美国临床肿瘤学会年会恶性血液病最新进展课件

June4 8 2010Chicago Illinois HematologicMalignanciesCCOIndependentConferenceCoverageofthe2010AmericanSocietyofClinicalOncologyAnnualMeeting CCOisanindependentmedicaleducationcompanythatprovidesstate of the artmedicalinformationtohealthcareprofessionalsthroughconferencecoverageandothereducationalprograms ThisprogramissupportedbyeducationalgrantsfromAmgen Bristol MyersSquibb Celgene GenentechBioOncology MillenniumPharmaceuticals Inc NovartisOncology andPfizer Inc AboutTheseSlides OurthankstothepresenterswhogavepermissiontoincludetheiroriginaldataUsersareencouragedtousetheseslidesintheirownnoncommercialpresentations butweaskthatcontentandattributionnotbechanged UsersareaskedtohonorthisintentTheseslidesmaynotbepublishedorpostedonlinewithoutpermissionfromClinicalCareOptions emailpermissions DisclaimerThematerialspublishedontheClinicalCareOptionsWebsitereflecttheviewsoftheauthorsoftheCCOmaterial notthoseofClinicalCareOptions LLC theCMEproviders orthecompaniesprovidingeducationalgrants ThematerialsmaydiscussusesanddosagesfortherapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration Aqualifiedhealthcareprofessionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed Readersshouldverifyallinformationanddatabeforetreatingpatientsorusinganytherapiesdescribedinthesematerials Faculty NicholasJ DiBella MDCo Chairman HematologyResearchCommittee USOncologyPresident RockyMountainCancerCentersAurora Colorado AnUpdateonHematologicMalignancies Overview PRIMA rituximabmaintenancevsobservationinpatientswithfollicularlymphomawhorespondedtoinductionwithrituximabpluschemotherapyPhaseIItrialofpanobinostatinrelapsed refractoryHodgkin slymphomaPhaseIItrialofR GemOxforpatientswithrelapsed refractoryDLBCLnotcandidatesforhigh dosetherapyDASISION phaseIIItrialofimatinibvsdasatinibinuntreatedCP CMLENESTndphaseIIItrialofnilotinib300mgBIDor400mgBIDvsimatinib400mgQDinnewlydiagnosedPh positiveCP CMLInvestigationofazacitidineinchronicmyelomonocyticleukemiaInvestigationofbortezomib lenalidomide dexamethasoneinnewlydiagnosedmultiplemyelomaCALGB100104 lenalidomidemaintenancevsplacebofollowingASCTinmultiplemyeloma Lymphomas Untreatedpatientswithhightumorburdenfollicularlymphoma InductionImmunochemotherapy8cyclesR CHOPorR CVPorR FCM Rituximabmaintenance375mg m2q8wfor2yrs n 505 Observation n 513 Response N 1019 OnlypatientswithCR CRu PRrandomizedtomaintenancetherapy 1patientdiedduringrandomization Stratifiedbyresponsetoinduction chemotherapyregimen andgeographiclocationpriorto1 1randomization 5 yrfollow up SallesGA etal ASCO2010 Abstract8004 PRIMA RituximabMaintenancevsObservationinPatientsWithFL PRIMA PrimaryEndpoint PFS MetatPlannedInterimAnalysis Rituximabmaintenancereducedtheriskofprogressionby50 SallesGA etal ASCO2010 Abstract8004 Reprintedwithpermission 1 0 0 8 0 6 0 4 0 2 0 0 6 12 18 24 30 36 Progression FreeRate Mos StratifiedHR 0 5095 CI 0 39 0 64P 0001 82 66 Rituximabmaintenance n 505 Observation n 513 PatientsatRisk n 506513 472469 443411 336289 230195 10382 1815 PRIMA BenefitsofRituximabMaintenancebySubgroup SallesGA etal ASCO2010 Abstract8004 Reprintedwithpermission All 60 FLIPI 1 FLIPI 2 FLIPI 3 R CHOP R CVP R FCM CR CRu PR 0 1 2 3 Category Subgroup HR n HR 95 CI All Age FLIPIindex Inductionchemotherapy Responsetoinduction 1018 624 394 216 370 431 768 222 28 721 290 0 49 0 45 0 59 0 38 0 39 0 61 0 43 0 69 0 51 0 52 0 45 0 38 0 64 0 33 0 62 0 39 0 90 0 19 0 77 0 25 0 61 0 43 0 67 0 31 0 59 0 44 1 08 0 13 2 07 0 38 0 70 0 29 0 72 FavorsMaintenance FavorsObservation