some cases, he said, patientscan be referred from specialist to spe-cialist in the effort to make a defini-tive diagnosis. The UndiagnosedCancer Clinic is designed to combatthat problem and get these patientsdiagnosed and started on a treatmentplan as quickly as possible. �

DIAGNOSIS

This clinic is designed to…get these patientsdiagnosed and started on a treatment plan asquickly as possible.

Genetics


Genetic Profiling Changing Clinical Practice in SomeAreas of OncologyBy John Schieszer

CHICAGO—Gene-expression profil-ing, combined with a novel chemoradi-ation regimen, may predict pathologiccomplete response in patients withesophageal cancer, according to newdata presented at the 46th annual meet-ing of the American Society of ClinicalOncology. New studies presented at thismeeting highlighted several new“genetic fingerprinting” techniques thatmay improve and guide chemo therapyin specific cancer populations.Researchers looked at pathologic

complete response rate and toxicity ina phase 2 trial involving 36 patientswith stage II to IVa esophageal cancer,29 (81%) of whom had undergone sur-gery in the course of their treatment.The treatment consisted of three 85-mg/m2 doses of oxaliplatin over thecourse of a month, a 625-mg/m2 twice-daily dose of oral capecitabine, andradiation therapy, followed by surgery 4to 6 weeks later. Two cycles of oxali-platin and capecitabine were givenpostoperatively. Gene-expression pro-filing (using microarrays by AgilentTechnology) was conducted on pri-mary tumor tissue.The researchers have found that

eight of the 29 patients who had theiresophagus removed following the oxali-platin regimen had no cancer in the sur-gical specimen (a 28% pathologic com-plete response rate). “Another clearresult is that this regimen is very well-

tolerated by patients without signifi-cant side effects,” said study investiga-tor Nikhil Khushalani, MD, who is anassistant professor of medicine atRoswell Park Cancer Institute. “Thereappear to be several gene pathwaysthat are enriched when studying differ-ent subgroups, the pathologic com-plete re sponse group versus the non-pathologic complete response group.”The study continues to accrue pa -

tients, and Khushalani expects to havemature survival data by fall 2010. “Ibelieve this is an efficacious regimen,and it’s definitely well-tolerated,” hesaid. “We hope that the exploratorygene-expression profiling results willtranslate into clinically meaningfulhypotheses that can be validated in alarge, preferably multicenter study.”

Genetic profiling to identifytrastuzumab resistance in breastcancer patientsOther researchers at Roswell Park

Cancer Institute are hoping to deter-mine whether genetic profiling mayeffectively identify which breast can-cer patients are most likely to respondto the drug trastuzumab.Trastuzumab interferes with a pro-

tein, known as the human epidermalgrowth factor receptor type 2 (HER2),which is linked to breast cancer.However, a high number of breast can-cer patients (approximately 50%)

don’t respond to the drug and experi-ence recurrence. Currently, there isgreat interest in research that mightelicit factors that drive responses.Over the past 2 years, researchers

looked at 41 breast carcinoma cases inwhich amplified HER2 levels were seenand for which fresh frozen tissue wasavailable. Of these patients, 12 weretreated with trastuzumab and three(25%) experienced recurrence. Amongthe 11 patients not treated with the drug,six (55%) had recurrence. Gene microar-rays were used to identify differentiallyexpressed genes for trastuzumab (respon-sive vs resistant).The investigators found that the dif-

ferentially expressed genes for recurrenceor nonrecurrence were distinct betweenthe group treated with tras tuzumab andthe group that was not treated with thedrug. The researchers hope that differen-tial expression of key genes identified inthis study may offer insights intotrastuzumab resistance among breastcancer patients. It is hoped that this type

of technology fingerprinting can lead tonew potential biomarkers for diagnosis,prognosis, and treatment.“The group that was treated with

trastuzumab and developed recurrencehad a genetic makeup different fromthose who were not treated and devel-oped recurrence,” said study investiga-tor Thaer Khoury, MD, who is an assis-tant professor of pathology andlaboratory medicine at Roswell ParkCancer Institute. “The idea from thebeginning was to know why thesepatients who are treated with tras -tuzumab develop recurrence and whythe others did not. There is definitelysomething going on, and we’re startingto understand these mechanisms.”Khoury, who presented the study

findings at the meeting, said theyshould be of particular interest to clini-cians working in this area of cancer.The message about treatment and howit should be guided is now changing, asmolecular markers are complementingclinical markers. �

The differentially expressed genes for recurrence ornon recurrence were distinct between the grouptreated with tras tuzumab and the group that was nottreated with the drug.

TOP_October 2010_Web_TOP 10/19/10 12:28 PM Page 8

ALOXI® provides powerful CINV prevention that can’t be ignored.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc.© 2010 Eisai Inc.All rights reserved. Printed in USA. ALO000083C 08/10

STARTS STRONG. LASTS LONG.

IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information

of its components

include headache (9%) and constipation (5%)

Please see the brief summary of the Full Prescribing Information on the adjacent page.References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on fi le. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

ALOXI is the only IV 5-HT3 receptor antagonist specifi cally approved for the prevention of both acute and delayed CINV Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

Lasts long against nausea following moderately emetogenic chemotherapy3

Powerful acute CINV prevention following highly emetogenic chemotherapy 4

Eisai offers: Contracting opportunities Reimbursement resources


Final Rule on Safety Informa -tion during Clinical TrialsThe US Food and Drug Ad min -

istration (FDA) issued a final rule thatclarifies what safety information mustbe reported during clinical trials ofinvestigational drugs and biologics.The new rule requires that certain safe-ty information that previously had notbeen required to be reported to theFDA be reported within 15 days of

becoming aware of an occurrence.These reports include:• Findings from clinical or epidemio-logic studies that suggest a signifi-cant risk to study participants

• Serious suspected adverse reactionsthat occur at a rate higher thanexpected

• Serious adverse events from bio -availability studies and bioequiva-lence studies.

NCCN Launches Guidelinesfor PatientsThe National Comprehensive Cancer

Network (NCCN) now offers a series ofNCCN Guidelines for Patients, con-sumer-friendly translations of theNCCN Clinical Practice Guidelines inOncology. The first two guidelinesreleased cover breast and lung cancers. “While there are a number of good

resources available to these women, only

the NCCN Guidelines for Patientsprovide the level of highly specific,current information that patientswant and need. We are very proud totake a leadership role in supportingthese guidelines and making themavailable to breast cancer patients,”said Diana Rowden, Survivorship andOutcomes Vice President at Susan G.Komen for the Cure, which supportedthe breast cancer guidelines throughgrant funding.The NCCN Guidelines for Pa -

tients are available at NCCN.com,which also features enhanced contentfor patients and caregivers. A link tothe NCCN Guidelines for Patients:Breast Cancer will also be available atkomen.org.

TRUST Study ConfirmsSafety and Efficacy ofErlotinibPatients previously believed unlikely

to benefit from erlotinib treatmentmay benefit from this treatment,according to recently released results ofthe Tarceva Lung Cancer SurvivalTreatment (TRUST) study (J ThoracOncol. 2010;10:1616-1622). This glob-al phase 4 open-label study in previ-ously treated patients with advancednon–small-cell lung cancer (NSCLC)confirmed the favorable efficacy andsafety profile of erlotinib in a large het-erogeneous NSCLC population.In a study of 6580 patients with

advanced NSCLC, progression-freesurvival and overall survival in thisstudy were 3.25 months and 7.9months, respectively, and the diseasecontrol rate. �

www.theOncologyPharmacist.com10 OctOber 2010 I VOL 3, NO 7

News Notes

FDA Approves DocetaxelInjection One-Vial Formulation The US Food and Drug Ad -

ministration (FDA) has ap proved anew one-vial formulation of doc-etaxel injection concentrate (Tax -otere, sanofi-aventis). This new for-mulation eliminates the initialdilution step, as well as the secondvial containing the diluent. Withthe one-vial formulation, the phar-maceutical ingredients and the 1-hour intravenous infusion adminis-tration remain unchanged.Docetaxel is approved for use in

treating patients at specific stages ofmetastatic and adjuvant breast can-cer, metastatic androgen-indepen-dent prostate cancer, advancednon–small-cell lung cancer, ad -vanced gastric adenocarcinoma,and locally advanced squamous cellcarcinoma of the head and neck.

Recent FDAApproval


www.ValueBasedCancer.com

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A new publication for your new vocabulary

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NCCN Roundtable: Clinical andEconomic Issues Impacting Cancer Care Delivery “Collision course” in sight

©2010 Engage Healthcare Communications, LLCContinued on page 24

Baltimore, MD—A long-held businesstruism is that “if you can’t measure it,you can’t manage it.” The application of this belief to the oncology setting was demonstrated at a session of theAssociation of Community Cancer Cen ters’ (ACCC) 36th Annual NationalMeeting. Kimberly Bergstrom, PharmD,chief clinical officer for McKessonSpecialty Care Solutions, told attendeesof the growing importance of developingand using standardized chemotherapytreatment regimens, and of the tools that

can benchmark performance and fostercompliance with treatment guidelines.Public and private payers are mov-

ing to control exploding healthcarecosts, Dr Bergstrom told attendees,and because increased cost controlwas inevitable, it is in providers’interest to get a seat at the table. “It is an important topic, because

this is one of those things, if we don’tget a handle on it, it’s going to happento us,” she said. “People and groupsand organizations are going to startdictating how we provide cancer care,and we can’t let that happen.”

Hollywood, FL—Clinical practiceguidelines issued by the NationalComprehensive Cancer Network(NCCN) are followed by conscien-tious oncologists in their everydaypractice, but they are developedbased on clinical efficacy and withoutregard to costs. At a roundtable heldduring the NCCN’s 15th AnnualConference, moderator CliffordGoodman, PhD, Senior Vice Presidentat The Lewin Group, predicted, “Theappropriate use of evidence-basedguidelines is on a collision coursewith the financial nonsustainability ofthe healthcare system.”

Dr Goodmanalluded to a levelof frustration thathas never beenhigher in cancercare. “Too manypatients are stilldying young. Weneed innovations and a cure,” he said.But the inadequacy of current treat-ments for cancer is no longer the mainproblem. Equally challenging, he sug-gested, is finding a means to pay forthe ever-costlier care that threatens tobankrupt the healthcare system. As society struggles to find solu-

tions, “the ground is shaking beneathus,” Dr Goodman commented.

Continued on page 8



By Audrey Andrews

SEER-Medicare Database AnalysisConfirms Expensive ProstateCancers Gaining SupremacyBut cost-effectiveness of this move remains to be determined

San Francisco, CA—The popularity ofminimally invasive radical prostatec-tomy (MIRP), intensity-modulatedradiation therapy (IMRT), and ofbrachytherapy combined with IMRTfor prostate cancer started to take offafter 2002, a new database analysishas confirmed.At the American Society of Clinical

Oncology’s 2010 Genitourinary Can -cers Symposium, Paul L. Nguyen,MD, presented the results of histeam’s analysis of data from theSurveillance, Epidemiology and EndResults (SEER)-Medicare database.Dr Nguyen, director of Prostate

Brachytherapy, Dana-Farber/Brigham

and Women’s Hospital, HarvardMedical School, Boston, and his co-investigators found MIRP jumpedfrom 1.5% of radical prostatectomies(RPs) in 2002 to 28.7% in 2005. Theyalso found that IMRT soared from8.7% of external radiation treatmentsfor prostate cancer to 81.7%. In addi-

By Rosemary Frei, MSc

New Tools Arriving to Measure andManage Chemotherapy CareBusiness, clinical concerns now connected in value-focused approach By Daniel Denvir

Breast Cancer Survival Improves,Thanks to New Therapies

The 2010 Genitourinary CancersSymposium: Progress in Multi -disciplinary Management was heldMarch 5-7 in San Francisco. All ses-sions emphasized a multidisciplinaryap proach to care; a number of thembrought out the cost and value issuesassociated with caring for genitouri-nary cancers.

Value-Based Cancer Carewill be at the ASCO Annual Meeting, June 4-8, in Chicago. Please visit us at booth 18121

Barcelona—Survival for patients withmetastatic breast cancer has improveddramatically in the last 20 years, espe-cially in the subgroup of patients withHER2-positive tumors, according toresearch presented at the 7th European

Breast Cancer Confer ence (EBCC7).This improvement, the researcherssuggest, is due to in creased use ofanthracyclines and the rise of targetedtherapies.“There is no doubt that trastuzu -

mab (Herceptin), which targets theHER2 gene, is the most important

By Colin Gittens


��

Photo by © ASCO/Todd Buchanan 2009

value-focused

payers

cost control

clinical practiceguidelines

cost effectiveness

efficacy

NCCN Roundtable: Clinical andEconomic Issues Impacting Cancer Care Delivery “Collision course” in sight

©2010 Engage Healthcare Communications, LLCContinued on page 24

Baltimore, MD—A long-held businesstruism is that “if you can’t measure it,you can’t manage it.” The application of this belief to the oncology setting was demonstrated at a session of theAssociation of Community Cancer Cen ters’ (ACCC) 36th Annual NationalMeeting. Kimberly Bergstrom, PharmD,chief clinical officer for McKessonSpecialty Care Solutions, told attendeesof the growing importance of developingand using standardized chemotherapytreatment regimens, and of the tools that

can benchmark performance and fostercompliance with treatment guidelines.Public and private payers are mov-

ing to control exploding healthcarecosts, Dr Bergstrom told attendees,and because increased cost controlwas inevitable, it is in providers’interest to get a seat at the table. “It is an important topic, because

this is one of those things, if we don’tget a handle on it, it’s going to happento us,” she said. “People and groupsand organizations are going to startdictating how we provide cancer care,and we can’t let that happen.”

Hollywood, FL—Clinical practiceguidelines issued by the NationalComprehensive Cancer Network(NCCN) are followed by conscien-tious oncologists in their everydaypractice, but they are developedbased on clinical efficacy and withoutregard to costs. At a roundtable heldduring the NCCN’s 15th AnnualConference, moderator CliffordGoodman, PhD, Senior Vice Presidentat The Lewin Group, predicted, “Theappropriate use of evidence-basedguidelines is on a collision coursewith the financial nonsustainability ofthe healthcare system.”

Dr Goodmanalluded to a levelof frustration thathas never beenhigher in cancercare. “Too manypatients are stilldying young. Weneed innovations and a cure,” he said.But the inadequacy of current treat-ments for cancer is no longer the mainproblem. Equally challenging, he sug-gested, is finding a means to pay forthe ever-costlier care that threatens tobankrupt the healthcare system. As society struggles to find solu-

tions, “the ground is shaking beneathus,” Dr Goodman commented.

Continued on page 8



By Audrey Andrews

SEER-Medicare Database AnalysisConfirms Expensive ProstateCancers Gaining SupremacyBut cost-effectiveness of this move remains to be determined

San Francisco, CA—The popularity ofminimally invasive radical prostatec-tomy (MIRP), intensity-modulatedradiation therapy (IMRT), and ofbrachytherapy combined with IMRTfor prostate cancer started to take offafter 2002, a new database analysishas confirmed.At the American Society of Clinical

Oncology’s 2010 Genitourinary Can -cers Symposium, Paul L. Nguyen,MD, presented the results of histeam’s analysis of data from theSurveillance, Epidemiology and EndResults (SEER)-Medicare database.Dr Nguyen, director of Prostate

Brachytherapy, Dana-Farber/Brigham

and Women’s Hospital, HarvardMedical School, Boston, and his co-investigators found MIRP jumpedfrom 1.5% of radical prostatectomies(RPs) in 2002 to 28.7% in 2005. Theyalso found that IMRT soared from8.7% of external radiation treatmentsfor prostate cancer to 81.7%. In addi-

By Rosemary Frei, MSc

New Tools Arriving to Measure andManage Chemotherapy CareBusiness, clinical concerns now connected in value-focused approach By Daniel Denvir

Breast Cancer Survival Improves,Thanks to New Therapies

The 2010 Genitourinary CancersSymposium: Progress in Multi -disciplinary Management was heldMarch 5-7 in San Francisco. All ses-sions emphasized a multidisciplinaryap proach to care; a number of thembrought out the cost and value issuesassociated with caring for genitouri-nary cancers.

Value-Based Cancer Carewill be at the ASCO Annual Meeting, June 4-8, in Chicago. Please visit us at booth 18121

Barcelona—Survival for patients withmetastatic breast cancer has improveddramatically in the last 20 years, espe-cially in the subgroup of patients withHER2-positive tumors, according toresearch presented at the 7th European

Breast Cancer Confer ence (EBCC7).This improvement, the researcherssuggest, is due to in creased use ofanthracyclines and the rise of targetedtherapies.“There is no doubt that trastuzu -

mab (Herceptin), which targets theHER2 gene, is the most important

By Colin Gittens


��

Photo by © ASCO/Todd Buchanan 2009

targeted therapies


CONTINUING EDUCATION

Historically, payers have not beenimportant participants in oncol-ogy drug utilization. As oncolo-

gy costs have escalated, however, payerinvolvement in oncology drug manage-ment has increased. Reimbursement andcoverage models are emerging to grapplewith the massive financial burden associ-ated with oncology treatment. Payershave become coparticipants with pro -viders, and recent experience has shownthat these two stakeholder groups can bepoles apart in their strategic goals. A meaningful dialogue between pay-

ers and providers will occur if payers rec-ognize provider management strategiesthat provide optimal outcomes. Com -plex issues comprise the basis forprovider clinical approaches, includingan understanding of the disease state,pharmacotherapeutic options, clinicalobjective options, adherence to guide-lines, and regulatory issues. Alignment ofgoals—clinical and monetary—is essen-tial for oncology care to achieve theprogress made possible by the impressiveadvancements in therapy, and to providepatients with value-based treatmentsthat balance cost, quality, and access.

Advances in Ph+ CML Approximately 0.6 to two cases of

Philadelphia chromosome–positivechronic myelogenous leukemia (Ph+CML) are diagnosed globally per100,000 persons each year. In theUnited States, 1.5 cases per 100,000persons are diagnosed annually.1,2Historically, chemotherapy with alky-lating agents and hydroxyurea provideda median survival of only 3 to 4 years.3Median survival improved to 6 to 7years in the early 1980s with the adventof interferon-alpha, but 10-year survivalrates were still only between 30% and40%, and patients had few options afterthe failure of first-line therapy.

The introduction of imatinib, a selec-tive BCR-ABL tyrosine kinase inhibitor(TKI), has revolutionized managementstrategies for patients with chronic-phase CML.4,5 By 2007, the annual mor-tality rate decreased to approximately1% to 2%, and the estimated 5-year sur-vival rate increased to approximately90%.2,3 This translates to an increasingdisease prevalence that may exceed200,000 cases within the next 20 years.With a median age of 65 years at diag-nosis, providing treatment that main-tains quality of life and valued produc-tivity is of major concern.

Optimal response and standard of careMuch has been learned regarding

accepted first-line therapy responsemilestones and the timing of thoseresponses in patients with chronic-phase CML since the introduction ofimatinib to clinical practice in 2001. Akey CML treatment strategy is to quick-ly, and as completely as possible, eradi-cate cells harboring the Philadelphiachromosome, thus avoiding or delayingthe development of mutations in theBCR-ABL gene that result in imatinibresistance. Patients with CML whohave suboptimal or no response to treat-ment are far more likely to experienceearly disease progression to advancedphase or blast crisis, in which long-termresponses to TKIs are unlikely to occur.6In the International Randomised

Study of Interferon versus STI571(IRIS), 98% of patients who hadachieved a complete cytogeneticresponse (CCyR) and major molecular

response (MMR) by 12 months werefree from progression to advanced phaseor blast crisis at 4 years compared with90% of patients who achieved CCyRwithout MMR by 12 months and 75%of patients who did not achieve CCyRby 12 months.7 Another significantpiece of evidence from the IRIS trialcame from the 8-year follow-up (Figure1).8 By year 8, patients responding toimatinib had a low overall risk of pro-gression to advanced phase or blast cri-sis.8 As seen in Figure 1, imatinib waseffective in preventing risk of prospec-tive progression events but not loss ofresponse or progression events thatoccur early (within years 1-4). A large proportion of patients who

fail to achieve adequate or optimalresponse to first-line imatinib harborresistance-conferring BCR-ABL muta-tions.9,10 Therefore, to improve long-term outcomes, treatment strategiesshould be more contingent on promptand early optimal response than on theidentification of patients who developresistance and relapse. Second-generation TKIs designed to

overcome imatinib resistance includenilotinib, dasatinib, bosutinib, and oth-ers.11 Although these agents haveproved to be effective second-line or“salvage” options, patients already har-boring BCR-ABL mutations have beenshown to have an increased likelihoodof relapse, as a result of the develop-ment of additional mutations.12 Because the goals of first-line therapy

should include preventing the emer-gence of therapy resistance and provid-ing the best possible option for long-

term survival, researchers have hypoth-esized that early diagnosis of CML,paired with immediate treatment withmore potent TKIs, may improve therate of early CCyR and further MMR(3-log reduction in BCR-ABL tran-scripts below standard baseline), andthus improve long-term outcomes inpatients with CML.

