ASH2010慢性髓性白血病12-10-2

慢性髓性白血病研究进展慢性髓性白血病研究进展-第第5252届届ASHASH会议重点解读会议重点解读 December 4-7,2010 Orlando,FL 山东大学齐鲁医院山东大学齐鲁医院纪春岩纪春岩 2010-12-122010-12-12（济南）（济南）第第5252届届ASHASH会议慢性髓性白血病相关文献会议慢性髓性白血病相关文献AbstractsLate breaking AbstractsOral and Poster AbstractsChronic Myeloid Leukemia-TherapyChronic Myeloid Leukemia-Biology and PathophysiologyEducation ProgramCML 2010:Where Are We Now and Where Can We Go?第一部分第一部分 CMLCML治疗治疗-TKI-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 （the German CML-Study IV）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（ENESTnd Trial）达沙替尼评价达沙替尼治疗的有效性和安全性（DASISION Trial）比较达沙替尼和伊马替尼治疗的有效性和安全性 （The S0325 Intergroup Trial）分析BCR-ABL激酶区突变与治疗反应的关系Oral and Poster Abstracts Late-breaking AbstractsSeven-YearFollow-upDataonSequentialProspectiveTrialsofImatinib400mgVs800mgDailyScheduleforFront-LineTreatmentofChronicMyeloidLeukemia(CML)Naveen Pemmaraju,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster III 3438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IM800mg（n=208）IM400mg（n=73）P值中位随访时间mos（范围）79(3-107)110(2-116)-累积CCyR率91%87%0.49累积MMR率87%78%0.0612 个月个月CCyR90%66%0.001*18个月个月MMR82%68%0.04*7年年EFS 86%76%0.049*7年TFS-0.467年OS-0.27因毒性中止治疗16(8%)6(8%)-Seven-YearFollow-upDataonSequentialProspectiveTrialsofImatinib400mgVs800mgDailyScheduleforFront-LineTreatmentofChronicMyeloidLeukemia(CML)Naveen Pemmaraju,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster III 3438结论-7年跟踪调查显示：与伊马替尼400mg相比，伊马替尼800mg 12 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-StudyIVRdiger Hehlmann,MD Oral Session:Chronic Myeloid Leukemia-Therapy:Optimizing Front-Line Therapy in CML 357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/ABLIS 0.01%-1012例CML患者入组（338例IM 800mg；324例IM 400mg；350例IM联合干扰素）-IM 800mg组，平均每日伊马替尼剂量628mg；IM 400mg组，平均每日伊马替尼剂量400mgRdiger Hehlmann,MD Oral Session:Chronic Myeloid Leukemia-Therapy:Optimizing Front-Line Therapy in CML 357结果-IM 800mg组12个月缓解率显著提高12个月累积CCyR:IM 800mg组为63%；IM 400mg及联合组为50%12个月累积MMR:IM 800mg组为54.8%；IM 400mg组为30.8%;联合组为34.7%36个月内IM 800mg组均有较高的CMR，且比IM 400mg组更快获得CMR初始治疗时间(月)累积发病率MMR(%)CMR(%)IM400n=306IM800n=328IM400+IFNn=336IM400n=306IM800n=328IM400+IFNn=33668.618.18.43 3.7 2.4 12 30.8 54.8 34.7 7.5 19.8 12.4 1850.368.454.121.2 33.4 23.6 246376.062.830.7 43 30.0 3679.381.670.745.5 56.8 40.5 SuperiorCMR-RateswithTolerability-AdaptedImatinib800MgVs.400MgVs.400Mg+IFNInCML:TheRandomizedGermanCML-StudyIVSuperiorCMR-RateswithTolerability-AdaptedImatinib800MgVs.400MgVs.400Mg+IFNInCML:TheRandomizedGermanCML-StudyIV Rdiger Hehlmann,MD Oral Session:Chronic Myeloid Leukemia-Therapy:Optimizing Front-Line Therapy in CML 357结论-大剂量伊马替尼治疗耐受性良好-伊马替尼800mg组比400mg组获得更高CMR-伊马替尼800mg组比400mg组有更多患者获得稳定CMR MolecularResponse1%BCR-ABLISat12MonthsIsAssociatedwithImprovedOverallandProgression-FreeSurvival:theRandomizedGermanCML-StudyIVMartin C.Mller,MD Oral Session:Chronic Myeloid Leukemia-Therapy:Rethinking Therapy Targets and Prognostic Factors 669目的-评估分子反应程度与生存的关系研究设计-848例CML患者入组-3个分子反应组(1%BCR-ABL/ABLIS)-12个月PFS和OS结果-12个月时，341例患者获得MMR(BCR-ABL/ABLIS1%-与BCR-ABL/ABLIS 1%组相比，BCR-ABL/ABLIS 0.1%-1%和MMR组3年PFS和OS更高Martin C.Mller,MD Oral Session:Chronic Myeloid Leukemia-Therapy:Rethinking Therapy Targets and Prognostic