Nonstratifiedanalysis 60 PRIMA RituximabMaintenanceAssociatedWithImprovedResponses SallesGA etal ASCO2010 Abstract8004 Reprintedwithpermission Patientsnotevaluated missingdata n 16inobservationarm n 22inrituximabarm Notevaluatedinrituximabmaintenancearm n 2 PRIMA SafetyDuringRituximabMaintenance SallesGA etal ASCO2010 Abstract8004 Reprintedwithpermission 100 80 60 40 20 0 Patients AnyAdverseEvent Grade 2Infections Grade3 4AdverseEvents Grade3 4Neutropenia Grade3 4Infections Observation n 508 Rituximabmaintenance n 501 1 1 4 4 35 52 22 37 16 23 PRIMA Conclusions 2yrsofrituximabmaintenanceassociatedwithsignificantlylongerPFSvsobservationinpatientswithfollicularlymphomawhorespondedtoinductionwithrituximabpluschemotherapyRituximabmaintenancefollowingR CHOPmaybenefitpreviouslyuntreatedpatientsmorethanrelapsedpatientsHRfollowingR CHOPinPRIMA 0 43 1 HRfollowingR CHOPinEORTCstudyofrelapsedpatients 0 69 2 Moreadverseeventsassociatedwithrituximabmaintenancetherapyvsobservation butqualityoflifenotaffectedLongerfollow upneededtoevaluateOSRituximabmaintenancemaynotbejustifiedunlessOSisimproved 1 SallesGA etal ASCO2010 Abstract8004 2 vanOersMH etal JClinOncol 2010 Epubaheadofprint SuredaA etal ASCO2010 Abstract8007 PanobinostatPhaseIIStudyinRelapsed RefractoryHodgkin sLymphoma Single agent open labelstudywithSimonoptimal2 stagedesignNullhypothesisORRP 15 vsalternativehypothesisORRP 30 Dose oralpanobinostat40mggiven3times wk eg MWF ina21 daytreatmentcycleDosedelayandmodificationallowedformanagementofadverseeventsResponseassessmentevery2cyclesbyCT MRI Stage1 Stage2 Stage1analysis SuredaA etal ASCO2010 Abstract8007 Reprintedwithpermission PanobinostatinRelapsed RefractoryHL HeavilyPretreatedPatientPopulation SuredaA etal ASCO2010 Abstract8007 Reprintedwithpermission PanobinostatinRelapsed RefractoryHL EfficacyData Completenormalizationdefinedasradiologicalregressiontonormalsizeofalllymphnodesandnodalmassesandcompletedisappearanceofallextranodallesions includingsplenicand orhepaticnodules SuredaA etal ASCO2010 Abstract8007 Reprintedwithpermission PanobinostatinRelapsed RefractoryHL SafetyAnalysis Mostcommon 10 treatment relatedadverseevents N 129 Reversiblethrombocytopeniaistheprincipaladverseevent7of100patients 7 withgrade3 4thrombocytopeniadiscontinuedbecauseofthisevent PanobinostatinRelapsed RefractoryHL Conclusions Panobinostatmonotherapydemonstrateddurableantitumoractivityinheavilypretreatedpatientswithrelapsed refractoryHodgkin slymphomaDiseasecontrolrate 86 Patientswithtumorreduction 71 ORR 26 Estimatedmediandurationofresponse 7 2mosReversiblethrombocytopeniamostcommontreatment relatedadverseevent SuredaA etal ASCO2010 Abstract8007 GnaouiTE etal ASCO2010 Abstract8011 Prospective Multicenter PhaseIITrialofR GemOxinRelapsed RefractoryDLBCL Induction Consolidation C1 C2 C3 C4 C5 C6 C7 C8 E R GemOx R GemOx R GemOx R GemOx R GemOx R GemOx R GemOx R GemOx W0 W2 W4 W6 W8 W10 W12 W14 W16 NoFollow up Responsetotreatment Evaluationofresponse ifCR CRu orPR startconsolidation Cyclesdelayeduntil Neutrophils 1x109cells LPlatelets 100 x109cells L GnaouiTE etal ASCO2010 Abstract8011 R GemOxinRelapsed RefractoryDLBCL Eligibility DLBCLdiagnosisorTransformedCD20 indolentlymphomabyWorldHealthOrganizationclassificationatrelapse60yearsofageorolderoryoungerthan60yearsofage 18yearsorolder allowedifNoteligibleforhigh dosechemotherapyorPreviousASCT MeasurablediseaseECOGperformancescore0 2RelapseafterfirstorsecondresponseofPRorbetterResponselessthanPRfollowingfirst linetreatmentPrevioustreatmentwith 