Key presentations on CML atASCO 2010The 2010 American Society of

Clinical Oncology (ASCO) annualmeeting provides the perfect forum forthe discussion of emerging data thataffect patient outcomes and treatmentstrategies, as well as the changing para-digm of standard of care. This articleprovides a review of several key presen-tations that may provide the basis forfuture decisions and policies as moreagents become available for the treat-ment of CML.

First-line treatment strategies:nilotinibThe Evaluating Nilotinib Efficacy and

Safety in Clinical Trials of Newly Ph+CML Patients (ENESTnd) trial is a glob-al, multicenter, randomized, phase 3 trialcomparing nilotinib 300 mg twice dailyand 400 mg twice daily with imatinib400 mg/day as first-line therapy in newlydiagnosed patients with chronic-phaseCML (N = 846).13,14 Patients were strati-fied by the Sokal risk score, with 28% ofpatients in each arm in the high-risk cat-egory.15 The primary end point is theMMR rate at 12 months, and a key sec-ondary end point is the durability of

ASCO 2010 Update on Chronic MyelogenousLeukemia: Payers’ and Providers’ Perspectives

PROGRAM P10057 • RELEASE DATE: SEPTEMBER 15, 2010 • EXPIRATION DATE: SEPTEMBER 15, 2011

ESTIMATED TIME TO COMPLETE: 1.0 HOUR

PHARMACISTS DESIGNATIONMedical Learning Institute, Inc., is ac -credited by the Accreditation Council

for Pharmacy Education (ACPE) as a pro vider ofcontinuing pharmacy education. Com pletion ofthis activity provides for 1.0 contact hour (0.1CEU) of continuing education credit. The univer-sal activity number for this activity is 468-9999-10-045-H01-P.

INSTRUCTIONS FOR CREDIT1. Read the article in its entirety2. Log on to www.TheOncologyPharmacist.com3. Select “Continuing Education”4. Click on this article’s title from the listshown

5. Select “Click here to complete the posttestand obtain a CE certificate online”

6. Complete and submit the CE posttest andCE Activity Evaluation

7. Print your Statement of Completion

This activity is provided free of charge to partici-pants. Upon completion of the evaluation andscoring 70% or better on the posttest, you willimmediately receive your certificate online. If youdo not achieve a score of 70% or better on theposttest, you will be asked to take it again. Pleaseretain a copy of the certificate for your records.

FACULTY DISCLOSURESBefore the activity, all faculty will disclose theexistence of any financial interest and/or relation-ship(s) they might have with the manufacturer(s)of any commercial product(s) to be discussedduring their presentation(s): honoraria, expenses,grants, consulting roles, speaker’s bureau mem-bership, stock ownership, or other special rela-tionships. Presenters will inform participants ofany off-label discussions.

The associates of Medical Learning Institute, Inc.,and Center of Excellence Media, LLC, have nofinancial relationships to disclose.

Michael Mauro, MD, has received research grants

from, and is a consultant to, Bristol-Myers Squibband Novartis Oncology.

Gary M. Owens, MD, is a consultant to Auxilium,Genzyme, GlaxoSmithKline, and Eli Lilly andCompany.

DISCLAIMERThe information provided in this CE activity isfor continuing education purposes only and isnot meant to substitute for the independentmedical judgment of a healthcare provider rela-tive to diagnostic and treatment options of aspecific patient’s medical condition.

SPONSORThis activity is jointly sponsored by Medical Learn -ing Institute, Inc., a nonprofit medical accreditationcompany, and Center of Excellence Media, LLC.

COMMERCIAL SUPPORTACKNOWLEDGMENTThis activity is supported by an educational grantfrom Novartis Pharmaceuticals.

TARGET AUDIENCEThis activity was developed for pharmacists andother healthcare professionals.

LEARNING OBJECTIVESUpon completion of this activity, participantswill be able to:• Explain the impact of key data from ASCO2010 on payers and providers regardingchronic myelogenous leukemia (CML)

• Assess potential clinical, business, andregulatory changes in CML

• Discuss patient-centered, value-basedcare for CML



www.TheOncologyPharmacist.com

MMR at 24 months. Median time fromdiagnosis to study entry was 31 days.Results after a median follow-up of 18.5months were reported during an oralabstract session by Richard Larson, MD,Director, Hem atologic MalignanciesClinical Research Program, University ofChicago Medical Center, Illinois.13,14 Results for the primary end point,

MMR rates at 12 months, are shown inFigure 2.13,14 The rates for nilotinib 300mg twice daily (44%) and 400 mg twicedaily (43%) were significantly higherand twice that for imatinib (22%, P<.001 for both comparisons).13 Rates ofMMR at 12 months among patientswith a high Sokal risk score were 41%,32%, and 17%, respectively.14 MMRrates continued to rise, and with a medi-an follow-up of 18.5 months, remain sig-nificantly higher for the two nilotinibarms compared with the imatinib arm(66%, 62%, and 40%, respectively; P <.001 for both comparisons).13 Forpatients who have had a real-time quan-titative polymerase chain reactionassessment after receiving 24 months ofstudy drug (N = 145), 86% (n = 49),88% (n = 48), and 48% (n = 48)achieved MMR, respectively. As report-ed by Saglio and colleagues, after amedian follow-up of 13.8 months, 50%of the intent-to-treat population hadachieved MMR 8.6 (nilotinib 300 mg)and 11.0 (nilotinib 400 mg) monthsafter randomization (median not yetachieved for patients receiving ima-tinib).14 As seen in Figure 2, CCyR ratesby 12 months were 80%, 78%, and 65%(P <.001 for both comparisons).13,14Also, significantly fewer patients receiv-ing nilotinib have progressed toadvanced phase or blast crisis comparedwith those receiving imatinib (0.7%,0.4%, and 4.2%; P = .006 and P = .003,respectively).13 No patient who had pro-gressed to advanced phase or blast crisishad achieved an MMR.Nilotinib and imatinib both had good

safety and adverse event profiles.Overall, grade 3 or grade 4 nonhemato-logic adverse events were uncommon inthe safety population (patients whoreceived at least one dose of the studydrug; N = 836).13,14 Rates of any gradenausea (33%), muscle spasms (26%),diarrhea (24%), and vomiting (16%)were higher for patients in the imatinibarm than for those in either nilotinibarm (12%, 7%, 8%, and 5%, 300 mgtwice daily; and 20%, 6%, 6%, and 9%,400 mg twice daily).13 Rash (32% and37%, respectively), headache (14% and22%, respectively), pruritus (15% and13%, respectively), and alopecia (8%and 13%, respectively) were more com-mon in the nilotinib arms (vs 12%, 8%,5%, and 4%, respectively, for patientsreceiving imatinib).13Fluid retention events of any grade

were more common in the imatinib arm.Pericardial and pleural effusion events

were rare in patients receiving eithernilotinib or imatinib, and there was noclinically relevant prolongation in QTinterval or decrease in left-ventricularejection fraction in patients receivingeither study drug. Lipase and amylaseelevations, abnormal liver functiontests, and hyperglycemia were higher inthe nilotinib arms, and some of theseevents were grade 3/4 (≤1% to 9%).Grade 3 and 4 hematologic events thatoccurred any time during the study areshown in Figure 3.14 Rates of grade 3/4anemia and thrombocytopenia inpatients receiving nilotinib (4% and4%, respectively; and 10% and 12%,respectively) were similar to those expe-rienced by patients receiving imatinib(5% and 9%), while the rate of neu-tropenia was approximately half (12%and 10%, respectively, vs 20%).On June 17, 2010, the US Food and

Drug Adminis tration (FDA) grantedaccelerated approval to nilotinib for thetreatment of adult patients with newlydiagnosed chronic-phase Ph+ CML. Therecommended nilotinib dose for this indi-cation is 300 mg twice daily, orally.16

First-line treatment strategies:dasatinibThe Dasatinib versus Imatinib Study

in Treatment-Naïve CML Patients(DASISION) is a multinational studythat randomized 519 patients with newlydiagnosed chronic-phase CML to receiveeither dasatinib 100 mg/day (n = 259) orimatinib 400 mg/day (n = 260).17,18Patients were stratified according to theHasford risk score, with 19% of patientscategorized as high risk in each arm.17-19Note that the Hasford categorizationplaces fewer patients in the high-riskgroup than does the Sokal risk score. The primary end point was the rate of

confirmed CCyR at 12 months, and sec-ondary end points included rate of MMR,time to confirmed CCyR and MMR, andduration of confirmed CCyR.17,18 Mediantime from diagnosis to study entry was 1month.18 Results after a minimum follow-up of 12 months and a median treatmentduration of 14 months were reported dur-ing an oral abstract session by HagopKantarjian, MD, Chair, Department ofLeukemia, Division of Cancer Medicine,University of Texas M.D. AndersonCancer Center, Houston.17Of patients receiving dasatinib, 77%

had a confirmed CCyR by 12 monthscompared with 66% of patients receiv-

ing imatinib (P = .067; Figure 4).17 TheMMR rate at 12 months was also signif-icantly higher for the dasatinib armcompared with the imatinib arm (46%vs 28%, P <.001), as was the rate of anMMR at any time (52% vs 34%, P<.001). Patients receiving dasatinib also

achieved MMR earlier than did patientsreceiving imatinib. Considering onlythe patients who achieved MMR, themedian time to MMR for patientsreceiving dasatinib was 6.3 months (vs9.2 months for patients who achieved

Patie

nts

with

eve

nt, %

AP indicates advanced phase; BC, blast crisis; CHR, complete hematologic response; IRIS,International Randomised Study of Interferon versus STI571; MCyR, major cytogenetic response.Source: Reference 8.

3.3

8

7

6

5

4

3

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Event: loss of CHR; loss ofMCyR; AP/BC; death duringtreatment

AP/BC

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1.5

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1.8 1.7

0.9 0.80.5 0.3

1.4 1.3

0.40 0

Years of receiving imatinib

Figure 2 The ENESTnd Trial: MMR and CCyR, by 12 Months

Patie

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ng to

ther

apy,

%

P <.001

P <.001

CCyR MMRa

Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg/day(n = 282) (n = 281) (n = 283)

aBCR-ABL transcript level ≤0.1% in peripheral blood on RQ-PCR assay, as expressed on theInternational Scale. Patients who did not undergo RQ-PCR assessment at 12 months were consideredto have had no response.CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-timequantitative polymerase chain reaction.Source: Reference 14.

P <.001

P <.001

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44 43

22

80 78

65

Figure 1 Annual Event Rates for Patients Receiving Imatinib in the IRIS Trial


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atol

ogic

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s, %

Anemia Neutropenia Thrombocytopenia

Source: Reference 14.

Figure 3 The ENESTnd Trial: Grade 3/4 Hematologic Toxicities

4

25

20

15

10

5

0

Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg/day(n = 282) (n = 281) (n = 283)

10

12

54

20

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12

9

Pericardial and pleuraleffusion events were rarein patients receivingeither nilotinib or imatinib.

www.theOncologyPharmacist.com OctOber 2010 I VOL 3, NO 7 13


MMR receiving imatinib, hazard ratio =2.01; P <.001). Rates of MMR at 12 months among

patients receiving dasatinib by Hasfordrisk score were 56% (low risk), 45%(intermediate risk), and 31% (high risk)

compared with patients receiving ima-tinib (36%, 28%, and 16%, respective-ly). Fewer patients receiving dasatinibhave progressed to advanced phase orblast crisis compared with those receiv-ing imatinib (1.9% vs 3.5%). No patient

who achieved an MMR has progressedto advanced phase or blast crisis.The rates of grade 3/4 cytopenias are

shown in Figure 5.17 In particular, therate of grade 3/4 neutropenia (21%) wascomparable to that observed in patientsreceiving imatinib (20%) and lowerthan that observed in patients receivingdasatinib second-line after imatinibresistance or intolerance (36%).17,20 Therate of thrombocytopenia was 19%among patients receiving dasatinib com-pared with 10% among those receivingimatinib. This, too, is lower than thatexperienced by patients receiving dasa-tinib second-line. Grade 3/4 nonhema-tologic adverse events were rare for bothtreatment arms.17Several events of any grade occurred

less frequently among patients receivingdasatinib than among those receivingimatinib, including nausea (8% vs 20%,respectively), vomiting (5% vs 10%,respectively), rash (11% vs 17%, respec-tively), muscle inflammation (4% vs17%, respectively), and fluid retention(19% vs 42%, respectively). Similarrates were seen with both agents for anygrade diarrhea (17% for both), fatigue(8% vs 10%), and headache (12% vs10%). Pleural effusion was reported onlyin the dasatinib arm (10%), with allbeing grade 1/2.17 Three patients in thedasatinib arm discontinued treatmentbecause of grade 2 pleural effusion.

Laboratory abnormalities, includinglipase and amylase elevations and abnor-mal liver function tests, were rare onboth arms, as was clinically relevant pro-longation in QT interval. On July 12, 2010, the FDA granted a

priority review designation to the appli-cation for dasatinib for the treatment ofadult patients with newly diagnosedchronic-phase Ph+ CML. A decision isexpected by late October 2010.

Following resistance or intoleranceto first-line therapy: bosutinibBosutinib is an orally bioavailable

dual SRC/ABLTKI that is active againstthe vast majority of imatinib-resistantBCR-ABL mutations, excluding T315I.Jorge Cortes, MD, Chair, CML Sectionof the Department of Leukemia, Divisionof Cancer Medicine, University ofTexas M.D. Anderson Cancer Center,

Houston, reported preliminary resultsfrom a phase 1/2 study that is investigat-ing the efficacy and safety of bosutinib inpatients with chronic-phase CML whofailed treatment with imatinib. A total of294 patients are enrolled in this study—18 from the phase 1 portion (bosutinib400, 500, or 600 mg/day) and 276 in thephase 2 portion (bosutinib 500 mg/day).21 Patients with complete hematologic

response (CHR), CCyR, or MMR atbaseline and patients lacking either abaseline or a postbaseline assessmentwere considered nonevaluable for therespective response. After a median treat-ment duration of 13.7 months and amedian follow-up of 23.8 months, 91% ofevaluable patients had achieved a CHR,50% of patients had achieved CCyR, and52% had achieved MMR. Median timeto CCyR was 12.3 months. Median pro-gression-free survival has not beenreached, and 94% of patients are stillalive at month 24. Treatment with bosutinib was general-

ly well tolerated (Figure 6).21 Diarrheawas the most common nonhematologictoxicity, reported in 84% of patients (9%,grade 3/4). It was most frequentlyobserved within the first few weeks oftreatment, and was manageable and sub-sided quickly. Twenty-five percent ofpatients required a dose reduction and2% of patients had to discontinue bosu-tinib because of diarrhea. Rash of anygrade was observed in 34% of patients,with 9% of patients experiencing rash ofgrade 3/4. Rash responded favorably tosymptomatic management strategies andseldom required dose reductions, inter-ruptions, or therapy discontinuation.Fluid retention was minimal. The mostcommon grade 3/4 toxicity was myelo-suppression. Grade 3/4 thrombocytope-nia was observed in 24% of patients,grade 3/4 neutropenia in 16%, and grade3/4 anemia in 12%. As with other TKIs, myelosuppression

most often occurred within the first fewmonths of therapy and did not requiredose reductions or interruptions in mostpatients. Grade 3/4 laboratory abnormal-ities, including hypermagnesemia (12%),hypophosphatemia (8%), lipase eleva-tions (7%), and abnormal liver functiontests (10% elevated alanine aminotrans-ferase and 5% elevated aspartate amino-transferase) were also observed.21These results demonstrate that bosu-

tinib has clinical efficacy in patients withchronic-phase CML who are resistant orintolerant to imatinib. A phase 3 ran-domized clinical trial comparing the effi-cacy of bosutinib with that of imatinib innewly diagnosed, previously untreatedpatients with chronic phase CML hasfinished accrual. Results should be avail-able by the end of 2010.


MMRbConfirmed CCyRa

aConfirmed on 2 consecutive assessments at least 28 days apart. Patients who had a first assessment ofCCyR at 12 months that was confirmed on a second assessment thereafter were considered to have had aconfirmed CCyR by 12 months.bBCR-ABL transcript level ≤0.1% in peripheral blood on RQ-PCR assay, as expressed on theInternational Scale.CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-timequantitative polymerase chain reaction.Source: Reference 17.

The DASISION Trial: Confirmed CCyR and MMR, by 12 Months (n = 258 in each group)

P = .067

P <.001

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46

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Figure 5 The DASISION Trial: Grade 3/4 Hematologic Toxicities

10

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Dasatinib 100 mg/dayImatinib 400 mg/day

Dasatinib 100 mg/dayImatinib 400 mg/day

Continued from page 13

ASCO 2010 Update on Chronic Myelogenous Leukemia: Payers’ and Providers’ Perspectives

Patie

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Figure 6 Common Adverse Events Associated with Bosutinib

84

Diarrhea Nausea Vomiting Rash Abdominal Fatiguepain

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36 34

21 21

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10

0

Any gradeGrade 3/4


92 3

9

1 1

Several events of anygrade occurred lessfrequently among patientsreceiving dasatinib thanamong those receivingimatinib, including nausea.

Figure 4




COMMENTARY

Redefining the Best Approach to CML TherapyBy Michael Mauro, MDAssociate Professor of Medicine, Oregon Health & Science University Knight Cancer Institute, Center for Hematological Malignancies, Portland

The International RandomisedStudy of Interferon versus STI571(IRIS) provided proof of principle

that a small molecule, BCR-ABLinhibitor, could be very effective anddurable therapy for chronic-phase chron-ic myelogenous leukemia (CML).1Response kinetics were clearly predictiveof outcome—timely complete cytogenet-ic response (CCyR) and molecularresponse are protective against relapseand progression. Disease risk, as assessedby the prognostic Sokal and Hasfordscores, has historically been predictive oflower response to interferon-alpha andchemotherapy, as well as relapse, regard-less of response to therapy. In the IRIS trial, we saw that

although high-risk disease was associat-ed with reduced response, achievementof relevant response, such as CCyR,mitigated subsequent risk of relapse orprogression. Unlike resistance to tradi-tional chemotherapy, which typicallyinvolves activation of a salvage molec-ular pathway, identified resistance toimatinib is most often associated withkinase domain mutations altering orprecluding imatinib binding, which canrestore BCR-ABL activity. Perhaps themost favorable element of responsekinetics to imatinib has been the find-ing that the modest number of loss-of-response and progression events in theIRIS trial occurred early and declinedsharply thereafter rather than persistingas a continual or growing threat.What have we learned from the two

studies, Evaluating Nilotinib Efficacyand Safety in Clinical Trials of NewlyPh+ CML Patients (ENESTnd)2 andDasatinib versus Imatinib Study in

Treatment-Naïve CML Patients (DASI-SION)3? Nilotinib and dasatinib areboth superior to imatinib for treatingnewly diagnosed patients with chronic-phase CML. Both drugs provided high-er rates of CCyR faster than imatinib.Better molecular responses were alsoobserved with these agents when com-pared with imatinib, and optimalresponses were seen across all prognos-tic groups. These two agents providedreduction in rates of progression toadvanced phase or blast crisis at earlytime points.2,3

Emerging questionsThe investigational second-genera-

tion tyrosine kinase inhibitor (TKI),bosutinib, may soon represent an addi-tional option for patients who are ima-tinib-resistant or -intolerant, althoughits common toxicities are different fromthose experienced by patients receivingimatinib, dasatinib, or nilotinib, andwith comparable efficacy, toxicity com-parison prominence increases. As newsecond-generation TKIs gain approvalby the US Food and Drug Admin -istration, we need to determine theirplace in our management strategies.Relevant questions in the context ofthis clinical debate include: • Why not continue to use imatinibas first-line therapy and then switchto a second-generation TKI at theearliest sign of inadequate responseor intolerance?

• Will early use of second-generationTKIs lead to more high-level resist-ance?

• Does the benefit match theexpense?

