精美幻灯美国临床肿瘤学会年会恶性血液病进展

精美幻灯美国临床肿瘤学会年会恶性血液病进展第1页/共51页HematologicMalignancies

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ofthe2010AmericanSocietyofClinicalOncologyAnnualMeeting*ThisprogramissupportedbyeducationalgrantsfromAmgen,Bristol-MyersSquibb,Celgene,GenentechBioOncology,

MillenniumPharmaceuticals,Inc.,NovartisOncology,andPfizer,Inc.第2页/共51页AboutTheseSlidesOurthankstothepresenterswhogavepermissiontoincludetheiroriginaldataUsersareencouragedtousetheseslidesintheirownnoncommercialpresentations,butweaskthatcontentandattributionnotbechanged.UsersareaskedtohonorthisintentTheseslidesmaynotbepublishedorpostedonline

withoutpermissionfromClinicalCareOptions(emailpermissions@)Disclaimer

ThematerialspublishedontheClinicalCareOptionsWebsitereflecttheviewsoftheauthorsofthe

CCOmaterial,notthoseofClinicalCareOptions,LLC,theCMEproviders,orthecompaniesprovidingeducationalgrants.ThematerialsmaydiscussusesanddosagesfortherapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration.Aqualifiedhealthcareprofessionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed.Readersshouldverifyallinformationanddatabeforetreatingpatientsorusinganytherapiesdescribedinthesematerials.第3页/共51页FacultyNicholasJ.DiBella,MD

Co-Chairman,HematologyResearchCommittee,USOncologyPresident,RockyMountainCancerCentersAurora,Colorado第4页/共51页AnUpdateonHematologicMalignancies:OverviewPRIMA:rituximabmaintenancevsobservationinpatientswithfollicularlymphomawhorespondedtoinductionwithrituximabpluschemotherapyPhaseIItrialofpanobinostatinrelapsed/refractoryHodgkin’slymphomaPhaseIItrialofR-GemOxforpatientswithrelapsed/refractoryDLBCLnotcandidatesforhigh-dosetherapyDASISION:phaseIIItrialofimatinibvsdasatinibinuntreatedCP-CMLENESTndphaseIIItrialofnilotinib300mgBIDor400mgBIDvsimatinib

400mgQDinnewlydiagnosedPh-positiveCP-CMLInvestigationofazacitidineinchronicmyelomonocyticleukemiaInvestigationofbortezomib,lenalidomide,dexamethasoneinnewlydiagnosedmultiplemyelomaCALGB100104:lenalidomidemaintenancevsplacebofollowingASCTinmultiplemyeloma第5页/共51页

Lymphomas第6页/共51页UntreatedpatientswithhightumorburdenfollicularlymphomaInductionImmunochemotherapy8cyclesR-CHOPorR-CVPorR-FCMRituximabmaintenance375mg/m2q8wfor

2yrs(n=505)Observation(n=513)Response*(N=1019)*OnlypatientswithCR/CRu/PRrandomizedtomaintenancetherapy;1patientdiedduringrandomization.Stratifiedbyresponsetoinduction,chemotherapyregimen,andgeographiclocationpriorto1:1randomization5-yrfollow-upSallesGA,etal.ASCO2010.Abstract8004.PRIMA:RituximabMaintenancevsObservationinPatientsWithFL第7页/共51页PRIMA:PrimaryEndpoint(PFS)MetatPlannedInterimAnalysisRituximabmaintenancereducedtheriskofprogressionby50%SallesGA,etal.ASCO2010.Abstract8004.Reprintedwithpermission.1.00.20061218243036Progression-FreeRateMosStratifiedHR:0.50

