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

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NOVEMBER 2009Volume 8, Supplement 4

Supplement to the american journalof hematology/oncology

WHAT’S INSIDE• HDAC Inhibitors and MDS: Ongoing Epigenetic Research • Novel Hypomethylating Agents Treat High-Risk MDS • New Hematopoietic Stem Cell Transplantation Strategies in

Multiple Myeloma • HDAC Inhibitors and Emerging Therapies for

Multiple Myeloma• Targeted-Therapy Regimens Highly Active in AML • …and more

Produced by

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

NEEDS ASSESSMENTThe introduction of monoclonal antibodies has led to new therapeutic options forthe management of hematologic malignancies. The use of these “targeted”agents against specific cell-surface receptors, enzymes, and proteins has becomean important strategy in the treatment of hematologic disorders,1 includingmyelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and multiplemyeloma (MM).

Allogeneic bone-marrow transplantation is the only curative option for MDS,2

but older patients are not appropriate candidates for this approach.3,4 As MDSaffects hematopoietic stem cells (leading to ineffective hematopoiesis), treatmentmay result in infection, transfusion-related anemia, and progression to AML.5 Theexploration of novel targets with relevance in myelopoiesis has stimulated thedevelopment of an array of agents that show promise in the treatment of MDS,providing an opportunity for improvements in quality of life and, possibly, pro-longed survival.

An increased understanding of the role that signaling pathways play in thepathogenesis of AML has also led to treatments that target known genetic markers and altered signaling pathways. Many of these approaches are designedto interfere with molecular genetic or epigenetic mechanisms.6 Other targetedapproaches currently under development may have therapeutic potential to complement high-dose chemotherapy and bone-marrow transplantation, but the major challenge remains to identify targets of critical pathophysiologic importance. These targets may be helpful in developing appropriate treatment forolder patients with AML, particularly those aged ≥65 years who are intrinsicallyresistant to chemotherapy.7

Novel therapies also have changed the standard approach to induction thera-py for patients with newly diagnosed MM who are eligible for autologous stemcell transplantation (SCT).8 For patients who are not eligible for autologous SCT,novel treatment has shown efficacy for newly diagnosed MM,9 and a steroid-inde-pendent salvage regimen has shown benefit for relapsed/refractory MM.10

The use of novel agents, alone and in combination, has emphasized theimportant role of the target in defining response. This supplement will focus onthe development of targeted treatment approaches that will expand the thera-peutic options for patients with hematologic malignancies.

REFERENCES1. Kuriakose P. Targeted therapy for hematologic malignancies. Cancer Control.2005;12:82-90.2. Itzykson R, Fenaux P. Optimal sequencing of treatments for patients withmyelodysplastic syndromes. Curr Opin Hematol. 2009;16:77-83.3. Stone RM. The difficult problem of acute myeloid leukemia in the older adult.CA Cancer J Clin. 2002;52:363-371.4. Alyea EP, Kim HT, Ho V. Comparative outcome of nonmyeloablative and mye-loablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;105:1810-1814.5. Stone R, Sekeres M, Garcia-Manero G, Lyons RM. Recent advances in low- andintermediate-1-risk myelodysplastic syndrome: developing a consensus for optimaltherapy. Clin Adv Hematol Oncol. 2008;6:1-15.6. Haferlach T. Molecular genetic pathways as therapeutic targets in acute myeloidleukemia. Hematology Am Soc Hematol Educ Program. 2008:400-411.7. Ravandi F, Burnett AK, Agura ED, Kantarjian HM. Progress in the treatment ofacute myeloid leukemia. Cancer. 2007;110:1900-1901.8. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plusdexamethasone compared with dexamethasone alone in newly diagnosed multi-ple myeloma: a clinical trial coordinated by the Eastern Cooperative OncologyGroup. J Clin Oncol. 2006;24:413-436.9. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan andprednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.10.Chanan-Khan A, Miller KC, Musial L, et al. Bortezomib in combination withpegylated liposomal doxorubicin and thalidomide is an effective steroid indepen-dent salvage regimen for patients with relapsed or refractory multiple myeloma:results of a phase II clinical trial. Leuk Lymphoma. 2009;50:1096-1101.

EDUCATIONAL OBJECTIVES After taking part in this educational activity, participants should be able to:• Assess the risk factors and current standards of care for patients with

hematologic malignancies • Describe the latest management approaches for hematologic malignancies,

including leukemia, multiple myeloma, and myelodysplastic syndromes• Identify appropriate management options based on emerging data on novel

agents that are being developed for the treatment of hematologic malignancies

TARGET AUDIENCEOncologists, hematologist-oncologists, hematologists, and other clinicians involvedin the care of patients with cancer

ACCREDITATION/CREDIT DESIGNATIONBoston University School of Medicine is accredited by the Accreditation Councilfor Continuing Medical Education to provide continuing medical education forphysicians.Boston University School of Medicine designates this educational activity for amaximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claimcredit commensurate with the extent of their participation in the activity.CME credit will be awarded provided this activity is used and completed accord-ing to instructions and a score of 70% or better is achieved. A certificate of creditwill be sent within 6 to 8 weeks of receipt of the test answers to those who suc-cessfully complete the examination.

Estimated time to complete this activity: 90 minutes

Program Code: E.ONCHAY09

Release Date: November 1, 2009Expiration Date: November 30, 2010

DISCLOSURE POLICYBoston University School of Medicine asks all individuals involved in the development and presentation of continuing medical education (CME) activities to disclose all relationships with commercial interests. This information is disclosedto CME activity participants. Boston University School of Medicine has proceduresto resolve any apparent conflicts of interest. In addition, faculty members areasked to disclose when any unapproved use of pharmaceuticals and/or devices is being discussed.

COURSE DIRECTORJ. Mark Sloan, MD, is a consultant for Global Cures and Veristat. He is on theSpeakers’ Bureau for Merck.

INDEPENDENT REVIEWERValshali Sanchorawala, MD, receives grant support from Celgene and Johnsonand Johnson.

Elizabeth Drury, Boston University School of Medicine, has nothing to disclose.

Liz Selkowe, Haymarket Medical Education, has nothing to disclose.

Susan Basilico, Haymarket Medical Education, has nothing to disclose.

DISCLOSURE OF OFF-LABEL USEUnlabeled/investigational uses of commercial products are discussed in thismonograph.

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

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The content of the supplement was drawn in part from sessions presented in 2009 at the 45th Annual Meeting of the American Societyof Clinical Oncology (ASCO) and the 14th Congress of the European Hematology Association (EHA). However, this independent continuing medical education activity is neither sponsored nor sanctioned by ASCO or EHA.

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

3

Novel Hypomethylating Agents Treat High-Risk Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS)is a collection of hematologicmalignancies that share an

insufficient production of normal bonemarrow or myeloid cells.With progress-ing bone marrow failure, patients gradu-ally display worsening cytopenias.1 Theprognosis and treatment of MDS varydepending on the patient’s InternationalPrognostic Scoring System (IPSS) score.Patients with a low/intermediate-1 riskscore may live with their disease for anumber of years and may be treated withbiologic, targeted therapies. Patients withan intermediate-2 or higher score are atincreased risk for transformation to acutemyeloid leukemia (AML), which mayjustify the use of more intensive therapiesand novel chemotherapeutic agents.2

Hypomethylating agents have been amajor focus of clinical research over thelast few years, particularly for patientswith high-risk MDS. The two best-studied hypomethylating agents are the

structurally similar nucleoside analogsazacitidine and decitabine.2 Azacitidineappears to improve overall survival, butMDS remains an incurable disease if notcured through allogeneic stem celltransplantation (SCT). However, mostpatients with MDS are older, with amedian age of 70 years at the time ofdiagnosis,3 and, therefore, are not appro-priate candidates for allogeneic SCT.

MDS is relatively common, with anincidence estimated as high as 50 casesper 100,000 people per year.1 Mortalityin patients with MDS is high, and mostpatients require transfusions, emergencydepartment visits, and hospitalizations.4

In higher-risk patients, progress hasbeen seen with the use of reduced-intensity conditioning allogeneic SCTin elderly patients and in studies of thehypomethylating agents azacitidine anddecitabine, leading to their approval forthe treatment of symptomatic MDS bythe FDA. The results of a landmark

phase III study showed a significant sur-vival benefit for azacitidine over con-ventional treatments in patients withhigher-risk MDS.5 This was the firsttime a drug had demonstrated animpact on survival in higher-riskMDS.6

Azacitidine and decitabine both inhibit DNA methyltransferases, the enzymes responsible for maintenance ofthe cell’s specific pattern of cytosinemethylation.7 Two dosing regimens ofdecitabine have demonstrated efficacy inMDS: 15 mg/m2 intravenously over 3 hours every 8 hours for 3 days every 6 weeks and 20 mg/m2 intravenouslyover 1 hour once daily for 5 consecutivedays every 4 weeks. At the AmericanSociety of Clinical Oncology annualmeeting in Orlando, Florida, DavidSteensma, MD, of the Mayo Clinic,Rochester, Minnesota, reviewed theresults of two randomized phase IIIstudies comparing the 3-day dosing

TABLE. RESPONSE TO TREATMENT WITH DECITABINE8

Study IDNumber/Regimen

Median no.of cycles

Overall CR (%)a

Overallimprovement

(%)Time to AML or

death (mos)

Progression-free survival

(mos)

Overall survival (mos)

RBC transfusionindependence

(%)

3-day regimen

D-0007(N=89)

3 9 30 10 7.3 12.8 23

EORTC-06011(N=119)

4 13 34 8.8 6.6 10.1 32

5-day regimen

DACO-020(N=99)

5 15 43 12.1 8.1 17.8 33

ID03-0180(N=93)

7 37 65 15.2 9.2 20.3 NA

aAs measured by IWG 2000 criteria; bPatients who became RBC transfusion independent while on-studyAML=acute myeloid leukemia; CR=complete response; IWG=International Working Group; RBC=red blood cell.Reprinted with permission from Steensma D, Kantarjian H, Wijermans P. Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)[ASCO Annual Meeting abstract 7011]. J Clin Oncol. 2009;27:15s.