1. Why not continue to use imatinib asfirst-line therapy and then switch to asecond-generation TKI at the earliestsign of inadequate response or intoler-ance? Waiting to use a more potent andmore effective agent may simply be toorisky. Aside from the Sokal and Hasfordrisk categorization scores, there is noprognostic tool available that will iden-tify patients needing more potent first-line therapy. Treating patients with sec-ond-generation TKIs at suboptimalresponse or failure needs to be recog-nized as salvage therapy—disease biolo-gy has likely changed or resistancemechanisms have become dominant bythis point, and optimal long-term out-comes are thus compromised, givenlower response and uncertainty regard-ing response duration. In the absence ofthe ability to select or personalize thera-py, the best strategy is to provide allpatients every opportunity to achieve anearly and deep response that is protec-tive against progression by using second-generation TKIs as primary therapy.2. Will early use of second-generationTKIs lead to more high-level resist-ance? We do not yet know if there is aplateau in progression-free survival(PFS) curves for the ENESTnd andDASISION trials, nor do we fullyunderstand the kinetics of late resist-ance with the second-generation TKIs.We do know that mutations related todrug resistance, as well as emergence ofadditional mutations over time,increase after an initial suboptimalresponse or treatment failure, necessi-tating the increasing use of a third TKIor of stem-cell transplantation. The ENESTnd and DASISION trials

demonstrated that optimal responserates were significantly greater in pa -tients receiving nilotinib or dasatinibcompared with those receiving imatinib.Such significant gains in early responseshould functionally reduce the numberof patients at risk for development ofresistance, because the genesis of resist-ant disease is linked to disease volume.Although time will add strength to thisargument, the early (12-18 months) dif-ferences in PFS, in light of the depth ofthese responses, may prove to be quiterelevant, because increasing the rapidityof response may shorten the time frameduring which resistance emerges.3. Does the benefit match theexpense? To answer this question, wemust look ahead to one important, yettheoretical future benefit—will we beable to eventually discontinue therapyand essentially “cure” chronic-phaseCML? The Stop Imatinib (STIM)study evaluated the persistence ofcomplete molecular remission afterstopping imatinib.4 In this pilot study,patients were required to be in com-plete molecular remission (thendefined as polymerase chain reactionundetectable) for at least 2 yearsbefore entering the study. Of the 69patients included in the study, 34 hadprevious interferon-alpha treatmentand 35 were treated only with imatinib.Median follow-up was 17 months. Ofthese 69 patients, 41 patients relapsed(loss of complete molecular response)within the first 7 months, 37 relapsedwithin the first 6 months, and tworelapsed after more than 6 months. Atmonth 12, the probability of remain-


ConclusionThese updates highlight the recent

advances in the treatment of CML;they can help payers and providers todevelop new approaches to the man-agement of this chronic disease andencourage multistakeholder collabora-tion to provide value-based care forpatients with CML. �

References1. Rohrbacher M, Hasford J. Epidemiology of chronicmyeloid leukaemia (CML). Best Pract Res Clin Haematol.2009;22:295-302. 2. Altekruse SF, Kosary CL, Krapcho M, et al, eds. SEER can-cer statistics review, 1975-2007. National Cancer Institute,2010. http://seer.cancer.gov/csr/1975_2007/. Accessed August10, 2010.3. Kantarjian H, O’Brien S, Cortes J, et al. Therapeuticadvances in leukemia and myelodysplastic syndrome over thepast 40 years. Cancer. 2008;113(7 suppl):1933-1952.4.Druker BJ. Translation of the Philadelphia chromosome into

therapy for CML. Blood. 2008;112:4808-4817.5. O’Brien SG, Guilhot F, Larson RA, et al; for the IRISInvestigators. Imatinib compared with interferon and low-dosecytarabine for newly diagnosed chronic-phase chronic myeloidleukemia. N Engl J Med. 2003;348:994-1004.6. Soverini S, Martinelli G, Rosti G, et al. ABL mutations inlate chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with agreater likelihood of progression to blast crisis and shorter sur-vival: a study by the GIMEMA Working Party on ChronicMyeloid Leukemia. J Clin Oncol. 2005;23:4100-4109. Epub2005 May 2.7.Hughes TP, Kaeda J, Branford S, et al; for the InternationalRandomised Study of Interferon versus STI571 (IRIS) StudyGroup. Frequency of major molecular responses to imatinib orinterferon alfa plus cytarabine in newly diagnosed chronicmyeloid leukemia. N Engl J Med. 2003;349:1423-1432.8. Deininger M, O’Brien SG, Guilhot F, et al. Internationalrandomized study of interferon vs STI571 (IRIS) 8-year followup: sustained survival and low risk for progression or events inpatients with newly diagnosed chronic myeloid leukemia inchronic phase (CML-CP) treated with imatinib. Blood.2009;114:abstract 1126.9. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib isvirtually always accompanied by clinical resistance, and muta-tions in the ATP phosphate-binding loop (P-loop) are associ-ated with a poor prognosis. Blood. 2003;102:276-283. Epub2003 Mar 6.

10. Jabbour E, Kantarjian H, Jones D, et al. Frequency andclinical significance of BCR-ABL mutations in patients withchronic myeloid leukemia treated with imatinib mesylate.Leukemia. 2006;20:1767-1773. Epub 2006 Jul 20.11. Branford S, Melo JV, Hughes TP. Selecting optimal sec-ond-line tyrosine kinase inhibitor therapy for chronic myeloidleukemia patients after imatinib failure: does the BCR-ABLmutation status really matter? Blood. 2009;114:5426-5435.Epub 2009 Oct 30.12. Soverini S, Gnani A, Colarossi S, et al. Philadelphia-posi-tive patients who already harbor imatinib-resistant Bcr-Ablkinase domain mutations have a higher likelihood of develop-ing additional mutations associated with resistance to second-or third-line tyrosine kinase inhibitors. Blood. 2009;114:2168-2171. Epub 2009 Jul 9.13. Larson RA, le Coutre PD, Reiffers J, et al. Comparison ofnilotinib and imatinib in patients (pts) with newly diagnosedchronic myeloid leukemia in chronic phase (CML-CP):ENESTnd beyond one year. J Clin Oncol. 2010;28(suppl15):abstract 6501.14. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTndInvestigators. Nilotinib versus imatinib for newly diagnosedchronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.Epub 2010 Jun 5.15. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimi-nation in “good-risk” chronic granulocytic leukemia. Blood.1984;63:789-799.

16. Tasigna (nilotinib) package insert. East Hanover, NJ:Novartis Pharmaceuticals Corporation; June 2010.17.Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib com-pared to imatinib (IM) in patients (pts) with newly diagnosedchronic-phase chronic myelogenous leukemia in chronic phase(CML-CP): twelve-month efficacy and safety from the phaseIII DASISION study. J Clin Oncol. 2010;28(suppl 18):abstractLBA6500.18. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib ver-sus imatinib in newly diagnosed chronic-phase chronicmyeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub2010 Jun 5.19. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prog-nostic score for survival of patients with chronic myeloidleukemia treated with interferon alfa. Writing committee forthe Collaborative CML Prognostic Factors Project Group. JNatl Cancer Inst. 1998;90:850-858.20. Sprycel (dasatinib) package insert. Princeton, NJ: Bristol-Myers Squibb Company; June 2009.21. Cortes JE, Kantarjian H, Brümmendorf T, et al. Safetyand efficacy of bosutinib (SKI-606) in patients (pts) withchronic phase (CP) chronic myeloid leukemia (CML) fol-lowing resistance or intolerance to imatinib (IM). J ClinOncol. 2010;28(suppl 15):abstract 6502.

Linda Ritter, PhD, participated in thedevelopment of this article.



COMMENTARY

Chronic Myelogenous Leukemia: Is It Time for a Change?By Gary M. Owens, MDPresident, Gary Owens Associates, Philadelphia, Pennsylvania

The multiple forms of leukemia,both acute and chronic, repre-sent a diverse group of hemato-

logic malignancies that can affectpatients from childhood onward; how-ever, leukemia is primarily a disease thataffects older individuals. According tothe National Cancer Institute Sur -veillance, Epidemiology and End Re -sults data, the incidence of all types ofleukemia is less than 10 cases per100,000 persons until the age of 50,when the incidence begins to risesharply and reach 65 per 100,000 per-sons by age 75.1As we learn in this article, Phila -

delphia chromosome–positive chronicmyelogenous leukemia (Ph+ CML)accounts for about 1.5 new cases annu-ally, or approximately 15% of all newlydiagnosed leukemia cases in the UnitedStates. The average age for CML isabout 65 years. More important, sincethe introduction of imatinib in 2001for the treatment of CML, the 5-yearsurvival rate for patients with CML hasreached 90%. Health plan medical and pharmacy

directors have often used the example ofimatinib for CML when speaking of“breakthrough” clinical products. Al -though the significant clinical advancein treatment of CML has been lauded byhealth plans, they also have reason to beconcerned, because of the potential forincreasing numbers of patients with thisdisease, and the accompanying growthin the cost of caring for what has nowbecome a long survival span for thischronic condition. Until now, planmanagement of this condition has been

minimal, with management strategiesmostly centering on prior authorizationof the tyrosine kinase inhibitor (TKI)agents used to treat CML and manage-ment of distribution through specialtypharmacy.In the main article, we learn about

the importance of an early completecytogenetic response (CCyR) and majormolecular response. Early CCyR andmajor molecular response are indicativeof the eradication of the Philadelphiachromosome harboring cells, thuspotentially avoiding the development ofmutations in the BCR-ABL gene thatcan lead to treatment resistance.According to data presented at therecent 2010 American Society forClinical Oncology meeting, thereappears to be a basis for a treatment par-adigm shift for newly diagnosed patientswith CML. The Evaluating NilotinibEfficacy and Safety in Clinical Trials ofNewly Ph+ CML Patients (ENESTnd)trial showed superior CCyR and majormolecular response rates for newly diag-nosed patients treated with nilotinibcompared with imatinib. Similarly, theDasatinib versus Imatinib Study inTreatment-Naïve CML Patients (DASI-SION) trial showed superior CCyR andmajor molecular response rates withdasatinib compared with imatinib.2,3The second-generation TKI, bosutinib,if approved, is likely to be initiallyreserved for treatment-resistant patients. The key question for health plans to

consider when managing benefits for thetreatment of CML is—What is theproper therapeutic strategy for newlydiagnosed and for existing patients?

Data from the ENESTnd and DASI-SION trials were published in the June17, 2010, issue of the New EnglandJournal of Medicine, documenting thatnilotinib and dasatinib are each superiorto imatinib for patients with newly diag-nosed Ph+ CML.2,3Does this mean plans should require

one of these treatments for all newlydiagnosed patients, or should the initialtreatment still be left up to the oncolo-gist, even if that may result in use of aproduct that has been shown to be clin-ically inferior? In general, health planswould prefer to preferentially pay formore effective treatments at the outset,even if the cost is increased. The dilem-ma for plans is how to provide the besttherapeutic option for their members,while working collaboratively withtreating physicians. The next obvious question will be—

Where will bosutinib be useful and howdoes it compare to the existing TKIs forCML? These are just a few of the manyunanswered questions that health plandecision makers face daily. With clinicaloutcomes being so critical, and the costof these agents being a major factor, wecannot afford to get this wrong. And thecare of CML and other leukemias isonly getting more complex. Accordingto the Pharmaceutical Research andManufacturers of America, 129 agentsare under development for the treat-ment of leukemia, second only to the202 drugs under development for solidorgan tumors.4 The questions of whatworks on whom, and when, will onlybecome geometrically more complex forclinicians and health plans.

We therefore should invest in re -search on genetic markers, comparativeeffectiveness research, and head-to-headtrials, such as the ENESTnd and DASI-SION trials, to determine the best ther-apies. The dilemma is, who will bear thecost of this kind of research? We knowthat manufacturers are hesitant to dosuch head-to-head trials, governmentfunding is limited for these trials, andhealth plans, with their relatively nar-row profit margins, cannot afford tosponsor such trials. Yet as the need forthis information continues to grow, weneed to be increasingly efficient in theuse of our healthcare resources. The healthcare system can no longer

afford to fund less-than-effective treat-ments when better options exist. Inaddition to funding research on thedevelopment of new drugs, we need tofind ways to fund the basic researchneeded to determine their place (if any)in therapy. Now is the time for all stake-holders to come together and find waysto accomplish this before the cost crisisworsens, and access to the best medicalcare is compromised. �

References1. Surveillance Research Program, National CancerInstitute. Surveillance, Epidemi ology and End Results: faststats. http://seer.cancer.gov/faststats. Accessed August 10,2010.2. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTndInvestigators. Nilotinib versus imatinib for newly diagnosedchronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. Epub 2010 Jun 5.3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib ver-sus imatinib in newly diagnosed chronic-phase chronicmyeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub2010 Jun 5.4. Pharmaceutical Research and Manufacturers of America.2009 report medicines in development for cancer.www.phrma.org/files/attachments/meds_in_dev/09-046PhRMACancer09_0331.pdf. Accessed August 11, 2010.


Redefining the Best Approach to CML Therapy

ing in complete molecular responsewas 45%.4 These results are quite intriguing and

suggest a subgroup of patients withundetectable disease that is sustainedby continued TKI therapy; the defini-tion of such a group can be reached rap-idly after drug withdrawal. Al though itis not currently recommended to stoptherapy outside of a closely monitoredclinical trial, as the number of patientsliving with chronic-phase CML growsand more patients achieve deeper andlong-lasting responses, the magnitudeof this potential increases. If greaterproportions of patients achieve better

quality remissions with first-line use ofsecond-generation TKIs, and this qual-ity facilitates the ability to discontinuetherapy, second-generation TKIs willunequivocally prove their worth.

2010 marks a redefinition of “besttherapy” for chronic-phase CMLHow do we manage chronic-phase

CML in 2010? I recommend the con-tinued use of imatinib in patients whohave already achieved an optimalresponse in the absence of clinical tox-icity, because there is currently no basisto switch a patient to a second-genera-tion TKI in the face of optimal re -

sponse to imatinib. I do, however, rec-ommend monitoring such patientsappropriately, and we should immedi-ately switch patients to a second-gener-ation TKI at the first clear sign ofdeveloping resistance. For patients who have recently initi-

ated imatinib, consideration of switch-ing to a second-generation TKI shouldbe made in the setting of suboptimalresponse or any sign of intolerance,more carefully defined given the avail-ability of multiple therapy options. Weare obligated to provide newly diag-nosed chronic-phase CML patientswith the best opportunity to achieve a

deep and long-lasting response, andfirst-line use of second-generation TKIsshould be the new gold standard. �

References1.Hughes TP, Kaeda J, Branford S, et al; for the InternationalRandomised Study of Interferon versus STI571 (IRIS) StudyGroup. Frequency of major molecular responses to imatinib orinterferon alfa plus cytarabine in newly diagnosed chronicmyeloid leukemia. N Engl J Med. 2003;349:1423-1432.2. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTndInvestigators. Nilotinib versus imatinib for newly diagnosedchronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. Epub 2010 Jun 5.3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib ver-sus imatinib in newly diagnosed chronic-phase chronicmyeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub2010 Jun 5.4. Mahon F-X, Rea D, Guilhot F, et al. Discontinuation ofimatinib therapy after achieving a molecular response inchronic myeloid leukemia patients. Blood (ASH AnnualMeeting Abstracts). 2009;114:abstract 859.




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CHICAGO—“Dasatinib 100 mg oncedaily should become frontline therapyin newly diagnosed chronic-phasechronic myelogenous leukemia,” saidDASISION (Dasatinib versus ImatinibStudy in Treatment-Naïve CMLPatients; CA180-056) lead investiga-tor Hagop M. Kantarjian, MD, TheUniversity of Texas, M. D. AndersonCancer Center, Houston. Kantarjian’sstatement was based on findings fromthe DASISION comparison of first-line dasatinib with first-line imatinibin patients with chronic-phase chronicmyelogenous leukemia (CP-CML).

Imatinib is the current gold standardfor CP-CML, Kantarjian pointed outin a presentation at the 2010 annualmeeting of the American Society ofClinical Oncology. Once-daily dasa-tinib, in earlier research, has inducedhigh rates of complete cytogeneticresponse (CCyR) and progression-freesurvival (PFS) in CML after imatinibfailure. In vestigations also haveshown that patients receiving ima-tinib who achieve a CCyR and amajor molecular response (MMR) by12 months have longer PFS andreduced risks of disease progression ordeath. MMR, the highest standard of

response, was defined by the presenceof ≤0.1% BCR-ABL transcripts. In aphase 2 study of first-line dasatinib,CCyR and MMR rates were high.

DASISION, a phase 3 study, was con-ducted at 108 centers in 26 countriesamong 519 patients (mean age, 47 years)

with newly diagnosed CML. Patientswere randomized to either dasatinib 100mg/day (n = 259) or imatinib 400mg/day (n = 260). Dose escalations todasatinib 140 mg once daily and to ima-tinib 600 mg to 800 mg once daily werepermitted for suboptimal response.

Patients were all enrolled within 1month of their initial diagnosis. Meanduration of therapy was 14 months. Theprimary end point was confirmed CCyRby 12 months, with confirmed CCyRdefined as a CCyR detected in two con-secutive assessments.

Dose escalations were reported in5% of patients receiving dasatinib andin 14% of patients receiving imatinib.Data analyses revealed CCyRs in 83%and 72% of patients in the dasatiniband imatinib arms, respectively (P =.0011), and confirmed CCyRs in 77%and 66% of patients in the two groups,respectively (P = .0067) at 12 months.An analysis of CCyR rates at 3, 6, 9,and 12 months revealed that the like-lihood of achieving a CCyR at allpoints remained at ~50% higher withdasatinib than with imatinib through-out (P <.001; hazard ratio, 1.53).MMR rates followed a similar pattern,with the 12-month rates at 46% fordasatinib 100 mg once daily and 28%for imatinib 400 mg once daily (P<.0001). Patients were twice as likelyto achieve MMR at any time withdasatinib versus imatinib. Median timeto achieving MMR was 6.3 months fordasatinib and 9.2 months for imatinib.

Also, progression to accelerated orblast phase was less frequent with dasa-tinib (1.9%) than with imatinib(3.5%). No patients who achievedMMR progressed to accelerated orblast phase. Twelve-month overall sur-vival was similar for both groups (dasa-tinib, 97.2%; imatinib, 98.8%).

Rates of thrombocytopenia and ane-mia were higher with dasatinib (throm-bocytopenia, 19% vs 10%; anemia, 10%vs 7%). Neutropenia occurred in about20% of patients with both agents.Adverse event–related discontinuationswere low at 1.2% for dasatinib and 0.4%for imatinib. Discontinuations for treat-ment failure occurred in 5% of patientstreated with dasatinib and 8.9% of thosetreated with imatinib. Pleural effusionwas more common with dasatinib (10%vs 0%), and superficial edema was morecommon with imatinib (9% for dasatinibvs 36% for imatinib).

Kantarjian concluded that dasatinib100 mg/day should be first-line therapyfor newly diagnosed CP-CML andcommented, “Based on the predictivevalue of complete cytogenetic respons-es, longer follow-up of first-line dasa-tinib may demonstrate better long-term outcomes than imatinib.” �

DASISION: More Responses Faster with FrontlineDasatinib in CML in Chronic PhaseBy Walter Alexander

Dasatinib 100 mg Once Daily Is Best Dose in Second-line CP-CMLCHICAGO—Four-year follow-up ofpatients with chronic-phase chronicmyelogenous leukemia (CP-CML) whohave been resistant, suboptimally re -sponsive, or intolerant to prior imatinibtherapy showed that dasatinib 100 mgonce daily has the most favorablerisk–benefit profile, with 66% progres-sion-free survival (PFS) and 82% overallsurvival (OS).

The findings also demonstrated thatresponses to dasatinib 100 mg once dailyat 12 months are predictive of PFS at 48months, said Neil P. Shah, MD, assistantprofessor of medicine at the University ofCalifornia, San Francisco, at the 2010annual meeting of the American Societyof Clinical Oncology.

Dasatinib, a potent tyrosine kinaseinhibitor, is indicated for treating ima-tinib-resistant or -intolerant patientswith CML (all phases) or Philadelphiachromosome–positive acute lymphoblas-tic leukemia.

“These findings argue, in general forthis population of patients, that a trial

of dasatinib for 1 year to see if they canachieve a CCyR [complete cytogeneticresponse] is reasonable. With a CCyR,you can expect a 4% to 5% chance oftheir disease transforming to accelerat-ed or blast phase,” Shah said.

Patients were randomized using a 2 ¥2 factorial design to one of four dasa-tinib treatment arms: 100 mg once daily(n = 167), 50 mg twice daily (n = 168),140 mg once daily (n = 167), and 70 mgtwice daily (n = 168). Prior analysis ofthe study had resulted in a change of theapproved dose from 70 mg twice daily tothe 100-mg once-daily dose. The cur-rent analysis evaluated efficacy and safe-ty in patients with a minimum follow-up of 48 months.

Similar percentages of patientsachieved the highest standard ofresponse, major molecular responses(MMRs) (44%, 100 mg once daily;43%, 70 mg twice daily; 42%, 140 mgonce daily; 41%, 50 mg twice daily).Fifty percent achieved CCyR in the100-mg once-daily group (49%-53%

for other doses). PFS, defined as no lossof complete hematologic response ormajor cytogenetic response, develop-ment of advanced disease, elevatedwhite blood cells, or death, was 66%for 100 mg once daily and 57% to 69%for other doses. OS was 82% for 100mg once daily and 75% to 83% forother doses. Rates of progression toaccelerated or blast phase for the 100-mg once-daily dose were 1.2% for eachof the first 3 years and 0% for year 4.

Landmark analysis of PFS accordingto response at 12 months with 100 mgonce daily showed that 93% of patientswho achieved an MMR (+ CCyR) hadPFS at 48 months, as compared with aPFS rate of 77% among patients whoachieved a CCyR but not an MMR at 12months. PFS for patients without a cyto-genetic response at 12 months was 45%.