95%CI:0.39-0.64

P<.000182%66%Rituximabmaintenance

(n=505)Observation

(n=513)PatientsatRisk,n506

513472

469443

411336

289230

195103

8218

15第8页/共51页PRIMA:BenefitsofRituximabMaintenancebySubgroupSallesGA,etal.ASCO2010.Abstract8004.Reprintedwithpermission.All≥60FLIPI≤1FLIPI=2FLIPI≥3R-CHOPR-CVPR-FCMCR/CRuPR0123CategorySubgroupHRnHR*95%CIAllAgeFLIPIindexInduction

chemotherapyResponseto

induction1018624394216370431768222287212900.490.450.590.380.390.610.430.690.510.520.450.38-0.640.33-0.620.39-0.900.19-0.770.25-0.610.43-0.670.31-0.590.44-1.080.13-2.070.38-0.700.29-0.72FavorsMaintenanceFavorsObservation*Nonstratifiedanalysis.<60第9页/共51页PRIMA:RituximabMaintenanceAssociatedWithImprovedResponsesSallesGA,etal.ASCO2010.Abstract8004.Reprintedwithpermission.Response,%Observation

(n=398)*Rituximab

(n=389)*PD40.720.3SD0.30PR7.37.2CR/CRu47.766.8n=190n=258†PatientswithCR/CRuafterinductionremaininginCR/CRu5675PatientswithPR/SDafterinductionconvertingtoCR/CRu3045*Patientsnotevaluated/missingdata:n=16inobservationarm;n=22inrituximabarm.

†Notevaluatedinrituximabmaintenancearm:n=2.第10页/共51页PRIMA:SafetyDuringRituximabMaintenanceSallesGA,etal.ASCO2010.Abstract8004.Reprintedwithpermission.100806040200Patients(%)AnyAdverse

EventGrade≥2

InfectionsGrade3/4

Adverse

EventsGrade3/4

NeutropeniaGrade3/4

InfectionsObservation(n=508)Rituximabmaintenance(n=501)<1<144355222371623第11页/共51页PRIMA:Conclusions2yrsofrituximabmaintenanceassociatedwithsignificantlylongerPFSvsobservationinpatientswithfollicularlymphomawhorespondedtoinductionwithrituximabpluschemotherapyRituximabmaintenancefollowingR-CHOPmaybenefitpreviouslyuntreatedpatientsmorethanrelapsedpatientsHRfollowingR-CHOPinPRIMA:0.43[1]

HRfollowingR-CHOPinEORTCstudyofrelapsedpatients:0.69[2]Moreadverseeventsassociatedwithrituximabmaintenancetherapyvsobservation,butqualityoflifenotaffectedLongerfollow-upneededtoevaluateOSRituximabmaintenancemaynotbejustifiedunlessOSisimproved1.SallesGA,etal.ASCO2010.Abstract8004.2.vanOersMH,etal.JClinOncol.2010;[Epubaheadofprint].第12页/共51页SuredaA,etal.ASCO2010.Abstract8007.PanobinostatPhaseIIStudyinRelapsed/RefractoryHodgkin’sLymphomaSingle-agent,open-labelstudywithSimonoptimal2-stagedesignNullhypothesisORRP≤15%vsalternativehypothesisORRP≥30%Dose:oralpanobinostat40mggiven3times/wk(eg,MWF)ina21-daytreatmentcycleDosedelayandmodificationallowedformanagementofadverseeventsResponseassessmentevery2cyclesbyCT/MRIStage1Stage2Stage1analysis第13页/共51页SuredaA,etal.ASCO2010.Abstract8007.Reprintedwithpermission.PanobinostatinRelapsed/RefractoryHL:HeavilyPretreatedPatientPopulationEvaluablePopulation(FullAnalysisSet)N=129Previouschemotherapyregimens,median(range)4(1-7)Previousradiotherapy,n(%)91(71)Noresponse(SD+PD)tolasttherapy,n(%)48(37)TimefromfirstAHSCTtorelapseinmos,median(range)8(1-198)Patientswithpreviousallogeneicstemcelltransplant,n(%)12(9)PatientswithadditionaltherapyafterAHSCT,n(%)103(80)第14页/共51页SuredaA,etal.ASCO2010.Abstract8007.Reprintedwithpermission.PanobinostatinRelapsed/RefractoryHL:EfficacyDataEvaluablePopulation(FullAnalysisSet)N=129CR(completenormalization),n(%)*4(3)PR(≥50%tumorreduction),n(%)29(22)SD,n(%)78(60)ORR(CR+PR),n(%)33(26)Diseasecontrol(CR+PR+SD),n(%)111(86)Patientswithreductionintumorsize,n(%)91(71)Mediantimetoresponse,wks(range)7(4-51)Mediandurationofresponse,mos(byKaplan-Meier)7.2+MedianPFS,mos(byKaplan-Meier)5.9+*Completenormalizationdefinedasradiologicalregressiontonormalsizeofalllymphnodesandnodal

