ASH慢性髓性白血病--.ppt

慢性髓性白血病研究进展-第52届ASH会议重点解读December4-7,2010Orlando,FL,2010-12-12（济南）,第52届ASH会议慢性髓性白血病相关文献,AbstractsLatebreakingAbstractsOralandPosterAbstractsChronicMyeloidLeukemia-TherapyChronicMyeloidLeukemia-BiologyandPathophysiologyEducationProgramCML2010:WhereAreWeNowandWhereCanWeGo?,第一部分CML治疗-TKI,伊马替尼比较大剂量与标准剂量伊马替尼治疗的有效性及安全性（theGermanCML-StudyIV）分析伊马替尼治疗的分子反应程度与生存的关系评估伊马替尼治疗老年患者的疗效及安全性评价伊马替尼治疗青少年患者的临床疗效尼洛替尼评估尼洛替尼治疗的有效性和安全性（ENESTndTrial）达沙替尼评价达沙替尼治疗的有效性和安全性（DASISIONTrial）比较达沙替尼和伊马替尼治疗的有效性和安全性（TheS0325IntergroupTrial）分析BCR-ABL激酶区突变与治疗反应的关系,OralandPosterAbstractsLate-breakingAbstracts,Seven-YearFollow-upDataonSequentialProspectiveTrialsofImatinib400mgVs800mgDailyScheduleforFront-LineTreatmentofChronicMyeloidLeukemia(CML),NaveenPemmaraju,MDPosterSession:ChronicMyeloidLeukemia-Therapy:PosterIII3438,目的-比较使用伊马替尼800mg与400mg作为CML一线治疗的长期临床疗效结果,Seven-YearFollow-upDataonSequentialProspectiveTrialsofImatinib400mgVs800mgDailyScheduleforFront-LineTreatmentofChronicMyeloidLeukemia(CML),NaveenPemmaraju,MDPosterSession:ChronicMyeloidLeukemia-Therapy:PosterIII3438,结论-7年跟踪调查显示：与伊马替尼400mg相比，伊马替尼800mg12个月CCyR、18个月MMR、7年PFS明显改善,但OS无差异-大剂量伊马替尼治疗CML有一定益处,SuperiorCMR-RateswithTolerability-AdaptedImatinib800MgVs.400MgVs.400Mg+IFNInCML:TheRandomizedGermanCML-StudyIV,RdigerHehlmann,MDOralSession:ChronicMyeloidLeukemia-Therapy:OptimizingFront-LineTherapyinCML357,目的-评价大剂量伊马替尼治疗初诊Ph+CML-CP患者的疗效研究设计-完全分子学缓解CMR被定义为BCR-ABL/ABLIS65years):ResultsoftheGermanCML-StudyIV,SusanneSaussele,MDPosterSession:ChronicMyeloidLeukemia-Therapy:PosterIII3411,结果有效性-年老与年轻患者间细胞遗传学和分子学缓解率无显著差异-IM400mg组中，年老比年轻患者更慢获得CCyR和MMR(CCvR:14.2月vs12.1月,p=.019;MMR:18.7月vs17.5月,p=.006）-IM800mg组中，两组间无差异(CCvR:7.7月vs8.9月,MMR:9.9月vs10.0月)-3年总生存率两组分别为94.7%和96.1%安全性-血液学不良反应：年老比年轻患者稍重-3、4级非血液学不良反应：无差异,TherapywithImatinibInElderlyCMLPatients(65years):ResultsoftheGermanCML-StudyIV,SusanneSaussele,MDPosterSession:ChronicMyeloidLeukemia-Therapy:PosterIII3411,结论-年老患者使用伊马替尼400mg和800mg均耐受性良好-应用伊马替尼800mg治疗，年老与年轻患者获得CCyR和MMR的中位时间无差异-应用伊马替尼400mg治疗，年老患者比年轻患者更慢获得CCyR和MMR,AnalysisofOutcomesInAdolescentsandYoungAdults(AYA)withChronicMyeloidLeukemia(CML)TreatedwithUpfrontTyrosineKinaseInhibitors(TKI),NaveenPemmaraju,MDPosterSession:ChronicMyeloidLeukemia-Therapy:Poster1234,目的-评价酪氨酸激酶抑制剂治疗青少年CML患者的临床疗效研究对象-年龄15至21岁的CML患者；移植患者排除结果,AnalysisofOutcomesInAdolescentsandYoungAdults(AYA)withChronicMyeloidLeukemia(CML)TreatedwithUpfrontTyrosineKinaseInhibitors(TKI),NaveenPemmaraju,MDPosterSession:ChronicMyeloidLeukemia-Therapy:Poster1234,结论-与青少年CML患者相比，年长患者CCyR明显提高；MMR和CMR也有升高趋势-青少年与年长CML患者EFS，TFS和OS无差别,ENESTndUpdate:ContinuedSuperiorityofNilotinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP),TimothyP.Hughes,MD,MBBSOralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome207,目的-评价尼洛替尼治疗初诊Ph+CML-CP患者的疗效和安全性(中位随访18个月的ENESTnd研究结果更新)研究设计-随机开放的多中心的3期临床研究-846例初诊CML-CP患者入组-主要终点：12个月MMR(0.1%BCR-ABLIS)-次要终点：24个月持续MMR-其他：24个月加速/急变率、EFS、PFS和OS,TimothyP.Hughes,MD,MBBSOralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome207,ENESTndUpdate:ContinuedSuperiorityofNilotinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP),结果,ENESTndUpdate:ContinuedSuperiorityofNilotinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP),TimothyP.Hughes,MD,MBBSOralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome207,结论与伊马替尼相比，尼洛替尼-加速/急变率和治疗失败率显著降低-CML相关死亡更少，OS更高-MMR，CMR和CCyR更高对于初诊Ph+CML-CP患者,尼洛替尼疗效优于伊马替尼,DasatinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP)IntheDASISIONTrial:18-MonthFollow-up,NeilShah,MD,Ph.D.OralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome206,目的-评价达沙替尼治疗初诊Ph+CML-CP患者的疗效和安全性(中位随访18个月的DASISION研究结果更新)研究设计-开放性、多中心的国际3期临床研究-519例初诊CML-CP患者入组-随机分为两组：达沙替尼100mgqd或伊马替尼400mgqd,DasatinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP)IntheDASISIONTrial:18-MonthFollow-up,NeilShah,MD,Ph.D.OralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome206,结果-达沙替尼的疗效和安全性与中位随访12个月结果一致,DasatinibVersusImatinibInPatientswithNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP)IntheDASISIONTrial:18-MonthFollow-up,NeilShah,MD,Ph.D.OralSession:ChronicMyeloidLeukemia-Therapy:OptimizingTreatmentOutcome206,结论中位随访18个月结果仍显示达沙替尼疗效优于伊马替尼达沙替尼耐受性良好,ARandomizedPhaseIITrialofDasatinib100MgVsImatinib400MgInNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP):TheS0325IntergroupTrial,JeraldP.Radich,MDSession:Late-BreakingAbstractsSessionLBA-6,目的-比较达沙替尼和伊马替尼治疗初诊Ph+CML-CP患者的疗效和安全性研究设计-随机开放、多中心的2期临床研究（SWOG,ECOG,CALGB,NCIC-CTG）-240例初诊CML-CP患者入组-主要终点：12个月BCRABLIS下降4log,ARandomizedPhaseIITrialofDasatinib100MgVsImatinib400MgInNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP):TheS0325IntergroupTrial,结果-达沙替尼组12个月分子反应更深，BCRABLIS中位下降3.3log；伊马替尼组中位下降2.8log（P=0.048）-两组获得HemCR和CCyR无显著差异-死亡、复发及进展均极少，OS和PFS相似-均无致命的不良反应，达沙替尼最常见的3、4级血液学不良反应是血小板减少,ARandomizedPhaseIITrialofDasatinib100MgVsImatinib400MgInNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP):TheS0325IntergroupTrial,JeraldP.Radich,MDSession:Late-BreakingAbstractsSessionLBA-6,结论达沙替尼和伊马替尼400mg治疗初诊Ph+CML-CP均有效，且耐受性好与伊马替尼相比，达沙替尼12个月时获得更深的分子反应达沙替尼和伊马替尼OS和PFS相似达沙替尼有更多的3、4级血液学不良反应,PatientswithChronicMyeloidLeukemiaInChronicPhaseCarryingMoreThanOneBCR-ABLKinaseDomainMutationExhibitPoorerResponseRatesandOutcomestoSecond-LineDasatinibComparedtoThosewithNoorOnlyOneBCR-ABLMutation,AlfonsoQuints-CardamaPosterSession:ChronicMyeloidLeukemia-Therapy:PosterII2297,目的-分析CML-CP患者BCR-ABL激酶区突变与治疗反应的关系研究设计-回顾性分析-1150例对伊马替尼耐药或不耐受、使用达沙替尼治疗的CML-CP患者入组-2期START-C(-013)、START-R(-017）、3期剂量优化试验(-034),PatientswithChronicMyeloidLeukemiaInChronicPhaseCarryingMoreThanOneBCR-ABLKinaseDomainMutationExhibitPoorerResponseRatesandOutcomestoSecond-LineDasatinibComparedtoThosewithNoorOnlyOneBCR-ABLMutation,AlfonsoQuints-CardamaPosterSession:ChronicMyeloidLeukemia-Therapy:PosterII2297,结果,PatientswithChronicMyeloidLeukemiaInChronicPhaseCarryingMoreThanOneBCR-ABLKinaseDomainMutationExhibitPoorerResponseRatesandOutcomestoSecond-LineDasatinibComparedtoThosewithNoorOnlyOneBCR-ABLMutation,AlfonsoQuints-CardamaPosterSession:ChronicMyeloidLeukemia-Therapy:PosterII2297,结论无论有、无BCR-ABL激酶区基线突变，达沙替尼疗效显著存在基线突变的CML-CP患者治疗反应率和PFS较低存在大于一个基线突变的CML-CP患者治疗反应率和PFS最低,第二部分：TKI耐药的机制研究-相关信号通路,JAK2信号STAT5信号Hedgehog信号通路NF-B信号Syk-Lyn-Axl信号通路,OralandPosterAbstracts,JAK2信号,Jak2RegulatesBcr-AblInCD34+CellsFromImatinibMesylate-ResistantCMLPatients-BastianellaPerazzona,Ph.D.JAK2-MediatedExtrinsicSurvivalofCMLStemCells:ExploringthePotentialCombinationofBCR-ABLandJAK2InhibitorsInVivo-ElieTraer,MD,PhDCombinedTargetingofBCR-ABLandJAK2withABLandJAK2InhibitorsIsEffectiveAgainstCMLPatientsLeukemicStem/ProgenitorCells-DonnaDeGeer,MSc,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1220OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:CMLStemCell/ProgenitorBiology199PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3404,JAK2信号,JAK2抑制剂明显降低BCR-ABL蛋白表达和磷酸酪氨酸177水平JAK2抑制剂有效诱导伊马替尼耐药的CD34+干、祖细胞死亡体内同时抑制BCR-ABL和JAK2表达，显著降低BCR-ABL表达的细胞数量,但骨髓毒性较大BCR-ABL和JAK2抑制剂联用可有效杀伤TKI耐受的CML干、祖细胞,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1220OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:CMLStemCell/ProgenitorBiology199PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3404,STAT5信号,DistinctFunctionsofStat5AandStat5BinChronicMyeloidLeukemia(CML):Stat5BIsImplicatedinSurvivalandSelf-RenewalandStat5AinImatinibResistance-AliG.Turhan,MD,PhDBcr-AblDirectlyActivatesStat5IndependentofJak2-OliverD.Hantschel,PhDHormone-ConditionalActivationofBcr-AblKinaseHighlightsStat5Anti-ApoptoticPathwayPriortoPromotingCellGrowth-RatanakanitHarnprasopwatAdaptorProteinLnkNegativelyRegulatesBcr-Abl-InducedCellProliferationthroughInhibitionoftheStat5SignalingPathway-TakayukiTabayashi,MD,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1214OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:NovelMolecularMechanismsandTargetsinCML511PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3380PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3406,STAT5信号,Stat5A在TKI耐药的CML细胞中异常激活，抑制Stat5A可逆转耐药；Stat5B在CML细胞生存和自我更新中起重要作用Bcr-Abl不依赖JAK2信号直接激活Stat5Bcr-Abl/Stat5通路通过整合多种效应分子(BCL-XL,HIF-1A,HSPA1A,WT1,PRAME)阻止细胞凋亡，成为治疗Ph+白血病的潜在分子靶点衔接蛋白Lnk通过抑制Stat5信号转导，负调控Bcr-Abl诱导的细胞增殖，将为Ph+白血病的治疗提供靶点,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1214OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:NovelMolecularMechanismsandTargetsinCML511PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3380PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3406,Hedgehog信号通路,HedgehogSignalingIsUsefulasaNovelMolecularMarkerforPredictingRelapseandResistanceDuringChronicMyeloidLeukemiaTreatment-MicheleCeaInhibitionofChronicMyeloidLeukemiaStemCellsbytheCombinationoftheHedgehogPathwayInhibitorLDE225withNilotinib-BinZhangHumanBlastCrisisLeukemiaStemCellInhibitionwithaNovelSmoothenedAntagonist-AliceShih,BS,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1215OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:NovelMolecularMechanismsandTargetsinCML514PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1223,Hedgehog信号通路,Hedgehog信号通路激活与BCR-ABL转录本升高直接正相关TKI耐药的CML患者存在Hedgehog信号通路异常激活，可预测复发和耐药阻断Hedgehog信号可抑制TKI耐药的CML细胞增殖Hedgehog抑制剂（LDE225）靶向白血病干细胞，与尼洛替尼联用可有效清除TKI治疗残留的白血病干细胞Hedgehog抑制剂（SMO拮抗剂）与达沙替尼联用抑制伊马替尼耐药的急变白血病干细胞自我更新,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1215OralSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:NovelMolecularMechanismsandTargetsinCML514PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1223,其他信号通路,NF-BDistinctRolesfortheNF-BPathwayInMyeloidandLymphoidTransformationandLeukemogenesisbyBCR-ABL-Mo-YingHsieh,BSSyk-Lyn-AxlQuantitativePhosphoproteomicsIdentifiedaNewSyk-Lyn-AxlSignallingPathwayInvolvedInResistancetoNilotinibInChronicMyeloidLeukemiaCells-RomainGioia,Ph,D,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1225PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3376,其他信号通路,NF-B在BCR-ABL表达的白血病细胞中，NF-B部分通过经典的IKK途径被激活NF-B信号在BCR-ABL表达的髓系及淋系白血病发病机制中扮演不同角色NF-B信号在产生和/或维持CML干细胞中发挥作用，IKKs将成为治疗Ph+白血病的新分子靶点Syk-Lyn-Axl定量磷酸蛋白质组学发现了一个新的Syk-Lyn-Axl信号通路其在尼洛替尼耐药中起重要作用,PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterI1225PosterSession:ChronicMyeloidLeukemia-BiologyandPathophysiology,excludingTherapy:PosterII3376,EducationProgram,探讨慢性期CML酪氨酸激酶抑制剂的优化治疗对于需要二线治疗的患者，我们应该做什么在2010年，CML还有哪些待解决的问题,第三部分继续医学教育CML2010:WhereAreWeNowandWhereCanWeGo？,伊马替尼（400mg/d）是初诊CML慢性期患者的标准治疗IRIS8年随访结果EFS、无加速/急变生存率分别是82%、92%TKI治疗大大降低CML死亡率部分患者仍存在耐药