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AboutTheseSlidesOurthankstothepresenterswhogavepermissiontoincludetheiroriginaldataUsersareencouragedtousetheseslidesintheirownnoncommercialpresentations,butweaskthatcontentandattributionnotbechanged.UsersareaskedtohonorthisintentTheseslidesmaynotbepublishedorpostedonlinewithoutpermissionfromClinicalCareOptionsDisclaimer

ThematerialspublishedontheClinicalCareOptionsWebsitereflecttheviewsoftheauthorsofthe

CCOmaterial,notthoseofClinicalCareOptions,LLC,theCMEproviders,orthecompaniesprovidingeducationalgrants.ThematerialsmaydiscussusesanddosagesfortherapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration.Aqualifiedhealthcareprofessionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed.Readersshouldverifyallinformationanddatabeforetreatingpatientsorusinganytherapiesdescribedinthesematerials.CurrentStateofAMLTherapyExcludingtheroughly20-30%ofgoodriskpatients,40-90%ofyoungerpatients(age18-59)achievingremissionaredestinedtorelapseCurrentStateofAMLTherapyExcludingtheroughly20-30%ofgoodriskpatients,40-90%ofyoungerpatients(age18-59)achievingremissionaredestinedtorelapseAllbutaveryselectsubsetofolderAMLpatients(>60)willdieduetorelapsedorrefractorydiseasePrognostic/predictivefactorsinAMLFactorCommentAgeMajorimpactatdiagnosisWBCContinuousvariablePriortherapyorMDS?KaryotypemaybemoreimportantExtramedullarydiseaseVariableDay14blastcountHigherpercentageworse#cyclesofinductionOnebetterthantwoCytogenetic/molecularprofileMajorImpactatdiagnosisGeneexpressionprofileCanfurthersubdividepatientsMicroRNAexpressionNeedsvalidationbyothergroupsGenesequencingFutureapplicationMRDdetectionatCR??;seemslikeitshouldbeusefulPrognostic/predictivefactorsinAMLFactorCommentBasisforTransplantrecommendation?AgeMajorimpactatdiagnosisYesWBCContinuousvariableNotsolelyPriortherapy?KaryotypemaybemoreimportantNotsolelyExtramedullarydiseaseVariableNotsolelyDay14blastcountHigherpercentageworseRarely#cyclesofinductionOnebetterthantwoRarelyCytogenetic/molecularprofileMajorImpactatdiagnosisYesGeneexpressionprofileCanfurthersubdividepatientsNotyetMicroRNAexpressionNeedsvalidationbyothergroupsNotyetGenesequencingFutureapplicationNotyetMRDdetectionatCR??;seemslikeitshouldbeusefulPossiblyforcytogenetics/FISHD?hnerK,etal.Haematologica2008;93:976-982.Reproducedwithpermission.