1anthracycline containingregimen GnaouiTE etal ASCO2010 Abstract8011 R GemOxinRelapsed RefractoryDLBCL ResponseData GnaouiTE etal ASCO2010 Abstract8011 R GemOxinRelapsed RefractoryDLBCL SafetyAnalysis CalculatedusingNationalCancerInstituteCommonToxicityCriteria version3 0 GnaouiTE etal ASCO2010 Abstract8011 11 4 4 2 3 10 12 11 2 9 0 4 8 12 16 No Yes 1yr 1yr 1yr 1yr 1yr 1yr PreviousRituximab DelayFromLastTreatmenttoR GemOx NoPreviousRituximab PreviousRituximab P 0286 P 0166 P 0001 MedianPFS Mos R GemOx PFSAccordingtoDelayFromLastTreatmentandPreviousRituximab GnaouiTE etal ASCO2010 Abstract8011 R GemOxinRelapsed RefractoryDLBCL Conclusions R GemOxasasalvageregimendemonstratedfavorablesafetyprofileandproducedhighORRinpatientswithrelapsed refractoryDLBCLwhowereunabletoreceivehigh dosechemotherapyORRafter4cycles 60 Patientswithearlyrelapse 1yrfromlasttreatment andpreviousrituximabtreatmenthadshortestPFSdurationwithR GemOxsalvagetherapy ChronicMyeloidLeukemia Patientswithpreviouslyuntreatedchronic phaseCML N 519 Dasatinib100mg day n 259 Imatinib400mg day n 260 5 yrfollow up StratifiedbyHasfordriskscore KantarjianH etal ASCO2010 AbstractLBA6500 DASISION RandomizedPhaseIIITrialofImatinibvsDasatinibinCP CML DASISION ResponseDefinitions KantarjianH etal ASCO2010 AbstractLBA6500 ConfirmedCCyRCCyRdetectedin2consecutiveassessmentsCCyRNoPh positivemetaphasesinbonemarrowMMRBCR ABL 0 1 DASISION CCyRRateby12Mos ITT KantarjianH etal ASCO2010 AbstractLBA6500 Reprintedwithpermission 100 80 60 40 20 0 CCyR CCyRby12Mos ConfirmedCCyRby12Mos P 0011 P 0067 83 72 77 66 Dasatinib100mgQD Imatinib400mgQD DASISION CCyRandMMRRatesOverTime ITT KantarjianH etal ASCO2010 AbstractLBA6500 DASISION PatientsMoreLikelytoAchieveMMRatAnyTimeWithDasatinib InpatientsachievingMMR mediantimetoMMR6 3moswithdasatinibvs9 2moswithimatinib KantarjianH etal ASCO2010 AbstractLBA6500 Reprintedwithpermission 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 Mos MMR P 0001 stratifiedlogrank Hazardratiofordasatiniboverimatinib 2 01 DasatinibImatinib DASISION DifferencesinAdverseEventsRatesWithDasatinibvsImatinib KantarjianH etal ASCO2010 AbstractLBA6500 Reprintedwithpermission 0 4 0 2 0 0 2 0 4 Anemia grade3 4Neutropenia grade3 4Thrombocytopenia grade3 4Myalgia NauseaVomitingRashDiarrheaFatigueHeadacheFluidretentionSuperficialedemaPleuraleffusion Ratedifference dasatinib imatinib withexact95 CI FavorsDasatinib FavorsImatinib Myalgia myalgia muscleinflammation andMSKpains Conclusions Dasatinibassociatedwithsuperiorefficacycomparedwithimatinibforfirst linetreatmentofCP CMLHigherandfasterratesofCCyR confirmedCCyR andMMRDasatinibgenerallywelltoleratedLowratesofgrade3 4hematologictoxicityResultssupportuseofdasatinibasfirst linetherapyforpatientswithnewlydiagnosedCP CML KantarjianH etal ASCO2010 AbstractLBA6500 PatientsnewlydiagnosedwithPh positiveCP CMLwithin6mos N 846 Nilotinib300mgBID n 282 Nilotinib400mgBID n 281 Imatinib400mgQD n 283 5 yrfollow up StratifiedbySokalriskscore Yr1 LarsonRA etal ASCO2010 Abstract6501 ENESTnd RandomizedPhaseIIITrialofImatinibvsNilotinibinPh PositiveCP CML ENESTnd PrimaryEndpoint MMRRateat12Mos ITTPopulation LarsonRA etal ASCO2010 Abstract6501 SaglioG etal NEnglJMed 2010 Epubaheadofprint Reprintedwithpermission 60 50 40 30 20 10 0 MMR P 0001 P 0001 44 43 22 Nilotinib300mgBID Nilotinib400mgBID Imatinib400mgQD n 282 n 281 n 283 ENESTnd CCyRRatesby12MosandOverall ITT Amongpatientswhohadacytogeneticassessmentat18mos n 442 846 theratesofCCyRwereNilotinib300mgBID99 nilotinib400mgBID99 imatinib89 LarsonRA