Recent Advances in the Treatment of Hematologic Malignancies

JANUARY 2009Supplement to the American Journal of Hematology/Oncology

HEMATOLOGIC MALIGNANCIES

Supported by an educational grant from Merck & Co, Inc.

Acute lymphoblastic leukemia,cutaneous T-cell lymphoma(CTCL), radioimmunothera-

py in lymphomas, chronic myeloge-nous leukemia (CML), anemia andmyelodysplastic syndromes (MDS),and multiple myeloma were thefocus of the National Comprehen-sive Cancer Network (NCCN) 3rdAnnual Congress: HematologicMalignancies. The program wasdesigned to present cutting-edgeoverviews of new treatmentapproaches recently incorporatedinto patient management, includ-ing newly approved agents.

These presentations included afocus on treatments such as histonedeacetylase inhibitors, for treatmentof cutaneous T-cell lymphoma, andimatinib and second-generation tyro-sine kinase inhibitors for chronicmyeloid leukemia, as well as othersthat have demonstrated promise inthe management of specific hema-tologic malignancies. Other presen-tations provided insight into howthe NCCN works to create guide-lines to reflect continually evolvingcurrent literature and practice.

RECENT ADVANCES IN THE TREATMENT OF

Selected Presentations:The NationalComprehensive CancerNetwork 3rd AnnualCongress: HematologicMalignancies

Pediatric Treatment Regimen inAdults with Acute LymphoblasticLeukemia May Improve Survival

BROOKLYN, New York—Admini-stration of a dose-intensified pediatricregimen in adults with acute lym-phoblastic leukemia (ALL) is feasiblewith acceptable toxicity, an approach thatmay translate into better survival foradults with ALL, according to a Dana-Farber Cancer Institute (DFCI) study.1

These provocative data, initial results ofa multicenter phase II study originallypresented at the 2007 annual meetingof American Society of Hematology(ASH), were reviewed by L. AndresSirulnik, MD, PhD, of Dana-Farber/Brigham and Women’s Cancer Center inBoston, Massachusetts, who acknowl-edged that treatment of adults with ALLremains unsatisfactory, in contrast to out-comes in children with the disease.During the past 2 decades, 5-year overallsurvival has remained relatively un-changed at 30% to 40% for patientsyounger than 60 years of age, <15% forthose older than 60 years, and <5% forthose older than 70 years.2

Approximately 4,300 new cases of ALLare diagnosed annually.Although at 30%,ALL is the most common form of child-

hood cancer, with a peak incidence at 3to 5 years, the bimodal peak is at age 50years. In fact, 60% of patients with ALLare older than 20 years of age, and ALLcomprises 11% of leukemia in adults.There is a slight male preponderance at62%. Despite gene expression profilingthat confirms ALL is a very heteroge-neous disease,3 all patients essentiallyreceive the same treatment.

Commonly used treatments for adultALL include the Linker or Larson regi-men, which includes five chemotherapydrugs in combination as described inresults of the Cancer and Leukemia

What’s InsideAdvances in Treatment of Multiple Myeloma . . . . . . . . . . . . . . . . . .6,7

Role of HDAC Inhibitors in Treatment of T-CellProliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

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Jointly sponsored by


HEMATOLOGIC MALIGNANCIESINDEPENDENT REVIEWERMichael J. Keating, MB, BSProfessor and InternistDepartment of HematologyThe University of Texas M.D. Anderson Cancer CenterHouston, Texas

TARGET AUDIENCEThis educational supplement is designed for oncologists, hematologists-oncologists, hematologists, and other rel-evant health-care professionals who wish to enhance theirknowledge about new treatment approaches and protocolsfor the management of hematologic malignancies.

NATIONAL COMPREHENSIVE CANCER NETWORK HEMATOLOGYCONGRESS

LEARNING OBJECTIVES

After taking part in this activity, participants should be better able to:1. Identify strategies for the long-term treatment of patients

with T-cell proliferative disorders, including cutaneous T-celllymphoma, and the management of adverse events

2. Integrate new approaches into the management of adultswith acute lymphoblastic leukemia

3. Discuss effective treatments for chemotherapy-refractorydiffuse large B-cell lymphoma (DLBCL) and the role ofradiotherapy in DLBCL

4. Evaluate recent clinical advances in the managementof intolerant/resistant chronic myeloid leukemia, includingthe use of first- and second-generation tyrosine kinaseinhibitors

5. Compare the efficacy and toxicity of validated induction,maintenance, and salvage first-line therapies for multiplemyeloma (MM)

6. Outline advances in supportive care for patients with MM

ACCREDITATIONThis activity has been planned and implemented inaccordance with the Essential Areas and policies of theAccreditation Council for Continuing Medical Education(ACCME) through the joint sponsorship of CME Consultantsand Haymarket Medical Education. CME Consultants isaccredited by the ACCME to provide continuing medical education to physicians.

CME DESIGNATIONCME Consultants designates this educational activity fora maximum of 1.0 AMA PRA Category 1 CreditTM.Physicians should only claim credit commensurate withthe extent of their participation in the activity.

RELEASE DATEInitial release date: January 15, 2009.Material expires one year from release date: January 15, 2010

OBTAINING CREDITTo receive credit, please complete the posttest, evaluation,and credit request form at the end of this booklet and returnto CME Consultants. Fax form to: 303-790-4876Estimated Time to Complete This Activity: 1 hour

DISCLOSURESIn direct response to the September 2004 ACCME Standards for Commercial Support, CME Consultants issued a conflict ofinterest policy dated January 2, 2005. The policy states that thedisclosure of potential financial conflicts of interest within the last12 months must be made and resolved prior to the date of theCME/CE activity where commercial support grants are to be usedto fund the activity. The following conflicts have been managedand resolved through CME Consultants’ Independent ReviewCommittee. Our intent is to assist learners in assessing the potential for bias in information that is present during theCME/CE activity. The faculty is also aware it is their responsibilityto inform the audience if discussion of any non-FDA-approveduses of pharmaceutical, medical equipment, prostheses, etc, will be included in their presentation.

FACULTY DISCLOSURESThe planners, managers, and anyone in a position to controlthe content of CME activities are also required to report anyconflicts of interest. The following conflicts have been man-aged and resolved through CME Consultants’ IndependentReview Committee:Michael J. Keating, MB, BS, has nothing to disclose.Steven M. Horwitz, MD, serves as a consultant for Merckand Co., Inc., Gloucester and Eisai. He receives honorariafrom Merck and Co., Inc. and receives research support fromGloucester, Allos, Genmab and Genzyme.Nick Zittell, Haymarket Medical Education, holds stockin Merck & Co., Inc., and Johnson & Johnson.Susan Basilico, Haymarket Medical Education, has nothing to disclose.Debra Hughes, Haymarket Medical Education, has nothing to disclose.Samantha Mattiucci, PharmD, CMEC, has nothing to disclose.Jennifer Furlong, CMEC, has nothing to disclose.

FDA DISCLOSURE STATEMENTThe contents of some CME activities may contain discussionof off-label uses of some of the agents mentioned. Pleaseconsult the prescribing information for full disclosure ofapproved uses.

Haymarket Medical Education25 Philips Parkway, Suite 105Montvale, NJ 07645201-799-4800www.mycme.com

2 January 2009

January 2009 3

Group B (CALGB) 9111 study,4 orhyper-CVAD (fractionated cyclophos-phamide, vincristine, doxorubicin, anddexamethasone).5 Kantarjian et al re-ported that the use of hyper-CVAD inadults with ALL results in a 5-year dis-ease-free survival of 38%.5 In contrast, inthe pediatric population, 5-year medianevent-free survival (time from completeremission to the first outcome event)was 83% for all patients and 87% ± 3%for those at standard risk. This outcomeis attributed not to the introduction ofnew agents but primarily to intensifica-tion of postremission therapy by substi-tuting dexamethasone for prednisoneand prolonging the asparaginase intensi-fication from 20 to 30 weeks. Childrenolder than 9 years of age were signifi-cantly more likely to have tolerated 25or fewer weeks of asparaginase (P<.01).6

A comparison of outcomes of adoles-cent/young adults with ALL on pediatricvs adult clinical trials conducted from1988-2000 in North America, France, theNetherlands, and Italy found that patientstreated in either a pediatric study or inan adult study achieved similar completeresponse rates, with the intensity ofpostremission therapy translating into sig-nificantly improved event-free survival.