Majorcytogeneticsubgroupsofacutemyeloidleukemia(AML)(excludingacutepromyelocyticleukemia)andassociatedgenemutationsByrdJC,etal.Blood2002;100:4325-4336.ThisresearchwasoriginallypublishedinBlood.?2002theAmericanSocietyofHematology.CALGBDatabase:OutcomesinAMLPatients<60yearsofAgebasedonKaryotypeatDiagnosisBMTversusConventionaltherapyforAMLwithpoorriskcytogeneticsSWOG/ECOGTrialSlovakML,etal.Blood2000;96:4075-4083.ThisresearchwasoriginallypublishedinBlood.?2000theAmericanSocietyofHematology.BMTversusConventionaltherapyforAMLwithpoorriskcytogeneticsEORTC-LG/GIMEMASuciuS,etal.Blood.2003;102:1232-1240.ThisresearchwasoriginallypublishedinBlood.?2003theAmericanSocietyofHematology.CurrentRoleofAllograftsforAMLPatients<60yearsinCR1AdverseriskcytogeneticsMostagreeallograftappropriateconsolidationatleastupto55-60yearsofageCurrentRoleofAllograftsforAMLPatients<60yearsinCR1AdverseriskcytogeneticsMostagreeallograftappropriateconsolidationatleastupto55-60yearsofageFavorableriskcytogeneticsNoroleingeneralCurrentRoleofAllograftsforAMLPatients<60yearsinCR1AdverseriskcytogeneticsMostagreeallograftappropriateconsolidationatleastupto55-60yearsofageFavorableriskcytogeneticsNoroleingeneralIntermediateriskcytogeneticsThisiswhereitgetscomplicatedRecentmeta-analysessuggestbenefitCornellisonetal,Blood,2007Korethatal,JAMA,2009MolecularProfilesofCytogeneticallyNormalAMLD?hnerH,etal.Blood.2009Oct30.[Epubaheadofprint].ThisresearchwasoriginallypublishedinBlood.?2009theAmericanSocietyofHematology.HeterogeneitywithinCytogeneticallyNormalAMLCategoryGeneMutationPrognosticImpactNPM1FavorableinabsenceofFlt3ITDFlt3ITD/alleleratioUnfavorableFlt3TKDControversialCEBPAFavorableMLLPTDUnfavorableRasNeutralWT-1ControversialRunx1UnfavorableImpactofGeneExpressioninCytogeneticallyNormalAMLCategoryGeneImpactofOverexpressionBAALCUnfavorableERGUnfavorableMN1UnfavorableMir181FavorableMetzelerKH,etal.JClinOncol.2009;27:5031-5038.Reprintedwithpermission.?2009AmericanSocietyofClinicalOncology.AllrightsreservedHighexpressionofBAALC,ERG,orMN1predictsshorteroverallsurvivalincytogeneticallynormalacutemyeloidleukemiaRiskStratifyingAMLBasedonCytogenetic/MolecularProfileGeneticgroup SubsetsFavorable t(8;21)(q22;q22);RUNX1-RUNX1T1 inv(16)(p13.1q22)ort(16;16)(p13.1;q22);CBFB-MYH11 MutatedNPM1withoutFLT3-ITD(normalkaryotype) MutatedCEBPA(normalkaryotype)Intermediate-I MutatedNPM1andFLT3-ITD(normalkaryotype) WildtypeNPM1andFLT3-ITD(normalkaryotype) WildtypeNPM1withoutFLT3-ITD(normalkaryotype)Intermediate-II t(9;11)(p22;q23);MLLT3-MLL CytogeneticabnormalitiesnotclassifiedasfavorableoradverseAdverse inv(3)(q21q26.2)ort(3;3)(q21;q26.2);RPN1-EVI1 t(6;9)(p23;q34);DEK-NUP214 t(v;11)(v;q23);MLLrearranged -5ordel(5q);-7;abnl(17p); complexkaryotype;monosomalkaryotypeD?hnerH,etal.Blood.2009Oct30.[Epubaheadofprint]ThisresearchwasoriginallypublishedinBlood.?2009theAmericanSocietyofHematology.BMTversusConventionaltherapyforAMLwithnormalcytogeneticsSchlenkRF,etal.NewEnglJMed.2008;358:1909-1918.Reprintedwithpermission?2009MassachusettsMedicalSociety.KorethJ,etal.JAMA2009;301:2349-2361.Reproducedwithpermission.OverallSurvivalBenefitofAllogeneicSCTforAMLinFirstCompleteRemissionCurrentStateofAMLTherapyAllogeneicHCTisthesinglemosteffectivetherapycurrentlyavailableforthepreventionofrelapseAllogeneicHCTisstillapotentiallyriskytherapyandmanytreatingphysiciansremainreluctanttorecommendinCR1untilmortalityratescanbesubstantiallyloweredWhichpatientswithAMLlessthan60yearsofagecanreasonablybeconsideredforallogratinginfirstremission?Mostdecisionswouldbemadebasedoncytogenetic/molecularriskgroupAdverseriskkaryotype:mostwouldagreeOtherintermediateriskcytogeneticabnormalities:choiceslikelyindividualizedCytogeneticallynormalDecisionbasedonmolecularrisk?ShouldallFlt3ITDpatientsbeallografted?WhatrecommendationsshouldbemadeforFlt3ITDgroup?Shouldallofthesepatientsbereferredforallograft?Onwhatbasis?Whataboutpatientsalreadyenteredonclinictrial(e.g.CALGB10603/Intergroup)?ShouldthesepatientsbetakenoffaclinicaltrialofTKIforastandardofcareallograft?Acallforprospective,multi-centerallografttrialsinfirstremissionAMLbasedonriskforrelapseThiscannowbeaccomplishedbasedonstudiessuggestingnosignificantdifferenceinoverallsurvivalcomparingmatchedsiblingtomatchedunrelateddonortransplantsSimilarOutcomesinAMLregardlessofDonorSourceScheteligJ,etal.JClinOncol.2008;26:5183-5191.Reprintedwithpermission.?2008AmericanSocietyofClinicalOncology.AllrightsreservedLog-rankp-value<0.0001n=1735n=2621n=2184n=2234Acallforprospective,multi-centerallografttrialsinfirstremissionAMLbasedonriskforrelapseThiscannowbeaccomplishedbasedonstudiessuggestingnosignificantdifferenceinoverallsurvivalcomparingmatchedsiblingtomatchedunrelateddonortransplantsWhatwouldbethepossiblestudydesigns?Randomizationtotransplantorconventionaltreatmentafterdonoridentified?Upfrontdesigntotransplantallunfavorableriskpatientsinfirstremissionifdonoridentified?PossibleprospectiveAMLTransplanttrialdesignsRandomizationtotransplantorconventionaltreatmentafterdonoridentifiedWouldrequiresubstantialproportionofpatientshavingadonoridentifiedWhattypeofconditioningandGVHDprophylaxis?Istherereallyastandardapproach?Howmuchheterogeneityintransplantapproachcouldbetolerated?Whatwouldbethebestendpoint,consideringtheimpactofchronicGVHDonsurvivalandQOL?PossibleprospectiveAMLTransplanttrialdesignsUpfrontdesigntotransplantallunfavorableriskpatientsinfirstremissionifdonoridentifiedWoulditrequireHerculeanefforttogetpatientsriskstratified,HLA-typed,anddonorsidentifiedinatimelyfashion?Whatproportionofpatientswouldhavetomakeittotransplanttobeconsideredsuccessful?Shouldallpatientshaveonetypeoftransplantapproachorberandomized(Ph2)totwoormorepromisingstrategies?Whatwouldbethestudyendpoint?DFS,overallsurvival,GVHDfree/relapsefreesurvivalcomposite?Whatdefinesa“suitabledonor”allograftforahighriskAMLpatientinfirstremission?Matchedsibling:YesMatchedunrelateddonor:YesMismatchedunrelateddonor(KIRmismatched?)Cooleyetal,Blood,2009Mismatchedumbilicalcordblood?Gutmanetal,BBMT,2009Haploidenticalrelated?Perugiaapproach(exvivoT-celldepletion)Hopkinsapproach(invivoalloreactiveT-celldepletion)CooleyS,etal.Blood2009;113:726-732.ThisresearchwasoriginallypublishedinBlood.?2009theAmericanSocietyofHematology.TransplantationusingdonorswithKIRBhaplotypesimprovesoverallsurvivalCiceriF,etal.Blood2008;112:3574-3581.ThisresearchwasoriginallypublishedinBlood.?2008theAmericanSocietyofHematology.EBMTAnalysis:LeukemiaFreeSurvivalforAMLPatientsReceivingHaploidenitcalTransplantationaccordingtodiseasestageOutcomesofmyeloablativeumbilicalcordbloodtransplantsforAcuteleukemiainCRcomparedtounrelateddonorsGutmanJA,etal.BiolBloodMarrowTransplant.2009;15:1122-1129.Reproducedwithpermission.MajorissueswithallograftinginAMLGVHDopportunisticinfectionRegimenrelatedorgantoxicityProhibitsuseinolderpatientsand/orthosewithco-morbiditiesShouldreducedintensityregimensbeusedinyoungerpatients?RELAPSETacklingthemajorissuesinallograftingforAMLPreventinggraftversushostdiseaseSirolimusbasedapproaches(currentlysubjectofBMTCTNrandomizedtrial0402)ExvivoT-celldepletionJustcompletedBMTCTNPhase2studyinAMLCR1/2OtherselectiveT-celldepletiontrialsPostTransplantcyclophosphamideHopkins,Seattle,MDACCconsortiumstudyingPolyclonalandmonoclonalantibodiesATG,Campath,othersManyothersRelapserateandsurvivalafter