4

schedule of decitabine with supportivecare and two phase II studies of the 5-day dosing schedule.8

Patients with MDS in these studieshad IPSS classification scores of inter-mediate-2 or high-risk and de novoMDS.The duration of overall improve-ment, defined as complete response pluspartial response plus hematologicimprovement, ranged between 9.2months and 11.3 months across all stud-ies.8 The researchers observed a trendtoward improved outcomes with anincreased number of decitabine treat-ment cycles.The best response was seenamong the 93 patients who received the5-day dosing schedule for 7 cycles,including an overall complete responserate of 37%, overall improvement rate of65%, and overall survival of 20.3 months(see table). Dr. Steensma stated thatincreasing the number of decitabinetreatment cycles that are administered topatients with MDS may provide addi-tional benefit.

A meta-analysis and systematic re-view of randomized, controlled trials byGurion and colleagues at the RabinMedical Center in Petach Tikva, Israel,yielded 4 trials comparing treatmentwith 5-azacitidine and decitabine to

conventional care (best supportive careor chemotherapy) in 952 patients withMDS.The results were presented at theEuropean Hematology Associationannual meeting in Berlin, Germany.9

Time to AML transformation or death,overall response, and toxicity wereassessed for all patients. Data for analysisof overall survival were available for 782patients in 3 of the 4 trials.

There was an overall survival advan-tage with treatment with 5-azacitidinecompared with conventional care, butnot with decitabine treatment, reportedDr. Gurion. Both hypomethylatingagents showed a significant advantage intime to AML or death and in overallresponse. As expected, a higher rate ofgrade 3/4 adverse events was observedwith use of the drugs compared withconventional care.

Developing higher hematologic re-sponses, improving quality of life, and pro-longing survival remain important treat-ment goals for patients with MDS.7

Azacitidine has become the new goldstandard for monotherapy against whichnewer upfront regimens for MDS mustbe tested. It may also serve as the back-bone for newer or combination regimensin the treatment of high-risk MDS.

REFERENCES1. Stone R, Sekeres M, Garcia-Manero G, Lyons RM.Recent advances in low- and intermediate-1-riskmyelodysplastic syndrome: developing a consensus foroptimal therapy. Clin Adv Hematol Oncol. 2008;6:1-15.

2.Advani A. Hypomethylating agents in the treatmentof myelodysplastic syndrome. Medscape. CME 2006.http://cme.medscape.com/viewarticle/522651.Accessed July 22, 2009.

3. Ravandi F. Clinical issues and future directions inhematologic malignancies: myelodysplastic syndromeand acute leukemias. Clinical Care Options. http://www.clinicaloptions.com/Oncology/Treatment%20Updates/Hematology%20Highlights/Virtual%20Presentations/Ravandi.aspx.Accessed June 2, 2009.

4. Lindquist K, Danese M, Knopf K, Mikhael J.Mortality and hospitalization in myelodysplastic syndromes (MDS) using the SEER-Medicare linkeddatabase [ASCO Annual Meeting abstract 7091].J Clin Oncol. 2009;27:15s.

5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.Efficacy of azacitidine compared with that of conven-tional care regimens in the treatment of higher-riskmyelodysplastic syndromes: a randomised, open-label,phase III study. Lancet Oncol. 2009;10:223-232.

6. Itzykson R, Fenaux P. Optimal sequencing of treat-ments for patients with myelodysplastic syndromes.Curr Opin Hematol. 2009;16:77-83.

7. Gore SD, Hermes-Desantis ER. Future directions inmyelodysplastic syndrome: newer agents and the role of combination approaches. Cancer Control. 2008;15:40-49.

8. Steensma D, Kantarjian H,Wijermans P. Clinicalexperience with different dosing schedules ofdecitabine in patients with myelodysplastic syndromes(MDS) [ASCO Annual Meeting abstract 7011].J Clin Oncol. 2009;27:15s.

9. Gurion R,Vidal L, Gafter-Gvili A, et al. Myelodys-plastic syndromes/hypomethylating agents [EHAAnnual Meeting abstract 0261]. Haematologica/HematolJ. 2009;94(suppl 20):104.

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

Predicting Outcomes of Allogeneic Stem Cell Transplantation

Younger patients with myelodys-plastic syndrome (MDS) whohave high-risk disease with mul-

tiple cytogenetic abnormalities are themost likely candidates for allogeneic stemcell transplantation (SCT), the onlyknown cure for the disease.1 Researchersare now attempting to predict whichpretransplant patient characteristics maylead to better overall survival andwhether azacitidine induction prior totransplantation affects outcome.

The World Health Organization(WHO) classification, along with thestate of disease at transplantation, are two

of the most powerful predictors for post-transplant survival,2 according to newresearch presented at the 2009 EuropeanHematology Association annual meetingin Berlin, Germany. The WHO classifi-cation of MDS incorporated data on theimportance of unilineage versus multi-lineage dysplasia.Studies have shown thatmultilineage dysplasia is associated with aworse outcome.2-4 Olga Lopez-Villar,MD, Hospital University of Salamanca,Salamanca, Spain, and colleagues re-viewed patient characteristics and out-comes for 190 patients with MDS whoreceived allogeneic SCT at 11 centers in

Spain between 1987 and 2008.2 Themedian age of patients was 49 years.They had a range of WHO classifica-tions, including refractory anemiawith/without ringed sideroblasts (6.9%),refractory cytopenia with multilineagedysplasia (7.6%), refractory anemia withexcess of blasts (RAEB)-1 (15.2%),RAEB-2 (23.4%), 5q-syndrome (1.4%),MDS unclassifiable (2.1%), myelodysplas-tic/myeloproliferative disease (13.1%),secondary acute myeloid leukemia (27%),and other MDS (2.8%). Patients withchronic myelomonocytic leukemia werealso included in the analysis.

5

About half (42%) of the patients weretreated with chemotherapy before trans-plantation. At transplant, 25.7% of thesepatients were in complete remission(CR) and 7.3% had a partial response.The rest of the patients received allogene-ic SCT without previous chemotherapy(53.2%) or underwent allogeneic SCT inprogression without previous chemo-therapy (3.7%). Myeloablative condition-ing was used in 72.3% of patients; 27.7%of patients were significantly older andreceived reduced-intensity conditioning.

At 10-year follow-up, the overall sur-vival rate was 51% and the event-freesurvival rate was 48% (see figure).WHOclassification was predictive for survival,reported Dr. Lopez-Villar. Disease statusat transplant significantly influenced theoutcome only for high-risk patients; bet-ter results were seen for patients in CR attransplant and those who did not receivepretransplant chemotherapy.2

Although patients with MDS receiveno clear benefit from cytotoxic induc-tion chemotherapy after allogeneic SCT,they may benefit from azacitidine therapy prior to transplantation.5

Christopher R. Cogle, MD, of theUniversity of Florida, Gainesville, andcolleagues analyzed posttransplant out-comes in 43 patients with MDS,including 9 patients who received aza-citidine before transplant and 34patients who did not.The patients whoreceived azacitidine were significantlyolder (P<.01), more immunosup-pressed at transplant (P<.05), and lesslikely to receive myeloablative condi-tioning (P<.05).The azacitidine groupalso was marginally more likely to havehigher disease burden and more likelyto have received a graft from an unre-lated donor. These patient characteris-tics reflect the current clinical use ofazacitidine as a bridge to transplant forolder patients who have no readilyavailable, matched, related donors.

Dr. Cogle reported at the AmericanSociety of Clinical Oncology annualmeeting in Orlando, Florida, that after amedian follow-up of 7 months, the

group that received azacitidine beforeallogeneic SCT demonstrated signifi-cantly higher donor chimerism at days30, 60, and 100 (P<.01). There was nodifference in the rates of acute andchronic graft-versus-host disease ormedian overall survival between the twogroups. However, those who receivedazacitidine pretransplant had a trendtoward higher relapses.

Induction with azacitidine results inhigher short-term donor chimerismposttransplant, said Dr. Cogle.This effectis probably due to increased immunosup-pression in an older population. Theincreased rate of relapse in the azacitidinegroup likely reflects the progressive natureof chemotherapy-insensitive disease attransplant. He said these results supportadministration of azacitidine prior totransplant for patients with MDS,although the data need to be confirmedby a randomized, controlled trial.

REFERENCES1.Advani A. Hypomethylating agents in the treatmentof myelodysplastic syndrome. Medscape. CME 2006.http://cme.medscape.com/viewarticle/522651.Accessed July 22, 2009.

2. Lopez-Villar O, Cordoba I, Martino R, et al.Allogenic stem cell transplant in MDS: results of the Spanish Registry [EHA Annual Meeting abstract 0252]. Haematologica/Hematol J. 2009;94(suppl 2):100.

3. Müller-Berndorff H, Haas PS, Kunzmann R, et al.Comparison of five prognostic scoring systems, theFrench-American-British (FAB) and World HealthOrganization (WHO) classifications in patients withmyelodysplastic syndromes: results of a single-centeranalysis. Ann Hematol. 2006;85:502-513. Epub 2006May 20.

4. Malcovati L, Della Porta MG, Pascutto C, et al.Prognostic factors and life expectancy in myelodysplasticsyndromes classified according to WHO criteria: a basisfor clinical decision making. J Clin Oncol. 2005;23:7594-7603. Epub 2005 Sep.

5. Cogle CR, Imanirad I, Scornik J,Wingard JR.Impact of azacytidine induction chemotherapies onpost-transplant outcomes in patients with myelodys-plastic syndromes [ASCO Annual Meeting abstract7032]. J Clin Oncol. 2009;27:15s.