DFCI ADULT ALL TRIALThese results led to the design of theDFCI adult ALL trial, which was initiatedin early 2000 and based on the high-riskarm of the DFCI Childhood ALLConsortium Protocol 00-01.6 Newlydiagnosed patients with ALL aged 18 to50 years with an ECOG performance sta-tus of 0, 1, or 2 were eligible for enrollmentin the study; excluded were those withBurkitt’s lymphoma or secondary ALL.The objectives were to determine the fea-sibility and toxicity of a pediatric regimenin adult patients with ALL; the proportionof patients who were able to complete thepostinduction asparaginase therapy; andefficacy based on disease-free survival,event-free survival, and overall survival.

TRIAL PROTOCOLThe trial protocol was composed ofinduction chemotherapy (doxorubicin,prednisone, vincristine, high-dose meth-otrexate, L-asparaginase, and tripoleintrathecal therapy), central nervous sys-tem prophylaxis (triple intrathecal thera-py and cranial radiation), consolidation,and maintenance phases. Consolidationtherapy was administered 10 times in3-week courses of doxorubicin, vin-cristine, dexamethasone, 6-mercapto-purine, and 30 weeks of L-asparaginasedose to maintain asparagine depletion (eg,level between 0.1 and 0.14). Continuationtherapy consisted of 3-week courses ofvincristine, dexamethasone, methotrexate,and 6-mercaptopurine for 2 years fromcomplete remission.

At the time study results were presentedat ASH, 89 patients had been enrolled andtreated. The first 75 eligible patients wereincluded in the analysis, 73 of whom haddata available.

The complete response rate was 84%.There were 12 induction failures (16%)and one induction death, from sepsis. Ninepatients developed pancreatitis, one ofwhom died (the only remission death inthe study). During the postremission peri-od, two patients developed osteonecrosis,14 thrombosis/embolism, and 23 neu-tropenic infection. Of the 51 patients forwhom asparaginase data were available, themean dose was 17,465 U/m2.

RATES OF OVERALL SURVIVALTwo-year event-free survival, defined astime to induction failure, inductiondeath, relapse from complete response orremission death was 72.5%. Disease-freesurvival, defined as time to relapse fromcomplete response or remission death,

was 75.9%. Overall survival was 73.2%.Median follow-up was 24.1 months(range, 0.56-60.6 months). These resultsconfirm administration of a dose-inten-sified pediatric regimen to adults withALL is feasible, with complete responserates similar to those of rates in other tri-als (Table).

In CALGB 9511, Wetzler et al exam-ined the role of asparagine depletionwith pegylated asparaginase in adultswith ALL and found that probability ofsurvival was longer in the 63 patientswith ALL who achieved asparaginedepletion compared with the 22 patientswho did not.7 Patients with B-lineageALL had an inferior disease-free survivaland overall survival compared withpatients with T-lineage ALL, the firsttime the relationship between im-munophenotype and asparagine deple-tion was reported.

REFERENCES1. DeAngelo DJ, Dahlberg S, Silverman LB, et al. A mul-ticenter phase II study using a dose intensified pediatricregimen in adults with untreated acute lymphoblasticleukemia. Blood. 2007;111:587.2. Rowe JM, Goldstone AH. How I treat acute lympho-cytic leukemia in adults. Blood. 2007;110:2268-2275.3. Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, sub-type discovery, and prediction of outcome in pediatricacute lymphoblastic leukemia by gene expression profil-ing. Cancer Cell. 2002;1:133-143.4. Larson RA, Dodge RK, Linker CA, et al. A randomizedcontrolled trial of filgrastim during remission inductionand consolidation chemotherapy for adults with acutelymphoblastic lymphoma: CALGB Study 9111. Blood.1998;92:1556-1564.5. Kantarjian HM, O’Brien S, Smith TL, et al. Results oftreatment with hyper-CVAD, a dose-intensive regimen, inadult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547-561.6. Silverman LB, Gelber RD, Dalton VK, et al. Improvedoutcome for children with acute lymphoblastic leukemia:results of Dana-Farber Consortium Protocol 91-01.Blood. 2001;97:1211-1218.7. Wetzler M, Sanford BL, Kurtzberg J, et al. Effectiveasparagine depletion with pegylated asparaginase results inimproved outcomes in adult acute lymphoblasticleukemia: Cancer and Leukemia Group B Study 9511.Blood. 2007;109:4164-4167.

TABLE. Complete response rates in adult acute lymphoblastic leukemia trials

Study

Complete Response Rates

After 1 cycle After 2 cycles

MRC XII/ECOG2992 51% 91%

CALGB 8811 62% 85%

Hyper-CVAD 74% 91%

DFCI 85% N/A; off study

Pediatric Treatment Regimen(continued from page 1)

4 January 2009

Sequential R-CHOP, Yttrium-90 IbritumomabTiuxetan (RIT) Found Safe and Effective inElderly Patients with Untreated DLBCLBROOKLYN, New York—In high-riskelderly patients with previously untreatedaggressive diffuse large B-cell lymphoma(DLBCL), the investigational regimenconsolidating rituximab-CHOP (R-CHOP) with yttrium-90 ibritumomabtiuxetan radioimmunotherapy (RIT) issafe and feasible, with high survival rates,results of a phase II clinical trial haveshown.1

Andrew D. Zelenetz, MD, PhD, ofMemorial Sloan-Kettering CancerCenter, in New York, reported on thestudy, which was originally presentedat the 10th International Conferenceon Malignant Lymphoma in Lugano,Switzerland, by a co-investigator, Paul A.Hamlin, MD.

RELAPSE RATEElderly patients with DLBCL ineligiblefor autologous stem cell transplantation(ASCT) have only one chance for cura-tive therapy. While the addition ofrituximab to conventional CHOPchemotherapy (combination cyclophos-phamide, doxorubicin, vincristine, andprednisolone) has improved outcomes inDLBCL, approximately 50% of thosewith high-intermediate and high-riskdisease by age-adjusted InternationalPrognostic Index (aaIPI) will relapse aftertreatment. Elderly patients with aaIPIhigh-intermediate and high-risk diseasehave 5-year overall survival rates of37% and 21%, respectively. Previously,Morschhauser and colleagues have shownthat yttrium-90 ibritumomab tiuxetanwas active in elderly patients withrelapsed and refractory DLBCL follow-ing treatment with CHOP or R-CHOP.2 Hamlin et al hypothesized thatconsolidation of R-CHOP with yttri-um-90 ibritumomab tiuxetan RIT

would improve outcomes by eradicatingminimal residual disease.

PATIENT CHARACTERISTICSAs of May 1, 2008, 63 patients, 23 maleand 40 female, untreated with histologi-cally confirmed DLBCL aged older than65 years at time or enrollment or age60-65 years ineligible for ASCT hadbeen enrolled in the study. Median agewas 75 years (range, 62-86 years) with71% of patients aged 70 years or older.Karnofsky performance status was<80% in 59% of patients (median,70%). Stage IV disease was present in73% of patients; 24% had stage III and3%, stage II disease. Extranodal sites >1were present in 43% and B symptomsin 46%. Prognostic score was high-intermediate in 54% of patients andhigh in 46%. Ninety-four percent ofpatients had at least one comorbid con-dition, with a median of 3 (range, 0-7),21% of which were heart-related. Atleast one moderate- or high-impactcomorbidity was observed in 86% ofpatients (Figure).

Standard R-CHOP was administered

q 21 days x 6 cycles with peg/granulo-cyte-colony-stimulating factor and dar-bepoetin alfa support. Patients with sta-ble disease after R-CHOP were eligiblefor RIT 6 to 9 weeks later. The studywas powered at 90% to detect a 20%increase in overall survival and progres-sion-free survival.

Of the 63 patients enrolled, 43were assessed for RIT following R-CHOP and 39 (91%) received RIT,34 (87%) a dose of 0.4 mCi/kg and 5(13%) a dose of 0.3 mCi/kg. Onepatient developed atrial fibrillation/congestive heart failure on day 0, onehad bone marrow cellularity <15%,one had platelets <100,000, and onewithdrew consent.