In general, first occurrence of anadverse event (AE) was encounteredearly in the treatment course (<24months). AEs were typically mild tomoderate. First occurrences of pleural

effusions (all grades) tended to occur at<24 months (15% by 24 months, 7%between 24 and 36 months, and 2%beyond 36 months). Neutropenia andthrombocytopenia (grade 3-4) occurredmostly within the first 12 months oftreatment (33% and 22% by 12 months,decreasing to 0% for both between 36and 48 months). Discontinuations dueto drug toxicity were lowest with the100-mg once-daily dose (16% vs 19%-26% for other doses).

Shah concluded that dasatinib 100mg once daily offers a more favorable4-year risk–benefit profile with similarefficacy but better tolerability thanother doses. He pointed out that thisanalysis is the longest follow-up report-ed for any tyrosine kinase inhibitor. Hecommented further, “I think the lessthan 4% rate of transformation toaccelerated or blast phase in a second-line setting, along with the 82% over-all survival, is rather encouraging.” �

—WA

Hagop M. Kantarjian, MD

Hematologic Cancers



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Making it a realityMSTI has “plans to beef up programs

that are partly already in place but needgreater funding, whether that is gettingearly screening with mammography at agreater intensity or getting more educa-tion within the communities,” said PaulG. Montgomery, MD, FACP, a medicaloncologist. “There has been some edu-cation, there needs to be more. Therehave been some mobile mammographyunits going to rural areas, there needs tobe more.” Funding from the NCCCPcontract should help MSTI providethese additional services and “allow usto make an impact.”

The action plans start by analyzingdata on their patients. These data showwhere MSTI needs to focus, includinggeographic areas and ethnic popula-tions. Then, areas with disparities aretargeted for what is needed. Mont -gomery gave this example: Geographicareas where patients disproportionatelypre - sent in the later stages of cancerscan be targeted for patient education,hopefully leading to improved earlydiagnosis and screening.

To help get information and servicesout to people, MSTI plans to expand itsservices beyond the Boise clinic, wheremost of the specialized clinics are cur-rently housed. With the high-risk breastcancer clinic, for example, all patientsmust travel to Boise. But, the plan is toexpand into the Twin Falls area, whichis about 130 miles away, and at a futuredate, perhaps into the Fruitland area,according to Jill Winschell, RN, abreast cancer nurse navigator.

Navigation services will expandbeyond the new clinic. MSTI is cur-rently looking to fill several positionsfor new navigators, starting with a nav-igator for the Twin Falls area and one forthe Fruitland area in the western end ofthe Treasure Valley, which is home to alarge Hispanic and rural population. Athird breast care navigator will be hiredfor additional western Idaho locations.

“These rural navigators will be situat-ed in those areas and begin to developcommunity resources and communityoutreach to occur directly in their com-munities,” said Winschell.

A second mobile mammographycoach also is in the works. The currentcoach is booked every day, except whenit is down for service, according toWinschell. “In fact, they have traveledup to Grangeville, which is 220 milesnorth. And we will be traveling intoOregon, which will be new for us.”

Disparities meet supportive carePsychosocial and survivorship re -

sources are expected to expand into allfive sites as well, which will help MSTIembrace another of the NCCCP pil-lars—“Enhance cancer survivorshipand palliative care services.” In addi-tion, “we have the opportunity to pro-vide supportive oncology clinics tomeet the advanced disease population,”said Alicia Rosales, LMSW, an oncolo-gy social worker.

A supportive care oncology clinic wasopened in May in the Boise location. “Itis not in replacement of the patients’visits to their primary oncologist, butsomething that is linked in parallel,”said Dan Zuckerman, MD, medicaldirector for the supportive care and sur-vivorship clinics. With this clinic,patients who require help from multiplesupportive disciplines now have a placeto go. The clinic offers dietitians, socialworkers, and physical therapists. Thereare plans to increase psychiatric servicesby hiring someone with a specific inter-est in psycho-oncology. Although dedi-cated psychosocial onco l ogy personnelcan be difficult to staff in rural areas,Zuckerman is hoping to use fundingfrom the NCCCP for this purpose. Thisfunding may also allow a supportiveoncology clinic to open in each of thefive sites. Rosales envisions a half- dayclinic of survivorship and a half-dayclinic of advanced disease patients,staffed by a multidisciplinary team. Theclinics would offer a dietitian, a socialworker, a psychiatrist, a pharmacist, anurse practitioner, and referrals to finan-cial counselors and physical therapists.

The rural location of its patientsaffects survivorship services as well.With patients in remote areas, survivor-ship services means “making sure thatpatients have the information, theresources, and the tools they need toempower themselves to lead healthylives. We have to take into account thatall of them may not have the opportu-nity to participate in exercise classes.We have to give them the informationabout how they can do it on their ownin their own geographic setting,” saidRosales.

Patient education is a similar chal-lenge. In the Hispanic community,many believe that cancer cannot be

cured. “It is even harder when thesegroups of workers are spread over a largearea, to be able to reach out and havethem understand that cancer can becured. A great deal of time and effortwill be needed to communicate thatearly diagnosis is important,” saidMontgomery. “We are hoping that wecan do more community outreach andinteraction with the people in thosecommunities to deal with a lot of thosedisparities and get the rural andHispanic population into the health-care system in a timely manner,” echoedWinschell. MSTI employs bothHispanic and Spanish-speaking oncolo-gists and nurses to help with theseefforts.

Clinical trials and biospecimenresearch

NCCCP sites are also tasked to“increase participation in clinical trials”

and “participate in biospecimenresearch initiatives to support personal-ized medicine.” Using funding from thecontract, MSTI will be able to start aphase 1 clinical trial program within thenext 2 years, “which will be a hugething because there is no place in Idahoor in our surrounding area that offersphase 1 trials,” said Zuckerman. At cur-rent, MSTI accrues only to phase 3 tri-als, usually from one of the cooperativegroups—Southwest Oncology Group,Radiation Therapy Oncology Group,National Surgical Adjuvant Breast andBowel Project, Eastern CooperativeOncology Group, and Cancer andLeukemia Group B—as well as to a lim-ited number of industry-sponsored andinvestigator-initiated phase 2 trials.

Biospecimen processing is alreadyunder way. In conjunction with BoiseVeterans Affairs Medical Center andBoise State University, MSTI has bro-ken ground on the building wherebiospecimens will be stored. “I thinkone of the things nationally is the NCI[National Cancer Institute] is trying tostandardize how biospecimens arestored and to enable researchers fromanywhere in the country to access thesebiospecimens,” said Zuckerman.

Meeting the challenge“The challenge is not only to deliver

best standards of care, but also to imple-ment that across our multiple sites.Many of our patients cannot come intoour main center in Boise, so our goaland our responsibility is to provide carein their own communities,” explainedZuckerman. Along with fellow NCCCPsite Billings Clinic Cancer Center inBillings, Montana, MSTI hopes to meetthe NCI’s challenge of providing the best evidence-based care to allAmericans. �

St. Luke’s Mobile Mammography Service brings mammography to the ruralareas of southwestern Idaho.

Reducing Disparities in Cancer Care ... Continued from cover

“These rural navigatorswill be situated in thoseareas and begin todevelop communityresources andcommunity outreach tooccur directly in theircommunities.”

—Jill Winschell, RNNurse Navigator

“Many of our patientscannot come into ourmain center in Boise, so our goal and ourresponsibility is toprovide care in their own communities.”

—Dan Zuckerman, MDMedical Director,

Supportive Care andSurvivorship Clinics

Cancer Center Profile



Routine HBV Screening in Cancer ImmunosuppressiveRecipients Find Evidence of Virus in SomeBy Wayne Kuznar

CHICAGO—Routine screening forhepatitis B virus (HBV) in all patientsbeing started on immunosuppressivetherapy uncovers a significant percent-age with HBV surface antigen (HBsAg)and HBV core antibody (HBcAb), saidEmmy Ludwig, MD, at the 2010 annualmeeting of the American Society ofClinical Oncology (ASCO).As such, she recommends a univer-

sal screening program for HBV at allcancer centers. Chemotherapy andimmuno suppressive drugs can causereactivation of HBV in persons whohave the virus, with morbid and poten-tially fatal consequences.The recommendation for universal

screening in this population is at oddswith ASCO, which recently issued a pro-visional clinical opinion stating that thenet benefits and harms of routine screen-ing for HBV are not known for cancerpatients who are about to receive cyto-toxic or immunosuppressive therapy aspart of their cancer therapy. The officialstance of ASCO, therefore, is that HBVscreening in cancer patients requiresclinical judgment. The opinion was pub-lished online on June 1 in the Journal ofClinical Oncology.All patients at Memorial Sloan-

Kettering Cancer Center who were start-ed on immunosuppressive therapy(chemo therapy and/or corticosteroids)were screened for HBV from June toDecember 2009, consisting of serologiesfor HBsAg and HBcAb and subsequentmeasurement of HBV polymerase chainreaction (PCR) if either test was positive. The screening program was begun after

Ludwig and her colleagues identifiedcases in their center in which HBV wasreactivated after immunosuppressivetherapy, four of whom died (three whohad solid tumors) and 19 of whom werehospitalized (one who required livertransplant). Two of the patients werebeing treated with steroids. In all, 1720 patients were screened

prior to immunosuppressive therapy.During those 6 months, 1.1% were

positive for HBsAg and 9.2% were posi-tive for HBcAb. Less than half withHBsAg were born in Asia, where HBV ispandemic. More than nine (91%) of 10positive tests were in patients with asolid tumor.

Four of the 155 patients in whomHBcAb was positive but HBsAg wasnegative had a positive HBV PCR,meaning that new HBV was being madedespite the negative HBsAg test.

If screening was positive, patientswere treated with prophylactic antivi-ral therapy with entecavir, 0.5 mg/day,which has proved 100% effective inpreventing reactivation, said Ludwig, a

gastroenterologist at Memorial-SloanKettering. Entecavir prophylaxis isgiven for the entire duration of cancertherapy and continued for an addition-al 6 months. �

OcTOber 2010 I VOL 3, NO 7 21www.TheOncologyPharmacist.com

Supportive Care

In the treatment of patients with documented iron defi ciency in whom oral administration is unsatisfactory or impossible

Making the Case for INFeD®

Broad usage1

• Allows FDA-approved treatment of a wide range of patients with documented irondefi ciency anemia

Proven safety profi le of iron dextran• In a retrospective analysis of 841,252 doses, dyspnea, hypotension, and neurological

symptoms were the most common major adverse drug events (ADEs)2

— The most common minor ADEs were nausea, vomiting, fl ushing, and pruritus2

• Serious adverse events are rare— In a nonuremic population, 3 serious adverse events occurred in 481 patients (0.6%)

receiving 2099 iron dextran injections (0.1%), with no fatalities reported3

— In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions requiring resuscitative medications was 0.0016% (7 episodes in 440,406 exposures)4

• Iron dextran products are not clinically interchangeable1

— Differ in chemical characteristics and may differ in clinical effectsImportant Safety Information1

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the fi rst therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD® administrations. Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD® administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD® only in patients in whom clinical and laboratory investigations have established an iron defi cient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. INFeD® should be used with caution in individuals with histories of signifi cant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron defi ciency. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.

Please see next page for references and brief summary of full Prescribing Information.

www.infed.com

© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. 06107 11/09Of the 1.63 billion prescriptions written inthe United States in 2009, 12% (190million) were written electronically, ac -cording to a Surescripts audit.

Did You Know?


Pharmacist/Nurse Model for Delivery of SupportiveCare Improves Patient SymptomsBy Karen Rosenberg

CHICAGO—Implementation of a rov-ing pharmacist/nurse model for support-ive care at the North Carolina CancerHospital resulted in a significant im -provement in patient symptoms, re -

searchers reported at a poster session atthe 2010 annual meeting of the Am -erican Society of Clinical Oncology.

The multidisciplinary Oncology Sup -portive Care Consult Service was start-

ed at the hospital in 2008. Members ofthe team include a medical oncologist, aclinical pharmacist practitioner, and aclinical nurse specialist. A novel featureof the service is that the pharmacist and

nurse travel to the individual outpa-tient adult oncology clinics (hematol-ogy/oncology, gynecologic oncology,surgical oncology, radiation oncology),resulting in more timely consults andless travel and in convenience forpatients, explained Stephen Bernard,MD. Service is available 5 days a week.A designated On cology SupportiveCare Clinic was added when a needwas identified to ac commodate com-plex cases and patients needing ongo-ing follow-up.

In the first 18 months, the servicesaw 89 new patients and there were 292encounters, including both new andreturn visits. Referrals were receivedfrom radiation oncology, medicaloncology, gynecologic oncology, andsurgical oncology and were for patientswith a variety of malignancies. Painmanagement was the primary reasonfor consults (75%); others were consti-pation (11%), nausea/vomiting (8%),anxiety/mood (4%), and spiritual (2%).New consults and established visitswith the service increased by 50% inthe second 6 months compared withthe first 6 months.

The most common recommenda-tions by the Oncology Supportive CareConsult Service were dosage increasesand addition of new medications.Improvements in symptom scores wereevident by the second visit and weremaintained beyond that visit. In a sam-ple of 49 patients, pain scoresdecreased from 4 to 2.7 (5 being themaximum), nausea from 4 to 1.4, andconstipation from 2 to 1.6.

The researchers noted that the serv-ice allowed the primary oncologist tofocus on disease management whilethe supportive care consult team fo -cused on managing symptoms of thedisease and treatment. A study using aformal tool to evaluate patient satisfac-tion with the service is under way. �


Supportive Care

References: 1. INFeD® full Prescribing Information. Watson Pharma, Inc. September 2009. 2. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001;37:743-749. 3. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731. 4. Walters BAJ, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442.

BRIEF SUMMARY: For full Prescribing Information, see package insert.

INDICATIONS AND USAGE: Intravenous or intramuscular injections of INFeD are indicated for treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deficiency.WARNINGS:Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities have followed the parenteral administration of iron dextran. Always have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration. Prior to the first therapeutic dose, administer a test INFeD dose of 0.5 mL. (See DOSAGE AND ADMINISTRATION.) Although reactions are usually evident within a few minutes, observe patients for at least one hour before administering the therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products.Iron dextran products differ in chemical characteristics and may differ in clinical effects. Iron dextran products are not clinically interchangeable.Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment.The maximum daily dose should not exceed 2 mL undiluted iron dextran.Risk in Patients with Underlying Conditions: INFeD should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease.Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease.Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate com-plexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters.The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of iron-carbohydrate complexes.PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias.INFeD should be used with caution in individuals with histories of significant allergies and/or asthma.Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first therapeutic dose of INFeD. (See BOXED WARNING and DOSAGE AND ADMINISTRATION: Administration.)Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-agonist agents may be required in these patients.Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD.Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gram-negative sepsis, primarily due to E. Coli.Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD. Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration.The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the administration of iron dextran.Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.

Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells.Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran.Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation.Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS. Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose. No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.Pediatric Use: Not recommended for use in infants under 4 months of age. (See DOSAGE AND ADMINISTRATION.)ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse. Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available. (See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.)Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycar-dia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.)Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis. Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea. Hematologic/lymphatic: Leucocytosis, lymphadenopathy. Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis – See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/fibrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inflammation; local phlebitis at or near intravenous injection site.Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness. Respiratory: Respiratory arrest, dyspnea, broncho spasm, wheez ing. Urologic: Hematuria. Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting. (See WARNINGS.)Miscellaneous: Febrile episodes, sweating, shivering, chills, mal aise, altered taste.OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50

of iron dextran is not less than 500 mg/kg in the mouse.

Rx OnlyRevised: September 2009

Address medical inquiries to:WATSONMedical CommunicationsP.O. Box 1953Morristown, NJ 07962-1953800-272-5525

Distributed by:Watson Pharma, Inc.Morristown, NJ 07962

Manufactured by:Patheon Italia S.p.A.Ferentino, Italy 03013

251279S0909

WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection.

Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration.Administer a test INFeD dose prior to the first therapeutic dose. If no signs or symptoms of anaphylactic-type reactions follow the test dose, administer the full therapeutic INFeD dose. During all INFeD administrations, observe for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran injection. Fatal reactions have also occurred in situations where the test dose was tolerated.Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions to INFeD.

A novel feature of theservice is that thepharmacist and nursetravel to the individualoutpatient adult oncologyclinics, resulting in moretimely consults and lesstravel and inconveniencefor patients.


CHICAGO—The benefit of bevaciz -umab in metastatic breast cancer wasmade clear in a meta-analysis of key tri-als presented by Joyce O’Shaughnessy,MD, of Baylor-Sammons Cancer Centerand US On cology, during the 2010annual meeting of the American Societyof Clinical Oncology.Three randomized trials—E2100,

AVADO, and RIBBON-1—that in -clude a total of 2447 patients havedemonstrated significantly improvedprogression-free survival (PFS) forbevacizumab combined with differentchemotherapy regimens for frontlinetreatment of metastatic breast cancer.In the pooled analysis, median PFSimproved by 2.5 months when beva-cizumab was combined with chemo -therapy compared with chemotherapyalone, regardless of hormone receptorstatus, sites of metastasis, disease-freeinterval, or prior adjuvant taxane use,O’Shaughnessy said. The chemotherapy regimens for

metastatic breast cancer included weeklypaclitaxel; every-3-week docetaxel; andcapecitabine, docetaxel or nanoparticlealbumin-bound (nab)-paclitaxel, anddoxorubicin or epirubicin. Ap proxi -mately 50% had received adjuvant thera-py. Median follow-up was 23 months to35 months. An overview of efficacy isshown in the Table.O’Shaughnessy and colleagues pooled

the individual results and arrived at an

overall PFS of 9.2 months with beva-cizumab versus 6.7 months with chemo -therapy alone, for a 36% reduction inrisk. All subgroups derived benefit frombevacizumab, including patients withadverse prognostic features. Responserates increased by an absolute 17% ver-sus controls.Overall survival (OS), however, was

not significantly improved in either theindividual trials or the pooled analysis.In the pooled population, OS was 26.7months with bevacizumab and 26.4months with chemotherapy alone; 1-year survival rates were 82% and 77%,respectively. There were no survival dif-ferences by subsets.“But in general, patients received mul-

tiple treatments upon progression,”O’Shaughnessy noted, which has a well-known effect on survival and thus makesit very difficult to show survival differ-ences between arms. In the nonbevacizumab arms, 71% of

patients received additional chemo ther-apy after the study, as did 65% of pa tientsin the bevacizumab arm. O’Shaugh nessypointed out that 50% of the chemother-apy-alone arm re ceived bevacizumab.An additional four anticancer agentswere given to 25% of patients.Bevacizumab use has been proved

safe, with treatment-related deathsreported for 2.1% of patients. Grade 3or higher adverse events included neu-tropenia, sensory neuropathy, and

hypertension in approximately 10% ofpatients; febrile neutropenia in 6.5% ofpatients; venous thromboembolism in2.8% of patients; and proteinuria in2.3% of patients.

OS benefit uncertainHope Rugo, MD, of the University

of California, San Francisco, posedsome reasons for the lack of OS bene-fit shown in the trials. “Line of therapyis important,” she pointed out. Studiesare less likely to show a survival bene-fit in the first-line unselected popula-tion, whose biology is “extremely het-erogeneous.” Late-line studies are morelikely to enroll a more homogeneousgroup of patients who have likelyresponded to prior treatments, have agood performance status, and havetumors associated with rapid relapse,which makes development of resis t-ance less likely, she said.

In addition, observation of an OSbenefit is dependent on survival timepostprogression, and short follow-up aswell as crossover treatments (50% ofthe control group received bevacizu -mab) make it highly unlikely for this tobe observed.Rugo said the future studies need to

hone in on which patients are morelikely to benefit from taking beva-cizumab. “Collaborative research andtumor biopsies are required to answerthe critical question of which patientsbenefit most from antiangiogenic ther-apy,” she concluded. �

Meta-analysis of Bevacizumab Trials in BreastCancer Show Longer PFSBy Caroline Helwick

PHARMACY CAREERS

Business Management Programs Help CliniciansImprove Healthcare DeliveryBy Eileen Koutnik-Fotopoulos

Healthcare is more than medicineand patient care. Physicians,pharmacists, nurses, and hospi-

tal administrators are realizing thathealthcare is also a business. As a result,healthcare professionals are looking forways to improve quality of care whilelowering costs. College and universitiesare answering the call with businessmanagement courses geared towardmedical professionals.“Healthcare has traditionally set itself

apart from other industries. It’s extreme-ly important to take best practices fromacross all industries and disciplines andlearn everything we can to deliver thehighest quality of care more efficiently,”says Judy Smith, MD, FACS, medical

director for the Roswell Park CancerInstitute in Buffalo, New York.The cost of cancer care and how to

best treat the disease are concerns forclinical professionals treating cancerpatients. “The high cost of cancercare in general is an issue. Our pa -tients and providers have high expec-tations, and we have to learn how tomanage the business of cancer better,”explains Smith.She notes how cancer is treated by

providers has changed. “It’s not justmanaging acute cancer but also long-term care.” Furthermore, the demand forcancer care is increasing because “of theaging population and the high numberof cancer survivors,” adds Smith.