Factors 669结论-更快、更深的分子反应与PFS和OS的提高有关-关键临界值似乎是1%BCR-ABL/ABLIS水平（与CCyR密切相关）MolecularResponse65years):ResultsoftheGermanCML-StudyIVSusanne Saussele,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster III 3411目的-评估伊马替尼治疗年龄大于65岁CML患者的疗效及安全性研究设计-以65岁为年龄分界，分为IM 400mg和800mg组-观测血液学、细胞遗传学、分子学缓解时间，总生存率和不良反应年龄65(n=150）65years):ResultsoftheGermanCML-StudyIVSusanne Saussele,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster III 3411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-IM 400mg组中，年老比年轻患者更慢获得CCyR和MMR(CCvR:14.2 月 vs 12.1 月,p=.019;MMR:18.7 月 vs 17.5 月,p=.006）-IM 800mg组中，两组间无差异 (CCvR:7.7 月 vs 8.9 月,MMR:9.9 月 vs 10.0 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-StudyIVSusanne Saussele,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster III 3411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MMRAnalysisofOutcomesInAdolescentsandYoungAdults(AYA)withChronicMyeloidLeukemia(CML)TreatedwithUpfrontTyrosineKinaseInhibitors(TKI)Naveen Pemmaraju,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster 1234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；移植患者排除结果年龄21(n=422)P 值总数Sokal危险度,n(%)低危中危高危12(92)1(8)0288(68)105(25)29(7)0.24300(69)106(24)29(7)CCyR,n(%)7(64)384(93)0.008 391/425中位达CCyR时间(月)333(2-64)MMR,n(%)7(64)359(87)0.0497366/424中位达MMR时间(月)966(2-78)CMR,n(%)1(9)160(39)0.06161/424中位达CMR时间(月)122424(3-84)5年无事件生存79900.265年无进展生存(%)100940.515年总生存(%)88930.9AnalysisofOutcomesInAdolescentsandYoungAdults(AYA)withChronicMyeloidLeukemia(CML)TreatedwithUpfrontTyrosineKinaseInhibitors(TKI)Naveen Pemmaraju,MD Poster Session:Chronic Myeloid Leukemia-Therapy:Poster 1234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)Timothy P.Hughes,MD,MBBS Oral Session:Chronic Myeloid Leukemia-Therapy:Optimizing Treatment Outcome207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OSTimothy P.Hughes,MD,MBBS Oral Session:Chronic Myeloid Leukemia-Therapy:Optimizing Treatment Outcome207中位随访18个月的总体有效性Nilotinib300mgbid(n=282)Nilotinib400mgbid(n=281)Imatinib400mgqd(n=283)MMR,%66P.0001*62P.0001*40Sokal危险度,%低危(n=103,n=103,n=104)706951中危(n=101,n=100,n=101)676339高危(n=78,n=78,n=78)595128BCR-ABLIS0.0032%,%21P.0001*17P.0001*6CCyR,%85P.001*82P=.017*74向加速/急变进展不包括克隆演进,n(%)2(0.7)P=.006*1(0.4)P=.003*12(4.2)包括克隆演进,n(%)2(0.7)P4log ARandomizedPhaseIITrialofDasatinib100MgVsImatinib400MgInNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP):TheS0325IntergroupTrial结果-达沙替尼组12个月分子反应更深，BCRABL IS 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IM400mg(n=123)DAS(N=123)2-sidedP*HemCR111(90%)104(86%)0.25CCyR40/58(69%)55/67(82%)0.0973log39/90(43%)58/99(59%)0.0424log18/90(20%)27/99(27%)0.314.5log13/90(14%)21/99(21%)0.2612个月OS99%100%0.6012个月PFS96%99%0.19ARandomizedPhaseIITrialofDasatinib100MgVsImatinib400MgInNewlyDiagnosedChronicMyeloidLeukemiaInChronicPhase(CML-CP):TheS0325IntergroupTrialJerald P.Radich,MD Session:Late-Breaking Abstracts Session LBA-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-ABLMutationAlfonso Quints-Cardama Poster Session:Chronic Myeloid Leukemia-Therapy:Poster II 2297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-ABLMutationAlfonso Quints-Cardama Poster Session:Chronic Myeloid Leukemia-Therapy:Poster II 