RESULTSIn the intent-to-treat population, overallsurvival (OS) and progression-free sur-vival (PFS) were 65% and 59%, respec-tively, at 22 months. At 26-month medi-an follow-up, OS was 82% and PFS was78%. Median PFS for patients who didnot receive RIT was 3.6 months, where-as for those in the RIT group, PFS had



FIGURE: Highest Impact Level of Comorbidity per Patient.

January 2009 5

not yet been reached at the time thestudy was presented. Overall sur-vival and PFS by aaIPI high-inter-mediate and high-risk were 84%and 49% and 75% and 42%, respec-tively. Responses improved follow-ing RIT in 11 patients, with eightpatients improving from an uncon-firmed (CRu) to a confirmed com-plete response (CR) and threepatients improving from a partialresponse (PR) to a CR/CRu.

ADVERSE EVENTSAdverse events reported includedneutropenia (6% grade 3 and 36%grade 4), anemia (15% grade 3), andthrombocytopenia (36% grade 3 and31% grade 4). Six patients had delayedblood count recovery for more than12 weeks. One patient developedmyelodysplasia and two patients diedafter RIT administration, one from asuspected brain hemorrhage and onefrom congestive heart failure.

An ongoing international phaseIII randomized clinical trial seekingto validate the role of consolidativeRIT following R-CHOP in elder-ly patients in complete remissionrecently closed to accrual. A USstudy is also planned that wouldinclude all patients with DLBCL,not just those at high risk.

REFERENCES1. Hamlin PA, Moskowitz CH, Wegner B, et al.Sequential RCHOP and Yttrium-90 ibritumomabtiuxetan (RIT) is a highly effective regimen forhigh risk elderly patients with untreated DLBCL.Ann Oncol. 2008;19(suppl 4):Iiv100. Abstract 054.

2. Morschhauser F, Illidge T, Huglo D, et al. Efficacyand safety of yttrium-90 ibritumomab tiuxetan inpatients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologousstem-cell transplantation. Blood. 2007;110:54-58.

OVERCOMING BARRIERSTO ADOPTION OF RIT

IN THE US

Andrew D. Zelenetz, MD, PhD, of Memorial Sloan-Kettering CancerCenter, noted that providing radioimmunotherapy (RIT) to patientsin the US requires a team effort, as does conventional chemother-

apy; the team just has different players.An RIT multidisciplinary team would include an oncologist, oncology

nurse, radiopharmacist, radiation safety officer, and nuclear medicineand/or radiation oncology personnel, each with a different role. Patientswith relapsed or refractory indolent lymphoma are appropriate, and earlytreatment is associated with excellent long-term outcomes. Treatment issafe and can be done in the outpatient setting for the vast majority ofpatients, and patient acceptance is high.

Nuclear medicine physicians and radiation oncologists should beidentified to help develop a team for a “1-call’’ coordination of care fordelivery of RIT.

14TH ANNUAL NCCN CONFERENCE SET FORMARCH 11 – 15, 2009

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicat-ed to improving the quality and effectiveness of care provided to

patients with cancer. Through the leadership and expertise of clinicalprofessionals at member institutions, NCCN develops resources that pre-sent valuable information to clinicians, patients, health-care administra-tors, and others who play a role in the health-care delivery system. As thearbiter of high-quality cancer care, NCCN promotes the importance ofcontinual quality improvement and recognizes the significance of creatingclinical practice guidelines appropriate for use by patients, clinicians, andother health care decision-makers. The primary goal of all NCCN initia-tives is to improve the quality, effectiveness, and efficiency of oncologypractice so patients can live better lives.

The NCCN 14th Annual Conference: Clinical Practice Guidelines &Quality Cancer CareTM will take place from March 11 – March 15, 2009,in Hollywood, Florida. Sessions on clinical practice guidelines will includeupdates on treatment of breast cancer, colon and rectal cancers, kidneycancer, melanoma, non-Hodgkin’s lymphomas, non-small-cell lung can-cer, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, andthyroid carcinoma. Information about the conference is available on-lineat http://www.nccn.org.

Serial Use of All Available Agents Can ProlongSurvival in Patients with Multiple Myeloma BROOKLYN, New York—Over the pastdecade, the increase in the number of ther-apeutic options for multiple myeloma haspresented a new challenge: how to use allof the therapies, and in what sequence, toachieve the maximum benefit for patients,according to Seema Singhal, MD, of theRobert H. Lurie Comprehensive CancerCenter of Northwestern University, inChicago, Illinois. Data to date indicate thatwhile using all available therapeuticoptions is critical in treating the patientwith multiple myeloma, which remains anincurable disease, sequencing of therapy islikely to be important as long as the patientdoes not pay a price in terms of survivaland quality of life.

EVOLUTION OF THERAPYThis conclusion is supported by theevolution of therapy for this disease, forwhich median survival was 7 months inthe 1960s pre-melphalan-prednisone eraand is currently 7 to 8 years with the useof novel agents. Dr. Singhal, speaking atthe National Comprehensive CancerNetwork 3rd Annual Congress: Hema-tologic Malignancies, reported that oneof her patients lived more than 23 yearsafter initial diagnosis of multiple myelo-ma (her cause of death was secondaryleukemia) through careful managementof agents, demonstrating serial use of

currently available options—includingthalidomide, bortezomib, and lenalido-mide—can prolong survival.1

The general approach to the patientwith multiple myeloma is to determinewhether hematopoietic stem cell trans-plantation (HSCT) is available andappropriate or not (Figure).1 If the for-mer, the most important caveat is toavoid administration of any agents thatmight damage stem cells.

OTHER APPROACHES POSSIBLEIf patients are ineligible for transplanta-tion, two approaches are possible: anapproach that incorporates melphalanplus prednisone and one that does not(the “non-MP” approach; Table).

In a randomized, controlled trial,Palumbo et al2 demonstrated that theaddition of thalidomide 100 mg/daycontinuously until relapse or progressivedisease to melphalan 4 mg/m2 for6 cycles plus prednisone 40 mg/m2 for6 cycles (MPT) resulted in a 76%response rate (16% complete response,12% near-complete response, and 48%partial response) compared with 47.6%for melphalan plus prednisone alone(MP; 2% CR, 5% NCR, 40% PR), adifference that was statistically significant(P<.001). Two-year event-free survivalrates were 54% for MPT and 27% for

MP. Three-year survival rates were 80%for MPT and 64% for MP. Rates ofgrade 3 or 4 adverse events were 48% inMPT patients and 25% in MP patients.There were 11 deaths due to toxicity inthe MPT group and four in the MPgroup; eight deaths due to progressionwere observed in those receiving MPTand 20 in those receiving MP.

LENALIDOMIDE, BORTEZOMIBA phase I/II, dose-escalating, noncom-parative, open-label study in 54 newlydiagnosed elderly patients with myelomafound that the addition of lenalidomideresulted in 81% of patients achieving atleast a partial response.3 Oral melphalanin doses ranging from 0.18 to 0.25mg/kg plus prednisone 2 mg/kg dayswas administered on days 1 to 4 withlenalidomide at doses ranging from 5 to10 mg on days 1 to 21, every 28 days fornine cycles. Maintenance therapy con-sisted of lenalidomide alone. Hema-tologic adverse events, although frequent,were manageable. Follow-up will deter-mine the potential for myelosuppressionwith prolonged use and response tosalvage therapy.

In a multicenter phase III trial of mel-phalan-prednisone with and withoutbortezomib,4 682 patients with previ-ously untreated multiple myeloma whowere not candidates for high-dosechemotherapy or HSCT were random-ly assigned to receive nine 6-week cyclesof melphalan 9 mg/m2 and prednisone60 mg/m2 on days 1 to 4, alone orin combination with bortezomib1.3 mg/m2 IV bolus on days 1, 4, 8, 11,22, 25, 29, and 32 during cycles 1 to 4and on days 1, 8, 22, and 29 during cycles5 to 9.