100

80

60

40

20

0

Event-free survival 48%

Overall survival 51%

Days

Pe

rce

nt

0 3 65 7 3 0 109 5 1460 1825 219 0 2555 29 20 3 285 3 650

FIGURE. Overall and event-free survival following allogeneic stem cell transplantation.2

Reprinted with permission from Lopez-Villar O, Cordoba I, Martino R, et al. Allogenic stem cell transplant in MDS: results of the Spanish Registry[EHA Annual Meeting abstract 0252]. Haematologica/Hematol J. 2009;94(suppl 2):100.

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EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

Lenalidomide Treatments in MyelodysplasticSyndrome for Higher-Risk and Young Patients

The advent of lenalidomide, ananalog of thalidomide, has pro-vided a breakthrough therapy

for patients with transfusion-dependentanemia due to low- or intermediate-riskmyelodysplastic syndrome (MDS) associ-ated with a deletion of chromosome 5q,with or without additional cytogeneticabnormalities.The drug reduces transfu-sion requirements and reverses cytologicand cytogenetic abnormalities in patientswho have MDS with the chromosome5q deletion.1 Patients with the 5q dele-tion syndrome, those with an isolated 5qdeletion, and those with lower Inter-national Prognostic Scoring System(IPSS) scores or lower transfusionrequirements at baseline are more likelyto experience a longer duration of trans-fusion independence with lenalidomidetreatments.2

One out of 6 patients with MDS car-ries the chromosome 5q deletion, andabout two-thirds of these patients havelow or intermediate-1 IPSS scores andrelatively favorable prognoses.The otherone-third have intermediate-2 or higherIPSS scores because of an increase inmarrow blasts and/or other chromoso-mal abnormalities.3 Lenalidomide is apotentially interesting treatment in high-er-risk MDS with del 5q because of thesensitivity of del 5q clones to the drug. Inthe pivotal study of lenalidomide inMDS with del 5q, 3 of 8 patients foundto have high or intermediate-2 IPSSscores had significant hematologicimprovement.1

The Groupe Francophone desMyélodysplasies, a French research group,conducted the first clinical trial to assessthe therapeutic efficacy of lenalidomidein higher-risk MDS patients with del 5q.3

The phase II study included 47 patients,median age 69 years, with higher-riskMDS, including 60% with high IPSSscores and 40% with intermediate-2 risk

scores. Chromosome 5q deletion wasisolated in 19% of the patients; 23% ofthe patients had one additional abnor-mality and 58% of the patients had morethan one additional abnormality. Thepatients received 10-mg doses of lena-lidomide once daily for 21 days every 4 weeks and completed a median of 2 cycles.

The overall response rate was 27%according to the International WorkingGroup 2006 criteria or 41% according tothe World Health Organization defini-tion of MDS in which patients who hadrefractory anemia with excess blasts intransformation were excluded. Sevenpatients achieved hematologic completeremission (CR),2 patients achieved mar-row CR, 4 patients had hematologicimprovement-erythroid, and 12 patientsbecame red blood cell transfusion-inde-pendent for a median duration of 6.5months. The median hematologic re-sponse was 6.5 months, and the medianCR duration was 11.5 months.

There was a close correlation between

cytogenetic and hematologic improve-ment, the researchers reported. Six of the9 patients with isolated del 5q achievedCR compared with only 1 of the 11patients with one additional abnormalityand none of the 27 patients with morethan one additional abnormality (seetable). Another significant predictor ofCR was pretreatment platelet counts of more than 100,000/mm3. A little more than one-third of patients with initial platelet counts of more than100,000/mm3 obtained CR comparedwith none of the patients with plateletcounts <100,000/mm3.

In this trial, lenalidomide showed littleefficacy in patients with higher-riskMDS with chromosomal abnormalitiesin addition to del 5q.The researchers aretesting a combination of lenalidomidewith chemotherapeutic drugs or hypo-methylating agents for these patientswith a poor prognosis.3

The immunomodulatory, antiangio-genic, and antiproliferative effects oflenalidomide also make it a potential

TABLE. PROGNOSTIC FACTORS OF COMPLETE REMISSION3

Factor Category n No. of CRs CR (%) P

Cytogenetic

Isolated del 5q 9 6 67 <.001

Single additional abnormality 11 1 9

>1 additional abnormality 27 0 0

Bone marrow blasts (%)

<20% 29 6 21 .16

>20% 18 1 5

Baseline platelet count G/L

>100 20 7 35 <.001

<100 27 0 0

CR=complete remission.Reprinted with permission. This research was originally published in Blood. Adès L, Boehrer S, Prebet T, et al. Efficacy andsafety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study.Blood. 2009;113:3947-3952. ©The American Society of Hematology.

7

therapy for pediatric patients with MDS.4

Stacey L. Berg, MD, Texas Children’sCancer Center, Houston, reported onthe results of a phase I and pharmacoki-netics study of lenalidomide in 46 chil-dren with recurrent or refractory solidtumors and 3 children with MDS at theAmerican Society of Clinical Oncologyannual meeting in Orlando, Florida.

Lenalidomide was administered orallyonce daily for 21 of 28 days in escalatingdoses of 15,25,40,55, and 70 mg/m2 perday for children with solid tumors and ina fixed dose of 5 mg/m2 per day for chil-

dren with MDS. After a median of 1cycle, none of the patients with MDShad a dose-limiting toxicity. The phar-macokinetic parameters were similar tothose seen in adults.4 No objectiveresponses were seen,but Dr.Berg report-ed that lenalidomide enhanced IL-2 andIL-15 concentrations in children withrecurrent or refractory solid tumor andwas well-tolerated.4

REFERENCES1. List A, Dewald G, Bennett J, et al; for theMyelodysplastic Syndrome-003 Study Investigators.Lenalidomide in the myelodysplastic syndrome with

chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.

2. List AF, Dewald GW, Bennett JM, et al. Long-termclinical benefit of lenalidomide (Revlimid) treatment in patients with myelodysplastic syndrome and chro-mosome deletion 5q [ASH Annual Meeting Abstracts].Blood. 2006;108:251.

3.Adès L, Boehrer S, Prebet T, et al. Efficacy and safetyof lenalidomide in intermediate-2 or high-riskmyelodysplastic syndromes with 5q deletion: results of aphase 2 study. Blood. 2009;113:3947-3952.

4. Berg SL, Russell H, Cairo M, et al. Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solidtumors or myelodysplastic syndrome (MDS): aChildren’s Oncology Group Phase I Consortium study [ASCO Annual Meeting abstract 100230].J Clin Oncol. 2009;27:15s.

An understanding of epigeneticchanges in myelodysplastic syndrome (MDS) led to the

development of the widely usedhypomethylating agents azacitidine anddecitabine.The importance of epigenet-ic therapy in the treatment of MDS moti-vated researchers to look for alternativetherapeutic strategies targeting othermechanisms that may contribute to aber-rant gene transcription and dysregulatedcell growth.1

Among the newer therapies intro-duced for refractory, relapsed, and resis-tant disease are histone deacetylase(HDAC) inhibitors. HDAC inhibitors

block deacetylation function, causingcell cycle arrest, differentiation, and/orapoptosis of many tumors.2 Histonedeacetylases are inhibited by variouscompounds, including phenylbutyrateand valproic acid (short-chain fattyacids), SNDX-275 (formerly MS-275)and MGCD0103 (benzamides), romi-depsin (a cyclic peptide), and vorinostatand trichostatin A (hydroxamic acids).1

In some early-phase clinical trials,HDAC inhibitors have exhibited potentantitumor activity in myeloid malignancy,suggesting their usefulness as novel cancertherapeutic agents. Preclinical data showmarked synergy between DNA methyl-

transferase inhibitors and HDAC in-hibitors, which indicates that HDACinhibitors may be more effective whenused in combination with other drugs forthe treatment of MDS. At least a dozenongoing phase I and II trials in MDS areinvestigating combination therapy withDNA methyltransferase inhibitors andHDAC inhibitors.1

As a class, HDAC inhibitors are limit-ed by toxicity due to myelosuppression,fatigue, and gastrointestinal symptoms.Patients with MDS commonly developthrombocytopenia, which is currentlylimited to treatment with platelet trans-fusions. An international study reportedat the American Society of ClinicalOncology annual meeting in Orlando,Florida, investigated the subcutaneous orintravenous administration of romi-plostim in thrombocytopenic patientswith MDS.3 Romiplostim is an Fc-pep-tide fusion protein (peptibody) that stim-ulates platelet production by the samemechanism as thrombopoietin, saidMikkael Sekeres, MD, of the ClevelandClinic, Cleveland, Ohio.

The phase II, multicenter, single-arm,open-label study included 28 patients,mean age 71 years, who had Internat-ional Prognostic Scoring System (IPSS)

HDAC Inhibitors and MyelodysplasticSyndrome: Ongoing Epigenetic Research

TABLE. EFFICACY IN PATIENTS COMPLETING ≥8 WEEKS OF ROMIPLOSTIM3

Weekly SC Biweekly SC Biweekly IV Total

Evaluable subjects 8 11 4 23

Platelet responsea 5 8 2 15

Platelet transfusion 4 3 2 9

IV = intravenous; SC = subcutaneous.aPlatelet response per IWG 2006: either complete response (peak platelet count ≥100 x 109L) or major response (increasefrom baseline in platelet count of ≥30 x 109L) in the absence of platelet transfusions during the first 8 weeks of treatment.Reprinted with permission from Sekeres M, Kantarjian H, Fenaux P, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with myelodysplastic syndrome (MDS) [ASCO Annual Meeting abstract 7009].J Clin Oncol. 2009;27:15s.

low or intermediate-1 risk MDS and amean baseline platelet count of up to50x109/L. Nineteen patients had re-ceived platelet transfusions in the pastyear. Patients received 750 µg of romi-plostim subcutaneously either weekly orbiweekly or intravenously biweekly.Mean duration of exposure to romi-plostim was 12 weeks.