massesandcompletedisappearanceofallextranodallesions(includingsplenicand/orhepaticnodules).第15页/共51页SuredaA,etal.ASCO2010.Abstract8007.Reprintedwithpermission.PanobinostatinRelapsed/RefractoryHL:SafetyAnalysisMostcommon(≥10%)treatment-relatedadverseevents(N=129)1007550250PercentagebyGrade

(Estimated)ThrombocytopeniaDiarrheaNauseaFatigueAnemiaVomitingNeutropeniaAnorexiaDysgeusiaAstheniaConstipationLeukopeniaGrade3/4Grade1/2Reversiblethrombocytopeniaistheprincipaladverseevent7of100patients(7%)withgrade3/4thrombocytopeniadiscontinuedbecauseofthisevent第16页/共51页PanobinostatinRelapsed/RefractoryHL:ConclusionsPanobinostatmonotherapydemonstrateddurableantitumoractivityinheavilypretreatedpatientswithrelapsed/refractoryHodgkin’slymphomaDiseasecontrolrate:86%Patientswithtumorreduction:71%ORR:26%Estimatedmediandurationofresponse:>7.2mosReversiblethrombocytopeniamostcommontreatment-relatedadverseeventSuredaA,etal.ASCO2010.Abstract8007.第17页/共51页GnaouiTE,etal.ASCO2010.Abstract8011.Prospective,Multicenter,PhaseIITrialofR-GemOxinRelapsed/RefractoryDLBCLInductionConsolidationC1C2C3C4C5C6C7C8ER-

GemOxR-

GemOxR-

GemOxR-

GemOxR-

GemOxR-

GemOxR-

GemOxR-

GemOxW0W2W4W6W8W10W12W14W16NoFollow-upResponse

to

treatmentEvaluationofresponse:ifCR,CRu,orPR,startconsolidationCyclesdelayeduntil:Neutrophils>1x109cells/LPlatelets>100x109cells/L第18页/共51页GnaouiTE,etal.ASCO2010.Abstract8011.R-GemOxinRelapsed/RefractoryDLBCL:EligibilityDLBCLdiagnosisorTransformedCD20+indolentlymphomabyWorldHealthOrganizationclassificationatrelapse60yearsofageorolderoryoungerthan60yearsofage(18yearsorolder)allowedifNoteligibleforhigh-dosechemotherapyorPreviousASCTMeasurablediseaseECOGperformancescore0-2RelapseafterfirstorsecondresponseofPRorbetterResponselessthanPRfollowingfirst-linetreatmentPrevioustreatmentwith≥1anthracycline-containingregimen第19页/共51页GnaouiTE,etal.ASCO2010.Abstract8011.R-GemOxinRelapsed/RefractoryDLBCL:ResponseDataResponse,%After4CyclesofR-GemOx(n=48)EndofTreatment(n=48)ORR60.445.8CR2323CRu2115PR178SD48PD1027Death817第20页/共51页GnaouiTE,etal.ASCO2010.Abstract8011.R-GemOxinRelapsed/RefractoryDLBCL:SafetyAnalysisToxicities,*%SafetyPopulation(N=48)Grade3Grade4HematologicThrombocytopenia2321Anemia212Neutropenia3142Febrileneutropenia40NonhematologicLiver150Neurologic80Kidney20*CalculatedusingNationalCancerInstituteCommonToxicityCriteria(version3.0).第21页/共51页GnaouiTE,etal.ASCO2010.Abstract803101211290481216NoYes<1yr≥1yr<1yr≥1yr<1yr≥1yrPrevious