Median age was 71 years (30% aged75 years or older), and a high propor-tion had advanced disease and high-risk

6 January 2009



HSCTavailable

and appropriate

Induction therapy

Stemcell

collection

Autograft 1 Autograft 2 Maintenance SalvagetherapyObservation

Autograft Maintenance

Observation

Maintenance Autograft Maintenance

Observation Observation

HSCTnot

available or appropriate

Induction therapy

Maintenance Salvagetherapy

Observation

FIGURE. General approach to the treatment of patients with multiple myeloma

January 2009 7

factors. Complete response rates wereachieved by 30% in the group thatreceived bortezomib, compared with 4%in the group that did not. Partialresponse rates were 40% and 31%,respectively. Median response durationand median time to progression, respec-tively, were 19.9 and 24 months in themelphalan-prednisone-bortezomib armand 13.1 and 16.6 months in the mel-phalan-prednisone arm. Two-year overallsurvival was 83% in the bortezomib-melphalan-prednisone arm vs 70% inthe melphalan-prednisone arm. Medianoverall survival had not been reached atthe time the data were presented.

Specific sequencing of the immu-nomodulatory agents in patients eligi-ble for second-line high-dose therapysuggest activity of lenalidomide fol-lowing thalidomide, with a lowerresponse rate observed than if no priorthalidomide had been administered.When thalidomide is administered fol-lowing lenalidomide, it remains unknownif thalidomide is active in patients withdisease who did not respond to or hadrelapsed on lenalidomide. In patientswith lenalidomide failure, a borte-zomib-based therapy, if not alreadyused, is preferable to thalidomide-basedtherapy.1

RELAPSED DISEASERichardson et al5 found that in relapseddisease, use of single-agent bortezomibresulted in significantly longer time to

progression, a higher response rate, andimproved survival when compared withhigh-dose dexamethasone alone.

Approaches to relapsed disease shouldconsider disease factors (tumor burden,tempo, biologic nature); patient factors(age, organ function, bone marrow func-tion); treatment factors (prior treatment,prior transplant, relapse to prior treat-ment approaches); and logistics (avail-ability of allogeneic stem cell donors,and access to clinical trials). Clinicaljudgment is the best determination ofwhen the disease is refractory.

Although relapse is inevitable inpatients with multiple myeloma, it ispossible to achieve subsequent goodresponses, including complete response,with current therapies as well as thepotential for prolonged survival. Thereare many treatment options with no

conclusive data on either best choice ofinitial therapy or optimum sequences.Patient considerations include likelihoodof response, cost, and quality of life.

REFERENCES1. Singhal S. Sequencing of therapies for multiplemyeloma. National Comprehensive Cancer Network.NCCN 3rd Annual Congress: Hematologic Malignan-cies. 2008.2. Palumbo A, Bringhen S, Caravita T, et al. Oral melpha-lan and prednisone chemotherapy plus thalidomide com-pared with melphalan and prednisone alone in elderlypatients with multiple myeloma: randomised controlledtrial. Lancet. 2006;367:825-831.3. Palumbo A, Falco P, Corradini P, et al. Melphalan,prednisone, and lenalidomide treatment for newly diag-nosed myeloma: a report from the GIMEMA—ItalianMultiple Myeloma Network. J Clin Oncol. 2007;25:4459-4465.4. San Miguel JF, Schlag R, Khuageva N, et al.Bortezomib plus melphalan and prednisone for initialtreatment of multiple myeloma. N Engl J Med. 2008;359:906-917.5. Richardson PG, Sonneveld P, Schuster M, et al.Extended follow-up of a phase 3 trial in relapsed multi-ple myeloma: final time-to-event results of the APEXtrial. Blood. 2007;110:3557-3560.

TABLE. Treatment approach for patients ineligible for transplantationMP approach Non-MP approach

First-line• MP-thalidomide: better than MP2

• MP-lenalidomide: no data vs MP3

• MP-bortezomib: better than MP4

• MP alone: not a good choice

First-line• Bortezomib + steroids• Thalidomide + steroids• Lenalidomide + steroids

Second-line• Different novel agent: ±MP

MP = melphalan plus

Second-line• Combination #2• Add MP

Third-line• Combination #3• Add MP

Control of Multiple Myeloma and ComplicationsEnables Treatment with Newer AgentsBROOKLYN, New York—The mostimportant supportive care issues forpatients with multiple myeloma resultsfrom bone complications, osteonecrosisof the jaw, peripheral neuropathy,

cytopenias, and thrombotic events.These disease complications demandeffective management so that patientsurvival can be extended and benefitsfrom newer agents can be attained,

according to Kenneth C. Anderson,MD, of Dana-Farber/Brigham andWomen’s Cancer Center, in Boston,Massachusetts.


8 January 2009



Osteolytic lesions are pathognomonicof myeloma bone disease, which occursin 80% of patients with multiple myelo-ma. Pathologic fracture, radiation ther-apy, surgical intervention, spinal cordcompression, and hypercalcemia ofmalignancy are all skeletal-related eventsthat can occur as potential complicationsof bone metastases. Radiotherapy maybe useful in specific situations for paincontrol spinal cord compression or toprevent or treat pathologic fractures;however, it may be toxic to normalmarrow function so should be usedjudiciously, according to a report pre-sented during the National Compre-hensive Cancer Network 3rd AnnualCongress: Hematologic Malignancies.1

ROLE FOR BISPHOSPHONATESAmerican Society of Clinical OncologyClinical Practice Guidelines andNCCN Clinical Practice Guidelines inOncology cite a role for bisphospho-nates in patients with multiple myelo-ma.2,3 Of the bisphosphonates that havebeen studied in patients with multiplemyeloma, IV pamidronate significantlydecreased time to first skeletal-relatedevents vs placebo (P>.001) and alsodecreased the pain score.4 Whenpamidronate and zoledronic acid werecompared, significantly more patientstreated with zoledronic acid were com-plete responders at day 7 and 10 (82.6%and 87%) compared with pamidronate(64% and 70%). Zoledronic acid alsoproduced a longer time to relapse.5

A study of pamidronate vs zoledron-ic acid in patients either with breastcancer or multiple myeloma found nodifferences between the two agentsin time to first skeletal-related event.6

However, zoledronic acid was foundto reduce the ongoing risk of skeletal-related events vs pamidronate, andpatients preferred the shorter infusiontime of zoledronic acid over that ofpamidronate.7

OSTEONECROSIS OF THE JAWPatients taking bisphosphonates shouldbe monitored for renal dysfunction andfor osteonecrosis of the jaw. The latter isa rare complication of bisphosphonatetherapy with unclear incidence and anunknown pathogenesis.

PERIPHERAL NEUROPATHYIncidence of peripheral neuropathy atdiagnosis among patients with multiplemyeloma has not been well documentedand, in fact, may be underreported.8

Peripheral neuropathy related to treat-ment with thalidomide has been report-ed in several studies, in some cases relat-ed to duration of disease,9-10 or treatmentduration and dose.11

CYTOPENIASThe severity of the grade of drug-induced myelosuppression in the formof neutropenia and thrombocytopeniaappears to be related to initial plateletcount.12 Among patients being treatedwith bortezomib, the number ofpatients requiring platelet and bloodtransfusions peaked within the first 2cycles in both treatment arms.13 Grade3/4 anemia (8%) thrombocytopenia,(10%) neutropenia, (21%) and febrileneutropenia (2%) have been observedin trials of lenalidomide plus dexa-methasone, rates of which were higherthan in the dexamethasone/placeboarm.14

THROMBOTIC EVENTSDeep vein thrombosis (DVT) and pul-monary embolism (PE) have beenobserved in trials of patients with mul-tiple myeloma; the question, especiallyfor deep vein thrombosis, is how muchof the incidence is related to the diseasevs the treatment. In the APEX (Assess-ment of Proteasome Inhibition forExtending Remissions) trial, rates ofDVT/PEs were low for both the borte-zomib and dexamethasone arms; whenuse of erythropoietin was controlled,thromboembolic event risk was lowerwith bortezomib vs dexamethasone.15

REFERENCES1. Anderson KC. Supportive care in multiple myeloma.National Comprehensive Cancer Network. NCCN 3rdAnnual Congress: Hematologic Malignancies. 2008.