2297总数(N=1150)24个月最佳反应24个月无进展生存12个月获得的治疗反应与相应的24个月无进展生存24个月总生存MCyRaCCyRa无基线突变,N=641410/633(64.8)354/633(55.9)83.2%CCyR96.5%93.5%PCyR94.3%Other75.1%有基线突变,N=402222/399(55.6)172/399(43.1)70.2%CCyR93.4%88.6%PCyR86.6%Other72.6%一个基线突变,N=332186/330(56.4)147/330(44.6)72.9%CCyR92.3%88.6%PCyR88.1%Other79.5%大于一个基线突变,N=7036/69(52.2)25/69(36.2)57.4%CCyR100%88.9%PCyR75%Other41.7%结果PatientswithChronicMyeloidLeukemiaInChronicPhaseCarryingMoreThanOneBCR-ABLKinaseDomainMutationExhibitPoorerResponseRatesandOutcomestoSecond-LineDasatinibComparedtoThosewithNoorOnlyOneBCR-ABLMutationAlfonso Quints-Cardama Poster Session:Chronic Myeloid Leukemia-Therapy:Poster II 2297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最低第二部分第二部分：TKITKI耐药的机制研究耐药的机制研究-相关信号通路相关信号通路JAK2信号STAT5信号Hedgehog信号通路NF-B信号Syk-Lyn-Axl信号通路Oral and Poster Abstracts JAK2JAK2信号信号Jak2RegulatesBcr-AblInCD34+CellsFromImatinibMesylate-ResistantCMLPatients-Bastianella Perazzona,Ph.D.JAK2-MediatedExtrinsicSurvivalofCMLStemCells:ExploringthePotentialCombinationofBCR-ABLandJAK2InhibitorsInVivo-Elie Traer,MD,PhD CombinedTargetingofBCR-ABLandJAK2withABLandJAK2InhibitorsIsEffectiveAgainstCMLPatientsLeukemicStem/ProgenitorCells-Donna DeGeer,MSc Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1220 Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:CML Stem Cell/Progenitor Biology 199 Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3404JAK2JAK2信号信号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Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1220 Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:CML Stem Cell/Progenitor Biology 199 Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3404STAT5STAT5信号信号DistinctFunctionsofStat5AandStat5BinChronicMyeloidLeukemia(CML):Stat5BIsImplicatedinSurvivalandSelf-RenewalandStat5AinImatinibResistance-Ali G.Turhan,MD,PhD Bcr-AblDirectlyActivatesStat5IndependentofJak2-Oliver D.Hantschel,PhDHormone-ConditionalActivationofBcr-AblKinaseHighlightsStat5Anti-ApoptoticPathwayPriortoPromotingCellGrowth-Ratanakanit HarnprasopwatAdaptorProteinLnkNegativelyRegulatesBcr-Abl-InducedCellProliferationthroughInhibitionoftheStat5SignalingPathway-Takayuki Tabayashi,MDPoster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1214Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:NovelMolecular Mechanisms and Targets in CML 511Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3380Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3406STAT5STAT5信号信号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Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1214Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:NovelMolecular Mechanisms and Targets in CML 511Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3380Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3406HedgehogHedgehog信号通路信号通路HedgehogSignalingIsUsefulasaNovelMolecularMarkerforPredictingRelapseandResistanceDuringChronicMyeloidLeukemiaTreatment-Michele Cea InhibitionofChronicMyeloidLeukemiaStemCellsbytheCombinationoftheHedgehogPathwayInhibitorLDE225withNilotinib-Bin ZhangHumanBlastCrisisLeukemiaStemCellInhibitionwithaNovelSmoothenedAntagonist-Alice