老年AML治疗陆益龙PPT课件

老年急性髓系白血病的治疗 江苏大学附属医院陆益龙 1 老年AML的流行病学 我国白血病发病率2 76 10万人 恶性肿瘤死亡病例中 白血病居第6位 男性 和第8位 女性 在儿童及35岁以下成年人居第1位 目前国内老年AML无明确的统计资料 2 2011年美国数据 KlepinHD SEER JClinOncol32 2014 3 KlepinHD SEER JClinOncol32 2014 4 老年急性白血病特点 5 KlepinHD JClinOncol 2014 32 1 老年AML根据患者特征的危险分层诱导治疗建议 危险分类特征治疗考虑良好生物学中等或不良生物学FrailECOGPS 3低强度治疗最好的支持治疗重要合并症 HAMs LD AraC 可以考虑低强度治疗 HCT CI 2 ADLs受损VulnerableECOGPS0 2可以考虑强烈治疗进行风险获益评估后HCT CI 2可以考虑强烈治疗ADLs受损或低强度治疗SPPB 9 3MS 77高负荷症状FitECOGPS0 1应该给予强烈治疗风险获益评估HCT CI 1考虑强烈治疗无上述危险因素甚至减低预处理剂量的异基因干细胞移植 6 KlepinHD JClinOncol 2014 32 1 7 良好 中等或不良生物学指标 8 造血细胞移植合并症指数 HCT CI 评分 Blood 2005Oct15 106 8 2912 9 9 NCCN 2017 关于年龄 60岁AML患者的诱导治疗建议 一 适合接受蒽环类 阿糖胞苷为基础的强烈诱导化疗 1 原发性AML 无预后不良细胞遗传学和分子标志 无前驱血液病史 非治疗相关性 A 临床试验 B 标准剂量AraC 100 200mg m2 dx7d IDA12mg m2 优先 或DNR60 90mg m2 dx3d或MTZ 12mg m2 dx3d 的方案 C 更低强度治疗 小剂量AraC 5 azacytidine decitabine 2017年去除 不适合化疗的因素 NCCN 年龄 体能状态 脏器功能 并发症等 低强度治疗 2010年NCCNAML指南首次提出 10 2 预后不良细胞遗传学 分子标志 前驱血液病史 治疗相关性AML A 临床试验 B 更低强度治疗 5 azacytidine decitabine C 标准剂量AraC 100 200mg m2 dx7d IDA12mg m2 优先 或DNR60 90mg m2 dx3d或MTZ 12mg m2 dx3d 的方案 D 氯法拉滨 标准剂量AraC III类推荐 2017年 二 不适合接受蒽环类 阿糖胞苷为基础的强化疗诱导 A 临床试验 B 更低强度治疗 5 azacytidine decitabine 优先选择 小剂量AraC C Clofarabine AraC III类推荐 2017年删除 C 最好的支持治疗 羟基脲 血制品支持 11 NCCN 2017 关于年龄 60岁AML患者的缓解后治疗建议 一 前期强化疗缓解者 1 减低预处理剂量的HSCT 2 临床试验 3 标准剂量AraC 100 200mg m2 dx5 7d 1 2疗程 蒽环类药物 IDA或DNR 4 体能状态较好 肾功能正常 染色体核型良好或正常伴良好分子标志者可以予Ara C1 1 5g m2 dx4 6剂量 1 2疗程 5 诱导治疗采用去甲化药物治疗者 去甲基化药物维持治疗 5 azacytidine或decitabine 每4 6周重复 至疾病进展 6 观察 二 较低强度治疗缓解者 1 减低预处理剂量的HSCT 2 临床试验 3 继续去甲基化药物维持治疗 5 azacytidine或decitabine 每4 6周重复 至疾病进展 12 NCCNGuidelinesVersion1 2018AcuteMyeloidLeukemia 13 NCCNGuidelinesVersion1 2019AcuteMyeloidLeukemia 14 15 16 17 Decitabine10天方案治疗AML 初诊 MDACC 具体用药 Induction 20mg m2IV 1hrdailyx10d 治疗前高白细胞者可以用羟基脲控制WBCcount 40 000 L Maintenance 20mg m2IV 1hrdailyx5d 方案调整 第一疗程后原始细胞 5 者 重复10天方案 第一疗程后原始细胞 5 者 改为5天方案 5天方案中 4级中性粒细胞减少 500 L 超过14天者可以减为4天 WilliamBlum PNAS 2010 107 7473 7478 18 共入组53例初诊AML患者 CR率47 总有效率64 达CR的中位疗程数为3疗程 治疗30天内死亡率2 8周内的死亡率15 中位OS55周 DFS46周 WilliamBlum PNAS 2010 107 7473 7478 19 Decitabine10天方案治疗效果 WilliamBlum PNAS 2010 107 7473 7478 20 Decitabine10天方案治疗效果 WilliamBlum PNAS 2010 107 7473 7478 21 Decitabine10天方案治疗不良事件 WilliamBlum PNAS 2010 107 7473 7478 22 ten daydecitabine 20mg m2 d 4Wrepeat Unfitforintensivechemotherapy UniversityofMaryland 共入组45例患者 初诊AML 年龄74 52 87 岁CR14例 31 CRi5例 11 总有效率42 中位有效疗程数2 1 4 中位总生存9 0月 有效者为19 4月 无效者为2 3月 OhioStateUniversity16例患者 74 66 85 岁CR率9 16 56 BhatnagarB Leuk55 7 1533 1537 YanP Blood 2012 120 12 2466 23 low dosecytarabine LDAC HerveDombretandRaphaelItzykson Hematology2017 24 NEnglJMed 2016Nov24 375 21 2023 2036 招募了116名成年AML或MDS患者参与地西他滨的单机构试验 以确定体细胞突变及其与临床反应的关系 地西他滨 20mg m2 d 10d 试验目的 1 AML和MDS患者TP53突变状态 2 了解第1周期第10天TP53突变清除率 对其中67例患者进行增强外显子组或基因板测序 并在多个时间点进行序列测序 以评估54例患者的突变清除模式 一个扩展队列包括32名在不同方案中接受地西他滨治疗的患者 Decitabine在TP53阳性的AML和MDS患者治疗中作用 