In an effort to improve RoswellPark’s operations and optimize patientcare, Smith is one of 68 studentsenrolled in Harvard Business School’sManaging Healthcare Delivery execu-tive education program. Launched inOctober 2009, the $22,000 nondegreeprogram consists of three 1-week ses-sions over 9 months.“More and more clinicians, particular-

ly clinical leaders, are recognizing that asignificant portion of their job is not onlyto deliver excellent care, but also tomanage and allocate resources appropri-ately,” says Cara M. Sterling, director ofthe healthcare initiative at HarvardBusiness School.“Clinicians tend to be fact-based

learners who appreciate the body ofknowledge related to managing people,applying information technologies, andunderstanding and designing manage-ment metrics, to name just a few, thatbusiness schools have to offer. Themajority, however, don’t have 2 years toinvest in an MBA program. This pro-gram was developed specifically forhealthcare delivery professionals whowant an immersive management educa-tion experience, but want to do it in thecontext of their current job,” explainsSterling. Sessions cover developing effective

operational models, teams, and deliverystrategies; managing performance of

Table Efficacy of Bevacizumab in Individual Trials

Median PFSTrial Non-BV arm BV arm HR P

E2100 5.8 11.3 0.48 <.001

AVADO 7.9 8.8 0.62 <.001

RIBBON-1 (capecitabine) 5.7 8.6 0.69 <.001

RIBBON-1 (taxane/anthracycline) 9.0 9.2 0.64 <.001

BV indicates bevacizumab; HR, hazard ratio; PFS, progression-free survival.

The number of prescription drugs aban -doned by patients at the pharmacy rose55% in the second quarter of 2010compared with 4 years earlier, The WallStreet Journal reports.

Did You Know?

Breast Cancer




clinical nature of serious adverse events(AEs) associated with the administrationof IV iron. This brief overview aims tochange this perception.

HistoryIn the early 20th century, Goetsch

and colleagues introduced colloidal fer-ric hydroxide for IV infusion as therapyfor patients with hypochromic ane-mias.10 Toxic reactions to this prepara-tion were frequent and severe and setthe stage for the admonition that IViron be reserved for only extreme clini-cal circumstances. In the 1940s, ironsaccharides—and shortly thereafter iron dextran—were introduced for clin-ical use and were associated with anacceleration of IV iron use for those situations in which oral iron was notadequate. In 1964, Marchasin andWallerstein showed the felicitousness oftotal dose infusions of up to 3000 mg ofa high-molecular-weight (HMW) irondextran in 45 iron-deficient patients(Imferon, Fisons PLC; no longer avail-able). All patients responded, and noserious toxicity was observed.11 Yet, itwas not until 1980, when Hamstra andcolleagues published their prospectiveexperience with 471 iron-deficientpatients who received IV iron dextran(Imferon), that the first large seriesappeared.12 In this study, three patientswere considered to have had “anaphy-lactoid” reactions, with symptoms andsigns including respiratory arrest,hypotension, purpura, cyanosis, dysp-nea, syncope, wheezing, and hives.There were no deaths. The authors con-cluded that IV iron should be reservedfor conditions in which oral iron couldnot be used.12 IV iron remained on thepharmacopeia, but its use was limited.In 1989, recombinant human eryth -

ropoietin (EPO) became available forthe treatment of dialysis-associated ane-mia. Shortly thereafter, numerous stud-ies showed the benefit of IV iron inoptimizing responses to EPO-treatedpatients, and the addition of IV iron tothe treatment paradigm in dialysis-asso-ciated anemia became standard prac-tice. At the end of 1991, low-molecular-weight (LMW) iron dextran (INFeD,Schein, now Watson Pharma) wasreleased for clinical use and rapidlyreplaced HMW iron dextran, whichwas removed from markets in 1992, asthe IV iron formulation used in dialysiscenters. In 1996, the initial review ofsafety was published. The authors con-cluded that AEs with LMW iron dex-tran were rare, and only a history ofallergies predicted otherwise infrequentAEs.13 At the same time, anotherHMW iron dextran (Dexferrum,American Regent) was approved as analternative to INFeD. No comparison

safety data were, or subsequently are,available.In 2002, ferric gluconate (Ferrlecit,

Schein, now Watson Pharma) andshortly thereafter iron sucrose (Venofer,American Regent) were introduced asalternatives to iron dextran in patientson dialysis. In two retrospective studies,Michael and colleagues as well asCoyne and colleagues concluded thatserious AEs were much more commonwith iron dextran than with ferric glu-conate,14,15 which rapidly replaced irondextran for dialysis-associated anemia.In 2004, however, Chertow and col-leagues published a retrospective reviewof 30 million doses of IV iron, reporting

that serious AEs were much more likelyto occur with the HMW formulationand concluding that when this productis avoided, the other preparations(LMW iron dextran, iron sucrose, ferricgluconate) are safe with an incidence ofserious AEs of <1:200,000.16 Five stud-ies, albeit all retrospective, corroboratedthese findings.17-21 However, a sixth ret-rospective analysis reported no differ-ence.22 Nonetheless, use of iron dextranin nephrology patients, for all intentsand purposes, remains negligible.

Barriers to IV iron useDespite the safety and efficacy

demonstrated in the nine prospectiveoncology studies, the clinical communi-ty’s larger perception of danger associat-ed with the use of IV iron persists.Although AE rates may be driven high-

er by HMW iron dextran, all iron sup-plementation products suffer the stig-ma.23 This incorrect perception is fur-ther driven by the near lack ofprospective comparison studies. Onlytwo small prospective studies and onemeta-analysis compared the efficacyand safety of LMW iron dextran withiron sucrose; no difference was seen.24-26Another reason contributing to the

sparse use of IV iron in oncology may bethe lack of consensus on how best toadminister the different products andthe benefit or lack thereof of premed-ication. Premedication, which has beenshown to be responsible for more sideeffects than IV iron itself27 and of noother clinical benefit, continues to bewidely used before IV iron administra-tion. After a test dose, acute myalgias(chest and back tightness) occur infre-quently without tachycardia, hypoten-sion, stridor, or periorbital edema.28 Thisreaction abates within minutes andrarely recurs with rechallenge. It is notrare for physicians and nurses unfamiliarwith the innocuous nature of the reac-tion to intervene with antihistaminesand pressors, which cause significantvasoactive reactions that are subse-quently attributed to the IV iron.Lastly, inconvenience may contribute

to the lack of widespread use of IV iron.In the United States (but not inEurope), payers do not allow the admin-istration of ESAs and IV iron on thesame day. This unsubstantiated regula-tion is fueled by the lack of ICD-9-CMcodes for iron-restricted erythropoiesisor functional iron deficiency. For ab -solute iron deficiency, ESAs are con-traindicated until iron is replete. Forthose common situations in chemother-apy-induced anemia when iron parame-ters suggest iron repletion, however,functional iron deficiency is often pres-ent, and addition of IV but not oral ironto the treatment paradigm, routinelyimproves responses to ESAs. If the onlyICD-9-CM code for iron deficiency,280.9, is placed on the billing form, theESA will not be reimbursed; if omitted,however, the IV iron will not be cov-ered. This conundrum remains.

Recent developmentsThe recent update to the Nation-

al Comprehensive Cancer Network(NCCN) guidelines provides new opti-mism.29 The NCCN recommends thatif iron is indicated, it should be givenintravenously. The guidelines specifical-ly proscribe HMW iron dextran bybrand and state that the preferred prod-uct is LMW iron dextran (ie, INFeD).Principals at the US Food and DrugAdministration (FDA), however, re -cently published a review of the AEreporting on iron dextrans using the

FDA AE reporting system, death cer-tificates, and emergency departmentvisits. They concluded that reactionswith all of the products are possibleand, using the current system, it is notpossible to determine the relative ratesof serious AEs with the absence ofhead-to-head trials.30Furthermore, three new IV iron prod-

ucts promise to allow complete replace-ment of iron intravenously in 15 min-utes or less. Of these, ferumoxytol(Feraheme, AMAG Pharmaceuticals)is approved in the United States as a510-mg bolus injection administeredover 17 seconds for patients with irondeficiency and chronic renal diseases.Data with higher doses are anticipatedin the near future as are safety and effi-cacy data in other conditions associatedwith iron deficiency. The other two products, iron carboxy-

maltose (Ferinject, Vifor Phar ma) andiron isomaltoside (MonoFer, Pharm a -cosmos), are approv ed in Europe. Ironcarboxymaltose can be administered as a1-g infusion over 15 minutes, and ironisomaltoside as a 15-minute infusion indoses up to 20 mg/kg.The safety and efficacy of IV iron

have been demonstrated with transfer-rin saturation up to 50% and serum fer-ritin levels up to 1000 ng/mL. Althoughall IV irons are associated with seriousAEs, current reporting mechanisms tellus nothing about relative frequency ofAEs. Based on the preponderance ofpublished literature, it appears prudentto use HMW iron dextran with caution.These data suggest it may be time torevisit the treatment paradigm toinclude the routine use of IV iron with-in these parameters. �

References1. Auerbach M, Ballard H, Trout JR, et al. Intravenousiron optimizes the response to recombinant human eryth -ropoietin in cancer patients with chemotherapy-relatedanemia: a multicenter, open-label, randomized trial. JClin Oncol. 2004;22:1301-1307.2.Henry DH, Dahl NV, Auerbach M, et al. Intravenousferric gluconate significantly improves response to epo-etin alfa versus oral iron or no iron in anemic patientswith cancer receiving chemotherapy. Oncologist.2007;12:231-242.3. Hedenus M, Birgegård G, Näsman P, et al. Additionof intravenous iron to epoetin beta increases hemoglo-bin response and decreases epoetin dose requirementin anemic patients with lymphoproliferative malig-nancies: a randomized multicenter study. Leukemia.2007;21:627-632.4. Pedrazzoli P, Farris A, Del Prete S, et al. Randomizedtrial of intravenous iron supplementation in patientswith chemotherapy-related anemia without iron defi-ciency treated with darbepoetin alpha. J Clin Oncol.2008;26:1619-1625.5. Bastit L, Vandebroek A, Altintas S, et al. Ran -domized, multicenter, controlled trial comparing theefficacy and safety of darbepoetin alpha administeredevery 3 weeks with or without intravenous iron inpatients with chemotherapy-induced anemia. J ClinOncol. 2008;26:1611-1618.6. Auerbach M, Silberstein PT, Webb RT, et al.Darbepoetin alfa 300 or 500 mmg once every 3 weekswith or without intravenous iron in patients withchemotherapy-induced anemia. Am J Hematol. June 4,2010. Epub ahead of print.

Revisiting the Use of IV Iron in Patients with Cancer Continued from cover

The NCCN recommendsthat if iron is indicated, it should be givenintravenously. Theguidelines specificallyproscribe HMW irondextran by brand andstate that the preferredproduct is LMW irondextran.

Supportive Care




Pharmacy Practice

7. Kim YT, Kim SW, Yoon BS, et al. Effect of intra-venously administered iron sucrose on the prevention ofanemia in the cervical cancer patients treated with con-current chemoradiotherapy. Gynecol Oncol. 2007;105:199-204.8. Beguin Y, Maertens J, De Prijck B, et al. Dar -bepoetin-alfa and I.V. iron administration after autolo-gous hematopoietic stem cell transplantation: aprospective randomized multicenter trial. Blood (ASHAnnual Meeting Abstracts). 2008;112:54.9. Dangsuwan P, Manchana T. Blood transfusion reduc-tion with intravenous iron in gynecologic cancerpatients receiving chemotherapy. Gynecol Oncol. 2010;116:522-525. 10. Goetsch AT, Moore CV, Minnich V. Observationson the effect of massive doses of iron given intra-venously to patients with hypochromic anemia. Blood.1946;1:129-142.11. Marchasin S, Wallerstein RO. The treatment ofiron-deficiency anemia with intravenous iron dextran.Blood. 1964;23:354-358.12. Hamstra RD, Block MH, Schocket AL.Intravenous iron dextran in clinical medicine. JAMA.1980;243:1726- 1731.13. Fishbane S, Ungureanu VD, Maesaka JK, et al. Thesafety of intravenous iron dextran in hemodialysispatients. Am J Kidney Dis. 1996;28:529-534.14. Michael B, Coyne DW, Fishbane S, et al; for theFerrlecit Publication Committee. Sodium ferric glu-conate complex in hemodialysis patients: adverse reac-tions compared to placebo and iron dextran. Kidney Int.2002;61:1830-1839.15. Coyne DW, Adkinson NF, Nissenson AR, et al; forthe Ferrlecit Investigators. Sodium ferric gluconatecomplex in hemodialysis patients. II. Adverse reactionsin iron dextran-sensitive and dextran-tolerant patients.Kidney Int. 2003;63:217-224.16. Chertow GM, Mason PD, Vaage-Nilsen O,Ahlmén J. On the relative safety of parenteral iron for-mulations. Nephrol Dial Transplant. 2004;19:1571-1575.17. Mamula P, Piccoli DA, Peck SN, et al. Total doseintravenous infusion of iron dextran for iron-deficiencyanemia in children with inflammatory bowel disease. JPediatr Gastroenterol Nutr. 2002;34:286-290.18. Fletes R, Lazarus JM, Gage J, Chertow GM.Suspected iron dextran-related adverse drug eventsin hemodialysis patients. Am J Kidney Dis. 2001;37:743-749.19. McCarthy JT, Regnier CE, Loebertmann CL,Bergstralh EJ. Adverse events in chronic hemodialysispatients receiving intravenous iron dextran––a compar-ison of two products. Am J Nephrol. 2000;20:455-462.20. Auerbach M. Finding a safe and effective intra-venous iron treatment for restless legs syndrome. SleepMed. 2010;11:429-430.21. Ondo WG. Intravenous iron dextran for severerefractory restless legs syndrome. Sleep Med. 2010;11:494-496.22. Walters BA, Van Wyck DB. Benchmarking irondextran sensitivity: reactions requiring resuscitativemedication in incident and prevalent patients. NephrolDial Transplant. 2005;20:1438-1442.23. Auerbach M, Glaspy J. What is the right balancebetween iron and erythropoiesis stimulating agents inchemotherapy induced anemia? European Journal ofClinical & Medical Oncology. 2009;1:17-20.24. Sav T, Tokgoz B, Sipahioglu MH, et al. Is there adifference between the allergic potencies of the ironsucrose and low molecular weight iron dextran? RenFail. 2007;29:423-426.25. Moniem KA, Bhandari S. Tolerability and efficacyof parenteral iron therapy in hemodialysis patients, acomparison of preparations. Transfus Alternat TransfusMed. 2007;9:37-42.26. Critchley J, Dundar Y. Adverse events associatedwith intravenous iron infusion (low-molecular-weightiron dextran and iron sucrose): a systematic review.Transfus Alternat Transfus Med. 2007;9:8-36.27. Barton JC, Barton EH, Bertoli LF, et al. Intravenousiron dextran therapy in patients with iron deficiencyand normal renal function who failed to respond to ordid not tolerate oral iron supplementation. Am J Med.2000;109:27-32.28. Auerbach M, Ballard H, Glaspy J. Clinical update:intravenous iron for anaemia. Lancet. 2007;369(9572):1502-1504.29. National Comprehensive Cancer Network. ClinicalPractice Guidelines in Oncology: Cancer- and Chemo -therapy-induced Anemia. V.2.2011. www.nccn.org/professionals/physician_gls/PDF/anemia.pdf. Accessed Sept -ember 13, 2010.30. Wysowski DK, Swartz L, Borders-Hemphill BV, etal. Use of parenteral iron products and serious anaphy-lactic-type reactions. Am J Hematol. 2010;85:650-654.

the Albany College of Pharmacy andHealth Sciences, New York.He said oncology pharmacists need

to be fully aware of the LBW2005equation. Pharmacists have historical-ly used the Devine formula, which wasbased on ideal body weight. Pai saidthat the Devine formula was notderived on solid scientific grounds.Along with Paloucek, he has publisheda paper outlining the history of thisformula (Ann Pharmacother. 2000;34:1066-1069).“The goal of calculating ideal body

weight was to get an estimate of leanbody weight. It is important to recognizethat many equations have been generat-ed over time to estimate lean bodyweight. All these previous equations arelimited in that they are linear equations.That is to say that the estimate of leanbody weight increases in proportion tototal body weight as one goes from 50 kgto say 250 kg,” Pai explained.

The LBW2005 equation is superiorto previous equations because it is non-linear and gives better estimates of leanbody weight according to Pai. Simplyput, the estimate of an individual sub-ject’s lean body weight using LBW2005increases by approximately twofoldeven though their total body weightincreases by fourfold (50-200 kg). Paiapplied this equation and demonstratedits superiority when dosing aminoglyco-sides, ertapenem, daptomycin, andvoriconazole. Several investigatorshave demonstrated this for agents otherthan antibiotics as well.At the ICAA meeting, Pai present-

ed the findings from his current studythat showed estimated lean bodyweight was more useful than measuredtotal body weight to decrease the phar-macokinetics of the drug ertapenem innormal weight and obese individuals.Lean body weight represents the “non-fat” or “fat-free weight” of a patient

based on his or her sex. This informa-tion may be helpful because it could beused to estimate the dose of drugs thatare similar to ertapenem.The researchers found that a higher

dose of ertapenem may be necessary inobese patients compared with nonobesepatients. Ertapenem is commonly givenbefore surgery to prevent infections. When most drugs now on the market

were approved for commercial use, littleinformation was available on dosingobese patients. For antibiotics, using adose that is too low could lead to treat-ment failure and increase bacterialresistance, resulting in superinfections.Pai said that an antimicrobial dose thatis too high could also lead to avoidableside effects. He and his colleagues notedthat improving outcomes in obesepatients with infections by using theappropriate antibiotic dose could reducemorbidity and mortality, and result insignificant cost savings. �

It May Be Time to Rethink Drug Dosing... Continued from cover

Beforethe research is published…

Beforethe guideline is issued…

Beforethe drug is approved…

The role of intrave n ous (IV) iron asan addition to erythropoiesis-stimulating agents (ESAs) to opti-

mize therapy in patients with anemia

from cancer or chemotherapy-induced

anemia has been examined in nine

prospective, randomized trials,1-9 all of

which showed improvement in ESA

response, time to maximal response,

reduction in ESA dose to reach maximal

response, and improvement in quality-of-

life parameters (when mea sured). The

observed benefit was independent of

baseline iron parameters, and although

responses were greater in iron-depleted

patients, significant benefit was seen in

patients who were iron replete at study

entry. One study, which was powered to

show a difference in red blood cell trans-

fusions, found a 36% reduction in the

number of patients transfused.5 In all

these studies, which represent data on

more than 1200 patients, no significant

toxicity was noted.Despite these data, there remains resist-

ance to the addition of IV iron to the stan-

dard treatment paradigm for cancer and

chemotherapy-induced anemia. This

resistance is, in large part, due to misinfor-

mation and misinterpretation about the

The Official Newspaper for the Hem/Onc Pharmacist

BOSTON—New data presented at the

50th Interscience Conference on Anti -

microbial Agents and Chemo therapy

(ICAAC) suggest that standard doses of

antibiotics may not be the right dose for

obese individuals and that obese patients

may need higher doses for some agents.

In addition, the researchers said that

more studies are needed to determine

correct dosages of drugs for the obese.“Stop using the ideal body weight

equations and its derivative (adjusted

body weight). Consider using lean body

weight–2005 (LBW2005) when esti-

mating kidney function in the morbidly

obese subject. Oncology pharmacists

need to study the role of LBW2005 for

dosing cancer chemotherapy agents as a

potential surrogate of body surface area.

This is important because body surface

area is not estimated differently for men

and women of equal height and weight.

LBW2005 gives you estimates by sex,

which is important due to known phys-

iological differences,” said Manjunath

Pai, PharmD, an associate professor at

PHARMACY PRACTICEIt May Be Time to Rethink Drug

Dosing in Your Obese Patients

By John Schieszer



SUPPORTIVE CARERevisiting the Use of IV Iron in

Patients with CancerBy Michael Auerbach, MDAuerbach Hematology Oncology Associates, Baltimore, Maryland

Fostering a Dialogue to Improve Patient Care & Outcomes

Submit your cases online today at www.myelomacases.com


ViewpointA New Rx for MedicinePage 6

Continuing EducationASCO 2010 Update on CMLPage 12

Hematologic CancersDasatinib vs Imatinib Study inTreatment-Naïve CMLDasatinib 100 mg once daily in second-line CP-CMLPage 18

Supportive CareRoutine HBV Screening in CancerImmunosuppressive RecipientsPage 21

Pharmacist/Nurse Model for Delivery of

Supportive CarePage 22Pharmacy CareersBusiness Management ProgramsPage 25Oncology Pharmacist Seeks MBA toPrepare for Future of HealthcarePage 28

Inside

©2010 Green Hill Healthcare Communications, LLC

OCTOBER 2010


VOL 3, NO 7

Members of St. Luke’s Mountain States Tumor Institute, from left: Dan

Zuckerman, MD; Alicia Rosales, LMSW; Jill Winschell, RN; and Paul G.

Montgomery, MD, FACP.