Of the 23 patients who completed 8 weeks of treatment, 15 (65%) achieved aplatelet response; 14 patients (61%) did notrequire a platelet transfusion during thisperiod (see table).The incidence of adverseevents (AEs) was similar in all groups, withfatigue and headache seen as the most com-mon AEs.Five patients experienced seriousAEs.The investigators concluded that romi-plostim appears to be well-tolerated andeffective in raising platelet counts and avoid-ing platelet transfusions in low and interme-diate-1 risk patients with MDS.

REFERENCES1. Griffiths EA, Gore SD. DNA methyltransferase and his-tone deacetylase inhibitors in the treatment of myelodys-plastic syndromes. Semin Hematol. 2008;45:23-30.2. Bhalla K, List A. Histone deacetylase inhibitors inmyelodysplastic syndrome. Best Pract Res Clin Haematol.2004;17:595-611.3. Sekeres M, Kantarjian H, Fenaux P, et al. Subcutaneousor intravenous administration of romiplostim in throm-bocytopenic patients with myelodysplastic syndrome(MDS) [ASCO Annual Meeting abstract 7009]. J ClinOncol. 2009;27:15s.

8

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

CYTOGENETIC EVOLUTION OF MYELODYSPLASTIC SYNDROME

Cytogenetic defects significantly influence overall survival of patients withMDS, as well as the risk for their disease to evolve into acute myelogenousleukemia. During the course of the disease, patients may develop otherchromosomal abnormalities. Italian researchers studied the prognostic rele-vance of these secondary defects in 153 patients with de novo MDS,1

reported Paolo Bernasconi, MD, of the Foundation IRCCS Polyclinic, SanMatteo, Pavia, Italy, at the European Hematology Association annual meet-ing in Berlin, Germany.

The patients, median age 60.5 years, were classified by French-American-British (FAB) and World Health Organization (WHO) criteria and IPSS score.They were followed for a median of 45.2 months. Disease progressionoccurred in 65 patients (42.4%), and the median progression-free intervalwas 65.2 months, Dr. Bernasconi reported.

On entrance to the study, 94 patients (61.4%) had primary chromosomaldefects. Cytogenetic evolution occurred in 47 patients (30.7%) according toFAB classification and in 41 patients (28.9%) according to WHO classification.

Cytogenetic evolution had a significant influence on overall survival andthe progression-free interval, he noted, and its impact remained signifi-cant even when other variables, including FAB/WHO classification, IPSSscore, primary defects, and IPSS cytogenetic categories, were considered.In early MDS, the presence of a secondary defect significantly affected thecourse of the disease for those diagnosed according to the FAB classifica-tion, but was not as relevant for those diagnosed according to the WHOclassification.

1. Bernasconi P, Klersy C, Boni M, et al. Cytogenetic evolution in MDS: Is it predictive of overall survival(OS) and the risk of MDS/AML evolution [EHA Annual Meeting abstract 0262] Haematologica/Hematol J.2009;94(suppl 2):104.

Targeted Therapies Treat Relapsed/Refractory Multiple Myeloma

Multiple myeloma is the secondmost common hematologiccancer.1 Although hemato-

poietic stem cell transplantation has im-proved the response rate and duration ofoverall survival, the disease remainsincurable. Research aimed at the molec-ular basis of multiple myeloma has led toa number of new treatment strategies.Clinical-trial results show remarkableefficacy with thalidomide, lenalidomide,or bortezomib as first-line therapy.2

Traditional chemotherapy for initialtreatment of patients with multiplemyeloma who are eligible for stem celltransplantation has been replaced withthalidomide, lenalidomide, or borte-zomib in combination with dexametha-sone.2 In addition, these novel drugs canbe incorporated into regimens used totreat transplant-ineligible patients orthose with relapsing disease. Mountingevidence points to the need for reevalu-ation of the role of stem cell transplanta-

tion in multiple myeloma.2

Development of these drugs has trans-formed the therapeutic management ofmultiple myeloma and catalyzed arenewed interest in other classes ofagents. New agents such as second-gen-eration proteasome inhibitors, immuno-modulators, histone deacetylase inhib-itors, heat shock protein 90 inhibitors,and alkylphospholipid Akt inhibitor per-ifosine, have shown promising preclinicalresults, encouraging safety profiles, and

9

early evidence of antimyeloma activity asmonotherapy or in combination withother conventional or novel treatments.3

The combination of bortezomib andpegylated liposomal doxorubicin is animportant addition to the therapeuticarmamentarium for the management ofrelapsed/refractory multiple myeloma.Bortezomib was the first proteasomeinhibitor to receive regulatory approvalfor this indication. Modulation of pro-teasome function, however, is also arational strategy for chemosensitization.A variety of agents, such as anthracy-clines, have shown synergistic activitywith bortezomib preclinically.4 This syn-ergism led to the evaluation of a regi-men of bortezomib with pegylated lipo-somal doxorubicin, which has induced apredictable and manageable toxicityprofile and has shown encouragingantimyeloma activity.

In an international, randomized, phase IIItrial, pegylated liposomal doxorubicinplus bortezomib compared to borte-zomib monotherapy demonstrated alonger time to progression, duration ofresponse, progression-free survival, andoverall survival.4,5 Benefits were also seenin almost all clinically relevant patientsubgroups, including those considered tohave high-risk disease.4

The pegylated liposomal doxorubicinplus bortezomib regimen has become oneof the standards of care for patients withrelapsed/refractory myeloma.Addition ofother active antimyeloma agents to thiscombination is being studied as well.

Although novel agents have demon-strated enhanced efficacy when com-bined with other antimyeloma agents,especially dexamethasone, the steroiddoses employed in multiple myelomaregimens were often poorly tolerated.Asher Chanan-Khan, MD, of theUniversity of Buffalo,Buffalo,New York,and colleagues investigated the efficacyof a steroid-free combination, includingbortezomib, pegylated liposomal doxo-rubicin, and thalidomide (VDT regi-men) in a phase II clinical trial of 23patients with relapsed/refractory myelo-

ma or other plasma cell cancers.6 Patientshad a median of five prior therapies, andtwo-thirds of them were refractory totheir last regimen.

The overall response rate was 55.5%,median progression-free survival was10.9 months, and median overall sur-vival was 15.7 months.The most com-mon adverse effects were fatigue andsensory neuropathy.

Dr.Chanan-Khan noted that this three-drug combination is an effective steroid-free salvage regimen with the ability toinduce durable remission, even in patientswith refractory multiple myeloma.

REFERENCES1. Dimopoulos M, Spencer A,Attal M, et al; for theMultiple Myeloma (010) Study Investigators. Lenali-domide plus dexamethasone for relapsed or refractory

multiple myeloma. N Engl J Med. 2007;357:2123-2132.

2. Saad AA, Sharma M, Higa GM.Treatment of multiplemyeloma in the targeted therapy era. Ann Pharmacother.2009;43:329-338. Epub 2009 Feb 3.

3.Mitsiades CS,Hideshima T,Chauhan D, et al. Emergingtreatments for multiple myeloma: beyond immunomod-ulatory drugs and bortezomib.Semin Hematol. 2009;46:166-175.

4. Shah JJ, Orlowski RZ,Thomas SK. Role of combina-tion bortezomib and pegylated liposomal doxorubicin inthe management of relapsed and/or refractory multiplemyeloma. Ther Clin Risk Manag. 2009;5:151-159. Epub2009 Mar 26.

5. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomizedphase III study of pegylated liposomal doxorubicin plusbortezomib compared with bortezomib alone in relapsedor refractory multiple myeloma: combination therapyimproves time to progression. J Clin Oncol. 2007;25:3892-3901.

6. Chanan-Khan A, Miller KC, Musial L, et al.Bortezomib in combination with pegylated liposomaldoxorubicin and thalidomide is an effective steroid inde-pendent salvage regimen for patients with relapsed orrefractory multiple myeloma: results of a phase II clinical trial. Leuk Lymphoma. 2009;50:1096-1101.

LENALIDOMIDE MONOTHERAPY SAFE, EFFECTIVEFOR RELAPSED/REFRACTORY MULTIPLE MYELOMA

Heavily pretreated, relapsed/refractory multiple myeloma patients can achieve a2-year median overall survival with lenalidomide monotherapy.1

Lenalidomide plus dexamethasone is effective for the treatment ofrelapsed/refractory multiple myeloma, but dexamethasone can lead to dose-limiting toxicities,1 noted Paul Richardson, MD, of the Dana-Farber CancerInstitute, Boston, Massachusetts. Richardson and colleagues conducted astudy of 222 patients with relapsed and refractory multiple myeloma whoreceived lenalidomide 30 mg/day once daily on days 1-21 every 28 days untildisease progression or intolerance. Two-thirds of the patients had receivedat least 3 previous treatment regimens.

Partial response or better was reported in 26% of patients, and minimalresponse was reported in 18%. Response rate was similar for patients whohad received 2 or fewer prior treatments (45%) and those who had received3 or more prior treatments (44%). Median time to progression was 5.2months, median progression-free survival was 4.9 months, and median over-all survival was 23.2 months.

The most common grade 3 or 4 adverse events were neutropenia (60%),thrombocytopenia (39%), and anemia (20%), which proved manageablewith dose reduction and supportive care. Grade 3 or 4 febrile neutropeniawas noted in 4% of patients.

Dr. Richardson noted that acceptable toxicities and activity support the use ofsingle-agent lenalidomide in patients with relapsed/refractory multiple myeloma,as well as the use of lenalidomide in steroid-sparing combinations. This studyshows that patients who are frail or who have very indolent relapse can be sal-vaged with just a single agent, with minimal adverse events.

1. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patientswith relapsed and refractory multiple myeloma. Blood. 2009;114:772-778. Epub May 26.