25 NEnglJMed 2016Nov24 375 21 2023 2036 26 Decitabine在TP53阳性的AML和MDS患者治疗效果 NEnglJMed 2016Nov24 375 21 2023 2036 27 PanelsBandCshowmutationclearanceobservedin2patientswithTP53mutations PanelDshowstherateofclearanceof21TP53mutationsidentifiedin16patients PanelEshowstherateofclearanceofmutations specifically ingenesthatweremutatedinatleast5ofthe54patientswithsamplesthatcouldbeevaluated TP53突变患者的临床反应 NEnglJMed 2016Nov24 375 21 2023 2036 28 AML低剂量化疗与靶向药物治疗的选择 HerveDombretandRaphaelItzykson Hematology2017 29 EpigeneticTherapyintheClinic 30 TargetingacutemyeloidleukemiawithTP53 independentvosaroxinFutureOncol 2017Jan 13 2 125 133 TP53 AML靶向治疗 VOSAROXIN 31 MRC MedicalResearchCouncil NCCN NationalComprehensiveCancerNetwork PS Performancestatus sc Subcutaneously TargetingacutemyeloidleukemiawithTP53 independentvosaroxinFutureOncol 2017Jan 13 2 125 133 32 TP53 AML靶向治疗 VOSAROXIN结论 InVALOR CR CRi CRpratesforpatientsreceivingvosaroxinwerecomparablebetweenpatientsyoungerthan60yearsandthoseof60yearsandolder 35vs38 respectively Forbothgroups thisresponseratewassignificantlyhigherthanequivalentlyagedpatientsreceivingcytarabinealone p 0 04forthose 60yearsandp 0 0001forthose 60years asignificantoverallsurvivalbenefitwasnotedonlyforpatientsof60yearsandolderwhoreceivedvosaroxinnosurvivalbenefitwasdetectedinyoungerpatientswhoreceivedvosaroxin TargetingacutemyeloidleukemiawithTP53 independentvosaroxinFutureOncol 2017Jan 13 2 125 133 33 venetoclaxincombinationtherapyforrelapsedandrefractoryacutemyeloidleukemia AmJHematol 2018 93 401 407 34 venetoclaxcombinationdrugs AmJHematol 2018 93 401 407 35 Documentedinfectiousandcytopenia relatedadverseevents AmJHematol 2018 93 401 407 36 venetoclax治疗结果 AmJHematol 2018 93 401 407 37 venetoclax治疗结果 AmJHematol 2018 93 401 407 38 A Allpatients n543 B PatientsachievingCR CRi n55 C PatientsachievingORR i e CR CRi PR MLFS n59 Overallsurvivalforpatientswithrelapsed refractorymyeloiddisorderstreatedwithVENcombinationstrategies AmJHematol 2018 93 401 407 39 venetoclax治疗结论 Low intensitychemotherapy includingHMAsorLDAC incombinationwithVENisaviablesalvageoption eveninmultiplyrelapsed refractorypatientswithAML MDS andBPDCN Notableresponseswereidentifiedinpatientswithdiploid intermediatecytogenetics RUNX1 and orIDH1 2mutations 40 对venetoclax有反应的基因表形 27 Leukemia 2016 31 2 301 9 28 Leukemia 2014 28 7 1557 60 30 NatMed 2015 21 2 178 84 hematoltransfuscellther 2019 41 2 169 177 41 VenetoclaxCombinedWithLow DoseCytarabineJClinOncol 2019May20 37 15 1277 1284 Adults60yearsorolderwithpreviouslyuntreatedAMLineligibleforintensivechemotherapywereenrolled Priortreatmentofmyelodysplasticsyndrome includinghypomethylatingagents HMA waspermitted Eighty twopatientsweretreatedattherecommendedphaseIIdose venetoclax600mgperdayorallyin28 daycycles withLDAC 20mg m2perday administeredsubcutaneouslyondays1to10 Keyendpointsweretolerability safety