T-celldepletioninAMLCR1AversaF,etal.JClinOncol.1999;17:1545-1550.Reprintedwithpermission.?1999AmericanSocietyofClinicalOncology.AllrightsreservedMSKCCpublishedandunpublishedBMTCTN0303:Multi-CenterTrialforAMLinCR1orCR2Age18-60Conditioningregimen:HyperfractionatedTBI(TBI)125cGy/fxat8-20cGy/minute:totaldose1375cGyover4days (-9through–6)Thiotepa5mg/kgfortwodays(-5and–4)ATGat2.5mg/kgonday–4Cytoxanat60mg/kgondays–3and–2CD34selectedG-CSFmobilizedPBonday0NopharmacologicalGVHDprophylaxisBMTCTN0303:PatientCharacteristics47patientsenrolled;44transplanted3patientswithdrewconsent(2)orprogressed(1)priortotransplantAge:mean46(21-59)Gender;M=16;F=28KPS100%:1790%:1780%:870%2Remissionstatus:CR1:37;CR2:7Poorriskkaryotype/molecularprofile:14/37CR1(38%)DevineSM,etal.ASH2009.Abstract655.OutcomesofAMLpatientsaged60orgreaterenteredonCALGBTrialsFaragS,etal.Blood.2006;108:63-73.ThisresearchwasoriginallypublishedinBlood.?2006theAmericanSocietyofHematology.CALGB100103