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EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

New Hematopoietic Stem Cell TransplantationStrategies in Multiple Myeloma

Akey therapeutic advance in thetreatment of multiple myelomawas the introduction of high-

dose melphalan therapy supported byautologous hematopoietic stem celltransplantation (SCT). Studies haveshown a significant increase in the rateof complete remission or very goodpartial remission with autologous SCTcompared with conventional chemo-therapy, and these results have led to sig-nificantly prolonged progression-free sur-vival and overall survival.1 Multiplemyeloma survival beyond 10 years hasbecome more common. Recent studiesshow superior 10-year event-free survivalestimates of 50% and overall survival esti-mates of 35%, which demonstrate that acure requires long-term follow-up.2

Despite a better outcome with high-dose therapy than with conventional-dose treatment, almost all patients withmultiple myeloma ultimately relapse.Several newer autologous SCT strate-gies, including double (or tandem)autologous SCT and nonmyeloablativeregimens, have been proposed to furtherincrease complete remission rates. TheInternational Myeloma Foundation isnow addressing issues regarding stem cellmobilization and autologous SCT inmyeloma in the context of new thera-pies.3 A tandem transplant procedureinvolves the administration of a secondcycle of high-dose melphalan and a sec-ond stem cell infusion within a fewmonths after the first procedure.4

However, appropriate timing for the useof tandem transplantation or nonmye-loablative regimens remains a question.5

Leyla Shune, MD, of the Universityof Minnesota, Minneapolis, Minnesota,and colleagues examined the outcomesin 51 patients with multiple myelomawho received allogeneic SCT either as sal-vage therapy (after failing a prior autolo-

gous SCT; 15 patients) or as plannedtherapy (36 patients). Patients in the sal-vage-therapy group were significantlyolder (median age 58 years) than those inthe planned-therapy group (median age49 years) and had a longer interval fromdiagnosis to transplant (median 47months versus 10 months), Dr. Shunereported at the American Society ofClinical Oncology (ASCO) annualmeeting in Orlando, Florida.

Of the 51 patients, 44 received anallogeneic SCT from an HLA-identicalsibling, 5 received umbilical cord blood (4 in the salvage-therapy group; 1 in theplanned-therapy group), and 2 receivedunrelated donor SCT (1 in eachgroup). Of the 36 patients in theplanned-therapy group, 13 underwent atandem transplant, ie, a planned autolo-gous SCT followed by nonmyeloabla-tive SCT from a sibling donor. Allpatients in the salvage-therapy groupand half of those in the planned-thera-py group received nonmyeloablativeallogeneic SCT. Patients in the salvage-therapy group had been more heavilypretreated.

A complete response was observed in34% of patients in the salvage-therapygroup and in 47% of patients in the

planned-therapy group. After a medianfollow-up of 24 months and 41months, relapse rates were similar.Two-year relapse rates were 28% in the sal-vage-therapy group compared with37% in the planned-therapy group(P=.7).The salvage-therapy group hadsignificantly lower rates of 2-year dis-ease-free survival than the planned-therapy group (16% vs 32%, P=.05).

Dr. Shune noted that patients whoreceived planned allogeneic SCT hadgood overall survival and low trans-plant-related mortality (see table).Although there was a lower relapse ratein the heavily pretreated salvage thera-py patients, a significantly higher rate oftransplant-related mortality at 1 year(47% in the salvage-therapy group vs22% in the planned-therapy group,P=.02) led to a lower rate of 2-yearsurvival (16% versus 57%, P=.003).

For patients with advanced multiplemyeloma, their baseline immune statuscan contribute to inconsistencies indonor engraftment and may also impedea maximal graft-versus-myeloma effectafter reduced-intensity allogeneic SCT.6

No specific salvage regimen has beendesigned for patients with multiple myelo-ma who may be candidates for reduced-

TABLE. TREATMENT OUTCOMES5

Outcomes

OutcomesSalvageTherapy

PlannedTherapy P-value

TRM at 1 year 47% 22% .02

Relapse/progression at 2 years 28% 37% .7

Survival at 2 years 16% 57% .003

DFS at 2 years 16% 32% .05

DFS=disease-free survival; TRM=treatment-related mortality.Reprinted with permission from Shune L, Weisdorf DJ, McClune B, et al. Allogeneic hematopoietic cell transplant for multiple myeloma: comparative results of planned therapy versus salvage therapy [ASCO Annual Meeting abstract 7035].J Clin Oncol. 2009;27:15s.

11

intensity allogeneic SCT. Saad Jamshed,MD, of Georgetown University, Wash-ington, DC, and colleagues conducted astudy to determine the efficacy and feasi-bility of an infusional conditioning regi-men for salvage and immune depletionbefore allogeneic SCT. Their hypothesiswas that a novel chemotherapeutic regi-men given prior to SCT in patients withmultiple myeloma might facilitate not onlydisease control but donor engraftment as well.

The infusional chemotherapy regimenconsisted of etoposide, vincristine, andadriamycin, with prednisone, cyclophos-phamide, and fludarabine. This six-drugregimen was administered in 21-day cyclesprior to reduced-intensity allogeneic SCTin a phase II fashion in 3 sequentialNational Cancer Institute clinical trials,Dr.Jamshed reported at the ASCO meeting.Atotal of 22 patients, median age 53 years,received chemotherapy targeting a CD4+T-cell count of less than 200 cells/µL.Patients achieving this CD4+T-cellcount after 1 or more cycles proceededto reduced-intensity SCT. Patients pro-ceeded to reduced-intensity SCT after amaximum of 5 cycles regardless of theCD4+ count or if their disease pro-gressed during chemotherapy.

The median time from initial therapyto transplant was 12 months, and themedian number of prior therapies was

2. Slightly less than two-thirds of thepatients had chemotherapy-sensitivedisease, and slightly more than two-thirds had received a novel agent.

After a median of 3 cycles of therapy,the overall response rate was 22% in 21evaluable patients.Three patients (13%)achieved a complete response/near-complete response, and 15 (68%) hadstable disease. Only 1 patient progressedon therapy. The median lymphocytecount decreased from 1423/µL to519/µL, and the CD4+ count de-creased from 320/µL to 115/µL.

Dr. Jamshed noted that patients tolerat-ed the therapy well with manageable tox-icities. The most common toxicity wasgrade IV neutropenia,which was observedin 77% of the administered cycles.Therewere only 6 episodes of neutropenic fever.Grade III infection was observed in 38% ofthe administered cycles.

The transplantation results show that 20of the 22 patients underwent reduced-intensity SCT from an HLA-matchedsibling. Of the 20 transplantation patients,14 (70%) achieved at least a very goodpartial response and 8 (40%) achieved a complete response/near-complete re-sponse. Median overall survival of patientsafter transplantation was 46.1 months.Engraftment results were evaluable for 19patients. All of the patients had medianDay 100 chimerism.

Acute graft-versus-host disease (GvHD)grade II-IV was observed in 9 of 19patients (47%), and chronic GvHD gradeIII-IV was observed in 9 of 17 patients(52%).Treatment-related mortality at 100days was 5% and at 60 months was 30%.

Dr. Jamshed reported that thischemotherapeutic combination is anactive regimen that allows for consis-tent engraftment of allogeneic progeni-tor cells from donors in patients withmultiple myeloma.

REFERENCES1. Harousseau J-L, Moreau P.Autologous hematopoieticstem-cell transplantation for multiple myeloma. N EnglJ Med. 2009;360:2645-2654.2. Barlogie B,Attal M, Crowley J, Harousseau J. Long-term follow-up of autotransplant (AT)-supported high-dose melphalan (hdm) for multiple myeloma (MM):update of Intergroup Francophone du Myelome(IFM), Southwest Oncology Group (SWOG), andArkansas (ARK) Total Therapy (TT) trials [ASCOAnnual Meeting abstract 8519]. J Clin Oncol.2009;27:15s.3. Giralt S, Stadtmauer EA, Harousseau JL, et al.International myeloma working group (IMWG) con-sensus statement and guidelines regarding the currentstatus of stem cell collection and high-dose therapy formultiple myeloma and the role of plerixafor (AMD3100). Leukemia. 2009 Jun 25. [Epub ahead of print].4. Barlogie B, Jagannath S, Desikan KR, et al.Totaltherapy with tandem transplants for newly diagnosedmultiple myeloma. Blood. 1999;93:55-65.5. Shune L,Weisdorf DJ, McClune B, et al.Allogeneichematopoietic cell transplant for multiple myeloma:comparative results of planned therapy versus salvagetherapy [ASCO Annual Meeting abstract 7035]. J ClinOncol. 2009;27:15s.6. Jamshed S, Fowler D, Neelapu S, et al. EPOCH-F: asalvage regimen for multiple myeloma prior to reducedintensity allogenic hematopoietic stem cell transplanta-tion [ASCO Annual Meeting abstract 8592]. J ClinOncol. 2009;27:15s.

HDAC Inhibitors and Emerging Therapies for Multiple Myeloma

With a greater understandingof the biology of multiplemyeloma, researchers have

begun to identify novel treatment strate-gies.These include a combination of thepotent histone deacetylase (HDAC)inhibitor vorinostat with two standardtherapies for multiple myeloma, lenalido-mide and dexamethasone, or an im-munoproteasome-specific inhibitor thatmay provide antimyeloma activity with

greater specificity and less toxicity thancurrent inhibitors.

Treatment of patients with relapsed/refractory multiple myeloma remainsextremely challenging and represents aspecific unmet medical need.Vorinostat,an oral inhibitor of Class I and II histonedeacetylase enzymes, enhances the anti-myeloma activity of other proapoptoticagents and provides potential synergisticactivity in combination with lenalido-

mide and dexamethasone.1,2

An early phase I study had found thatoral vorinostat was generally well-toler-ated in patients with advanced multiplemyeloma, with modest activity in re-lapsed/refractory disease.This warrantedstudies using vorinostat in combinationwith other antimyeloma agents.3,4

David S. Siegel, MD, PhD, of Hack-ensack University Medical Center,Hackensack, New Jersey, and colleagues

12

conducted a phase I, multicenter, open-label, nonrandomized, dose-escalationstudy to evaluate vorinostat pluslenalidomide and dexamethasone inpatients with relapsed/refractory multi-ple myeloma.1 Dr. Siegel reported theresults of this trial at the EuropeanHematology Association annual meetingin Berlin, Germany. Of 18 patientsassessed to date for safety, 16 (89%) expe-rienced ≥1 adverse events (AEs) and 13patients (72%) experienced a total of 32drug-related AEs, which were mostlymild or moderate in severity. The mostfrequently reported drug-related AEswere diarrhea in 8 patients (44%), fatiguein 6 patients (33%), neutropenia in 6patients (33%), and thrombocytopenia in5 patients (28%). Serious AEs werereported in 3 patients, with only 1 (diar-rhea) considered drug related;no patientsdiscontinued because of AEs.