responserates durationofresponse DOR andoverallsurvival OS 42 Medianagewas74years range 63to90years 49 hadsecondaryAML 29 hadpriorHMAtreatment and32 hadpoor riskcytogeneticfeatures Early 30 day mortalitywas6 Fifty fourpercentachievedcompleteremission CR CRwithincompletebloodcountrecovery mediantimetofirstresponse 1 4months ThemedianOSwas10 1months 95 CI 5 7to14 2 andmedianDORwas8 1months 95 CI 5 3to14 9months VenetoclaxCombinedWithLow DoseCytarabineJClinOncol 2019May20 37 15 1277 1284 43 Optimizingvenetoclaxdose HematolOncol 2019Jun28 doi 10 1002 hon 2646 IncombinationwithanHMA increasingconcentrationsofvenetoclax uptothoseassociatedwithalessthanorequalto400 mgoncedaily QD dose wereassociatedwithahigherprobabilityofresponse withatrendforflatordecreasingprobabilitiesofresponsethereafter IncombinationwithLDAC increasingconcentrationsofvenetoclaxwereassociatedwithhigherprobabilitiesofresponse withnoplateauobserved Increasingconcentrationsofvenetoclaxwerenotassociatedwithincreasingprobabilityofanysafetyeventexceptforaslightincreaseingrade3orworseinfectionswithHMAs tolerabilityissueswereobservedatdosesofgreaterthanorequalto800mgQDineachstudy 44 Exposure responseanalysessupporttheuseofvenetoclax400mgQDincombinationwithanHMA600mgQDincombinationwithLDAC ie thenexthighestdoseevaluatedbelow800mgineachcombination safelymaximizetheprobabilityofresponseinelderlypatientswithnewlydiagnosedAML Optimizingvenetoclaxdose HematolOncol 2019Jun28 doi 10 1002 hon 2646 45 Venetoclax VEN hasshownencouragingactivitywhencombinedwithhypomethylatingagents HMAs inbothnewlydiagnosedandrelapsed refractory r r AML Aldossetal 2018 DiNardoetal 2019 Thecombinationiswell toleratedeveninfrailpatientsandisassociatedwithlowtreatment relatedmortality TRM DiNardoetal 2019 ApoptosismediatedbyvenetoclaxappearstobeTP53 independent Andersonetal 2016 VEN HMAactivitywasobservedacrossvarioushigh riskleukaemiagenetics Aldossetal 2018 DiNardoetal 2019 VenetoclaxandhypomethylatingagentsinTP53 mutatedacutemyeloidleukaemiaIbrahimAldoss2019 46 临床资料32adultswithTP53mAMLwhoweretreatedwithVEN HMA Onepatientwithr rAMLwasunevaluableforresponsebecauseofdeathfromsepsis10daysafterinitiatingtherapy Themedianagewas68years 22 85 Sixteen 16 31 52 patientshadr rAMLwhile15 48 patientswerenewlydiagnosed Themajorityofpatientshadcomplexcytogenetics n 24 77 Themedianvariantallelefrequency VAF forTP53mwas56 range 3 95 9 29 patientshadmorethanoneTP53mutation Nineteen 61 patientshadadditionalsomaticmutations DecitabinewastheHMAusedinthemajorityofcases 90 andwasmorefrequentlygivenasa5 dayscheduleratherthana10 dayschedule 52 vs 39 VenetoclaxandhypomethylatingagentsinTP53 mutatedacutemyeloidleukaemiaIbrahimAldoss2019 47 结果16 52 experiencedaresponse including7CRand9CRi Responsewasachievedafteramedianof2 range 1 3 cycles Minimalresidualdisease MRD definedas 0 01 bymultiparameterflowcytometryinareferencelaboratory