血液肿瘤中心刘红星tkis治疗耐药突变及改进

TKIs治疗中的耐药突变及治疗改进血液•肿瘤中心医学检验科刘红2014-05-21 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryHongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryHongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryABL1和BCR-BCR-ABL1蛋白的自我DanielW.SherbenouandBrianJ.DrukerJ.Clin.Invest.WePromotetheApplications&InnovationsofLaboratoryWeisbergE,etal.NatRevCancer.2007;7(5):345-WePromotetheApplications&InnovationsofLaboratory突变积累的内在原WePromotetheApplications&InnovationsofLaboratory IKZF1缺失、TP53突变的内在原能抑制CML肿瘤干细胞中的氧自由基和DNA的氧激酶活 氧自由 DNA氧化损*P<.01incomparisonwithuntreatednormalcells,**P<.05incomparisonwithuntreatedCML-CPandnormalcells,and***P<.05incomparisonwithuntreatedCML-CPWePromotetheApplications&InnovationsofLaboratoryCML/CML-CP小WePromotetheApplications&InnovationsofLaboratoryTKIs耐药突变的WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTKIs耐药突变的一般规激酶区突变是TKI耐药的最导致药 不管是否使用TKIs耐药的突变是在TKIs耐药其它IKZF1、TP53 突变也会发生并促使病情进同一突变对不同的TKIs耐药程度有可作WePromotetheApplications&InnovationsofLaboratorySimonaSoverini,et MutationsinPhiladelphiahromosome–PositiveAcuteLymphoblasticLeukemia;FromtheImatinibtotheSecond-GenerationTyrosineKinaseInhibitorEraSimonaSoverini,etWePromotetheApplications&InnovationsofLaboratory换用二代TKIs 突变的动态变SimonaSoverini,etal.Blood.2013;122(9):1634-WePromotetheApplications&InnovationsofLaboratory耐药突变动态变化的根源在于耐药性WePromotetheApplications&InnovationsofLaboratory 检测到的Imtinib耐药突变（2010年统计HongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory应对耐药或进一步提高疗WePromotetheApplications&InnovationsofLaboratory从更成功的实践中总结经CML:TKI+WePromotetheApplications&InnovationsofLaboratory二代、三代

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干扰地高三尖杉酯碱。。WePromotetheApplications&InnovationsofLaboratoryDeepMolecularResponseIsReachedbytheMajorityofPatientsTreatedWithImatinib,PredictsSurvival,andIsAchievedMoreQuicklybyOptimizedHigh-DoseImatinib:ResultsFromtheRandomizedCML-StudyIV

MayaKoren-Michowitz,etal.HematolOncol2012;30:200–5WePromotetheApplications&InnovationsofLaboratory二代TKI：结合力WeisbergE,etal.NatRevCancer.2007;7(5):345-WePromotetheApplications&InnovationsofLaboratory用Imatinib进行一线治疗，但治疗12个月仍未获CCyR

WePromotetheApplications&InnovationsofLaboratoryDasatinibversusImatinibinPatientswithNewlyDiagnosedChronicMyeloidLeukemiainChronicPhase(CML-CP)intheTrial:18-MonthFollow-ShahNetProcASH WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory对部分耐药突变有效，但对T315I突变仍肉豆OliverHantschelHaematologica.2012;97(2):WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTargetingBcr-AblbycombiningallostericwithATP-binding-siteinhibitors.ZhangJ,etal.Nature.2010Jan28;463(7280):501-6.WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory P<0.0001联合应用Dasatinib、地和L-天门冬酰胺酶著延长致瘤小鼠的缓解Chemotherapeuticagentscircumventemergenceofdasatinib-resistantBCR-ABLkinasemutationsinaprecisemousemodelofPhiladelphiachromosome–positiveacutelymphoblasticleukemiaNidalBoulos,etal.Blood.2011;117(13):3585-95WePromotetheApplications&InnovationsofLaboratoryImatinib联用长效干扰素获得更好的ImatinibplusPeginterferonAlfa-2ainChronicMyeloidLeukemiaClaudePreudhomme,etNEnglJMed2010;363:2511-WePromotetheApplications&InnovationsofLaboratoryImatinib联用干扰素更快获得Theresponsetoimatinibandinterferon-αismorerapidthantheresponsetoimatinibalone:aretrospective ysisof495Philadelphia-positivechronicmyeloidleukemiapatientsinearlychronicphaseFrancescaPalandri,etal.WePromotetheApplications&InnovationsofLaboratoryImatinib+PegIFNaVS.

Theresponsetoimatinibandinterferon-αismorerapidthantheresponsetoimatinibalone:aretrospective ysisof495Philadelphia-positivechronicmyeloidleukemiapatientsinearlychronicphaseFrancescaPalandri,etWePromotetheApplications&InnovationsofLaboratoryVEGFplasmaVEGFlowVEGFplasmaInterferondecreasesVEGFlevelsinpatientswithchronicmyeloidleukemiatreatedwithimatinibL.Legrosa,etLeukemiaResearch38(2014)WePromotetheApplications&InnovationsofLaboratory遗传多态性影响TKIsWePromotetheApplications&InnovationsofLaboratory加用BIM或BH3模拟剂，可能会有辅助的效AnnetteS.Gillings,etal.FEBSJournal276(2009)WePromotetheApplications&InnovationsofLaboratory遗传缺失型/SNP与治疗反应有具有BIM缺 AcommonBIMdeletionpolymorphismmediatesintrinsic kinaseinhibitorsincancerKingPanNg,etal.NatMed.2012;18(4):521-8WePromotetheApplications&InnovationsofLaboratory我们的资WePromotetheApplications&InnovationsofLaboratory耐药突变检测及报告WePromotetheApplications&InnovationsofLaboratoryTKI耐药突变检测的方法DanJones,etal.JMolDiagn2009,WePromotetheApplications&InnovationsofLaboratory 检测方可以检测所有的激酶区耐药采用超保真聚合酶WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTKIs耐药突变检测及结果解还是 法最实盲目追求突变的检测灵敏度没有意义，5%耐药突变是在动态演融 融 （可能）非耐药的突变在报告时 或给予文字提突变对各种TKIs的耐药资料可以随 查WePromotetheApplica