The maximum tolerated dose has notyet been established. Dose-limiting eval-uation is ongoing at dose level 5 (see table), which consists of vorinostat400 mg on days 1-7 and 15-21 in com-bination with lenalidomide 25 mg ondays 1-21 and dexamethasone 40 mg ondays 1,8,15,and 22 in each 28-day cycle.No dose-limiting toxicity was observed.Dose escalation continues to determine

the maximal tolerated dose.Of 15 patients evaluable for efficacy, 11

(73%) experienced a clinical benefit withthe combination therapy. Completeresponse was achieved in 1 patient, partialresponse in 4 patients, minimal responsein 1 patient, stable disease in 5 patients,and progressive disease in 4 patients.Theoverall response rate was 40%. Twopatients who had received prior lenalido-mide therapy had a partial response, and 3had stable disease. Twelve patients re-mained on treatment, and 6 patients dis-continued due to disease progression.

Dr. Siegel said these preliminary resultssuggest the combination of vorinostatwith lenalidomide and dexamethasonemay represent an effective and convenientoral combination therapy that is active andgenerally well-tolerated in the treatmentof relapsed/refractory multiple myeloma.1,2

The combination of vorinostat plusthe proteasome inhibitor bortezomib forpatients with multiple myeloma has alsobeen found to be well-tolerated andactive in two phase I trials, even amongsome patients with prior exposure tobortezomib.5

The proteasome has emerged as animportant target for cancer therapy withthe approval of bortezomib, the first pro-teasome inhibitor approved for relapsed/

refractory multiple myeloma. However,many patients with multiple myeloma donot respond to bortezomib, and othersdevelop resistance. Also, nonspecific pro-teasome inhibitors such as bortezomibinduce peripheral neuropathy and othertoxicities that may prevent administrationof full doses.6 The immunoproteasome is avariant of the proteasome and is foundpredominantly in hematopoietic cells. Itdiffers from the constitutive proteasomefound in most other cells and is beinginvestigated as a target for specific inhibi-tion in multiple myeloma.

Deborah J. Kuhn, MD, of the Universityof Texas MD Anderson Cancer Center,Houston,Texas, and colleagues conducted astudy in which they identified IPSI-001 as aspecific inhibitor of immunoproteasome.6

IPSI-001 induced accumulation of ubiqui-tin-protein conjugates, proapoptotic pro-teins, and activated caspase-mediated apo-ptosis. It potently inhibited proliferation inmyeloma patient samples and other he-matologic malignancies and was able to overcome conventional and novel drug resistance, including resistance to borte-zomib. Dr. Kuhn noted that these findingsprovide a rationale for the translation of thisemerging therapy into clinical testing.

REFERENCES1. Siegel D,Weber D, Mitsiades C, et al. Combinedvorinostat, lenalidomide and dexamethasone therapy inpatients with relapsed or refractory multiple myeloma: aphase I study [EHA Annual Meeting abstract 0387].Haematologica/Hematol J. 2009;94(suppl 2):155.2. Siegel D,Weber DM, Mitsiades CS, et al.Vorinostat incombination with lenalidomide and dexamethasone inpatients with relapsed/refractory multiple myeloma: aphase I study. Poster presented at: 45th American Societyof Clinical Oncology Annual Meeting; May 29-June 2,2009; Orlando, Florida.3. Richardson PG, Mitsiades CS, Colson K, et al. Finalresults of a phase I trial of oral vorinostat (suberoylanilidehydroxamic acid, SAHA) in patients with advanced multiple myeloma [ASH Annual Meeting Abstracts].2007;110:1179.4. Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid,SAHA) in patients with advanced multiple myeloma.Leuk Lymphoma. 2008;49:502-507.5.Weber D, Badros AZ, Jagannath S, et al.Vorinostat plusbortezomib for the treatment of relapsed/refractory multiple myeloma: early clinical experience [ASH Annual Meeting Abstracts]. Blood. 2008;112:871.6. Kuhn DJ, Hunsucker SA, Chen Q, et al.Targeted inhibition of the immunoproteasome is a potent strategyagainst models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood. 2009;113:4667-4676.

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

TABLE. ESCALATING DOSING SCHEMES1

Dosing Regimens

Dose Level

Vorinostat Dose (mg qd)7 days on, 7 days off

(Days 1-7 and Days 15-21)per cycle*

Lenalidomide Dose (mg qd) x 21 days

(Day 1 through Day 21)per cycle*†

Dexamethasone Dose(mg qd)

(Days 1, 8, 15, and 22per cycle*)

1 300 10 40

2 400 10 40

3 400 15 40

4 400 20 40

5 400 25 40

*Each cycle was 28 days.†Aspirin 81 mg/day was given for prophylactic anticoagulation.

Reprinted with permission from Siegel D, Weber D, Mitsiades C, et al. Combined vorinostat, lenalidomide and dexamethasonetherapy in patients with relapsed or refractory multiple myeloma: a phase I study [EHA Annual Meeting abstract 0387].Haematologica//Hematol J. 2009;94(suppl 2):155.

Targeted Therapy for Acute Myeloid LeukemiaWith Farnesyltransferase Inhibitor Tipifarnib

Acute myeloid leukemia (AML) ismainly a disease of the elderly,with a median age of 67 years at

diagnosis among all Americans.1 In gen-eral, patients with AML who are >60years of age and receive conventionaltherapy have a poor outcome, with lessthan half of these patients with good per-formance status achieving a completeresponse.The median survival of patientswith AML who are aged >60 yearsranges from 7 to 14 months.2 Inferioroutcomes often can be attributed to ahigher frequency of complex cytogenet-ic abnormalities, which are identified inmore than half of all adult patients withAML,3 and an inability to tolerateaggressive chemotherapy.

The aim of therapy in elderly patientswith AML is remission,even if the remis-sion is short-lived.4 Standard intensivetreatment for patients with AML <80years of age can reduce the chances ofearly death and improve quality of lifelonger than palliation alone.4

The integration of cytogenetic aber-rations and molecular mutations intotreatment decisions can help clinicianscategorize most patients with AML intoprognostically relevant subgroups. Thisinformation is the basis for the develop-ment of treatment strategies to targetgenetic mutations or epigenetic path-ways. As researchers have learned moreabout the development of leukemia, theyhave identified new targets for therapy,including FLT3-kinase signaling, theKIT receptor kinase, farnesyltransferaseinhibitors,hypermethylation, and histonedeacetylases.3 The goal of targeted thera-py is to maximize the treatment ofleukemia with fewer adverse effects.

A number of trials have been under-taken with farnesyltransferase inhibitors.Monotherapy with the farnesyltrans-ferase inhibitor tipifarnib exhibits mod-est activity against AML.5 Jeffrey E.

Lancet, MD, of H. Lee Moffitt CancerCenter and Research Institute, Univer-sity of South Florida, Tampa, and col-leagues conducted a multicenter phase IIstudy of tipifarnib in 158 patients, medi-an age 74 years, with previously untreat-ed, “poor-risk” AML.6 Poor risk wasdefined as any of the following: ≥65 yearsof age, adverse cytogenetic profile (eg,–5/5q, –7/7q, +8, abn 11q, complex ≥3unrelated abnormalities), AML arisingfrom antecedent hematologic disorder,and therapy-related AML. Completeremission was achieved in 22 patients(14%).Another 15 patients achieved par-tial remission or hematologic improve-ment for an overall response rate of 23%.The duration of complete remission wasa median of 7.3 months. Completeresponders survived for a median of 18months.

A multivariate analysis found a nega-tive correlation with survival for adversekaryotype, age ≥75 years, and poor per-formance status. Early death was rare inthe absence of progressive disease, anddrug-related nonhematologic seriousadverse events were observed in about

half of the patients.In addition to its clinical activity as

monotherapy, tipifarnib has shown addi-tive or synergistic in vitro effects whencombined with several antileukemiadrugs.5 Preclinical studies showed thattipifarnib acts synergistically with thetopoisomerase II poison etoposide. Thisfinding led to a multicenter phase I trialof tipifarnib plus etoposide in 84 elderlypatients with AML, median age 77, whowere not candidates for conventional ther-apy, which had as principal investigatorJudith E. Karp, MD, of Johns HopkinsSidney Kimmel Cancer Center, Balti-more, Maryland.

The patients received 224 cycles oforal tipifarnib 300-600 mg twice dailyfor 14 or 21 days plus oral etoposide100-200 mg daily on days 1-3 and 8-10.Dr. Karp noted that the 14-day regimenof tipifarnib was better tolerated. Dose-limiting toxicities of grade 4 mucositis,grade 3 hyperbilirubinemia, and multior-gan failure occurred with the 21-dayregimen of tipifarnib.