RituximabDelayFromLastTreatmenttoR-GemOxNoPrevious

RituximabPreviousRituximabP=.0286P=.0166P<.0001MedianPFS(Mos)R-GemOx:PFSAccordingtoDelayFromLastTreatmentandPreviousRituximab第22页/共51页GnaouiTE,etal.ASCO2010.Abstract8011.R-GemOxinRelapsed/RefractoryDLBCL:ConclusionsR-GemOxasasalvageregimendemonstratedfavorablesafetyprofileandproducedhighORRinpatientswithrelapsed/refractoryDLBCLwhowereunabletoreceivehigh-dosechemotherapyORRafter4cycles:60%Patientswithearlyrelapse(<1yrfromlasttreatment)andpreviousrituximabtreatmenthadshortestPFSdurationwithR-GemOxsalvagetherapy第23页/共51页

ChronicMyeloidLeukemia第24页/共51页Patientswithpreviouslyuntreatedchronic-phaseCML(N=519)Dasatinib100mg/day(n=259)Imatinib400mg/day(n=260)5-yrfollow-upStratifiedbyHasfordriskscoreKantarjianH,etal.ASCO2010.AbstractLBA6500.DASISION:RandomizedPhaseIIITrialofImatinibvsDasatinibinCP-CML第25页/共51页DASISION:ResponseDefinitionsKantarjianH,etal.ASCO2010.AbstractLBA6500.ConfirmedCCyRCCyRdetectedin2consecutiveassessmentsCCyRNoPh-positivemetaphasesinbonemarrowMMRBCR-ABL≤0.1%第26页/共51页DASISION:CCyRRateby12Mos(ITT)KantarjianH,etal.ASCO2010.AbstractLBA6500.Reprintedwithpermission.100806040200CCyR(%)CCyR

by12MosConfirmedCCyR

by12MosP=.0011P=.006783727766Dasatinib

100mgQDImatinib

400mgQD第27页/共51页DASISION:CCyRandMMRRatesOverTime(ITT)KantarjianH,etal.ASCO2010.AbstractLBA6500.Outcome,%Dasatinib(n=259)Imatinib(n=260)PValueCCyR3mos54316mos73599mos786712mos8372.0011MMR3mos80.46mos2789mos391812mos4628<.0001第28页/共51页DASISION:PatientsMoreLikelytoAchieveMMRatAnyTimeWithDasatinibInpatientsachievingMMR,mediantimetoMMR6.3moswithdasatinibvs9.2moswithimatinibKantarjianH,etal.ASCO2010.AbstractLBA6500.Reprintedwithpermission.1008060402000369121518212427MosMMR(%)P<.0001(stratifiedlogrank)Hazardratiofordasatinib

overimatinib:2.01DasatinibImatinib第29页/共51页DASISION:DifferencesinAdverseEventsRatesWithDasatinibvsImatinibKantarjianH,etal.ASCO2010.AbstractLBA6500.Reprintedwithpermission.-0.4-Anemia,grade3/4

Neutropenia,grade3/4

Thrombocytopenia,grade3/4

Myalgia*

Nausea

Vomiting

Rash

Diarrhea

Fatigue

Headache

Fluidretention

Superficialedema

PleuraleffusionRatedifference(dasatinib-imatinib)withexact95%CIFavorsDasatinibFavorsImatinib*Myalgia=myalgia,muscleinflammation,andMSKpains.第30页/共51页ConclusionsDasatinibassociatedwithsuperiorefficacycomparedwithimatinibforfirst-linetreatmentofCP-CMLHigherandfasterratesofCCyR,confirmedCCyR,andMMRDasatinibgenerallywelltoleratedLowratesofgrade3/4hematologictoxicityResultssupportuseofdasatinibasfirst-linetherapyforpatientswithnewlydiagnosedCP-CMLKantarjianH,etal.ASCO2010.AbstractLBA6500.第31页/共51页Patientsnewlydiagnosedwith

