与急性粒细胞白血病

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ToddAFehnigerHematologyGrandRoundMarch13,2009Lenalidomidetherapyforuntreatedacutemyeloidleukemiainolderadults(>60yearsofage) DisclosureClinicalstudyfundedinpartbyCelgeneNon-FDAapproveduseofRevlimid(lenalidomide) Case71yoMpresentedwithdyspnea,fatigue,andpancytopeniaPerformancestatus:ECOG1PMH:HTN,GERD,BPHPE:petechiae,paleCBCWBC1900/uL(ANC190/uL)Hgb6.7g/dLPlts74,000/uLfDifferential:33%blastsBlood113:1002,2009 CaseBonemarrowbiopsyandaspirate30%cellular90%myeloblastsFABM0(undifferentiated)Flow:CD34+CD33+CD13+CD117+Routinecytogenetics:trisomy1347,XY+13[5]/46,XY[15]FLT3ITD:PositiveBlood113:1002,2009 Case:DxBoneMarrowandCytogeneticsBMAspirateLederstain AcuteMyeloidLeukemiainpatients>60yearoldMedianageofAMLis65-7013,410newAMLcases/8,990deathsin200714.5/100,000inadults>60years0.7/100,00inadults<60yearsMajorityofpatientsdonotreceivespecifictherapy(bestsupportivecare)Mediansurvival<1year OlderAML:PrognosisandStandardTherapies?7+3:mediansurvival~8-13monthsLowdoseara-c:~9monthsNCCN:Investigationalagentsrecommendedas1stlinetherapyPrognosis,Resultswithcurrenttherapyoptions,andoverviewofinvestigationalagentsSummarizedinMikeMartin’sWashUHeme/OncgrandroundspresentationfromFebruary2008MartinandAbboud.BoodRev22:311,2008EliahEsteyJClinOncol25:1908,2007 OlderAMLbiology:continuumwithmyelodysplasticsyndrome(MDS)CytogeneticsinolderAMLlowerpercentageoffavorableriskcytogeneticst(8;14),t(15;17),inv(16)Higherpercentageofunfavorablecytogenetics-5,-7,+8,complexFrequentlyarisesfromMDSorinitialdiagnosesasAMLwithmultilineagedysplasiaResistanttotraditionalchemotherapy(MDR1)Presentationwitha‘hypoproliferative’,MDStypepicturecommon MDSandlenalidomideEfficacyoflenalidomideinMDS.ListAetal.NEJM352:5492005LenalidomideinMDSwith5qdeletion.ListAetal.NEJM355:1456,2006Phase2studyoflenalidomideintransfusion-dependent,lowandint-1riskMDSwithkaryotypesotherthandeletion5q.Blood111:86,2008.Asmallnumberofpatientswithclonalcytogeneticabnormalities(non-5q-)andexcessblastshadcytogeneticresponsesandCRs(IpresentedthistopicatWashUHeme/OncGrandRounds6/10/2005asafellow:myinterestledtothecurrentstudy!) Hypothesis:LenalidomidehasactivityinacutemyeloidleukemiaOneofmyfellowclinicalprotocols(withRaviVij) StudydesignPhaseII,single-institution,investigator-initiated,prospective,open-labelstudySimon2stagedesign(n=12evaluableinstage1)PrimaryEndpoint:CR(CRc/CRm/CRi)IWGcriteriawithadditionofSDSecondaryEndpoints:safety,IWGresponsecriteria,overallsurvival,event-freesurvival,anddurationofremissionEligibility:UntreatedAMLage>60yo(priorMDS,therapyrelated,denovoalleligible)Exclude:5q-andfavorableriskcytogenetics Stage1/Cohort1Schema ChesonJCO2007IWGCriteriaforAML 06-0907:Stage1(Cohort1)ResultsWHOIWGCriteria:(n=15totalpatients)CRc:1(duration:9months)PR:2(duration:6and>12months-ongoing)SD:4(duration:3,3,4,7months)Treatmentfailure–indeterminatecause:6Rash,Sepsis,CardiacArrestProgressivedisease<2cyclesLen(n=3)MorphologicleukemiafreeBMatd15w/PDatd30Treatmentfailure–resistantdisease:2 Len(NoLen) Stage2/Cohort2SchemaStage2=Cohort2N=27patientsIndependentanalysis PreliminaryResults–Cohort2(n=25sofar)Unpublished Case:ClinicalCoursePt.007 Case:Follow-upBM(%)020406080100Day0Day15Day30Day75LDcycle1BMblastsBMcellularityWBCcountHemoglobin(g/dL)024681012Day0Day15Day30Day75LDcycle1HemoglobinPlatelets02.04.06.08.010.0050100200250300Platelets(x103/L)WBC(x103/L)150 CRAspirate100XCRLeder10XCRLeder100X Lenalidomide:Mechanism?NNHOOONH2BlockAngiogenesisDirectEffectsontumorAltercytokineprofilesImmunemodulationPhosphatasemodulationLenalidomide(Revlimid)MultipleMyelomaLymphomaMDS(w/5q-)ActivityPotentialMechanism(s)CLLAML LenalidomidehasactivityinAML–howdoesitwork?ModulationofNKcellresponses?CorrelativestudiesevaluatingNKcellspriorto,during,andaftertherapyDirecteffectsonAML?BMblastsatDx:Invitrolenalidomideexposure,followblastcelldeathcomparedtovehicle;correlationtoresponse?Leukemiamicroenvironment?FlowforCXCR4onAMLblastsThiswouldbeagreatprojectforafellow! AcknowledgmentsRaviVijAlissaNelsonKimTrinkausJackiePaytonBMT/leukemiaphysiciansandteammembersASCOFoundationSitemanCancerCenterDisclosures:ThisstudywasfundedinpartbyCelgeneNon-FDAapproved(investigational)useofRevlimid(lenalidomide)Nofinancialinterest