In the group receiving 14-day tipi-farnib, complete remissions were

13

TABLE. COMPARISON OF 14-DAY VERSUS 21-DAY TIPIFARNIB ADMINISTRATION5

14 days (A) 21 days (B) P

Toxicity, no. (%) of patients

Grade 3 mucositis 2/54 (4) 4/30 (13) .18

Induction death 3/54 (6) 6/30 (20) .06

Efficacy, day to begin cycle 2, median(range)

30 (29-43) 35 (29-46)

Complete remission, no. (%) of patients 16/54 (30) 5/30 (17) .29

Reprinted with permission. This research was originally published in Blood. Karp JE, Flatten K, Feldman EJ, et al. Active oralregimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyl-transferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. Blood. 2009;113:4841-4852. ©The AmericanSociety of Hematology.

achieved in 16 of 54 patients (30%) com-pared to 5 of 30 patients (17%) in thegroup receiving 21-day tipifarnib (seetable). Complete remissions occurred in50% of two 14-day tipifarnib cohorts,including patients who received tipi-farnib 600 mg and etoposide 100 mg andthose who received tipifarnib 400 mgand etoposide 200 mg.These two dosageschedules will be tested in a randomizedphase II trial. In addition, the tipifarnibplus etoposide combination inducedcomplete remissions in 9 of 43 patients(21%) with adverse cytogenetics.

Dr. Karp noted that tipifarnib plusetoposide is a promising orally bioavail-

able regimen that yielded encouragingclinical results and warrants further evalu-ation in elderly patients with AML whoare not candidates for conventional induc-tion chemotherapy owing to advancedage, poor-risk biologic disease features,and/or the presence of significant non-hematologic comorbidities. Future studieswill need to compare these two-drugcombinations, as well as single-agent oraletoposide, to low-dose cytarabine and oralclofarabine, which also show activity inelderly patients with AML.

REFERENCES1. Surveillance, Epidemiology and End Results. SEER StatFact Sheet-Acute Myeloid Leukemia. http://seer.cancer.

gov./statfacts/html/amyl.html.Accessed August 9, 2009.2.Abou-Jawde RM, Sobecks R, Pohlman B, et al.Therole of post-remission chemotherapy for older patientswith acute myelogenous leukemia. Leuk Lymphoma.2006;47: 689-695.3. Haferlach T. Molecular genetic pathways as therapeutictargets in acute myeloid leukemia. Hematology Am SocHematol Educ Program. 2008:400-411.4. Juliusson G,Antunovic P, Derolf A, et al.Age and acutemyeloid leukemia: real world data on decision to treatand outcomes from the Swedish Acute LeukemiaRegistry. Blood. 2009;113:4179-4187.5. Karp JE, Flatten K, Feldman EJ, et al.Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777,Zarnestra) combined with etoposide. Blood. 2009;113:4841-4852.6. Lancet JE, Gojo I, Gotlib J, et al.A phase 2 study of thefarnesyltransferase inhibitor tipifarnib in poor-risk and el-derly patients with previously untreated acute myeloge-nous leukemia. Blood. 2007;109:1387-1394.

14

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

Two new targeted-therapy regi-mens,one a novel schedule of themethylating agent decitabine and

the other an FLT3-kinase inhibitor com-bined with standard chemotherapy, appearto be highly active in patients with acutemyeloid leukemia (AML).

Decitabine, which was described else-where in this supplement, is a pyrimi-dine analog that leads to hypomethyla-tion, which, in turn, promotes tumorsuppressor genes and differentiation inAML. William Blum, MD, Ohio StateUniversity, Columbus, and colleagueshad previously established an optimaldose of 20 mg/m2/day of decitabine forthe treatment of AML, with promisingclinical activity seen in poor-risk olderpatients.1 In the current phase II study, thisdose of decitabine was given to 33 previ-ously untreated patients with AML aged≥60 years, median age 74 years, who werenot candidates for intensive chemotherapyor who had refused it.2

Induction therapy with intravenousdecitabine 20 mg/m2/day was adminis-tered on days 1-10 of 4-week cycles. IfAML persisted, individuals received arepeat of the 10-day course.Patients who

responded were given maintenance ther-apy with 3-5-day courses, depending onthe degree and duration of neutropenia.

Of the 33 patients, 15 had either sec-ondary AML or treatment-related AML.Cytogenetic texting showed that 13 ofthese patients had complex karyotype,defined as ≥3 abnormalities, 13 had nor-mal karyotype, and 1 had t(8;21) chro-mosomal translocation. Nearly all of thepatients (31 of 33) had at least two poor-risk factors, including age ≥70 years, aprior hematologic disorder, unfavorablekaryotype, or ECOG 2 performancestatus.

As shown at the American Society ofClinical Oncology annual meeting inOrlando,Florida, 14 of 33 patients (42%)achieved complete remission (CR) and19 of 33 patients (58%) achieved eitherCR or complete remission with insuffi-cient hematologic recovery (CRi). CRwas observed in all subsets of disease andcytogenetic risk groups, and the durationof CR to the meeting date ranged from2 to >14 months. For 6 patients whorelapsed after CR, the median time frominitial response to relapse was 6.5months. The median follow-up is 8

months for the 19 surviving patients.Median overall survival has not beenreached.2

Patients received a median number of5 cycles. Most (9 of 14 patients) whoachieved CR required only 1 cyclebefore achieving an initial response.Those patients who had CRi as initialresponse needed 1 to 3 (median 1) morecycles to achieve full CR.

Nonhematologic toxicities were infre-quent, but 24 of 33 patients (73%) hadinfection and/or febrile neutropenia.Within 8 weeks, 15% of patients died asa result of infection.

Dr. Blum noted that this novel sched-ule of induction decitabine therapy,along with modified maintenance thera-py based on outcome, was highly activein this poor-risk group of patients withAML.2 The promising survival data sug-gest that a comparative study with inten-sive therapy is warranted.

PATIENTS WITH FLT3 MUTATIONSThe high incidence of FLT3 mutations(35%-40%) found in patients with AMLhas led to the development and studies ofspecific FLT3-tyrosine kinase inhibitors.3

Targeted-Therapy Regimens Highly Active in Acute Myeloid Leukemia

15

A handful of unspecific inhibitors ofFLT3 kinase signaling, includingsorafenib, have also been investigated fortreatment of this disease. Sorafenib, anorally active multikinase inhibitor withpotent activity against FLT3 kinase, hasbeen shown to induce apoptosis inFLT3-mutant human AML cell lines.4

In a phase I study of patients withAML, monotherapy with sorafenib inescalating doses was well-tolerated withno myelosuppression and with significantclinical activity predominantly in patientswith FLT3 mutations. Farhad Ravandi,MD, University of Texas MD AndersonCancer Center in Houston, reported theresults of a phase I/II study at theEuropean Hematology Association ann-ual meeting in Berlin, Germany.4 Theobjective of the study was to determinethe clinical activity and tolerability of acombination of sorafenib and standardAML chemotherapy.

In the phase I portion of the study, 10patients,median age 34 years,with relapsedAML were treated with cytarabine 1.5 g/m2 over 24 hours daily for 4 days (3 days for patients aged >60 years) andidarubicin 12 mg/m2 daily for 3 days alongwith escalating doses of sorafenib 400 mgevery other day, 400 mg daily, and 400 mgtwice daily for 7 days during induction.Patients who achieved CR received up to5 courses of consolidation with idarubicin8 mg/m2 daily for 2 days and cytarabine0.75 g/m2 daily for 3 days plus continuoussorafenib 400 mg twice daily for up to 28days per cycle.The treatment cycles wererepeated every 4 to 6 weeks.

The patients had a median of 2 priortherapies.Seven patients were FLT3-ITDpositive, and 4 achieved CR. Sorafenib400 mg twice daily was established as asafe induction dose, noted Dr. Ravandi.

In the phase II portion of the study, 48patients, median age 53 years, were treat-ed, including 12 patients with FLT3-ITD and 2 with FLT3-TKD.4 Cyto-genetic studies showed that 20 patientswere diploid, 5 were +8, 5 were -5/-7,3 were t(9;11), and 11 were miscella-neous; cytogenetic information wasunavailable for 4 patients. The FLT3-

mutation burden was low in blasts from4 patients and high in 10. Seven patientswere FLT3-ITD+/NPM1- and 1 wasFLT3 D835+/NPM1-.

A total of 45 patients were evaluablefor response, of whom 38 patients (84%)achieved CR (34 patients) or completeremission with incomplete plateletrecovery (CRp; 4 patients), including all14 patients with FLT3 mutations. Fourpatients were resistant to therapy. Dr.Ravandi noted that the regimen was well-tolerated with some grade 3 and higheradverse events possibly related to the addi-tion of sorafenib during induction.Theseincluded hyperbilirubinemia (6 patients),elevation of transaminases (3 patients),diarrhea and colitis (4 patients), rash (3 patients), pancreatitis (1 patient), peri-carditis (1 patient), elevated creatinine (1 patient), and cardiac/hypertension (3 patients). During induction, 3 patientsdied from pneumonia.

With a median follow-up of 28weeks, the probability of survival at 6 months in this study is 85%. Nine

patients have relapsed with a median CRduration of 8 months. Among thepatients with FLT3 mutation, 6 haverelapsed and 8 remain in CR.

The researchers also performed correl-ative blood studies that confirmed potentactivity of sorafenib against ERK andFLT3 signaling. Dr. Ravandi observedthat sorafenib can be safely combinedwith idarubicin and cytarabine to inducea high CR rate, particularly in patientswith FLT3 mutations.

REFERENCES1. Blum WG, Klisovic RB, Hackanson B, et al. Phase Istudy of decitabine alone or in combination with valproicacid in acute myeloid leukemia. J Clin Oncol.2007;25:3884-3891.

2. Blum WG, Klisovic R, Liu S, et al. Efficacy of a novelschedule of decitabine in previously untreated AML, age60 or older [ASCO Annual Meeting abstract 7010].J Clin Oncol. 2009;27:15s.

3. Haferlach T. Molecular genetic pathways as therapeutictargets in acute myeloid leukemia. Hematology Am SocHematol Educ Prog. 2008:400-411.

4. Ravandi F,Andreeff M, Garcia-Manero G, et al.Combination of idarubicin, high-dose cytarabine andsorafenib is highly effective in achieving remission innewly diagnosed, FLT3-mutated acute myeloid leukemia(AML) [EHA Annual Meeting abstract 0831].Haematologica/Hematol J. 2009;94(suppl 2):335.

