（优质课件）骨髓增生异常综合征

骨髓增生异常综合征 Myelodysplasticsyndromes MDS 1 2 一组起源于造血干细胞 HSC 的异质性的克隆性疾病 以 外周血一系或多系减少 骨髓增生正常或亢进伴病态造血和 高风险向急性白血病转化为特征 Agroupofclonalneoplasms heterogeneous Hematopoieticstemcells HSC orprogenitors CytopeniaMyelodysplasia ineffectivehematopoiesisIncreasedriskofblastictransformation preleukemia smoulderingleukemia 定义 3 MDSvsAML Blood 2013 121 3811 4 发病情况 发病年龄 成人发病为主 老年更多见 轻微男性发病优势发病率 美国报告为2 12 10万 70岁以上者50 10万 IntJHematol2001 73 405 5 高龄 外因 原发性 继发性MDS tMDS 烷化剂 表鬼臼毒素类 先天 家族性MDSHSC增生失控 分化受阻 细胞凋亡增加细胞遗传学异常 5 5q 7 7q 基因水平的改变 AML1 MDS1 EVI1融合基因表观遗传学调控异常 病因 发病机理 6 分类 FAB 1976 1982中国1986WHO 2000 2008 2016 7 FAB1976 DysmyelopoieticsyndromesRARAEB BrJHaematol1976 33 451 8 MDS FAB1982 9 FAB WHO2000 与AML界限 骨髓原始细胞降为20 RAEB t归入AML 但有t 8 21 t 15 17 inv 16 t 16 16 等核型异常者即使小于20 也应诊断为白血病CMML MDS MPD 10 WHO2000 11 WHO2000 2008 增加RN RT 与RA一起组成RCUD 重新定义MDS U 不再包括RN和RT 增加ChildhoodMDS RCC RCMD与RCMD RS合并t MDS t AML不再区分原因 烷化剂or鬼臼毒素类 12 WHO2008 13 WHO2016 MDSwithsinglelineagedysplasia MDS SLD MDSwithmultilineagedysplasia MDS MLD MDSwithringsideroblasts MDS RS MDS RSandsinglelineagedysplasia MDS RSSLD MDS RSandmultilineagedysplasia MDS RSMLD MDSwithexcessblasts MDS EB1 MDS EB2 MDSwithisolateddel 5q 5q syndrome MDS unclassifiable MDS U Provisionalentity Refractorycytopeniaofchildhood RCC 14 15 CHIP ICUS 16 Clonalhematopoiesisofindeterminatepotential CHIP acquiredclonalmutationsidenticaltothoseseeninMDScanoccurinthehematopoieticcellsofapparentlyhealthyolderindividualswithoutMDS Provisionalcategory idiopathiccytopeniaofundeterminedsignificance ICUS 17 Myeloproliferativeneoplasms MPN MastocytosisMyeloid lymphoidneoplasmswitheosinophiliaandrearrangementofPDGFRA PDGFRB orFGFR1 orwithPCM1 JAK2Myelodysplastic myeloproliferativeneoplasms MDS MPN Myelodysplasticsyndromes MDS MyeloidneoplasmswithgermlinepredispositionAcutemyeloidleukemia AML andrelatedneoplasmsAMLwithrecurrentgeneticabnormalitiesAMLwithmyelodysplasia relatedchangesTherapy relatedmyeloidneoplasmsAML NOSMyeloidsarcomaMyeloidproliferationsrelatedtoDownsyndromeTransientabnormalmyelopoiesis TAM MyeloidleukemiaassociatedwithDownsyndromeAcuteleukemiasofambiguouslineageB lymphoblasticleukemia lymphomaT lymphoblasticleukemia lymphomaProvisionalentity Naturalkiller NK celllymphoblasticleukemia lymphoma WHOmyeloidneoplasmandacuteleukemiaclassification 18 Myeloproliferativeneoplasms MPN JAK2 MPL CALRmutations Chronicmyeloidleukemia CML BCR ABL11Chronicneutrophilicleukemia CNL CSF3Rmutation Polycythemiavera PV Primarymyelofibrosis PMF PMF prefibrotic earlystagePMF overtfibroticstageEssentialthrombocythemia ET Chroniceosinophilicleukemia nototherwisespecified NOS MPN unclassifiable 19 Myelodysplastic myeloproliferativeneoplasms MDS MPN Chronicmyelomonocyticleukemia CMML Atypicalchronicmyeloidleukemia aCML BCR ABL1 Juvenilemyelomonocyticleukemia JMML MDS MPNwithringsideroblastsandthrombocytosis MDS MPN RS T MDS MPN unclassifiable 20 临床表现 差异大 早期低危患者无症状贫血发热 感染出血一般无肝脾淋巴结肿大转化为急性白血病老年患者多有合并症 21 RecommendationsandDefinitionsinMDS RecommendationsDifferential 500inBM 200cellsinPBNumber 200forGandE 30cellsformeg Ringsideroblasts 5irongranulesencircling 1 3ofthenucleusMinimaldysplasticchanges goodqualityofsmear 10 inonesinglecellline or 10 withrecurrentabnormalcytogeneticsCytopenia 6month Transfusion dependent macrocyticanemiaHgb 10g dLANC 1 5x109 LPLT 100 x109 LConstantblastcount5 19 22 MorphologicFeatures Blasts MyeloblastsDysmyelopoiesis Dyserythropoiesis Dysgranulopoiesis DysmegakaryopoiesisTrephinebiopsy Cellularity Myelofibrosis reticulin MDSwithfibrosis Reportestimated ofCD34 blasts Dysmegakaryopoiesis CD61 ALIP abnormallocalizedimmatureprecursors 23 红系病态造血 Normal Ringedsideroblasts 24 粒系病态造血 25 巨核系病态造血 26 诊断 鉴别诊断 PB cytopenia s