Ph-positive

CP-CMLwithin6mos(N=846)Nilotinib300mgBID(n=282)Nilotinib400mgBID(n=281)Imatinib400mgQD(n=283)5-yrfollow-upStratifiedbySokalriskscoreYr1LarsonRA,etal.ASCO2010.Abstract6501.ENESTnd:RandomizedPhaseIIITrialofImatinibvsNilotinibinPh-PositiveCP-CML第32页/共51页ENESTnd:PrimaryEndpoint—MMRRateat12Mos(ITTPopulation)LarsonRA,etal.ASCO2010.Abstract6501.SaglioG,etal.NEnglJMed.2010;[Epubaheadofprint].Reprintedwithpermission.6050403020100MMR(%)P<.0001P<.0001444322Nilotinib300mgBIDNilotinib400mgBIDImatinib400mgQDn=282n=281n=283第33页/共51页ENESTnd:CCyRRatesby12MosandOverall(ITT)Amongpatientswhohadacytogeneticassessmentat18mos

(n=442/846),theratesofCCyRwereNilotinib300mgBID99%,nilotinib400mgBID99%,imatinib89%LarsonRA,etal.ASCO2010.Abstract6501.Reprintedwithpermission.100806040200CCyR(%)Mo12Overalln=282n=281n=283n=282n=281n=283807865858274P<.0001P<.001P<.001P=.017Nilotinib300mgBIDNilotinib400mgBIDImatinib400mgQD第34页/共51页LarsonRA,etal.ASCO2010.Abstract6501.ENESTnd:ConclusionsLongerfollow-upofENESTndtrialcontinuestoshowsuperiorratesofMMRandCCyRwithnilotinib300mgBIDor400mgBIDvsimatinib400mgQDinnewlydiagnosedPh-positive

CP-CMLLowereventrates(progressionordeath)withnilotinibvsimatinibNilotinibgenerallywelltoleratedatbothdoses,grade3/4adverseeventssimilartoimatinibAccordingtoinvestigators,thesedatasupportuseofnilotinibasstandardfirst-linetherapyforCMLOnJune17,2010,theFDAapprovednilotinibforthetreatmentofadultpatientswithnewlydiagnosedPh-positiveCP-CML第35页/共51页

ChronicMyelomonocyticLeukemia第36页/共51页SafetyandEfficacyofAzacitidineinCMMLFewdataareavailabletoguidemanagementofCMMLCurrentstudyarecordsreviewofCMMLpatients(N=38)treatedwithazacitidineat1institutionAzacitidineadministration75mg/m2/dayfor7daysor100mg/m2/dayfor5daysRepeatedevery4wksResponsecriteriaPatientsconsideredevaluableforresponsewith≥1azacitidinecycleAssessedbymodifiedInternationalWorkingGroupcriteriaCostaRB.ASCO2010.Abstract6574.第37页/共51页AzacitidineinCMML:ResponseandOverallSurvivalEfficacyAzacitidine(n=36)PValueORR,%42CR11PR3Hematologicimprovement28OverallmedianOS,mos12Responders13.02Nonresponders9CostaRB.ASCO2010.Abstract6574.第38页/共51页AzacitidineinCMML:ConclusionsRetrospectivereviewdemonstratedactivityofazacitidineinCMMLNearlyonehalfofpatientsrespondedtoazacitidineMedianOSsignificantlylongerinrespondingvsnonrespondingpatientsAzacitidinegenerallywelltoleratedCytopeniamostfrequentadverseevent(25%)AzacitidineshouldbeevaluatedincombinationwithnovelagentstodetermineifitfurtherimprovesresponseratesandsurvivalinCMMLCostaRB.ASCO2010.Abstract6574.第39页/共51页