CYTARABINE DERIVATIVE SAFE IN PATIENTS WITHSECOND SALVAGE ACUTE MYELOID LEUKEMIA

A novel derivative of cytarabine administered as second salvage therapy has manage-able toxicity in AML patients.

A multicenter phase II study led by Francis J. Giles, MD, University of Texas HealthSciences Center, San Antonio, assessed cytarabine 5'-elaidic acid ester (CP-4055)when given as second salvage therapy in 40 patients with AML, median age 48 years,who were refractory/relapsed to two previous chemotherapeutic regimens.1

The patients received CP-4055 2,000 mg/m2/day over 24 hours on days 1-5 every 3 weeks. The majority of the patients had previous ara-C-based therapy.

In the first 20-patient cohort, the most frequently reported adverse events ofgrade 3 or higher were myelosuppression, abdominal pain, colitis, diarrhea, nausea,fatigue, and elevated liver function tests (LFTs), Dr. Giles reported at the AmericanSociety of Clinical Oncology annual meeting in Orlando, Florida. Clinical activity wasobserved in 3 patients, 2 who achieved CR and 1 who had complete remission withincomplete platelet recovery. Dr. Giles noted that toxicity was manageable, and drugcontinuation was recommended.

Of all 40 patients, 7 (18%) had LFT elevations of grade 3 or more and 4 (10%)had LFT elevations of grade 2. Clinical activity has also been reported among the second 20-patient cohort in this ongoing trial.

1. Giles FJ, O’Brien S, Rizzieri DA, et al. A phase II study with CP-4055 in patients with second salvage AML [ASCOAnnual Meeting abstract 7047]. J Clin Oncol. 2009;27:15s.

16

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

Novel Compounds Successfully Treat Acute Myeloid Leukemia in Elderly Patients

Several novel compounds currentlyin clinical trials show preliminarypromise as therapies for traditional-

ly difficult-to-treat elderly patients withacute myeloid leukemia (AML).

Most patients with AML who are aged≥65 years are intrinsically resistant to inten-sive chemotherapy because of knownpoor-risk factors. Typically, older patientshave been treated either with best support-ive care (typically hydroxyurea) or withlow-dose Ara-C.1 However,many targetedapproaches are currently under develop-ment that may be of use for elderly patientswith AML.A major challenge remains toidentify targets of critical importance.Some of those targets attempt to inhibittyrosine kinases and farnesyltransferases,promote apoptosis, inhibit hypomethyla-tion of DNA by using DNA methyltrans-ferase inhibitors or histone deacetylaseinhibitors, or induce angiogenesis.2

Often, elderly patients with AML arediscouraged about receiving treatmentowing to high treatment-related mortali-ty and low response rates. The novelchemotherapy drug temozolomide, anoral alkylating agent, has been shown tobe effective in patients with AML wholack expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leu-kemic blasts. Studies show that long-termexposure to temozolomide in low dosescan significantly inhibit AGAT activity.3

Interim results of an ongoing phase IIclinical trial were reported by the leadinvestigator, Bruno Medeiros, MD,Stanford University, Stanford, California,at the American Society of ClinicalOncology (ASCO) annual meeting inOrlando, Florida. In this study, temozolo-mide therapy is being tailored to high-riskpatients with AML according to theirAGAT methylation-promoter status.Patients who demonstrate AGAT activityreceive conventional doses of temozolo-mide 200 mg/m2 orally for 7 days, and

those with no AGAT activity receive protracted doses of temozolomide100 mg/m2 orally for 14 days followed byconventional doses of temozolomide.

The first 15 patients, median age 78years, have completed treatment, includ-ing 8 patients with de novo AML and 5 with secondary AML. Nine patientshad a normal karyotype, and 3 had acomplex karyotype. Two patients hadonly an NPM1 mutation, and 1 had anNPM1/FLT3-ITD mutation.

Complete remission (CR) was achievedin 6 of 13 patients after 1 cycle of therapy,and 3 patients remained in remission for amedian duration of 22 weeks. With amedian follow-up of 38 weeks, the medi-an overall survival for all patients is 12weeks and for responders is 26.5 weeks.

Nonhematologic toxicities were mini-mal. Hematologic toxicities associatedwith treatment were difficult to distinguishfrom disease-related cytopenias. Diseaseprogression led to the death of 7 patients,and 2 patients died of neutropenic sepsis.

Dr.Medeiros noted that the preliminarydata suggest that temozolomide therapymay be individualized according to AGATactivity for elderly patients with AML.

OTHER EMERGING THERAPIESResults of a multicenter phase II studywith the topoisomerase II inhibitorvoreloxin were reported at ASCO byMichael Maris, MD, Rocky MountainBlood and Marrow Transplant Program,Denver, Colorado. Clinical activity wasshown with 2 dosing schedules in previ-ously untreated elderly patients with denovo or secondary AML who wereunlikely to benefit from standardchemotherapy.4 Eleven of 29 patients(38%) achieved a CR or a completeremission with incomplete plateletrecovery (CRp) with 3 weekly vorelox-in doses. Interim results showed CR orCRp for 6 of 21 evaluable patients (29%)

with 2 weekly voreloxin doses, with 2patients in heme recovery.

In an international, retrospective phaseII study, the novel sulfonyl hydrazinealkylating agent laromustine inducedCR or CRp in about one-quarter ofelderly patients with AML and adversecytogenetics. Laromustine also led to a12% 1-year overall survival comparedwith no response in patients whoreceived low-dose Ara-C or best sup-portive care,1 reported Robert Hills,MD, Cardiff University School ofMedicine,Cardiff,Wales, at the EuropeanHematology Association (EHA) annualmeeting in Berlin, Germany.

In a multicenter, European phase I/IIstudy, the aminopeptidase inhibitor tose-dostat elicited a bone marrow response in11 of 35 elderly patients (31.4%) withrelapsed/refractory AML, including 6 CRs and 5 partial responses.5 In addi-tion,4 patients achieved complete hemato-logic recovery and 1 reached a cytogeneticresponse, reported Gert Ossenkoppele,MD, VU University Medical Center,Amsterdam, the Netherlands, at EHA.Median overall survival was 131.5 days.Tosedostat was well-tolerated over expo-sures up to 12 months in these patientswith a poor prognosis and will be testedin a pivotal trial in relapsed AML.

REFERENCES1. Hills R, O’Brien S, Schiller G, Giles F. Laromustine,novel sulfonylhydrazine alkylating agent for older patientswith AML [EHA Annual Meeting abstract 307].Haematologica/Hematol J. 2009;94(suppl 2):121.2. Stone RM. Induction and postremission therapy:new agents (AML). Leukemia. 2003;17:496-498.3. Medeiros BC, Gotlib JR, Coutre SE, et al. Interimresults of protracted low doses of temozolomide in high-risk acute myeloid leukemia [ASCO AnnualMeeting abstract 7052]. J Clin Oncol. 2009;27:15s.4.Maris MB,Ravandi F, Stuart R, et al.A phase II study ofvoreloxin as single agent therapy for elderly patients (pts) withnewly diagnosed acute myeloid leukemia (AML) [ASCOAnnual Meeting abstract 7048]. J Clin Oncol. 2009;27:15s.5. Ossenkoppele G, Hooftman L, Zweegman S, et al.Aminopeptidase inhibitor, tosedostat (TSD, CHR-2797)for elderly/previously treated patients with AML/highrisk MDS [EHA Annual Meeting abstract 1065].Haematologica/Hematol J. 2009;94(suppl 2):429.

17

1. In patients with myelodysplastic syndrome (MDS),both a 3-day and a 5-day dosing schedule of decit-abine have demonstrated efficacy in clinical trials.a. Trueb. False

2. In a study of patients with MDS who received allo-geneic stem cell transplantation, what was the 10-year overall survival rate?a. 25%b. 48%c. 51%d. 65%

3. Which of the following drugs approved for the treatment of hematologic malignancies has immunomodulatory, antiangiogenic, and antiprolifer-ative effects?a. Lenalidomideb. Azacitidinec. Decitabined. Bortezomib

4. Histone deacetylase inhibitors may be more effec-tive when used in combination with other drugs forthe treatment of MDS.a. Trueb. False

5. In patients with relapsed/refractory multiple myelo-ma, which drug combination is an effective steroid-free salvage regimen?a. Bortezomib plus pegylated liposomal doxorubicin

and thalidomideb. Thalidomide plus lenalidomide and bortezomibc. Bortezomib plus lenalidomide and rituximabd. Melphalan plus doxorubicin and vincristine

6. In patients with advanced multiple myeloma, a six-drug infusional chemotherapy regimen failed to facilitate donor engraftment.a. Trueb. False

7. In a study of relapsed/refractory multiple myeloma,which combination of oral agents resulted in a 73%clinical benefit?a. Thalidomide, melphalan, prednisoneb. Vorinostat, lenalidomide, dexamethasonec. Bortezomib, melphalan, prednisoned. Bortezomib, melphalan, lenalidomide

8. In a study of elderly patients with acute myeloid leukemia, which combination of agents led to complete remissions in 21% of patients with adversecytogenetics?a. Cytarabine and oral clofarabineb. Cytarabine and daunorubicinc. Tipifarnib and etoposided. Cytarabine and idarubicin

9. In a study of patients with relapsed AML, which agent was added to standard chemotherapy and induced an 84% complete remission rate?a. Sorafenibb. Decitabinec. Azacitadined. Gemtuzumab

10. Targeted therapies currently under investigation in clinical trials for elderly patients with AML include which of the following agents?a. Tosedostatb. Laromustinec. Voreloxind. Temozolomidee. All of the above

Please darken the circle on page 18 with the correct answer to each question.

5. A B C D

6. A B

7. A B C D

8. A B C D

9. A B C D

10. A B C D E

18

EMERGING TARGETED THERAPIES FOR HEMATOLOGIC MALIGNANCIES:LEAVING A GENETIC AND EPIGENETIC IMPRINT FOR BETTER OUTCOMES

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