Reducing Disparities inCancer Care: St. Luke’sMountain States TumorInstitute Embraces NCCCP PillarBy Dawn Lagrosa

S t. Luke’s Mountain States Tumor Institute (MSTI) provides

advanced cancer care to patients at clinics in Boise, Fruitland,

Meridian, Nampa, and Twin Falls, Idaho. Spanning more than

180 miles across southwestern Idaho, MSTI cares for patients from

rural areas and from metropolitan areas. Because of geographic iso-

lation, many people in rural areas present at later stages of disease. In

addition, large Hispanic populations in the rural counties of the state

are not getting screened for cancers on recommended timelines.

“Reduce cancer healthcare disparities” is the first of seven pillars

with which National Cancer Institute Community Cancer Centers

Program (NCCCP) sites are tasked. These inequalities of care include

access to cancer screening, treatment, and research. The staff at

MSTI hopes to reduce disparities in care for their patients with help

from their new contract as a member of the NCCCP.

CANCER CENTER PROFILE



Hem/Onc Pharmacist

You read it first in

� � ��


As the economy slowly recoversfrom the financial crisis, youmay be looking for ways to boost

the minuscule interest payments you areearning on your money. Although manydifferent options and strategies forincreasing your income stream are avail-able, they may not be appropriate foryour situation. Before making any deci-sions, do research and shop around forthe best rates.

Savings accountsA savings account is the most conven-

ient place to save money whether it iswith your local bank or credit union.Most people also have this accountlinked directly to their primary checkingaccount to make it easy to transfermoney to savings. It is important to lookat the interest rate you are earning fromthis account. Depending on where youbank and the type of account you have,the interest rate could be anywhere fromless than 1% up to 4% or more. Thenational average for a basic savingsaccount is about 0.80%. You may findthat community banks are offering better

interest rates, compared with the bignational banks. Visit www.bankrate.comto find the top-yielding bank and creditunion savings deals.

Money marketsIf you are not satisfied with the inter-

est rates from your savings accounts, con-sider a money market account. This typeof account can serve as your checkingaccount in many situations and can aver-age 3% to 4% interest. If you decide tolink your money market account to yourchecking account, make all deposits tothe money market account. Keep theminimum needed in the checkingaccount to avoid fees and transfer moneyto the checking account only when nec-essary. A money market account doeshave restrictions. Because the moneyheld in this account is invested different-ly, higher balance requirements, a limit-ed number of withdrawals per month orquarter, and a limited number of checksto be written per month may apply.

Checking accountsAn interest-bearing checking account

is another option. How much moneyyou regularly keep in your checkingaccount and how often you need toaccess the money or write checks willhelp determine whether you will bene-fit from this type of account. The aver-age interest earned with regular check-ing accounts is less than 1.5%, withmost checking accounts earning 0.5%interest. Although the low rate ofreturn is not going to maximize yourearnings even with a high balance inyour checking account, some interest isbetter than none. Keep in mind thatmost checking accounts that earn inter-est also charge monthly fees if you donot maintain a minimum balance. Thismay not be an issue if you always keep alarge balance in your checking account.Local and national banks also offer

what is called reward checkingaccounts. You can earn higher interest(about 4%) with no principal risk. Toearn this higher yield, you typicallyhave to make one monthly directdeposit into your account and use yourdebit card at least 10 times per month.A word of caution: If you cannot meet

the account requirements, your interestrate can drop to 0.25%.

Certificate of deposit If your financial situation allows for

locking up some of your money to get ahigher interest rate, consider a certificateof deposit (CD). A CD is a time deposit,which means you are tying up some ofyour money for a specific amount of timebefore you can withdraw it. If you with-draw early, you will lose interest and pos-sibly principal. This fixed-income invest-ment is most often issued by banks. Youcan purchase short- or long-term CDsranging from 1 month to years. Thisoption guarantees a fixed amount ofinterest, which is added to your accountperiodically throughout the term of theCD. If you decide to purchase a longer-term CD, you can withdraw the interestpayments as they are received.You may decide that you want sever-

al options for saving money dependingon your financial situation. Whateveryou decide, make sure your money isworking as hard as it can and providingyou with a return on your investment. �

How to Keep Your Money Earning InterestBy Eileen Koutnik-Fotopoulos

Personal Finance


daily operations and processes; and fos-tering an environment of learning andleadership. Between the modules, par-ticipants work on projects that are rel-evant to their organization and relateto the curriculum.In the first session, students com-

plete a series of exercises that aremeant to encourage self-reflection andhelp identify areas of organizationalopportunity. Participants also completeonline tutorials in finance and ac -counting. In the second session, partic-ipants write a business plan for a newservice line or rewrite the plan for anexisting one. Faculty keep in touchwith the students by sending periodic“healthcare in the news” articles, rec-ommended readings, and surveys aboutspecific management issues, accordingto Sterling.“Managing healthcare delivery has

become increasingly complex,” saysHarvard Business School professorRichard Bohmer, MBChB, MPH, facul-ty chair of the Managing HealthcareDelivery program. “Individuals whoattend this program are looking for theright balance between clinical manage-ment and science.“If you want to run an organization

more effectively, you have to design anorganization that runs well,” explains

Bohmer. He points out that individualsin a nonmanagerial role, such as in apractice with oncologists, also can bene-fit from the Harvard program. In anoncology practice, for example, staffneeds to have an appreciation for base-line managerial principles to bring peo-ple together to work effectively and toget the highest quality outcomes for thepractice and patients.Managing Healthcare Delivery is not

the only program available for the med-ical community. Duke University’sFuqua School of Business has just starteda 1-year Master of Management inClinical Informatics degree program inpartnership with the Duke Center forHealth Informatics. The cost of the pro-gram is around $48,000.The program will allow students to

develop business knowledge in tandemwith advanced health informationtechnology (IT) skills. Curriculumrequirements include seven manage-ment courses and five informaticscourses, including a new practicumexperience to be completed in a real-world setting at Duke.Duke has a long history in business

management and healthcare manage-ment programs. This new graduate pro-gram is the “intersection of those two,”according to Randy Sears, assistant direc-

tor of Masters of Management inClinical Informatics.“IT alone is not a panacea to improve

the patient experience or to impact thecost of healthcare. IT needs to be mar-ried to process improvement and organ-ization innovation to change para-digms. Bringing this all together is ourfocus at Fuqua,” comments Kevin A.Schulman, MD, director of Duke’sHealth Sector Management program.At the University of St. Thomas in St.

Paul, Minnesota, students complete nineprograms over 24 months to receive acertificate in Advanced Health CareManagement. The university, in partner-ship with the Minnesota Medical GroupManagement As sociation, developedthis educational program to help organi-zations prepare for the future of health-care. The cost is $375 per program.Program topics meet seven core com-

petencies determined by the Universityof St. Thomas and the MinnesotaMedical Group Management As -sociation. Core competencies includeleadership, finance, operations, market-ing, IT, human resources, and care deliv-ery and policy. Participants will be edu-cated on new ideas, strategies, and toolsto improve their organization; learn the-ory and participate in experientialinstruction that will provide the tools to

integrate knowledge learned into organi-zations’ operations; gain education andexposure to ideas and concepts beyondwhat healthcare professionals experiencein their daily role; and network withother healthcare professionals.Vanderbilt University’s Owen Grad -

uate School of Management graduatedits first Master of Management in HealthCare class in September 2009. The 1-year, part-time, 30-credit-hour degreeprogram targets physicians, nurses, andother clinical professionals. The programcost for the 2008-2009 academic yearwas $43,000, according to the universi-ty’s website.The program is organized into three

main components: core general businessclasses, healthcare-focused business class-es, and a yearlong team strategy project.Specific courses include managerial eco-nomics, services marketing, managerialaccounting, finance, operations, andhealthcare leadership. �

PHARMACY CAREERS

Business Management Programs... Continued from page 23

It is estimated that the generic oncologymarket in the United States will be $35billion after 2011, The Economic Times/India Times reports.

Did You Know?


Who’s YourNominee

TOPPharmacist?

for

The Oncology Pharmacist is pleased to announce

the inaugural T.O.P. Pharmacist award. The award

will recognize an oncology pharmacist nominated

by his/her peers for an outstanding contribution

to oncology pharmacy practice, research, or

education in 2010.

The four leading nominees will be profiled in

the February issue of The Oncology Pharmacist.

Readers will have an opportunity to vote for the

winner online at www.TheOncologyPharmacist.

com/award or by visiting The Oncology Pharmacist

booth at the 2011 HOPA meeting. The winner will

be announced in the April issue of The Oncology

Pharmacist.

Nomination forms are available atwww.TheOncologyPharmacist.com/award


Hem/Onc Pharmacist

�� TOP_October 2010_v6_TOP 10/18/10 12:45 PM Page 27

Scott A. Soefje, PharmD, BCOP,has more than 20 years of pharma-cy experience. He started as a hos-

pital staff pharmacist, has held severalpositions in academia, and workedbriefly in industry. Currently, he is direc-tor of pharmacy operations and directorof the oncology residency program atThe University of Texas Health ScienceCenter at San Antonio. Just this pastsummer, however, he em barked on a newventure—a master of business adminis-tration (MBA) program at GeorgeWashington University. Soefje is part ofa new trend, with more business schoolsoffering programs geared specifically tostudents with an interest in healthcareadministration [see story on page 24]. Hehopes that with a combination of clinicalexperience and management training, hewill be able to help his institution dealwith the financial and administrativechallenges in oncology practice today.

How did you get started in oncologypharmacy?I got my bachelor of science in phar-

macy back in the ’80s. I then worked ina hospital pharmacy and, during thattime, I started working on a master’s inhospital administration thinking thatthe administrative route was the way Iwanted to go. But I was accepted to thedoctor of pharmacy program at theUniversity of Texas before I finished themaster’s, and I felt that I couldn’t doboth programs at the same time. I chosethe doctor of pharmacy program andthen went on to a residency at TheUniversity of Texas Health ScienceCenter at San Antonio and a fellowshipat The M. D. Anderson Cancer Center.When I completed the fellowship

there were no oncology jobs, and I

heard about a position at Texas TechUniversity in Lubbock, where they werejust starting a pharmacy school. I was thefirst pharmacy practice faculty to arriveon campus, 6 months before my boss.After a few years, a position opened up atthe Veterans Affairs hospital in SanAntonio, which is my home town, and Imoved there. I took a position in indus-try for awhile and then moved to my cur-rent position at The University of TexasHealth Science Center in San Antonio,where I am director of pharmacy opera-tions and also director of the oncologyresidency program.

So why did you decide to go back toschool at this point in your career?I’ve always enjoyed the administrative

side of things and found I understand it.But in my role as a director, I began torealize that there were things that I wasdiscussing with the CEOs, CFOs, andaccountants that I didn’t fully under-stand. I thought I had two options. Icould do on-the-job training or I couldget formal training. About 1 year ago, Istarted looking into online MBA pro-grams and, ultimately, enrolled in theGeorge Washington University programin August. It has a healthcare focus anda very strong leadership focus, and itoffers classes that I think will be very rel-evant to my job. There are 120 people in the pro-

gram, all with an interest in health-care. Some are just out of a bachelor’sdegree program, while others are quiteadvanced in their careers. There areseveral physicians in the group, someclinicians who want to be better ableto manage their practice, and somehospital administrators who want moreformal training.

Do you think now with the currenteconomy and concerns about health-care reform concerns it’s more impor-tant than ever before for pharmaciststo have management experience aswell as clinical training?Yes. I remember back in the ’80s when

I was talking to Roger Anderson at M. D.Anderson he said that in the future,those who reach the level of director willbe clinically trained people who under-stand the business side of hospital admin-istration, not someone with an MBA ora master’s degree who doesn’t understandthe clinical side. That’s one of the rea-sons I went back to school. With thechanges coming in healthcare, I figuredthat someone with a clinical backgroundwho understands clinical practice andhas an MBA, has to be marketable. Considering that cancer care is not

going to get cheaper over the next fewyears and that we’re going to have tomake decisions about what drugs to useand when, about how to integrate all ofthese factors into oncology protocols,somebody with both clinical and admin-istration training is going to be in a goodposition.Some schools are now offering pro-

grams that combine pharmacy trainingand business administration. For in -

stance, the University of Florida has anonline program in conjunction withStetson University that offers a com-bined degree, an MBA and a master’sin hospital pharmacy. I can already see how I can apply

what I’m learning in my present posi-tion. Even though the Cancer Therapyand Research Center is part of TheUniversity of Texas Health ScienceCenter, we practice as a physicians’practice, much like community prac-tices. We’re not part of a hospital sys-tem, so we’re dealing with the same sortof economic issues they’re facing on adaily basis. We’re thinking of opening aretail pharmacy here, and this programwill prepare me to do that. Just takingthe marketing class has gotten methinking about how I can apply market-ing to clinical pharmacy practice, evenwithin the institution. As part of our oncology residency

program, we’ve set up monthly man-agement training sessions where we sitdown with the residents and go overthings like strategic planning, phar-macoeconomics, and budgeting tohelp prepare them to deal with theseissues. I think this will serve themwell in the future, whatever directiontheir careers take. �

Experienced Oncology Pharmacist Seeks MBA toBetter Prepare for Future of HealthcareAn interview with Scott A. Soefje, PharmD, BCOP

By Karen Rosenberg

NATIONAL HARBOR, MD—Pre -liminary results of an ongoing trial sug-gest that a combination of trastuzumab,bevacizumab, and docetaxel is safe andeffective as first-line therapy in womenwith metastatic breast cancer (MBC).Fourteen of the 18 patients treated to

date had a partial response or stable dis-ease, a clinical benefit rate of 77.7, theinvestigators reported.Previous studies have demonstrated

the efficacy of trastuzumab combinedwith bevacizumab in MBC but the high

rate of cardiotoxicity was a concern.Docetaxel has also been shown to beeffective alone or combined withtrastuzumab or bevacizumab. In the cur-rent study, Bhuvaneswari Ramaswamy,MD, of Ohio State University, Col -umbus, and her colleagues studied thesafety and efficacy of the three drugscombined in previously untreatedwomen with HER2-positive MBC.Their findings on the first 18 patientsenrolled in the ongoing trial werereported at the 2010 American Society

of Clinical Oncology Breast CancerSymposium.All patients received six cycles of

trastuzumab, bevacizumab, and do cetax-el, after which docetaxel could be dis-continued at the physician’s discretion.The other two agents were continueduntil disease progression or develop-ment of unacceptable toxicity. Median progression-free survival was

56 weeks. Eight patients had a partialresponse and six had stable disease. Grade 3 and 4 nonhematologic tox-

icities included nausea, fatigue, diar-rhea, wound dehiscence, retinaledema, pulmonary embolism, neuropa-thy, nephrotic syndrome, and hyper-tension. Grade 3 and 4 hematologictoxicities were neutropenia and febrileneutropenia. One patient had anasymptomatic drop in left ventricularejection fraction after three cycles oftherapy, but no grade 3 or 4 cardiotox-icity was observed.Accrual in the study is continuing

at two institutions. �

BREAST CANCER

Combination of Agents Shows Promise in MBC

“We’ve set up monthly managementtraining sessions where we sit downwith the residents and go over thingslike strategic planning, pharm aco -economics, and budgeting to helpprepare them to deal with theseissues. ” —Scott A. Soefje, PharmD, BCOP

Pharmacy Careers




O N C O L O G Y D R U G C O D E S

Medications Used for the Treatment of Breast Cancer

Current MedicareFDA- code price allowableapproved Compendia listed (AWP-based (ASP + 6%), CPT ®

generic (Brand) HCPCS code: for breast off-label use for pricing), effective effective administrationname code description cancer breast cancera 10/1/10 10/1/10-12/31/10 codes

Breast cancer forms in tissues of the breast, usuallythe ducts (tubes that carry milk to the nipple) andlobules (glands that make milk). It occurs in bothmen and women, although male breast cancer israre. The following sections will assist healthcareprofessionals and payers by providing appropriatecoding, billing, and reimbursement informationassociated with the management of breast cancer.

The following sections include:• Associated ICD-9-CM codes used for theclassification of breast cancer

• Drugs that have been FDA-approved in thetreatment of breast cancer

• Drugs that are compendia listed for off-labeluse for breast cancer based on clinical stud-ies that suggest beneficial use in some cases.Please note: if a check mark appears in theFDA column it will NOT appear in thecompendia off-label use column

• Corresponding HCPCS/CPT® codes and code descriptions

• Current Code Price (AWP-based pricing)• Most recent ASP plus 6% (Medicare allow-able), if applicable

• Possible CPT® Administration Codes foreach medication

Associated ICD-9-CM Codes Used for Breast Cancer174 Malignant neoplasm of female breast

Includes: breast (female)connective tissuesoft partsPaget’s disease of:breastnipple

Use additional code to identify estrogen receptorstatus (V86.0, V86.1)

Excludes: skin of breast (172.5, 173.5)174.0 Nipple and areola174.1 Central portion174.2 Upper-inner quadrant174.3 Lower-inner quadrant174.4 Upper-outer quadrant174.5 Lower-outer quadrant174.6 Axillary tail174.8 Other specified sites of female breast

Ectopic sites

Inner breastLower breastMalignant neoplasm of contiguous oroverlapping sites of breast whosepoint of origin cannot be determinedMidline of breastOuter breastUpper breast

174.9 Breast (female), unspecified

175 Malignant neoplasm of male breastUse additional code to identify estrogen receptorstatus (V86.0, V86.1)

Excludes: skin of breast (172.5, 173.5)175.0 Nipple and areola175.9 Other and unspecified sites of male

breastEctopic breast tissue, male

PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650

www.RJHealthSystems.com

This information was supplied by:

anastrozole J8999b: prescription drug, � NDC NDC N/A(Arimidex) oral, chemotherapeutic, level level

not otherwise specified pricing pricinganastrozole S0170: anastrozole, oral, �� $13.48 S0170: N/A(Arimidex) 1 mg not payable

by Medicarebacillus J9031: bCG (intravesical) �� $169.10 $114.93 96413, 96415Calmette-Guerin per installation(Tice BCG, TheraCys)bevacizumab J9035: injection, bevacizumab, �� $68.50 $58.44 96413, 96415(Avastin) 10 mgcapecitabine J8520: capecitabine, oral, �� $8.52 $6.85 N/A(Xeloda) 150 mgcapecitabine J8521: capecitabine, oral, �� $28.41 $22.58 N/A(Xeloda) 500 mgcarboplatin J9045: injection, carboplatin, �� $48.55 $3.70 96409, 96413, 96415(Paraplatin) 50 mgcisplatin J9060: cisplatin, powder �� $4.33 $1.50 96409, 96413, 96415(Platinol AQ) or solution, per 10 mgcisplatin J9062: cisplatin, �� $21.66 $7.49 96409, 96413, 96415(Platinol AQ) 50 mgcyclophosphamide J8530: cyclophosphamide, �� $2.09 $0.83 N/A(Cytoxan) oral, 25 mgcyclophosphamide J9070: cyclophosphamide, �� $10.57 $5.96 96409, 96413, 96415(Cytoxan) 100 mg (all 100-mg NDCs

inactive: 500-mg NDCs used to calculate code price)



O N C O L O G Y D R U G C O D E SSupplied by: RJ Health Systems




cyclophosphamide J9080: cyclophosphamide, �� $21.15 $11.92 96409, 96413, 96415(Cytoxan) 200 mg (all 100-mg NDCs

inactive: 500-mg NDCs used to calculate code price)

cyclophosphamide J9090: cyclophosphamide, �� $52.87 $29.79 96409, 96413, 96415(Cytoxan) 500 mgcyclophosphamide J9091: cyclophosphamide, �� $95.21 $59.59 96409, 96413, 96415(Cytoxan) 1 gramcyclophosphamide J9092: cyclophosphamide, �� $171.35 $119.18 96409, 96413, 96415(Cytoxan) 2 gramdaunorubicin citrate J9151: injection, daunorubicin �� $68.00 $57.66 96413liposome citrate, liposomal formulation, (DaunoXome) 10 mgdocetaxel J9171: injection, �� $24.29 $18.01 96413(Taxotere) docetaxel, 1 mgdoxorubicin J9000: injection, doxorubicin �� $13.20 $3.04 96409(Adriamycin) hydrochloride, 10 mgdoxourubicin HCl J9001: injection, doxorubicin �� $613.03 $486.80 96413liposome hydrochloride, all lipid (Doxil) formulations, 10 mg epirubicin J9178: injection, �� $5.38 $1.80 96409, 96413(Ellence) epirubicin HCl, 2 mg estradiol J8499b: prescription drug, �� NDC NDC N/A(Estrace) oral, non-chemotherapeutic, level level

not otherwise specified pricing pricingetoposide J8560: etoposide, oral, �� $57.33 $28.48 N/A(Vepesid) 50 mgexemestane J8999b: prescription drug, �� NDC NDC N/A(Aromasin) oral, chemotherapeutic, level level

not otherwise specified pricing pricingexemestane S0156: exemestane, �� $13.50 S0156: not N/A(Aromasin) 25 mg payable by