MultipleMyeloma第40页/共51页UpdatedAnalysisofPhaseI/IITrialofVRDinNewlyDiagnosedMultipleMyelomaPhase1uptoeight3-wkcyclesat5doselevels;phaseIIdose:25mg/1.3mg/m2lenalidomide/bortezomib+20-mgdexamethasonePatientswith≥PRcouldproceedtoASCTafter≥4cyclesAfter8cycles,respondingpatientscouldreceivemaintenance3-wkcyclesoflenalidomide(Days1-14),andwklybortezomib(Days1,8),atdosestoleratedatendofcycle8plusdexamethasone10mg(Days1,2,8,9)AndersonKC,etal.ASCO2010.Abstract8016.Reprintedwithpermission.D12458911121421BzBzBzBzDexDexDexDexDexDexDexDexLendaily第41页/共51页VRDinNewlyDiagnosedMM:PatientDispositionatLongerFollow-upN=66Ontreatment:15%Received≥8cyclesofall3agents:59%Discontinued≤cycle8:n=28(42%);proceededtoASCT(n=13),treatmentcompletedperprotocol(n=6),adverseevent(n=3),consentwithdrawn(n=3),death(n=1),physiciandecision(n=1),nonprotocoltherapy(n=1)Discontinuedduringmaintenance:n=28(42%);treatmentcompletedperprotocol(n=10),diseaseprogression(n=8),consentwithdrawn(n=4),proceededtoASCT(n=3),adverseevent(n=1),physiciandecision(n=1),other(n=1)Overall,proceededtoASCT:47%AndersonKC,etal.ASCO2010.Abstract8016.第42页/共51页VRDinNewlyDiagnosedMM:UpdatedOutcomesMedianfollow-up:27.3mosPatientsurvivalwithoutdiseaseprogression:n=44MediandurationofresponsenotreachedMedianPFSandOSnotreachedEstimated24-moPFS:68%(95%CI:55%to78%)Estimated24-moOS:95%(95%CI:86%to98%)At1yr,53patientshadnotprogressed(26withASCT,

27withoutASCT)NosignificantdifferenceinPFSbetweenthosewithASCTandthosewithoutAndersonKC,etal.ASCO2010.Abstract8016.第43页/共51页ResponsesAssociatedWithBortezomib,Lenalidomide,DexamethasoneAndersonKC,etal.ASCO2010.Abstract8016.33262717112029370102030405060708090100Allpatients

(N=66)PatientsinphaseIIonly

(n=35)CRNearCRVerygoodPRPRPatients(%)BestResponses第44页/共51页SummaryCombinationtherapywithbortezomib,lenalidomide,dexamethasoneactiveinnewlydiagnosedmultiplemyelomapatientsAllpatientsachievedPRorbetterwithhighratesofCR,nearCR,orverygoodPREstimated2-yrOSrate(withoptionforASCTifinPRafter4cycles):95%Treatmentwelltolerated:toxicitiesmostlylowgradeandmanageableMostfrequentgrade3/4adverseevents:neutropenia(14%)andlymphopenia(14%)6%ofpatientsexperienceddeepveinthrombosisorpulmonaryembolismBortezomib,lenalidomide,dexamethasonemayofferbasisforafuturestandardofcarefornewlydiagnosedmultiplemyelomaAndersonKC,etal.ASCO2010.Abstract8016.第45页/共51页CALGB100104:LenalidomidevsPlaceboMaintenanceFollowingASCTforMMMcCarthyPL,etal.ASCO2010.Abstract8017.Lenalidomide10mg/daywithdoseadjustmentsto5-15mg(n=210)Placebo(n=208)CRPRSDMelphalan200mg/m2+ASCTRestaging

Days90-100Stratifiedbasedondiagnosticβ2Ma