2. Kyle RA, Yee GC, Somerfield MR, et al. AmericanSociety of Clinical Oncology 2007 clinical practice guide-line update on the role of bisphosphonates in multiplemyeloma. J Clin Oncol. 2007;25:2464-2672.

3. NCCN Clinical Practice Guidelines in Oncology.Multiple myeloma. V.2.2009. Available at www.nccn.org.Accessed October 10, 2008.

4. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy ofpamidronate in reducing skeletal events in patients withadvanced multiple myeloma. Myeloma Aredia StudyGroup. N Engl J Med. 1996;334:488-493.

5. Major P, Lortholary A, Hon J, et al. Zoledronic acid issuperior to pamidronate in the treatment of hypercal-cemia of malignancy: a pooled analysis of two random-ized, controlled clinical trials. J Clin Oncol. 2001;19:558-567.

6. Rosen LS, Gordon D, Kaminski M, et al. Long-termefficacy and safety of zoledronic acid compared withpamidronate disodium in the treatment of skeletal com-plication in patients with advanced multiple myeloma orbreast carcinoma: a randomized, double-blind, multicen-ter, comparative trial. Cancer. 2003;98(8):1735-1744.

7. Chern B, Joseph D, Joshua D, et al. Bisphosphonateinfusions: patient preference, safety and clinic use.Support Care Cancer. 2004;12(6)463-466.

8. Anderson K, Richardson P, Chanan-Khan A, et al.Single-agent bortezomib in previously untreated multiplemyeloma (MM): results of a phase II multicenter study. JClin Oncol. 2006 ASCO Annual Meeting ProceedingsPart I. Vol 24, No 18S (June 20 Supplement), 2006. 7504.

9. Tosi P, Zamagni E, Cellini C, et al. Neurologicaltoxicity of long-term (>1 yr) thalidomide therapy inpatients with multiple myeloma. Eur J Haematol. 2005;74:212-216.

10. Mileshkin L, Stark R, Day B, et al. Development ofneuropathy in patients with myeloma treated with thalido-mide: patterns of occurrence and the role of electrophysi-ologic monitoring. J Clin Oncol. 2006;24:4507-4514.

11. Offidani M, Corvatta L, Marconi M, et al. Commonand rare side-effects of low-dose thalidomide in multiplemyeloma: focus on the dose-minimizing peripheral neu-ropathy. Eur J Haematol. 2004;72:403-409.

12. Lonial S, Waller EK, Richardson PG, et al. Evaluationof the severity and risk of thrombocytopenia withbortezomib therapy in relapsed and refractory multiplemyeloma. Haematologica. 2004;5:S130: Abstract 371.

13. Lonial S, Waller EK, Richardson PG, et al. Risk factorsand kinetics of thrombocytopenia associated with borte-zomib for relapsed, refractory multiple myeloma. Blood.2005;106:3777-3784.

14. Weber DM, Chen C, Niesvizky R, et al. Lenalidomideplus high-dose dexamethasone provides improved overallsurvival compared to high-dose dexamethasone alone forrelapsed or refractory multiple myeloma (MM): results ofa North American phase III study (MM-009). J ClinOncol. 2006 ASCO Annual Meeting Proceedings Part I.Vol 24, No 18S (June 20 Supplement), 2006. 7521.

15. Lonial S, et al. Presentation at the InternationalMyeloma Workshop, Kos, Greece, June 25-30, 2007;Abstract 622.

Control of Multiple Myeloma(continued from page 7)

Treatment of Cutaneous T-Cell LymphomaFocuses on Stage, Minimizing Adverse EventsBROOKLYN, New York—Treatmentapproaches for cutaneous T-cell lym-phoma (CTCL) should be based on dis-ease stage, stratified by skin-directed orsystemic involvement, and may includecombination therapies for optimalresponses, according to Steven M.Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York,who provided a broad overview ofCTCL diagnosis, staging, and currenttreatment regimens at the NationalComprehensive Cancer Network 3rdAnnual Congress: Hematologic Malig-nancies.

RATES HAVE DOUBLEDRates of CTCL, a fairly rare disease thatcomprises mycosis fungoides and Sézarysyndrome, has doubled to nearly 3,000cases annually in the US compared with1998-2002,1 most likely due to betterdiagnostic techniques than to a trueincrease in development of the disease.2

Mycosis fungoides, the most commonprimary skin lymphoma, occurs at a peakage of 55 to 60 years, although it canpresent at any age, including in the veryelderly. The ratio of males to femaleswith the disease is 2:1, which affects allraces. The most common presentation isa classic, thin, fairly pruritic patch innon–sun-exposed areas, such as the innerupper arms, in the bathing trunk area, thethighs, and the buttocks (stage T1). Thepatch is flat, and the skin is usually red.

The next skin stage (T2) is plaque,which is also pruritic. Scale thicker thana patch but not as thick as a tumor canoccur. Patches are also present; therefore,it is sometimes referred to as “patchplaque disease,” or “patch plaque stage.”In people with dark skin, plaque canappear as a brown (not red) lesion, orsometimes be hypopigmented. Ulcer-ative or very pigmented lesions can

occur with tumors (T3). In patients withT4 disease, more than 80% of the skin isred and infiltrated.

PROGNOSIS TIED TO DISEASE STAGEA diagnosis of mycosis fungoides andSézary syndrome is confirmed by biop-sy of suspicious skin sites and a der-matopathology slide review with clinicalcorrelation. Staging is based on a com-plete physical examination and laborato-ry and imaging studies.3 The TNMB(skin, nodes, viscera, blood) system isused for classification and staging,4 withstage 1A denoting limited patch/plaque(<10% of the total skin surface), no sig-nificant blood involvement, low bloodtumor burden, and no clinically abnor-mal lymph nodes or visceral involve-ment. Stage IV denotes a combinationof skin, lymph node, viscera, and bloodinvolvement.3 A Sézary flow cytometricstudy for CD3, CD4, CD7, CD8, andCD26 assesses for expanded CD4+ cellswith increased CD4/CD8 ratio thatmay be indicative of high blood tumorburden that is prognostically important(eg, the same clone present in the bloodand skin). Prognosis—risk of progressionand survival—is tightly tied to diseasestage; however, even people withadvanced disease may live a decade ormore.5

Chest x-rays are adequate for milddisease. Contrast-enhanced CT orwhole body PET scan are usually indi-cated for patients with stage T2 disease.3

PET scans are more useful at indicatingareas that should be biopsied; multiplebiopsies should be avoided as woundinfections are common in this patientpopulation. Bone marrow biopsy israrely necessary.

Treatment regimens suggested by theNational Comprehensive Cancer Net-work divide therapies into skin-directed

therapies, systemic therapies, and combi-nation therapies.3 Given a lack of collab-orative phase III clinical trials, treatmentsas indicated in the guidelines should notbe interpreted as a “preferred order.”2

OVERVIEW OF THERAPY FOR CTCLFor limited/localized skin involvement,therapies include topical corticosteroids,topical chemotherapy (nitrogen mustardand carmustine), local radiation, topicalbexarotene, and phototherapy. For gen-eralized skin involvement, suggestedtreatments include topical cortico-steroids, topical chemotherapy (mech-lorethamine and carmustine), photo-therapy and, for those with severe skinsymptoms, generalized thick plaque ortumor disease, or poor response to othertherapies, total skin electron beam ther-apy. Often, choice of initial therapy isbased on logistics and patient preference(eg, topical administration of carmustinevs traveling for phototherapy). Total skinradiation can induce a 100% responserate for 6 months to 2 years; in somecases, this may be all the treatment apatient needs. To date, there is no

January 2009 9


TABLE: Adverse effects oftreatments for CTCL2

Fairly safe—minimal side effectsBexarotene capsulesVorinostatMethotrexateExtracorporeal photochemotherapy

Fairly safe—some side effectsInterferonSingle-agent chemotherapyDenileukin diftitox

Less safe—more side effectsAlemtuzumabCombination chemotherapyAllogeneic transplantation

evidence to suggest that earlier use ofaggressive therapies decreases risk ofmoving to a higher disease stage.2

SYSTEMIC THERAPIESFor patients with refractory disease, sys-temic therapies are indicated. Category Asystemic therapies (defined as havingmilder adverse effects and therefore saferfor long-term use) include retinoids,interferons, histone deacetylase (HDAC)inhibitors such as vorinostat, extracor-poreal photopheresis, the fusion toxindenileukin diftitox, and methotrexate(≤100 mg per week). Those in categoryB (defined as having a more rapid onsetof response) are liposomal doxorubicinand gemcitabine for first-line treatmentand, for second-line treatment, chloram-bucil, pentostatin, etoposide, cyclophos-phamide, temozolomide, andmethotrexate (>100 mg per week).

