骨髓增生异常综合征

骨髓增生异常综合征（Myelodysplasticsyndromes,MDS）2一组起源于造血干细胞(HSC)的异质性的克隆性疾病,以①外周血一系或多系减少②骨髓增生正常或亢进伴病态造血和③高风险向急性白血病转化为特征。•Agroupofclonalneoplasms;heterogeneous;•Hematopoieticstemcells(HSC)orprogenitors;•Cytopenia•Myelodysplasia;ineffectivehematopoiesis•Increasedriskofblastictransformation:-preleukemia,smoulderingleukemia定义3MDSvsAMLBlood.2013;121:3811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MDS•HSC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MDSMPNLeukemiaProliferation↑↑↑Differentiation↓−↓Apoptosis↑−↓6分类•FAB:1976;1982•中国1986•WHO:2000;2008;20167FAB1976Dysmyelopoieticsyndromes•RA•RAEBBrJHaematol1976,33:4518MDS(FAB1982)%RingedSideroblastsPBBlastsBMBlastsPBMonocytesRA1%5%RARS15%1%5%RAEB5%5-20%RAEB-T5%21-30%CMML5%≤20%1x109/L9FAB→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/MPD10WHO2000PBblastsBMblasts1RA5%5%lowrisk2RARSRS≥15%3RCMD4RCMD-RSRS≥15%5Del(5q)6RAEB-15%5-9%highrisk7RAEB-25-19%10-19%8MDS-UWHO2000→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）12RCUDRefractorycytopeniaswithunilineagedysplasiaRArefractoryanemiaRNrefractoryneutropeniaRTrefractorythrombocytopeniaRARSRefractoryanemiawithbringsideroblastsRCMDRefractorycytopeniaswithunilineagedysplasiaRAEB-1Refractoryanemiawithexcessblasts,type1RAEB-2Refractoryanemiawithexcessblasts,type2del(5q)MDSassociatedwithisolatedDel(5q)RCCChildhoodMDS,includingrefractorycytopeniaofchildhood(RCC,provisional)MDS-UMDS,unclassifiableWHO2008WHO20161.MDSwithsinglelineagedysplasia(MDS-SLD)2.MDSwithmultilineagedysplasia(MDS-MLD)3.MDSwithringsideroblasts(MDS-RS)MDS-RSandsinglelineagedysplasia(MDS-RSSLD)MDS-RSandmultilineagedysplasia(MDS-RSMLD)4.MDSwithexcessblasts(MDS-EB1,MDS-EB2)5.MDSwithisolateddel(5q)(5q-syndrome)6.MDS,unclassifiable(MDS-U)7.Provisionalentity:Refractorycytopeniaofchildhood(RCC)1415CHIP&ICUS16•Clonalhematopoiesisofindeterminatepotential(CHIP):acquiredclonalmutationsidenticaltothoseseeninMDScanoccurinthehematopoieticcellsofapparentlyhealthyolderindividualswithoutMDS.•Provisionalcategory：idiopathiccytopeniaofundeterminedsignificance(ICUS)171.Myeloproliferativeneoplasms(MPN)2.Mastocytosis3.Myeloid/lymphoidneoplasmswitheosinophiliaandrearrangementofPDGFRA,PDGFRB,orFGFR1,orwithPCM1-JAK24.Myelodysplastic/myeloproliferativeneoplasms(MDS/MPN)5.Myelodysplasticsyndromes(MDS)6.Myeloidneoplasmswithgermlinepredisposition7.Acutemyeloidleukemia(AML)andrelatedneoplasms①AMLwithrecurrentgeneticabnormalities②AMLwithmyelodysplasia-relatedchanges③Therapy-relatedmyeloidneoplasms④AML,NOS⑤Myeloidsarcoma⑥MyeloidproliferationsrelatedtoDownsyndrome⑦Transientabnormalmyelopoiesis(TAM)⑧MyeloidleukemiaassociatedwithDownsyndrome8.Acuteleukemiasofambiguouslineage9.B-lymphoblasticleukemia/lymphoma10.T-lymphoblasticleukemia/lymphoma11.Provisionalentity:Naturalkiller(NK)celllymphoblasticleukemia/lymphomaWHOmyeloidneoplasmandacuteleukemiaclassification18Myeloproliferativeneoplasms(MPN)(JAK2,MPL,CALRmutations)•Chronicmyeloidleukemia(CML),BCR-ABL11•Chronicneutrophilicleukemia(CNL)(CSF3Rmutation)•Polycythemiavera(PV)•Primarymyelofibrosis(PMF)•PMF,prefibrotic/earlystage•PMF,overtfibroticstage•Essentialthrombocythemia(ET)•Chroniceosinophilicleukemia,nototherwisespecified(NOS)•MPN,unclassifiable19Myelodysplastic/myeloproliferativeneoplasms(MDS/MPN)1.Chronicmyelomonocyticleukemia(CMML)2.Atypicalchronicmyeloidleukemia(aCML),BCR-ABL1(-)3.Juvenilemyelomonocyticleukemia(JMML)4.MDS/MPNwithringsideroblastsandthrombocytosis(MDS/MPN-RS-T)5.MDS/MPN,unclassifiable20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RecommendationsandDefinitionsinMDS•Recommendations•Differential:500inBM,200cellsinPB•Number:200forGandE,30cellsformeg.•Ringsideroblasts:≥5irongranulesencircling≥1/3ofthenucleus•Minimaldysplasticchanges(goodqualityofsmear)•10%inonesinglecellline*•or10%withrecurrentabnormalcytogenetics•Cytopenia(≥6month),Transfusion-dependent,macrocyticanemia•Hgb10g/dL•ANC1.5x109/L•PLT100x109/L•Constantblastcount5-19%22MorphologicFeatures•Blasts：Myeloblasts•Dysmyelopoiesis;Dyserythropoiesis;Dysgranulopoiesis;Dysmegakaryopoiesis•Trephinebiopsy:Cellularity;Myelofibrosis(reticulin,MDSwithfibrosis);Reportestimated%ofCD34+blasts;Dysmegakaryopoiesis(CD61);ALIP(abnormallocalizedimmatureprecursors)23红系病态造血NormalRingedsideroblasts24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：dysplasia•BMbiopsy：ALIP•Flowcytometry•Cytogenetic：5q-/-5,-7•Molecular：NGS•MA,AA,PNH,MPN,AML27AMLwithlessthan20%blastsMDSwithPNHfeaturesAMLFABM6whenerythroblastsare50%MDSwithhypocellularmarrowMDSwithfibrosisMDSwiththrombocytosisPNHMPNAAMDSAML28MinimalDiagnosticCriteriainMDS(A)PrerequisitecriteriaConstantcytopeniainoneormoreofthefollowingcelllineages:erythroid(hemoglobulin11gdL-1);orneutrophilic(ANC1500µ-1);ormegakaryocytic(platelets100,000µL-1)Exclusionofallotherhematopoieticornon-hematopoieticdis