BMsmear dysplasiaBMbiopsy ALIPFlowcytometryCytogenetic 5q 5 7Molecular NGSMA AA PNH MPN AML 27 28 MinimalDiagnosticCriteriainMDS PrerequisitecriteriaConstantcytopeniainoneormoreofthefollowingcelllineages erythroid hemoglobulin15 ringedsideroblasts5 19 BlastcellsinbonemarrowsmearsTypicalchromosomalabnormality conventionalkaryotypingorFISH ValentP etal LeukemiaResearch2007 727 736 29 MinimalDiagnosticCriteriainMDSCont d C Co criteria forpatientsfulfilling A butnot B Typicalclinicalfeatures macrocytictransfusion dependentanemia 典型临床特征 输血依赖大细胞贫血AbnormalphenotypeofBMcellsindicativeofamonoclonalpopulationdeterminedbyflowcytometry单克隆表型 流式Molecular MonoclonalcellpopulationinHUMARAassay genechipprofiling orpointmutationanalysis e g RASmutations 单克隆表型 基因异常Markedlyandpersistentlyreducedcolony formationofBMor andcirculatingprogenitorcells CFU assay 骨髓集落培养减低 ValentP etal LeukemiaResearch2007 727 736 30 MDS治疗原则 治疗方案设计要求个体化 分层personalizationstratification 支持 对症治疗仍是主要措施 Bestsupportivecare 红细胞 血小板输注 CSFs EPO抗感染去铁治疗FDA批准的药物 3个 去甲基化药物 阿扎胞苷 5 azacytidine2004 地西他滨 decitabine 2006 中国2009 来那度胺 lenalidomide 2005 del 5q 首选造血干细胞移植 31 HypomethylatingCytosineAnalogues 地西他宾FDA2006 阿扎胞苷FDA2004 32 地西他滨 Decitabine Dacogen 15 30mg m2 10 50mg intravenouslydaily3 5days cycle 33 DecitabinePharmacologyMechanismofAction DecitabineisanS phasespecificagentAntineoplasticactivityattributedtoInhibitionofcellproliferationathigherdosesincorporationintoDNAblockingofDNAsynthesiscytotoxicitynonreversiblecovalentlinkingwithDNAmethyltransferaseInductionofhypomethylationatlowerdosespromotingcelldifferentiationre expressionoftumorsuppressorgenesstimulationofimmunemechanismssuppressionoftumorgrowth 34 HypomethylatorsvsIntensiveChemoRxinMDSwith10 30 Blasts 330pts 93 28 RxwithHMAand237 72 withchemoRxMVA worsesurvivalwithchemoRx Nazha Blood122 abst2788 2013 35 来那度胺 Lenalidomide 瑞复美 AntiangiogenicImmunomodulatoryimidedrugs IMiDs 5q syndrome10mg dayorallyMultiplemyeloma 36 Thalidomide 沙利度胺 反应停 developedbyGermanpharmaceuticalcompanyGr nenthalsoldfrom1957to1961topregnantwomen asanantiemetictocombatmorningsicknessandasanaidtohelpthemsleepapproximately10 000childrenwerebornwithseveremalformities includingphocomelia SealBaby 1991Dr GillaKaplanatRockefellerUniversityshowedthatthalidomideworkedinleprosybyinhibitingtumornecrosisfactoralpha 37 其它治疗选择 免疫抑制剂 ATG CsA Dexamethasone小剂量化疗 Low dosecytarabine DA亚砷酸ATRAAmifostine阿米福汀 氨磷汀 Clinicaltrials 38 预后 39 40 Prognosticmodels IPSSIPSS RWPSSOthers GlobalMDACCmodel MDACClowerriskmodel Impactofcomorbidities 41 发病机制及分子治疗 细胞遗传学异常分子遗传学 基因结构 异常表观遗传学调控紊乱 42 Nybakken16 145 158 CytogeneticfindingsinMDS 43 44 DistributionofrecurrentmutationsandkaryotypicabnormalitiesinMDS 45 MutationallandscapeinMDS Haferlachetal Leukemia2013 46 Targetedsequencingofalimitednumberofgenescandetectmutationsin80 to90 ofMDSpatients themostcommonlymutatedgenesinMDSareSF3B1 TET2 SRSF2 ASXL1 DNMT3A RUNX1 U2AF1 TP53 andEZH2 MutationsofTP53 SF3B1 TP53mutationisassociatedwithaggressivediseaseinMDSingeneralandappearstopredictpoorerresponsetolenalidomideinpatientswithdel 5q WithregardtoMDSwithringsideroblasts MDS RS recurrentmutationsinthespliceosomegeneSF3B1arefrequentinMDSandareassociatedwiththepresenceofringsideroblasts So ifanSF3B1mutationisidentified adiagnosisofMDS RSmaybemadeifringsideroblastscompriseasfewas5 ofnucleatederythroidcells 47 Impactofmutationofp53orDNMT3AonsurvivalofMDSptsw HSC 48 表观遗传学调控异常epigenetics 不涉及基因一级结构改变的表达调控机制 即基因DNA序列不发生改变的情况下 基因的表达水平与功能发生改变 并产生可遗传的表型三大特征 DNA序列本身不变 可遗传 可逆性RegulationoftranscriptionDNAmethylation甲基化Histonemodifications组蛋白修饰ChromatinremodelingPseudogenesRegulationofpost transcriptionNon codingRNA microRNA siRNA lncRNARiboswitch 49 DNA甲基化的基本作用 抑制基因表达 50 DNA histones Nucl