Use of the Severity Weighted Assess-ment (SWAT) tool can help determineresponse in individual patients; for exam-ple, if a partial response is observed onvorinostat, an oral HDAC inhibitorapproved for the treatment of cutaneousmanifestations of CTCL in previouslytreated patients who have persistent, pro-gressive, or recurrent disease,6,7 and thepatient is not pruritic, maintaining thatpartial response may be preferable tomoving to a more toxic chemotherapyin an attempt to induce a completeresponse.2 Photopheresis is generally well

tolerated long-term and is more appro-priate for patients with Sézary syndrome.

Combination therapies (skin-directedplus systemic) include phototherapy plusa retinoid, interferon, or photopheresis;or total skin electron beam plus photo-pheresis. Combination therapies (sys-temic plus systemic) include retinoidplus interferon; bexarotene plus deni-leukin diftitox, or photopheresis pluseither a retinoid, interferon, or retinoidplus interferon.

Alemtuzumab (anti-CD52) has alsobeen tested; however, 50% of patients inan early study had infections, two ofwhich were fatal.8 A more recent study inpatients with erythrodermic CTCL low-ered the dose (3 mg day 1; 10 mg day 3;and 10 to 15 mg every other day for4 doses) and administered it subcuta-neously, stopping when the Sézary cellsdecreased to <1,000/mm3. Treatment wasrepeated when Sézary cell values increasedto >2,000/mm3; this strategy may allowthe disease to be controlled at a less toxicdose. No infections were reported.9

Most patients end up on combina-tions of skin-directed and systemic ther-apies, in part because single agents con-fer partial responses; however, combina-tion chemotherapy is usually limited tothe treatment of advanced-stage disease.For patients with advanced disease, datafrom use of allogeneic stem cell trans-plantation are providing increasing evi-dence of durable clinical cytogenetic andmolecular remissions in CTCL.10 In con-trast, autologous stem cell transplantationdoes not provide a durable response.

The adverse effects of treating patientswith CTCL using a stage-based approachare summarized in Table.

REFERENCES1. Criscione VD, Weinstock MA. Incidence of cutaneousT-cell lymphoma in the United States, 1973-2002. ArchDermatol. 2007;143:854-859.

2. Horwitz SM. Treatment of cutaneous T-cell lymphoma.National Comprehensive Cancer Network. NCCN 3rdAnnual Congress: Hematologic Malignancies. 2008.

3. National Comprehensive Cancer Network. PracticeGuidelines in Oncology. Non-Hodgkin’s Lymphoma.V.3.2008. 2008;MFSS-1. Available at: www.nccn.org.Accessed October 2, 2008.

4. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions tothe staging and classification of mycosis fungoides andSézary syndrome: a proposal of the International Societyfor Cutaneous Lymphomas (ISCL) and the cutaneouslymphoma task force of the European Organization ofResearch and Treatment of Cancer (EORTC). Blood.2007;110:1713-1722.

5. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, HoppeRT. Long-term outcome of 525 patients with mycosisfungoides and Sézary syndrome. Arch Dermatol. 2003;139:857-866.

6. Mann BS, Johnson JR, He K, et al.Vorinostat for treat-ment of cutaneous manifestations of advanced primarycutaneous T-cell lymphoma. Clin Cancer Res. 2007;13:2318-2322.

7. Mann BS, Johnson JR, Cohen MH, et al. FDA approvalsummary: vorinostat for treatment of advanced primarycutaneous T-cell lymphoma. Oncologist. 2007;12:1247-1252.

8. Lundin J, Hagberg H, Repp R, et al. Phase 2 studyof alemtuzumab (anti-CD52 monoclonal antibody) inpatients with advanced mycosis fungoides/Sézary syn-drome. Blood. 2003;101:4267-4272.

9. Bernengo MG, Quaglino P, Comessatti A, et al. Low-dose intermittent alemtuzumab in the treatment of Sézarysyndrome: clinical and immunologic findings in 14patients. Haematologica. 2007;92:784-794.

10. Molina A, Zain J, Arber DA, et al. Durable clinical,cytogenetic, and molecular remissions after allogeneichematopoietic cell transplantation for refractory Sézarysyndrome and mycosis fungoides. J Clin Oncol. 2005;23:6163-6171.

10 January 2009



Treatment of Cutaneous T-Cell(continued from page 9)

NCCN Releases New Clinical Practice Guidelinesin Oncology for Myelodysplastic Syndromes

Peter L. Greenberg, MD, of Stanford Comprehensive Cancer Center, inPalo Alto, California, presented an overview of anemia and myelodys-plastic syndromes (MDS) during the National Comprehensive CancerNetwork (NCCN) 3rd Annual Congress: Hematologic Malignancies.Approaches for the management of MDS include determination ofthe following: clinically relevant cytopenia(s); age (younger or older

than 60 years); performance status (excellent, good, poor); IPSS(International Prognostic Scoring System) risk category (low, interme-diate-1, intermediate-2, or high); and whether the patient is a candi-date for hematopoietic stem cell transplantation (based on factorssuch as age, performance status, and donor availability). New NCCNGuidelines for MDS1 were released after his presentation.

REFERENCE1. NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes.V.1.2009. Available at www.nccn.org. Accessed October 10, 2008.

January 2009 11

The Expanding Role of HDAC Inhibitors inCTCL, Other T-Cell Proliferative Disorders

Interview with Steven M. Horwitz,MD, Memorial Sloan-KetteringCancer Center

How do patients with cutaneous T-celllymphoma (CTCL) respond to treat-ment with histone deacetylase (HDAC)inhibitors?

Dr. Horwitz: Currently, there is onlyone clinically approved HDAC, vorino-stat, which was initially developed atMemorial Sloan-Kettering CancerCenter (MSKCC).A number of othersare in development. A Phase II studyconducted by Madeleine Duvic, MD,and colleagues at the University ofTexas M.D. Anderson Cancer Centerlooked at three different dosing sched-ules: daily dosing, twice daily dosing,and intermittent dosing. With continu-ous dosing, there was about a 30%response rate.1 A larger phase IIb studyof 74 patients showed very repro-ducible results, again, about a 30%response rate.2 The majority of patientshad advanced-stage disease and hadreceived at least two other therapies,including bexarotene.

What was the safety and efficacy profileof vorinostat in those trials?

Dr. Horwitz: Vorinostat was reason-ably well tolerated. There was a certainamount of low-grade fatigue, anorex-ia, nausea, and diarrhea. There wasvery little hematologic toxicity, usuallylow-grade thrombocytopenia. A sig-nificant minority of patients respond-ed, and some of those responses werefairly durable, lasting longer than 6months. It was approved based on that

data. As an interesting side note, itlooked like from both of the phase IIstudies that there was a decrease initching out of proportion to response.Vorinostat has become a standard sec-ond-line or third-line systemic regi-men for CTCL.

What is the status of other HDACs indevelopment?

Dr. Horwitz: Single-agent activity ofHDACs is most obvious and mostpronounced for CTCL; therefore, alot of other drugs in development arelooking at that, at least as a possibleindication. Anecdotal activity of dep-sipeptide (romidepsin) was observedin a large phase I study at theNational Cancer Institute. This agentrecently completed a multicenterphase II registration study [interimresults presented at ASH 20063] inCTCL.4 PXD101, now called belino-stat, is in phase II study for CTCL,and results with LBH589, panobino-stat, also in phase II studies, wereupdated at ASCO this past year forCTCL.5 The idea is that differentHDAC inhibitors have differentpotencies; different classes of HDACsinclude pan-HDAC inhibitors andmore specific HDAC inhibitors.Right now we really do not knowwhat the best drug is at what dose forwhat disease. A lot of people are look-ing at CTCL with HDACs as singleagents because it is a disease whereagents do not have to be combined tomeasure activity.