Medicarefluorouracil J9190: injection fluorouracil, �� $3.37 $1.74 96409(Adrucil) 500 mgfluoxymesterone J8499b: prescription drug, �� NDC NDC N/A(Androxy) oral, non-chemotherapeutic, level level

not otherwise specified pricing pricingfulvestrant J9395: injection, fulvestrant, �� $97.29 $83.02 96402(Faslodex) 25 mggemcitabine J9201: injection, �� $177.83 $148.35 96413(Gemzar) gemcitabine hydrochloride,

200 mggoserelin acetate J9202: goserelin acetate � $451.19 $194.29 96372, 96402(Zoladex 3.6 mg ONLY) implant, per 3.6 mghydroxyurea J8999b: prescription drug, �� NDC NDC N/A(Hydrea) oral, chemotherapeutic, level level

not otherwise specified pricing pricinghydroxyurea S0176: hydroxyurea, oral, �� $1.28 S0176: not N/A(Hydrea) 500 mg payable by

Medicareifosfamide J9208: injection, ifosfamide, �� $56.40 $34.15 96413, 96415(Ifex) 1 gram






irinotecan J9206: injection, irinotecan, �� $31.48 $6.12 96413, 96415(Camptosar) 20 mgixabepilone J9207: injection, ixabepilone, �� $73.76 $63.74 96413, 96415(Ixempra) 1 mglapatinib ditosylate J8999b: prescription drug, �� NDC NDC N/A(Tykerb) oral, chemotherapeutic, level level

not otherwise specified pricing pricingletrozole J8999b: prescription drug, �� NDC NDC N/A(Femara) oral, chemotherapeutic, level level

not otherwise specified pricing pricingleucovorin calcium J0640: injection, leucovorin �� $3.60 $1.05 96372, 96374, 96409(Wellcovorin) calcium, per 50 mgleuprolide J9217: leuprolide acetate �� $493.20 $208.22 96402(Eligard, (for depot suspension), Lupron Depot) 7.5 mgleuprolide J9218: leuprolide acetate, �� $27.52 $4.79 96402(Lupron) per 1 mglomustine J8999b: prescription drug, �� NDC NDC N/A(CeeNu) oral, chemotherapeutic, level level

not otherwise specified pricing pricinglomustine S0178: lomustine, oral, �� $10.59 S0178: not N/A(CeeNu) 10 mg payable by

Medicaremedroxyprogesterone J1051: injection, �� $9.67 $8.12 96402(Depo-Provera) medroxyprogesterone acetate,

50 mgmegestrol J8999b: prescription drug, � � NDC NDC N/A(Megace) oral, chemotherapeutic, level level

not otherwise specified pricing pricingmegestrol S0179: megestrol acetate, �� $0.66 S0179: not N/A(Megace) oral 20 mg payable by

Medicaremelphalan J8600: melphalan, oral, �� $5.68 $4.80 N/A(Alkeran) 2 mgmelphalan J9245: injection, �� $1,922.50 $1,401.83 96409, 96413(Alkeran) melphalan hydrochloride, 50 mgmethotrexate J8610: methotrexate, �� $3.61 $0.12 N/Asodium oral, 2.5 mgmethotrexate J9250: methotrexate sodium, �� $0.29 $0.19 96372, 96374, 96401,sodium 5 mg 96409, 96450methotrexate J9260: methotrexate sodium, �� $2.86 $1.89 96372, 96374, 96401,sodium 50 mg 96409, 96450mitomycin J9280: mitomycin, �� $67.20 $20.77 96409(Mutamycin) 5 mgmitomycin J9290: mitomycin, �� $218.40 $83.07 96409(Mutamycin) 20mgmitomycin J9291: mitomycin, �� $300.00 $166.15 96409(Mutamycin) 40 mgmitoxantrone J9293: injection, mitoxantrone �� $106.50 $40.83 96409, 96413(Novantrone) hydrochloride, per 5 mgoxaliplatin J9263: injection, �� $8.25 $4.71 96413, 96415(Eloxatin) oxaliplatin, 0.5 mg







paclitaxel J9265: injection, �� $15.54 $7.45 96413, 96415(Taxol) paclitaxel, 30 mgpaclitaxel J9264: injection, �� $11.20 $9.38 96413protein-bound paclitaxel protein-boundparticles (Abraxane) particles, 1 mgpemetrexed J9305: injection, � $61.65 $51.44 96409(Alimta) pemetrexed, 10 mgprednisone J7506: prednisone, �� $0.04 $0.04 N/A

oral, per 5 mgtamoxifen J8999b: prescription drug, �� NDC NDC N/A(Nolvadex) oral, chemotherapeutic, level level

not otherwise specified pricing pricingtamoxifen S0187: tamoxifen citrate, �� $1.89 S0187: not N/A(Nolvadex) oral, 10 mg payable by

Medicaretestolactone J8999b: prescription drug, �� NDC NDC N/A(Teslac) oral, chemotherapeutic, level level

not otherwise specified pricing pricingthiotepa J9340: injection, � $138.00 $114.09 51720, 96409(Thiotepa) thiotepa, 15 mgtoremifene citrate J8999b: prescription drug, �� NDC NDC N/A(Fareston) oral, chemotherapeutic, level level

not otherwise specified pricing pricingtrastuzumab J9355: injection, �� $78.26 $68.28 96413, 96415(Herceptin) trastuzumab, 10 mgtriptorelin J3315: injection, �� $870.00 $181.93 96372, 96402(Trelstar Depot, triptorelin pamoate, Trelstar LA) 3.75 mgtopotecan J8705: topotecan, � $89.73 $77.10 N/A(Hycamtin) oral, 0.25 mgtopotecan J9350: injection topotecan, �� $1,306.10 $1,090.84 96413(Hycamtin) 4 mgvinBLAStine J9360: injection, �� $3.18 $1.64 96409

vinblastine sulfate, 1 mgvinCRIStine J9370 : vincristine sulfate, �� $5.83 $3.98 96409(Vincasar) 1 mgvinCRIStine J9375: vincristine sulfate, �� $11.66 $7.96 96409(Vincasar) 2 mgvinCRIStine J9380: vincristine sulfate, �� $29.15 $19.90 96409(Vincasar) 5 mgvinorelbine J9390: injection, �� $42.60 $11.05 96409(Navelbine) vinorelbine tartrate, per 10 mgaCompendia references available upon request.bWhen billing a non-classified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for Nolvadex) in Column 24D and the drug name, strength, and National DrugCode (NDC) in Box 19 in order to ensure appropriate reimbursement.

ReferencesHCPCS Level II Expert 2010 • Current Procedural Terminology (CPT®) 2010 (CPT © copyright 2010 American Medical Association. All rights reserved. CPT® is a registered trademark of the AmericanMedical Association) • ICD-9-CM for Professionals Volumes 1 and 2, 2010 • The Drug Reimbursement Coding and Pricing Guide by RJ Health Systems International, LLC, Volume 7, Number 4, 4thQuarter 2010 • FDA-approved indication (from the product’s prescribing information) • National Cancer Institute® • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC,Wethersfield, Connecticut • CMS (Centers for Medicare & Medicaid Services), Medicare Allowable 4th Quarter 2010 (effective dates 10/1/10-12/31/10).

Prices listed herein are effective as of October 1, 2010.



Hematologic Cancers

Western Lifestyle Responsiblefor UK Breast Cancer SurgeLONDON—A Western lifestyle char-acterized by an excess of food and alco-hol and a lack of exercise may explainincreasing breast cancer rates in theUnited Kingdom, new data suggest.Findings from the World Cancer

Research Fund (WCRF) show that thebreast cancer rate in the United Kingdomis more than four times higher than ineastern Africa, which has the lowestbreast cancer rate worldwide.The organization recently reported

that 87.9 women per 100,000 in theUnited Kingdom were diagnosed withbreast cancer in 2008 versus only 19.3women per 100,000 women in easternAfrica, which includes Kenya andTanzania.Cancer experts have suggested that the

growing gap in breast cancer ratesbetween rich and poor countries may bepartly a function of better surveillanceand diagnosis in wealthier countries.They also emphasize, however, thatlifestyle is an important contributor.In fact, it is estimated that 40% of

breast cancer cases in the UnitedKingdom, or more than 18,000 cases peryear, could be avoided if women adopteda healthier lifestyle involving a betterdiet, more exercise, and less alcohol.Women in eastern Africa consume less

alcohol than UK women and are lesslikely to be obese. They are also more

likely to breastfeed, and breastfeeding hasbeen associated with a lower rate of breastcancer.Rachel Thompson, MD, with the

WCRF, said that breast cancer is not theonly cancer for which lifestyle may be acontributor. In fact, roughly a third of themost common cancers in the UnitedKingdom could be prevented by lifestylechanges, she noted.

No Evidence that StatinsCause CancerSTOCKHOLM—Statins do not in -crease the risk of cancer, according to theresults of a large meta-analysis released atthe European Society of CardiologyCongress 2010.Researchers from the University of

Oxford, United Kingdom, and theUniversity of Sydney, Australia, said in anews release that their results will “reas-sure the millions of people worldwidewho are taking statins to lower choles-terol levels and clarify earlier researchthat had raised concerns of a causal link.”The data are from the Cholesterol

Treatment Trialists’ Collaboration, whichreviewed data from 170,000 patientsenrolled in 26 trials. Overall, 10,000patients developed cancer and more than3500 died of cancer.“Statin therapy had no adverse effect

on cancer at any site or in any group ofindividuals, irrespective of their choles-terol levels,” said principal investigator

Jonathan Emberson, MD, of theUniversity of Oxford. “There was alsono association of cancer with statindose or duration.”The study was funded by the UK

Medical Research Council, the BritishHeart Foundation, and the NationalHealth and Medical Research Council(Australia).

Overactive Bladder withoutHematuria May Be CancerSymptomTORONTO—Overactive bladder (OA B)symptoms without hematuria may be apresenting symptom of bladder cancer,researchers reported at the joint annualmeeting of the International Con -tinence Society and InternationalUrogynecological Association.Most patients with bladder cancer

present with hematuria.Jeffrey Weiss, MD, of State

University of New York DownstateCollege of Medicine in Brooklyn, andcolleagues searched a database for theyears 1998 through 2008 to identifypatients without hematuria who under-went cystoscopy as part of an evalua-

tion for refractory OAB.Overall, 1420 patients underwent cys-

toscopy, and eight were found to havebladder cancer. The mean duration ofOAB symptoms was 3.3 years.In all cases, the initial biopsy in

patients with bladder cancer demon-strated low-grade Ta transitional carci-noma that, in most cases, resembled atypical papillary transitional cell tumoron cystoscopy. At a mean follow-up of5.2 years, four (50%) patients had expe-rienced one or two recurrences and twohad disease progression—in one case tocarcinoma in situ and in the other caseto high-grade T3 disease.The study also found that bladder can-

cer was 10 times more common inwomen with OAB than men with OABdespite the fact that it is two to threetimes more common in men than inwomen in the general population.Because OAB symptoms without

hematuria may be an initial symptomof bladder cancer, patients with OABsymptoms even without hematuriashould be advised to undergo cys-toscopy to rule out underlying bladdercancer, the authors said. �

INTERNATIONAL NEWS

Reports from the European Society of Cardiology Congress and the JointAnnual Meeting of the International Continence Society and InternationalUrogynecological AssociationBy Jill Stein

Aresearch-based educational pro-gram aimed at enhancing com-munication between non-

Hodgkin lymphoma patients and theirhealthcare providers has just beenlaunched and is available for healthcareproviders.Framing Life With Lymphoma was

developed by the Cancer SupportCommunity, which unites TheWellness Community and Gilda’sClub World wide, and was supportedby a grant from Cephalon.“Non-Hodgkin lymphoma is the

seventh most common cancer, yet themajority of people who are diagnosedhave very little information on thedisease and how it may impact their

lives,” said David Henry, MD, clinicalprofessor of medicine at PennsylvaniaHospital and the physician advisor forFraming Life With Lymphoma.The program contains simple tip

sheets outlining ways to approacheach conversation the patient is likelyto encounter from diagnosis throughtreatment. The information was creat-ed through input from an expert steer-ing committee and a national surveyof 150 hematologists/ oncologists and133 patients with indolent lymphoma. The survey found that 96% of physi-

cians and 86% of patients felt theircommunication could be made moreefficient with informational aids. Thesurvey also revealed that about two in

five patients do not ask all theirintended questions during visits, usu-ally because they don’t remember. “This survey shows that it is critical

that patients have resources to helpthem understand their condition andtreatment options. This helps themcommunicate more effectively withtheir physicians,” Henry said. “In addition to providing informa-

tion, physicians need to work withtheir patients to create a team-basedapproach to treatment,” he added.“Working as a team creates an envi-ronment where informed patients aremore comfortable addressing theirconcerns and questions, and this canhave a positive impact on their overall

treatment experience.”Kim Thiboldeaux, president and

CEO of the Cancer SupportCommunity, also applauded the pro-gram.“We hope Framing Life WithLymphoma will become an importantresource for the lymphoma communi-ty,” she said. “A clear majority ofpatients and physicians reported thatdiscussion materials would improvetheir conversations. That is what thisprogram aims to do.”The patient tip sheets for newly

diagnosed patients and those undergo-ing treatment, along with the surveyresults and other program information,can be downloaded at www.FramingLifeWithLymphoma.org. �

New “Tip Sheets” Help NHL Patients Communicate withthe Oncology TeamBy Caroline Helwick

Statin therapy had no adverse effect on cancer at anysite or in any group of individuals, irrespective of theircholesterol levels.


A Newsletter Series for Cancer Care Professionals

Center of Excellence Media, along with Editor-in-ChiefSagar Lonial, MD, of Emory University, are pleased tooffer your multidisciplinary cancer team this series ofnewsletters focusing on the challenges of treatingpatients with multiple myeloma.

SAGAR LONIAL, MDAssociate Professor of

Hematology and Oncology Emory University School of Medicine

� Earn Continuing Education Credits �

Each newsletter will feature:

These activities are supported by an educational grant from Millennium Pharmaceuticals, Inc.

• Front-line Therapy• Maintenance Settings• Transplant Settings• Retreatment Settings

• Non-Transplant Patients• Cytogenetics• Side Effect Management• Bone Health

• Contributions from thought-leadingphysicians, nurses, and pharmacists

• Continuing Education credits availableto physicians, nurses, and pharmacists

Presents the Third Annual Curriculum for CONSIDERATIONS IN MULTIPLE MYELOMA

PARTICIPATE TODAY at www.COEXM.com

8-part newsletter series

CASE STUDY DISCUSSIONS:

For complete learning objectives and accreditation information, please refer to each activity.

Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

These activities are jointly sponsored by


High Responses in Melanoma for Wool Dye/OcularStain Rose Bengal By Walter Alexander

Positive findings in treatment ofmetastatic melanoma were amongthe highlights of June’s 2010

annual meeting of the American Societyof Clinical Oncology (ASCO). For ipi -limumab, there was the remarkableachievement of being the first to show asurvival advantage in a randomized clin-ical trial. But whereas ipilimumab is aninvestigational human monoclonal anti-body and a product of the most sophisti-cated of modern medical technologies,the agent in the second successfulmetastatic melanoma trial, Rose Bengal,has a more humble pedigree.The clinical trial of Rose Bengal injec-

tions (PV-10, a 10% Rose Bengal solu-tion) revealed a 79% response rate inmetastatic melanoma patients, andshowed responses in “bystander” lesionsthat were not injected, suggesting a sys-temic immune response, according toSanjiv Agarwala, MD, who is sectionchief of oncology and hematology at St.Luke’s Cancer Center in Bethlehem,Pennsylvania. But for the story of howRose Bengal evolved in stages over morethan 130 years from its original applica-tion as a coal tar–derived wool dye, EricWachter, PhD, Provectus cofounder and

senior vice president, provided a historyin an interview at ASCO.

History of Rose BengalIn 1882, German patent No. 32584

was granted to Ghnem for a new familyof wool dyes. Ghnem took differenthalogens and added them to fluoresceinto produce molecules with different col-ors. The name, Rose Bengal, arose pre-sumably from the fact that the deep rosyred color was similar to that of the mid-dle-of-the-forehead dot indicating mar-riage in women of the Bengali region ofIndia. In Chemistry of the OrganicDyestuffs (Nietzki R. London, UK:Gurney & Jackson; 1892), the principalconstituents of Rose Bengal were iden-tified as iodine derivatives of di- andtetrachlorofluorescein, with those pre-pared from tetrachlorophthalic acidbeing the bluest. The original RoseBengal version combined two iodines,and subsequent modifications throughthe 1920s adding two more iodines ledto the current form. It was its color-imparting properties,

however, that led to Rose Bengal’s pre-dominant medical use; in 1914 Römer,Cobb, and Lohlein reported on its role

in combating ocular pneumococcalinfections when added to SafraninVictoria Yellow. Kleefeld’s discovery, in1919, that Rose Bengal was an effectivestain for visualizing corneal ulcersopened the door to its widespread use asan ocular biological staining agent. AsRosettes and Minims, that use contin-ues today, based on separate improve-ments over many decades by Sjögren,Norn, and Marsh.A parallel development of Rose

Bengal as an intravenous marker forimpaired liver function began in the1920s through the work of Delprat. Inthe 1950s, Taplin devised a more sensi-tive radioisotope labeling with 131I RBDiagnostic. By the late 1980s, radio labeling had been eclipsed and replaced as thepreferred diagnostic strategy when directvisualization of the liver was afforded bymagnetic resonance imaging and com-puted tomography scanning.None of this, of course, suggests anti-

neoplastic efficacy. The application ofRose Bengal as a cancer treatment cameabout indirectly. Wachter and col-leagues, all of whom had met working atOak Ridge National Laboratory, werelooking at photodynamic therapy, aprocess in which agents become cytotoxic when exposed to light (usuallyfrom lasers), and in the late 1990s whilelooking for a candidate agent with anti-neoplastic activity, they hired a commer-cial data search service that identifiedseveral hundred potential substances.Through their own internal screeningprocess they narrowed the candidates toonly those agents with powerful effects,and among these was Rose Bengal.At the same time that the Provectus

preclinical tests were showing RoseBengal to be worthy of deeper study, theresearchers stumbled on a three-linesentence in a 1986 journal article (ItoA, et al. J Natl Cancer Inst. 1986;77:277-281) on a study that was, inessence, a failed attempt to show can-cer-stimulating properties in RoseBengal, which was then used in Japan asa food-coloring agent (Red Food No.105). The Japanese researchers notedno tumorigenicity for Rose Bengal in astrain of particularly tumor-prone mice,but offhandedly mentioned withoutcomment that the higher the concen-tration of the Rose Bengal solution, thelower the tumor rate.This further fired the Provectus Rose

Bengal investigations and the nexttest, for Wachter, was giving up on thephotodynamic treatment aspect. “I wasa laser expert, and I was very psyched

about finding this perfect molecule togo with our exciting laser techniques.”His cofounders, Craig Dees (a molecu-lar virologist) and Tim Scott (a chemi-cal engineer), were worried that thelaser/photodynamic technology wastoo sophisticated for routine use in theclinic, and that severe phototoxicity,requiring patients to stay not only outof direct sunlight but also away fromintense indoor lighting for up to sever-al weeks, would hamper wide accept-ance. Dees and Scott, after a fewmonths of modifications and testing,presented Wachter with incontrovert-ible proof that the laser/photodynamicaspect was unnecessary to the dramaticanticancer effect of Rose Bengal, nowin its PV-10 form. Subsequent animaland human studies confirmed thatagent’s potency and selectivity forablating cancers.