Shih,BSPoster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1215Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Novel Molecular Mechanisms and Targets in CML 514Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1223HedgehogHedgehog信号通路信号通路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Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1215Oral Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Novel Molecular Mechanisms and Targets in CML 514Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1223其他信号通路其他信号通路NF-BDistinctRolesfortheNF-BPathwayInMyeloidandLymphoidTransformationandLeukemogenesisbyBCR-ABL-Mo-Ying Hsieh,BSSyk-Lyn-AxlQuantitativePhosphoproteomicsIdentifiedaNewSyk-Lyn-AxlSignallingPathwayInvolvedInResistancetoNilotinibInChronicMyeloidLeukemiaCells-Romain Gioia,Ph,DPoster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1225Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3376其他信号通路其他信号通路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Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster I 1225Poster Session:Chronic Myeloid Leukemia-Biology and Pathophysiology,excluding Therapy:Poster II 3376Education Program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第三部分 继续医学教育继续医学教育CML 2010:Where Are We Now and Where Can We Go？伊马替尼（400mg/d）是初诊CML慢性期患者的标准治疗IRIS 8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和疾病进展第二代TKI治疗伊马替尼耐药的CML-CP患者，仅50%获CCyR，加速期患者获得CCyR率更低CMLCML治疗现状治疗现状TKITKI治疗治疗CCyRCCyR比较比较不同类型白血病死亡率比较不同类型白血病死亡率比较TKITKI优化治疗优化治疗优化TKI治疗有助于达到CML治疗最佳疗效并克服部分耐药的发生-增加剂量-换用第二代TKIBaccaraniM,etal.J Clin Oncol.2009Nov2;Epubaheadofprint.DOI:10.1200/JCO.2009.25.0779.疗效最佳疗效最佳疗效欠佳疗效欠佳治疗失败治疗失败警惕警惕基线基线NANANANANANA 高危高危 CCA/Ph+CCA/Ph+*3 3个月个月CHRCHR和至少获得次要和至少获得次要CyRCyR(Ph+65%)(Ph+65%)未获得未获得CyRCyR(Ph+95%)(Ph+95%)CHR CHRNANA6 6个月个月至少获得至少获得PCyRPCyR(Ph+35%)(Ph+35%)35%)(Ph+35%)未获得未获得 CyRCyR(Ph+95%)(Ph+95%)NANA1212个月个月CCyRCCyRPCyRPCyR(Ph+1-35%)(Ph+1-35%)35%)(Ph+35%)MMR MMR 1818个月个月MMRMMR MMR MMR CCyRCCyRNANA任何时间任何时间疾病稳定或改善的疾病稳定或改善的MMRMMR Loss of MMR Loss of MMR Mutations Mutations 丧失丧失CHRCHR 丧失丧失CCyRCCyR 突变突变 CCA/Ph+CCA/Ph+*任何转录本水平任何转录本水平的升高的升高 CCA/Ph-CCA/Ph-*CCA/Ph+=Ph+细胞出现克隆性染色体异常；CCA/Ph+尽管发生于治疗过程中，但是它是诊断时的一个警惕因素（例如，克隆进展是治疗失败的一个标记物）。需要进行两次连续性的细胞遗传学检测，并且需要在至少两个Ph细胞中发现同一CCA。MMR指的是BCR-ABL1与ABL1或其他管家基因的比率；按照国际标准是0.1%。BCR-ABL1激酶结构域突变依然对伊马替尼敏感。BCR-ABL1激酶结构域突变对伊马替尼不敏感。CCA/Ph-=Ph-细胞出现克隆性染色体异常。伊马替尼治疗反应标准伊马替尼治疗反应标准治疗失败或反应欠佳的优化治疗方案治疗失败或反应欠佳的优化治疗方案增加伊马替尼治疗剂量至600-800mg有助于控制CML-TOPS研究显示高剂量伊马替尼治疗更快获得CCyR（6个月CCyR分别是57%和45%）；12个月CCyR两组间无差异，分别是70%和66%；24个月累积CCyR、EFS、PFS、OS无差异-长期疗效有待进一步观察换用第二代TKI-M.D.Anderson两项单中心研究显示达沙替尼和尼洛替尼克服部分伊马替尼耐药或不耐受耐药的克隆选择耐药的克隆选择-基因不稳定性基因不稳定性 CML生物学共同点：BCR-ABL导致的基因不稳定性疾病进展和耐药都与之相关克隆选择的临床意义克隆选择的临床意义TKI一线治疗失败，第二代TKI并非万能治疗初期应用强力TKI可减少耐药克隆的产生需要有效的监测治疗反应方法疗效预测疗效预测功能研究：药物转运泵活性检测-Oct-1活性高，伊马替尼治疗反应率高基因研究：SNP分析-基因多态性与治疗反应相关早期BCR-ABL反应-治疗3个月后BCR-ABL水平与治疗反应密切相关突变检测-ELN和NCCN建议BCR-ABL水平升高或对治疗丧失反应时检测突变CML“Cure”CML“Cure”的定义的定义“Cure”Cure”词典定义减轻疾病症状（relieve of the symptom od the disease）终止疾病状态（end a disease,condition,or problem）保存；防腐（preserve meat,fish,ect.by salting drying or smoking）CMLMost primitive CML cell 对TKI耐药移植也无法去除CML“stem cells”CML“Cure”CML“Cure”定义减轻疾病症状检测不到BCR-ABL转录本待解决的问题待解决的问题如何最佳利用第二代TKIs治疗分子学复发是否有意义，如何处理特定ABL突变CMR是否是相对有用的终点期待T315I突变的有效治疗