Was the low incidence of myelosuppres-sion similar across HDAC studies?

Dr. Horwitz: Yes. There tends to besome thrombocytopenia, usually lowgrade, and it seems to be reversiblewhen the drug is held. There’s very lit-tle or no neutropenia; there’s very littleanemia. The majority of the publisheddata in CTCL is primarily vorinostat;data on other agents has mostly beenpresented in abstract form.

Is there a role for this class of agents onother T-cell proliferative disorders?

Dr. Horwitz:We have very little infor-mation on that. There’s a lot of interestin studying romidepsin. When theNational Cancer Institute (NCI) didtheir phase II study with CTCL, theyalso had several cohorts of pretreatedpatients with aggressive or peripheralT-cell lymphoma, and they reportedcomplete and partial response in bothpatients with CTCL as well as inpatients with various subtypes ofperipheral T-cell lymphoma (PTCL).6

Romidepsin was pretty well tolerated.However, with this agent in particularthere were some concerns about car-diac toxicity because there werearrhythmias, including fatalities, in afew of the patients early on in thestudy. However, the NCI group con-ducted an exhaustive review of electro-cardiograms and, on average, there wasminimal QT prolongation. In retro-spect, it looks like the patients whohad cardiac toxicity may have hadother reasons underlying their heartproblems or were on other medica-tions that contributed to prolongedQT. We have seen very little cardiac


12 January 2009



txicity in the studies we are doing now,but we’ve been very careful about notincluding other medicines that couldpredispose people to arrhythmias.

How do HDAC inhibitors compare withother newer agents, such as the targetedtherapies?

Dr. Horwitz: Unless you considerHDAC inhibitors as targeted to thegenome, I don’t believe they are verynarrowly targeted. You have a wide rangeof changes on gene expression, on pro-tein stability; in fact, there are so manybroad-based changes it is very hard at thispoint to say specifically the reason for theresponses in certain diseases. Is it hittinga specific molecular lesion or a specificmarker or a specific feature of these cells?The reason HDAC inhibitors work maybe different from disease to disease or dif-ferent from HDAC to HDAC at differ-ent doses. It is possible at some point inthe future that we’ll understand there is avery specific reason why they work.

Is there any activity in lymphomas, apartfrom CTCL?

Dr. Horwitz: The vast majority ofpatients have had mycosis fungoides andSézary syndrome. In the vorinostat phaseI trial, there were some responders withHodgkin’s lymphoma and large B-celllymphoma. Larger studies are lookinginto activity in other lymphomas, mostlyas part of combination regimens. Onequestion would be, because we see activ-ity in CTCL and PTCL, is this somehowT-cell specific? Or, within the group ofT-cell lymphomas, are there going to becertain diseases that respond well andcertain ones that do not? That’s anotherarea where we don’t have a full under-standing.

Looking ahead 2 to 3 years, do yousee other types of HDAC inhibitorsemerging specifically to treat CTCL orother hematologic malignancies or solidtumors?

Dr. Horwitz: It’s a very small market;a very rare disease. We’ll have results onthe other drugs in development forCTCL. There does appear to be single-agent activity across the class. We arealready seeing combinations of vorino-stat with bexarotene and some peoplewho treat CTCL have combinedvorinostat with extracorporeal photo-pheresis or interferon. A lot of preclin-ical data suggest that HDACs wouldcombine well with drugs like the pro-teasome inhibitors, such as bortezomib,or with certain chemotherapies, such asgemcitabine, in myeloma and solidtumors. Studies will confirm whetherthe combinations are safe or get betteractivity.

What about using HDAC inhibitorssuch as vorinostat as sequential therapyfor the treatment of CTCL, including asfirst-line treatment?

Dr. Horwitz: Treatments do tend towork better in first-line than they dosecond-line and third-line. However,not much has been done in terms offirst-line chemotherapy. People aretalking about combining these drugswith other chemotherapies for first-linelymphoma, like CHOP (cyclophos-phamide; doxorubicin/hydroxydoxo-rubicin; vincristine; and prednisone),but those studies are just in develop-ment; I haven’t seen any results. Itwould make sense that it would be abetter first-line (protocol), but foraggressive lymphomas, it’s hard to justgive single agents first-line. We probablywill have to wait for combinations. ForCTCL, there’s no reason why peoplecouldn’t look at vorinostat as initial

therapy.The label is for relapsed disease,and many people with CTCL don’tneed systemic therapy early on. As wedevelop safer systemic therapies likethese, if someone needs systemic thera-py as their initial therapy, there is noreason why it wouldn’t be active.

Do you have any other concludingremarks?

Dr. Horwitz: There will probably beupdates of studies or new studies pre-sented at the American HematologySociety meeting in early December.Wemight get some data on the vorinostatregistration study. They did tumorbiopsies, looking at gene expressionprofiles as part of the pre- and post-dosing of the drug.That data might beinteresting in the sense that we mayhave a better understanding of whysome patients responded—or didn’t—or those more important mechanismsthat could be correlated with response.

REFERENCES1. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oralvorinostat (suberoylanilide hydroxamic acid, SAHA) forrefractory cutaneous T-cell lymphoma (CTCL). Blood.2007;109:31-39.

2. Olden EA, Kim YH, Kuzel TM, et al. Phase IIb mul-ticenter trial of vorinostat in patients with persistent,progressive, or treatment refractory cutaneous T-celllymphoma. J Clin Oncol. 2007;25:3109-3115.

3. Lerner A, Demierre MF, Whittaker S, et al.Romidepsin (depsipeptide, FK288) induces clinicallysignificant responses in treatment-refractory CTCL:interim report of a phase II multicenter study. Blood.2006;108: Abstract 2468.

4. Kim YH, Reddy S, Kim EJ. Romidepsin (depsipep-tide) induced clinically significant responses in treat-ment-refractory CTCL: an international, multicenterstudy. Blood. 2007;110: Abstract 123.

5. Duvic M, Vanaclocha F, Bernengo MG, et al. Phase IIstudy of oral panobinostat (LBH589), a potent pan-deacetylase inhibitor, in patients with refractory cuta-neous T-cell lymphoma (CTCL). J Clin Oncol. 2008;26(May 20 suppl); Abstract 8555.

6. Pickarz RL, Frye R, Turner M, et al. Phase II trial ofromidepsin, FK228, in cutaneous and peripheral T-celllymphomas: clinical activity and molecular markers.Blood. 2006;108: Abstract 2469.

The Expanding Role of HDAC(continued from page 11)

BROOKLYN, New York—For treat-ment of patients with chronic myeloidleukemia (CML), the tyrosine kinaseinhibitor (TKI) imatinib is effective inmost patients. If responses are suboptimal,the imatinib dose can be increased from400 mg to 800 mg or a second-genera-tion TKI, such as dasatinib, nilotinib, bosu-tinib, or INNO 406, may be substituted,according to a review of the recent liter-ature presented by Susan O’Brien, MD,of the University of Texas M.D.Anderson Cancer Center, in Houston,Texas, during the National Comprehen-sive Cancer Network 3rd AnnualCongress: Hematologic Malignancies.1

For patients who are imatinib resis-tant, second-generation agents may beused, although Dr. O’Brien cautionedthat these new TKIs should not be usedfrontline outside of clinical trials. Use ofagents in combinations, including front-line and in advanced-stage disease, awaitdata from ongoing clinical trials.