etal ASCO2010 Abstract6501 Reprintedwithpermission 100 80 60 40 20 0 CCyR Mo12 Overall n 282 n 281 n 283 n 282 n 281 n 283 80 78 65 85 82 74 P 0001 P 001 P 001 P 017 Nilotinib300mgBID Nilotinib400mgBID Imatinib400mgQD LarsonRA etal ASCO2010 Abstract6501 ENESTnd Conclusions Longerfollow upofENESTndtrialcontinuestoshowsuperiorratesofMMRandCCyRwithnilotinib300mgBIDor400mgBIDvsimatinib400mgQDinnewlydiagnosedPh positiveCP CMLLowereventrates progressionordeath withnilotinibvsimatinibNilotinibgenerallywelltoleratedatbothdoses grade3 4adverseeventssimilartoimatinibAccordingtoinvestigators thesedatasupportuseofnilotinibasstandardfirst linetherapyforCMLOnJune17 2010 theFDAapprovednilotinibforthetreatmentofadultpatientswithnewlydiagnosedPh positiveCP CML ChronicMyelomonocyticLeukemia SafetyandEfficacyofAzacitidineinCMML FewdataareavailabletoguidemanagementofCMMLCurrentstudyarecordsreviewofCMMLpatients N 38 treatedwithazacitidineat1institutionAzacitidineadministration75mg m2 dayfor7daysor100mg m2 dayfor5daysRepeatedevery4wksResponsecriteriaPatientsconsideredevaluableforresponsewith 1azacitidinecycleAssessedbymodifiedInternationalWorkingGroupcriteria CostaRB ASCO2010 Abstract6574 AzacitidineinCMML ResponseandOverallSurvival CostaRB ASCO2010 Abstract6574 AzacitidineinCMML Conclusions RetrospectivereviewdemonstratedactivityofazacitidineinCMMLNearlyonehalfofpatientsrespondedtoazacitidineMedianOSsignificantlylongerinrespondingvsnonrespondingpatientsAzacitidinegenerallywelltoleratedCytopeniamostfrequentadverseevent 25 AzacitidineshouldbeevaluatedincombinationwithnovelagentstodetermineifitfurtherimprovesresponseratesandsurvivalinCMML CostaRB ASCO2010 Abstract6574 MultipleMyeloma UpdatedAnalysisofPhaseI IITrialofVRDinNewlyDiagnosedMultipleMyeloma Phase1uptoeight3 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 D1 2 4 5 8 9 11 12 14 21 Bz Bz Bz Bz Dex Dex Dex Dex Dex Dex Dex Dex Lendaily VRDinNewlyDiagnosedMM PatientDispositionatLongerFollow up N 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 VRDinNewlyDiagnosedMM UpdatedOutcomes Medianfollow up 27 3mosPatientsurvivalwithoutdiseaseprogression n 44MediandurationofresponsenotreachedMedianPFSandOSnotreachedEstimated24 moPFS 68 95 CI 55 to78 Estimated24 moOS 95 95 CI 86 to98 At1yr 53patientshadnotprogressed 26withASCT 27withoutASCT NosignificantdifferenceinPFSbetweenthosewithASCTandthosewithout AndersonKC etal ASCO2010 Abstract8016 ResponsesAssociatedWithBortezomib Lenalidomide Dexamethasone AndersonKC etal ASCO2010 Abstract8016 33 26 27 17 11 20 29 37 0 10 20 30 40 50 60 70 80 90 100 Allpatients N 66 PatientsinphaseIIonly n 35 CR NearCR VerygoodPR PR Patients BestResponses Summary Combinationtherapywithbortezomib lenalidomide dexamethasoneactiveinnewlydiagnosedmultiplemyelomapatientsAllpatientsachievedPRorbetterwithhighratesofCR nearCR orverygoodPREstimated2 yrOSrate withoptionforASCTifinPRafter4cycles 95 Treatmentwelltolerated toxicitiesmostlylowgradeandmanageableMostfrequentgrade3 4adverseevents neutropenia 14 andlymphopenia 14 6 ofpatientsexperienceddeepveinthrombosisorpulmonaryembolismBortezomib lenalidomide dexamethasonemayofferbasisforafuturestandardofcarefornewlydiagnosedmultiplemyeloma AndersonKC etal ASCO2010 Abstract8016 CALGB100104 LenalidomidevsPlaceboMaintenanceFollowingASCTforMM McCarthyPL etal ASCO2010 Abstract8017 Lenalidomide10mg daywithdoseadjustmentsto5 15mg n 210 Placebo n 208 CRPRSD Melphalan200mg m2 ASCT RestagingDays90 100 Stratifiedbasedondiagnostic 2MandthalidomideandlenalidomideuseduringInduction Patie