Background

Resultsinbestgrouparestillpoor(n=276)

CR1 Age60-75 Receivefirstconsolidationonrandomizedtrial2-yearDFS24%3-yearDFS17%InitialresultssuggestthatRICallograftsarefeasibleinolderpatientswithAMLHegenbartatal,JCO2006Wongetal,Blood,2005ManyothergroupsBut…..virtuallyallofthepublishedstudiesareretrospective,highlyheterogeneous,orlackastandardizedapproach.Fewifanyhaveaskedaspecificquestioninaspecificpatientpopulation

CALGBTrialinAMLCR1Age>60Thefludarabine/busulfanregimenwaschosenin2003basedonthescantamountofavailabledataatthetimeCALGB100103

InitialStatisticalDesignPrimaryEndpoint:2yearDFSAimforimprovementfrom20to40%Trialwouldrequire36patientsInitialestimate:shouldtake~36monthstocompleteenrollmentPoorInitialAccrualto

CALGB100103:Why?TrialActivationDate:1/15/04ModificationstoCALGB100103MadenotethatSWOGtrialinthispatientpopulationwasclosedduetopooraccrualFormedProtocolteamwithBMTCTNandjoinedofficiallybyCTNinJune2006(BecameCALGB100103/CTN0502)ProtocolTeamDecisions:Addedvolunteerunrelateddonors(10/10)AddedrabbitATG(forallpatients)RemovedDLIfromprotocolLoweredDFSgoalto35%at2yearsIncreasedtargetaccrualgoalto61patients

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