STEADY SURVIVAL INCREASEThe proportion of patients survivingearly-phase CML treated at M.D.Anderson Cancer Center has increasedsteadily since 1965, as has the under-standing of the biology of the disease,which has translated into significantimprovement in long-term prognosis.2

With the introduction of the TKI ima-tinib, which has become the standardtherapy for CML based on its activityand mild toxicity profile, the estimated6-year overall survival rate is 91% (88%in the intent-to-treat group), accordingto the International Randomized studyof Interferon versus STI571 (IRIS).3

In the IRIS study, 1,106 patients wererandomly assigned to either imatinib orinterferon plus Ara-C (cytarabine) andevaluated for hematologic and cytogenet-

ic responses, event-free survival, progres-sion to accelerated-phase (AP) or blastcrisis (BC), overall survival, and frequen-cy of adverse events and discontinuations.A 6-year follow-up analysis of the IRISpopulation found that continuous treat-ment of chronic-phase CML with ima-tinib induces durable responses in a highpercentage of patients with a decreasingrate of relapse and a favorable long-termsafety profile. Most grade 3/4 adverseevents occurred early and declined inincidence with continued therapy. Apartfrom age, the only prognostic factor iden-tified was low hemoglobin level.3

In a recent subanalysis of the IRISstudy, Larson et al4 found that adequateplasma concentration of imatinib isimportant for good clinical response.4

Once patients have failed on imatinib, 4-year survival rates for those with chron-ic-phase CML is 65%; median survivalhad not been reached.5

Prior to transplantation, a second TKImay be used. Nilotinib and dasatinib areboth approved for CML after imatinibfailure. More pleural effusion wasobserved with dasatinib, which was asso-ciated with cardiac history, hypertension,

and dosing schedule than the other twoagents.6 Data on clinical responses to thesecond-generation TKIs after imatinibfailure suggest dasatinib is more activebut also more toxic (Table).

Trials are ongoing with the combina-tion of imatinib and second-generationTKIs, such as nilotinib.

REFERENCES1. O’Brien S. Update on frontline therapy of CML withimatinib and results with second generation tyrosinekinase inhibitors. National Comprehensive CancerNetwork 3rd Annual Congress: Hematologic Malignan-cies. 2008.

2. Quintás-Cardama A, Cortes JE. Chronic myeloidleukemia: diagnosis and treatment. Mayo Clin Proc. 2006;81:973-988.

3. Hochhaus A, Druker BJ, Larson S, et al. IRIS 6-year fol-low-up: sustained survival and declining annual rate oftransformation in patients with newly diagnosed chronicmyeloid leukemia in chronic phase (CML-CP) treatedwith imatinib. Blood. 2007;110: Abstract 25.

4. Larson RA, Druker BJ, Guilhot F, for the IRIS(International Randomized Interferon vs STI571) StudyGroup. Imatinib pharmacokinetics and its correlation withresponse and safety in chronic-phase chronic myeloidleukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022-4028.

5. Kantarjian H, O’Brien S, Talpaz M, et al. Outcome ofpatients with Philadelphia chromosome-positive chronicmyelogenous leukemia post-imatinib mesylate failure.Cancer. 2007;109:1556-1560.

6. Quintás-Cardama A, Kantarjian H, O’Brien S, et al.Pleural effusion in patients with chronic myelogenousleukemia treated with dasatinib after imatinib failure. J ClinOncol. 2007;25:3908-3914.

January 2009 13

New Tyrosine Kinase Inhibitors Show Promisein Chronic Myeloid Leukemia

TABLE. Second-generation tyrosine kinase inhibitors in patients withchronic-phase CML-CP after imatinib failure1

Dasatinib % Nilotinib % Bosutinib %ResponseCHRMCyRCCyR

915949

745234

844232

ToxicityMyelosuppressionEffusionsLiverRashLipase/glucose

+++++++–

++–+++

+–++–

Median follow-up (months) 15 12 3CHR=complete hematologic response; MCyR=major cytogenetic response; CCyR=complete cytogenetic response

1. In the pediatric population with acute lymphoblasticleukemia (ALL), median survival has been extendedprimarily by intensification of post-remission therapy.a. Trueb. False

2. According to a study of the role of aspargine depletion withpegylated asparaginase in adults with ALL, which of thefollowing is true?a. Survival was longer in those who achieved

asparagine depletion.b. Patients with B-lineage ALL had a higher rate of

disease-free survival.c. Patients with T-cell lineage had a lower rate of

overall survival.d. No relationship was found between

immunophenotype and asparagine depletion.

3. What percentage of high-risk elderly patients withdiffuse-large B-cell lymphoma achieves 5-year survival?a. 47%b. 35%c. 27%d. 21%

4. Which of the following is the single best determinantof whether multiple myeloma (MM) is refractory?a. Prior treatmentb. Agec. Clinical judgmentd. Bone marrow function

5. In what percentage of patients with MM doosteolytic lesions occur?a. 45%b. 56%c. 74%d. 80%

6. Which of the following is a rare complication ofbisphosphonate therapy?a. Peripheral neuropathyb. Cytopeniac. Osteonecrosis of the jawd. Thrombosis

7. Vorinostat is indicated for the treatment of:a. Newly diagnosed cutaneous T-cell lymphoma

(CTCL)b. Refractory CTCLc. ALLd. MM

8. Which of the following agents is not a histonedeacetylase inhibitor?a. Alemtuzumabb. Belinostatc. Romidepsind. Vorinostat

9. For patients with chronic myeloid leukemia who fail onimatinib, which of the following second-generation tyrosinekinase inhibitors (TKIs) may be used?a. Dasatinibb. Nilotinibc. Bosutinibd. All of the above

10. Which of the following second-generation TKIs hasbeen more often associated with pleural effusion?a. Bosutinibb. Dasatinibc. Imatinibd. Nilotinib

POSTTEST – PROJECT ID: 5717ES15On page 16, please write the correct answer to each question.



14 January 2009

January 2009 15

RECENT ADVANCES IN THE TREATMENT OFHEMATOLOGIC MALIGNANCIES

PROJECT ID: 5717ES15

Fax to: 303-790-4876

EVALUATION FORM

To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings,please take a few minutes to complete this evaluation form. You must complete this evaluation form to receiveacknowledgment for completing this activity.

Please answer the following questions by circling the appropriate rating:Scale: 1 = Strongly Disagree 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree

Extent to Which Program Activities Met the Identified ObjectivesAfter completing this activity, I am now better able to:

• Identify strategies for the long-term treatment of patients with T-cell proliferative disorders, including cutaneous T-cell lymphoma, and the management ofadverse events

1 2 3 4 5

• Integrate new approaches into the management of adults with acute lymphoblastic leukemia

1 2 3 4 5

• Discuss effective treatments for chemotherapy-refractory diffuse largeB-cell lymphoma (DLBCL) and the role of radiotherapy in DLBCL

1 2 3 4 5

• Evaluate recent clinical advances in the management of intolerant/resistantchronic myeloid leukemia, including the use of first- and second-generationtyrosine kinase inhibitors

1 2 3 4 5

• Compare the efficacy and toxicity of validated induction, maintenance,and salvage first-line therapies for multiple myeloma (MM)

1 2 3 4 5

• Outline advances in supportive care for patients with MM 1 2 3 4 5

Overall Effectiveness of the ActivityThe content presented:

Was timely and will influence how I practice 1 2 3 4 5Enhanced my current knowledge base 1 2 3 4 5

Addressed my most pressing questions 1 2 3 4 5

Provided new ideas or information I expect to use 1 2 3 4 5

Addressed competencies identified by my specialty 1 2 3 4 5

Avoided commercial bias or influence 1 2 3 4 5

Impact of the ActivityName one thing you intend to change in your practice as a result of completing this activity:

Please list any topics you would like to see addressed in future educational activities:

Fax to: 303-790-4876

RECENT ADVANCES IN THE TREATMENT OFHEMATOLOGIC MALIGNANCIES

PROJECT ID: 5717ES15

EVALUATION FORM (continued)

Follow-upAs part of our continuous quality improvement effort, we conduct postactivity follow-up surveys to assess theimpact of our educational interventions on professional practice. Please indicate if you would be willing to partici-pate in such a survey:

❑ Yes, I would be interested in participating in a follow-up survey.❑ No, I’m not interested in participating in a follow-up survey.

If you wish to receive acknowledgment for completing this activity, please complete the posttest by selecting the best answer to each question, complete this evaluation verification of participation, and fax to: 303-790-4876.

Posttest Answer Key

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Request for Credit: (check one) ❑ MD ❑ Other

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For Physicians OnlyI certify my actual time spent to complete this educational activity to be:

❑ I participated in the entire activity and claim 1.0 credit(s).

❑ I participated in only part of the activity and claim _____ credits.

Documents

Recent Advances in the Treatment of Hematologic Malignancies