Rose Bengal for melanomaThe phase 2 trial presented at ASCO

enrolled 80 patients with measurablestage III-IV melanoma, all of whomreceived initial treatment with PV-10 inup to 20 cutaneous, subcutaneous, ornodal lesions. Investigators were allowedto leave one or two lesions untreated.The primary end point was response rateof injected lesions. Agarwala reported that among the

first 40 subjects to complete the study,33% achieved complete remission,28% partial remission, and 20% stabledisease in their target lesions. Also,33% of 21 subjects with evaluablebystander lesions achieved completeremission of these lesions, along with10% achieving partial remission, and14% achieving stable disease. Meanprogression-free survival for all subjectswas 8.5 months. Patients with com-plete remissions achieved significantlylonger progression-free survival (11.1months) than those with stable diseaseor progressive disease (2.8 and 2.7months, respectively).No grade 4 or 5 adverse events were

attributed to PV-10, and overall,adverse events were predominantlymild to moderate.Agarwala concluded that, “The safety

and efficacy profile of PV-10 comparesfavorably with available and emergingoptions for this patient population.”Beyond melanoma, PV-10 is current-

ly being evaluated in treatment of pri-mary and metastatic tumors of theliver. Ultimately, systemic administra-tion of PV-10 may be explored for cer-tain indications, Wachter said. �

CARTOON

Skin Cancer



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CHICAGO—Findings of a new studysuggest that an antiemetic regimen con-taining a single intravenous (IV) 150-mg dose of fosaprepitant dimegluminein combination with a 5-hydroxytrypta-mine type 3 (5-HT3) antagonist anddexamethasone appears to be compara-ble with a 3-day regimen of aprepitantwith a 5-HT3 antagonist and dexa m-ethasone for the prevention of chemo -therapy-induced nausea and vomiting(CINV).The findings from the Evaluation of

Fosaprepitant in Single-dose Schedule(EASE)-017 study, which were present-ed at the 46th annual meeting of theAmerican Society of Clinical Oncology,showed that the regimen containing150-mg fosaprepitant dimeglumine wasnot inferior to the regimen with oralaprepitant.“The results of this study demon-

strate that an antiemetic regimen witha single, 150-mg injection of fos-aprepitant provides similar protectionagainst CINV as a 3-day regimen oforal aprepitant, which has becomepart of the standard of care for patientsreceiving highly emetogenic chemo -therapy,” said lead study investigatorSteven Grunberg, MD, a professor of

medicine and pharmacology at theUniversity of Vermont, Burlington.“These findings are important becauseprevention of CINV is a major con-cern, and this formulation of aprepi-tant could potentially provide dosingflexibility to prevent CINV.”Currently, aprepitant is approved as a

part of a 3-day regimen for the preven-tion of acute and delayed nausea andvomiting associated with initial andrepeat courses of moderately emeto-genic and highly emetogenic cancerchemotherapy, including high-dose cis-platin. In this phase 3, randomized, dou-ble-blind, parallel-group, noninferioritystudy, researchers studied 2322 patients,all of whom were naïve to cisplatintherapy and were scheduled to receivecisplatin-based chemotherapy at a doseof 70 mg/m2 or higher. Of the patientsrandomized, 2247 patients were includ-ed in the analysis. The study’s primaryend point was the proportion of patientswho reported no vomiting and no use ofrescue therapy (complete response) inthe overall phase (0-120 hours after ini-tiation of cisplatin-based chemothera-py). The secondary end point was theproportion of patients who reported acomplete response (no vomiting and no

use of rescue therapy) in the delayedphase (25-120 hours after initiation ofcisplatin-based chemotherapy).The investigators found that 71.9%

of patients who received an antiemeticregimen that included a single, 150-mgdose of fosaprepitant plus ondansetron32 mg IV and dexamethasone 12 mgorally on day 1, and dexamethasone 8 mg orally on day 2, and dexametha-sone 8 mg orally twice daily on days 3and 4 achieved a complete response inthe overall phase of chemotherapy (0-120 hours after initiation of cisplatinchemotherapy). That was comparablewith the 72.3% of those receiving anantiemetic regimen containing a 3-dayoral regimen of fosaprepitant (fos-aprepitant 125 mg orally, ondansetron32 mg IV, and dexamethasone 12 mgorally on day 1, fosaprepitant 80 mgorally once daily on days 2 and 3, anddexamethasone 8 mg orally once dailyon days 2 through 4).In addition, 74.3% of patients treat-

ed with the regimen containing thesingle, 150-mg dose of fosaprepitantachieved a complete response in thedelayed phase (25-120 hours after cis-platin-based chemotherapy), com-pared with 74.2% of patients treated

with a regimen containing a 3-day doseof fosaprepitant.The overall incidence and types of

adverse events were generally consis-tent between the two treatmentgroups. The most frequently reporteddrug-related clinical adverse events inboth the group receiving a single, 150-mg dose of fosaprepitant and the groupreceiving oral aprepitant were asthe-nia, constipation, anorexia, diarrhea,and nausea.“With the intravenous treatment,

there was some venous irritation, but thenumbers were very small,” said Grunbergin an interview with The OncologyPharmacist. “In terms of efficacy, there isequivalence. With the single dose, it isgoing to add convenience because thepatients won’t have to take the pills athome. A lot of policies require preautho-rization and, if there is just one single IV,there are no pills going home so thereis no authorization and so it is a bene-fit to the patient. There is also benefitfor the office because they are sure thepatient is compliant and they don’thave to deal with getting preauthoriza-tion for getting a tripack. So, there areeconomic, social, and medical advan-tages with this single dose.” �

Single-dose IV Regimen Comparable with 3-DayRegimen for Prevention of CINVBy John Schieszer

Palonosetron Demonstrates Benefits over Other 5-HT3 Receptor Antagonists in Lung Cancer PatientsBy Caroline Helwick

CHICAGO—Among patients withlung cancer on highly emetogenicchemo therapy, those receiving palo -nosetron throughout all cycles ofchemo therapy had a 31% lower risk ofchemo therapy-induced nausea andvomiting (CINV) associated with anemergency department or hospitalvisit, than patients receiving other 5-hydroxy tryptamine type 3 (5-HT3) re -ceptor antagonists (RAs).The study was presented by Hind T.

Hatoum, PhD, of the Center of Pharm a -coeconomic Research at the Universityof Illinois at Chicago during the 46thannual meeting of the AmericanSociety of Clinical Oncology.The study compared the risk of serious

CINV among 1692 lung cancer patientsinitiated on cisplatin-based chemothera-py who were started and maintained on a 5-HT3–based prophylactic strategy,including palo nosetron, dolasetron,

granisetron, or ondansetron. Patientswere identified from claims data (Phar-Metrics) between 2005 and 2008 andstratified into one of two groups:palonosetron throughout all cycles ofchemotherapy (n = 390) and any other5-HT3–based regimen (n = 1302).CINV events were identified from

emergency department and hospitalclaims with codes of nausea, vomiting,and/or dehydration. The two groupswere compared for the risk of CINV,controlling for age, sex, comorbidity,and chemotherapy treatment days.The two treatment groups had com-

parable comorbidities, with no signifi-cant differences in the CharlsonComorbidity Index.The most widely represented chemo -

therapy regimens were cisplatin/etopo-side (25%), cisplatin alone (7%), andcisplatin/docetaxel/etoposide (6%).In what Hatoum called a “real-

world practice,” the average patientreceiving palonosetron had signifi-cantly fewer claims of both 5-HT3

RAs and all antiemetics, as comparedwith patients receiving all other 5-HT3 RAs: 6.4 versus 12.4 for other5-HT3 RA claims (P <.0001), and 8.5versus 14.7 in all antiemetic claims (P <.0001).This represents 42% fewer antiemet-

ic claims and 58% fewer 5-HT3 RAclaims for palonosetron compared withpatients who received other agents,Hatoum noted. With palonosetron, fewer patients

experienced CINV events leading toemergency department or hospital vis-its: 16.4% versus 22.6% (P <.01) in theunadjusted analysis, which remained asignificant 31% reduction (P <.05) inthe adjusted analysis.Palonosetron-treated patients also

had, on average, significantly fewer cis-

platin treatment days: 4.9 versus 5.7days (P <.0001). “We cannot ascertainwith 100% certainty what this means,but we suspect these patients were ableto have the dose pushed higherbecause they had less nausea and vom-iting. They did not have to delay treat-ment; and therefore, there were fewertreatment days,” Hatoum suggested.In addition, 51.0% of patients used

palonosetron without combining itwith the neurokinin-1 (NK1) antago-nist aprepitant and/or dexametha-sone, compared with 45.6% of thealternate group. Palonosetron, in con-trast to other 5-HT3 RAs, differential-ly in hibits “crosstalk” between NK1

re ceptors and 5-HT3 signaling path-ways, and exhibits prolonged inhibi-tion of receptor function, Hatoumexplained, suggesting that “it mayhave properties such that you don’tneed the NK1 antagonist.” �

Supportive Care



TARGET AUDIENCEThis activity is intended for hematologists, oncologists and others whoare involved with the care of patients with Chronic LymphocyticLeukemia (CLL).

STATEMENT OF NEEDCLL is the most common type of leukemia in the United States, withover 15,000 new cases per year, characterized by the accumulation ofmonoclonal B cells in the bone marrow, peripheral blood, and lymphoidtissue. Primarily a disease of the elderly, the median survival for CLLvaries substantially: many patients survive more than 10 years after diagnosis, but a subset of symptomatic patients have shorter lifeexpectancies—in the range of 1.5 to 6 years. The clinical/research bodyof knowledge in CLL is rapidly changing and represents a challenge forthe whole treatment team.

EDUCATIONAL OBJECTIVESOn completion of this activity, participants should be able to:

• List the essential steps in diagnosis and treatment planning of theCLL patient

• Select CLL treatment regimens based on patient characteristics• Define data supporting the benefit/risk ratio of upfront, relapsed,

and refractory CLL setting• Define strategies to manage fludarabine-resistant CLL• Describe emerging therapies in CLL

www.coexm.com/ace02.aspLOG ON TODAY TO PARTICIPATE

Release Date: April 29, 2010Expiration Date: April 28, 2011

In collaboration with

FACULTYNeil E. Kay, MD Professor Department of Medicine Mayo ClinicRochester, Minnesota

Michael Keating, MDCourse ChairProfessor of Medicine �Deputy Department Chairman�Department of Leukemia�M.D. Anderson Cancer Center�Houston, Texas

This activity has been approved for 1.5 AMA PRA Category 1 Credits™. For further information and to participate, please go to: www.coexm.com/ace02.asp

This activity is supported by an educational grant fromGenentech BioOncology and Biogen Idec.

Chronic Lymphocytic LeukemiaThe Essentials of Patient Care

A TOP_October 2010_v6_TOP 10/18/10 12:39 PM Page 39

A Friday Satellite Symposium preceding the 52nd ASH

Annual Meeting

December 3, 2010 Rosen Centre Hotel Ballrooms A & B, Orlando, Florida

Challenging Cases in Multiple Myeloma A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is jointly sponsored by the University of Cincinnati, Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.

Register online today atwww.myelomacases.com/register

This continuing medical education symposium will serve as a forum for discussion of cur-rent questions and concerns regarding the treatment and management of patientsthrough the multiple myeloma (MM) life cycle. A panel of domestic and internationalmyeloma experts will be joined by representatives from community cancer care facili-ties and private oncology practices. By thoroughly engaging participants with interac-tive cases and physician point-counterpoint-style discussions, this symposium will provideevidence-based treatment and management recommendations and address newtreatment regimens and management strategies based on recent clinical trials andemerging data. In addition to considering differences in domestic and internationalcare, barriers and/or limitations faced by community cancer centers and private-prac-tice oncologists will be debated.

This activity has been developed for hematologists and medical oncologists, as well asnurses, pharmacists, and other allied health professionals who are interested in meetingthe challenges faced when treating patients with multiple myeloma in academic andcommunity settings.

TARGET AUDIENCE

ACKNOWLEDGMENT

At the end of this activity participants will be able to:• Apply early management strategies that consider new diagnostic and staging criteriafor SMM, MGUS, and MM and new imaging studies in order to improve prognosis foryour patients.

• Evaluate novel therapeutic regimens as induction therapy for your patients consider-ing an SCT in order to provide the most rapid response and allow the largest amountof stem cell collection, while maintaining safety and tolerance.

• Integrate novel agent-based regimens that provide optimal outcomes and a survivalbenefit into your management strategy for patients ineligible for SCT after appraisingemerging data from clinical trials.

• Identify patient- and disease-associated factors that impact choice of therapeuticagent and formulate management strategies using a risk-adapted approach to treatment of MM.

• Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myelomapatients across the life cycle of the disease.

LEARNING OBJECTIVES

PROGRAM DESCRIPTION

Leon Dragon, MD, FACPMedical DirectorKellogg Cancer CenterNorthshore University HealthSystemHighland Park, IL

Charles M. Farber, MD, PhDSection Chief of Hematology and OncologyDepartment of MedicineCarol G. Simon Cancer Center, Morristown, NJ

Shoba Kankipati, MDAssociate Physician EPIC Care East Bay Partners in Cancer CareSan Francisco Bay Area, CA

Jonathan L. Kaufman, MD Assistant Professor Blood and Marrow Transplantation Department of Hematology and Medical Oncology Emory University School of Medicine Member, Winship Cancer Institute Emory University, Atlanta, GA

Stefan Knop, MDUniversity Hospital WürzburgWürzburg, Germany

Noopur Raje, MDAssociate Professor of MedicineHarvard Medical SchoolDirector, Center for Multiple MyelomaMassachusetts General HospitalBoston, MA

G. David Roodman, MD, PhDProfessor of MedicineVice Chair for Research Department of MedicineDirector, Myeloma ProgramDirector, Bone Biology CenterUniversity of Pittsburgh Medical CenterPittsburgh, PA

Ari Umutyan, MDRedwood Regional Medical GroupHematology and Medical OncologyNapa, CA

ACCREDITATION INFORMATION Physician AccreditationThe University of Cincinnati designates this activity for a maximum of 3 AMA PRA Category1 Credits™. The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.Physicians should only claim credit commensurate with the extent of their participationin the activity.

Registered Pharmacy DesignationMedical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 3.0 contact hours (0.3 CEUs)of continuing education credit.

The universal activity number for this activity is 0468-9999-10-058-L01-P.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)

Provider approved by the California Board of Registered Nursing, Provider Number15106, for 3.0 contact hours.

12:30 - 1:00 PM Registration and Lunch Service

1:00 - 1:10 PM Welcome and Introduction Sundar Jagannath, MD - Chair

CASE PRESENTATIONSEach case will be presented by an expert faculty member and discussed by the international and community panel.

1:10 – 1:40 PM Case 1: Difficult diagnosis G. David Roodman, MD, PhD

1:40 – 2:10 PM Case 2: Newly diagnosed, stem cell transplant eligible patientSundar Jagannath, MD

2:10 – 2:40 PM Case 3: First-line therapy in a non-SCT eligible patient Stefan Knop, MD

2:40 – 3:10 PM Case 4: Multiple risk factors Jonathan L. Kaufman, MD

3:10 – 3:40 PM Case 5: Treatment of MM across the life cycle Noopur Raje, MD

3:40 - 3:50 PM Question & Answer Session

3:50 - 4:00 PM Closing Remarks Sundar Jagannath, MD

PROGRAM AGENDA

CHAIR: Sundar Jagannath, MDProfessor, Hematology and Medical OncologyMount Sinai School of Medicine’s Tisch Cancer Institute Director of the Multiple Myeloma Program, The Mount Sinai Medical CenterNew York, NY

FACULTY

�� TOP_October 2010_v6_TOP 10/15/10 2:55 PM Page 40

Meetings

adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting,and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have beenidentified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolongedpancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like :syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viralinfections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk.However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL AmongLpatients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic LeukemiaAmong patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. Patients 70 years or older received lower dose intensity of fludarabine andscyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicor mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided theRituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Revised 02/2010 (4851501)

Jointly Marketed by:Biogen Idec Inc. 5200 Research Place San Diego, CA 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) isindicated for the treatment of patients with: Relapsed or refractory, low-grade orfollicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, afterfirst-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positiveNHL in combination with CHOP or other anthracycline-based chemotherapy regimens.Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patientswith previously untreated and previously treated CD20-positive CLL. Limitations of useRituxan is not recommended for use in patients with severe, active infections.WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe,including fatal, infusion reactions. Severe reactions typically occurred during the firstinfusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medicalmanagement (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusionreactions as needed. Depending on the severity of the infusion reaction and the requiredinterventions, temporarily or permanently discontinue Rituxan. Resume infusion at aminimum 50% reduction in rate after symptoms have resolved. Closely monitor thefollowing patients: those with pre-existing cardiac or pulmonary conditions, those whoexperienced prior cardiopulmonary adverse reactions, and those with high numbers ofcirculating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure,hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis,some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patientswith NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burdenconfers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. Thesereactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoiddermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety ofreadministration of Rituxan to patients with severe mucocutaneous reactions has notbeen determined. [See Boxed Warning, Adverse Reactions.] Progressive MultifocalLeukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases.The majority of patients with hematologic malignancies diagnosed with PML receivedRituxan in combination with chemotherapy or as part of a hematopoietic stem celltransplant. The patients with autoimmune diseases had prior or concurrentimmunosuppressive therapy. Most cases of PML were diagnosed within 12 months oftheir last infusion of Rituxan. Consider the diagnosis of PML in any patient presentingwith new-onset neurologic manifestations. Evaluation of PML includes, but is not limitedto, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxanand consider discontinuation or reduction of any concomitant chemotherapy orimmunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitis wasapproximately 4 months after the initiation of Rituxan and approximately one month afterthe last dose. Screen patients at high risk of HBV infection before initiation of Rituxan.Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBVinfection for several months following Rituxan therapy. Discontinue Rituxan and anyconcomitant chemotherapy in patients who develop viral hepatitis, and instituteappropriate treatment including antiviral therapy. Insufficient data exist regarding thesafety of resuming Rituxan in patients who develop hepatitis subsequent to HBVreactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial,fungal, and new or reactivated viral infections can occur during and up to one yearfollowing the completion of Rituxan-based therapy. New or reactivated viral infectionsincluded cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. [See Adverse Reactions.] CardiovascularDiscontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxanadministration in patients with NHL. Renal toxicity has occurred in patients whoexperience tumor lysis syndrome and in patients with NHL administered concomitantcisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not anapproved treatment regimen. Monitor closely for signs of renal failure and discontinueRituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leadingto death, can occur in patients receiving Rituxan in combination with chemotherapy. Inpostmarketing reports, the mean time to documented gastrointestinal perforation was 6(range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation andinstitute appropriate treatment for complaints of abdominal pain. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines followingRituxan therapy has not been studied and vaccination with live virus vaccines is notrecommended. Laboratory Monitoring In patients with lymphoid malignancies, duringtreatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions].s Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. s Progressive Multifocal Leukoen cephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].s

counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy,obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias. [See Adverse Reactions]. The duration of cytopeniasscaused by Rituxan can extend months beyond the treatment period. ADVERSEREACTIONS The most common adverse reactions of Rituxan (incidence ≥25%)observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia. Clinical Trials Experience in Lymphoid MalignanciesBecause 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 practice. The data described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1926). The population included 679 patients with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination withfludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever,schills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxanwas administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL areceiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Previously Untreated Low-Grade NHL In Study 4,patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared to patients who received no furthertherapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan armcompared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCL In Studies 6 and 7, [L see Clinical Studies]s the following adverse reactions,regardless of severity, were reported more frequently (≥5%) in patients age ≥60 yearsreceiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). CLL The data below reflectLexposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 9 or Study 10 [see Clinical Studies]. The age range was s30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Wholey 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic Systemy p y 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendagespp g 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory Systemp y y 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and NutritionalDisorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive Systemg y 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous Systemy 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal Systemy 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular Systemy 25 3Hypotension 10 1Hypertension 6 1

9-13 NEW YORK, NYChemotherapy Foundation Symposiumwww.chemotherapyfoundationsymposium.org

4-7 ORLANDO, FLAmerican Society of HematologyAnnual Meetingwww.hematology.org

5-9 ANAHEIM, CAAmerican Society of Health-SystemPharmacists Midyear Clinical Meetingwww.ashp.org

8-12 SAN ANTONIO, TXSan Antonio Breast Cancer Symposiumwww.sabcs.org

20-22 SAN FRANCISCO, CAGastrointestinal Cancers Symposiumwww.gicasymposium.org

17-19 ORLANDO, FLGenitourinary Cancers Symposiumwww.gucasymposium.org

NOVEMBER 2010

9-13 HOLLYWOOD, FLNational Comprehensive CancerNetwork Annual Congresswww.nccn.org

23-26 SALT LAKE CITY, UTHematology/Oncology PharmacyAssociation 7th Annual Conferencewww.hoparx.org

24-26 WASHINGTON, DCAssociation of Community CancerCenters Annual National Meetingwww.accc-cancer.org

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CLL8 TRIAL (N=817) REACH TRIAL (N=552)RITUXAN-NAIVE PATIENTS

8.3month

improvementin median

PFS

5.0month

improvementin median

PFS

In first-line CLL1.7-year follow-up

39.8 monthsR-FC

31.5 monthsFC

vs

In relapsed/refractory* CLL2.1-year follow-up

26.7 monthsR-FC

21.7 monthsFC

vs

DRIVING BETTEROUTCOMESRITUXAN+FC improved median PFS in first-line and previously treated CLL1,2

In the CLL8 trial2

RITUXAN+FC more than doubled CR in first-line CLL compared with FC alone (36% vs 17%; p<0.0001)

In the REACH trial2

Patients who responded to RITUXAN+FC (n=167) maintained their responses for nearly 2 years longer (48 months vs 27 months; p=0.0294) than those treated with FC alone (n=134)

NOW IN THE TREATMENT OFCHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

IndicationRITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.RITUXAN is not recommended for use in patients with severe, active infections.

BOXED WARNINGS RITUXAN administration can result in serious, including fatal, adverse reactions. These include infusion reactions,

tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML)

Warnings and Precautions RITUXAN can also result in serious, including fatal, adverse reactions. These include hepatitis B reactivation with fulminant hepatitis and hepatic failure resulting in death; other infections, including bacterial, fungal, new or reactivated viral infections; cardiovascular events; severe, including fatal, renal toxicity; and abdominal pain, bowel obstruction and perforation, in some cases leading to death

Additional Important Safety Information The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia

In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment

For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS.Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

* In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2

R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response.

Treatment considerationsThese trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1

©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved. 10021501 May 2010

References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc.

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