骨髓增生異常綜合征培訓(xùn)課件

骨髓增生異常綜合征一組起源于造血干細(xì)胞(HSC)的異質(zhì)性的克隆性疾病,以①外周血一系或多系減少②骨髓增生正?；蚩哼M(jìn)伴病態(tài)造血和③高風(fēng)險向急性白血病轉(zhuǎn)化為特征。Agroupofclonalneoplasms;heterogeneous;Hematopoieticstemcells(HSC)orprogenitors;CytopeniaMyelodysplasia;ineffectivehematopoiesisIncreasedriskofblastictransformation:-preleukemia,smoulderingleukemia定義MDSvsAMLBlood.2013;121:3811發(fā)病情況發(fā)病年齡：成人發(fā)病為主，老年更多見，輕微男性發(fā)病優(yōu)勢發(fā)病率：美國報告為2-12/10萬；70歲以上者50/10萬(IntJHematol2001,73:405)高齡，外因；原發(fā)性、繼發(fā)性MDS：tMDS（烷化劑、表鬼臼毒素類）先天/家族性MDSHSC增生失控、分化受阻、細(xì)胞凋亡增加細(xì)胞遺傳學(xué)異常：-5/5q-，-7/7q-基因水平的改變；AML1-MDS1-EVI1融合基因表觀遺傳學(xué)調(diào)控異常病因、發(fā)病機(jī)理MDSMPNLeukemiaProliferation↑↑↑Differentiation↓?↓Apoptosis↑?↓分類FAB:1976;1982中國1986WHO:2000;2008;2016FAB1976DysmyelopoieticsyndromesRARAEBBrJHaematol1976,33:451MDS(FAB1982)%RingedSideroblastsPBBlastsBMBlastsPBMonocytesRA<1%<5%RARS>15%<1%<5%RAEB<5%5-20%RAEB-T>5%21-30%CMML<5%≤20%>1x109/LFAB→WHO2000

與AML界限：骨髓原始細(xì)胞降為20%RAEB-t歸入AML；但有t(8;21)、t(15;17)、inv(16)/t(16;16)等核型異常者即使小于20%也應(yīng)診斷為白血病CMML:MDS/MPDWHO2000

PBblastsBMblasts

1RA<5%<5%

lowrisk2RARSRS≥15%3RCMD

4RCMD-RSRS≥15%5Del(5q)

6RAEB-1<5%5-9%

highrisk7RAEB-25-19%10-19%

8MDS-U

WHO

2000→2008

增加RN、RT，與RA一起組成RCUD;重新定義MDS-U（不再包括RN和RT）增加ChildhoodMDS（RCC）RCMD與RCMD-RS合并t-MDS/t-AML不再區(qū)分原因（烷化劑or鬼臼毒素類）RCUDRefractorycytopeniaswithunilineagedysplasiaRArefractoryanemiaRNrefractoryneutropeniaRTrefractorythrombocytopeniaRARSRefractoryanemiawithbringsideroblastsRCMDRefractorycytopeniaswithunilineagedysplasiaRAEB-1Refractoryanemiawithexcessblasts,type1RAEB-2Refractoryanemiawithexcessblasts,type2del(5q)MDSassociatedwithisolatedDel(5q)RCCChildhoodMDS,includingrefractorycytopeniaofchildhood(RCC,provisional)MDS-UMDS,unclassifiableWHO2008WHO2016MDSwithsinglelineagedysplasia(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)CHIP&ICUSClonalhematopoiesisofindeterminatepotential(CHIP):acquiredclonalmutationsidenticaltothoseseeninMDScanoccurinthehematopoieticcellsofapparentlyhealthyolderindividualswithoutMDS.Provisionalcategory：idiopathiccytopeniaofundeterminedsignificance(ICUS)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/lymphomaWHOmyeloidneoplasmandacuteleukemiaclassificationMyeloproliferativeneoplasms(MPN)

(JAK2,MPL,CALRmutations)Chronicmyeloidleukemia(CML),BCR-ABL11Chronicneutrophilicleukemia(CNL)(CSF3Rmutation)Polycythemiavera(PV)Primarymyelofibrosis(PMF)PMF,prefibrotic/earlystagePMF,overtfibroticstageEssentialthrombocythemia(ET)Chroniceosinophilicleukemia,nototherwisespecified(NOS)MPN,unclassifiable

Myelodysplastic/myeloproliferativeneoplasms(MDS/MPN)Chronicmyelomonocyticleukemia(CMML)Atypicalchronicmyeloidleukemia(aCML),BCR-ABL1(-)Juvenilemyelomonocyticleukemia(JMML)MDS/MPNwithringsideroblastsandthrombocytosis(MDS/MPN-RS-T)MDS/MPN,unclassifiable臨床表現(xiàn)差異大、早期低危患者無癥狀貧血發(fā)熱、感染出血一般無肝脾淋巴結(jié)腫大轉(zhuǎn)化為急性白血病老年患者多有合并癥RecommendationsandDefinitionsinMDSRecommendationsDifferential:500inBM,200cellsinPBNumber:200forGandE,30cellsformeg.Ringsideroblasts:≥5irongranulesencircling≥1/3ofthenucleusMinimaldysplasticchanges(goodqualityofsmear)

>10%inonesinglecellline*or<10%withrecurrentabnormalcytogeneticsCytopenia(≥6month),Transfusion-dependent,macrocyticanemia

Hgb<10g/dLANC<1.5x109/LPLT<100x109/LConstantblastcount5-19%MorphologicFeaturesBlasts：MyeloblastsDysmyelopoiesis;Dyserythropoiesis;Dysgranulopoiesis;DysmegakaryopoiesisTrephinebiopsy:Cellularity;Myelofibrosis(reticulin,MDSwithfibrosis);Reportestimated%ofCD34+blasts;Dysmegakaryopoiesis(CD61);ALIP(abnormallocalizedimmatureprecursors)紅系病態(tài)造血NormalRingedsideroblasts

粒系病態(tài)造血巨核系病態(tài)造血診斷、鑒別診斷PB：cytopenia(s)BMsmear：dysplasiaBMbiopsy：ALIPFlowcytometryCytogenetic：5q-/-5,-7Molecular：NGSMA,AA,PNH,MPN,AMLAMLwithlessthan20%blastsMDSwithPNHfeaturesAMLFABM6whenerythroblastsare>50%MDSwithhypocellularmarrowMDSwithfibrosisMDSwiththrombocytosisPNHMPNAAMDSAMLMinimalDiagnosticCriteriainMDSPrerequisitecriteria Constantcytopeniainoneormoreofthefollowingcelllineages:erythroid(hemoglobulin<11gdL-1);orneutrophilic(ANC<1500μ-1);ormegakaryocytic(platelets<100,000μL-1) Exclusionofallotherhematopoieticornon-hematopoieticdisordersasprimaryreasonforcytopenia/dysplasiabMDS-related(decisive)criteriaDysplasiainatleast10%ofallcellsinoneofthefollowinglineagesinthebonemarrowsmear;erythroid;neutrophilic;ormegakaryocyticor>15%ringedsideroblasts5-19%BlastcellsinbonemarrowsmearsTypicalchromosomalabnormality:conventionalkaryotypingorFISHValentP,etal.LeukemiaResearch2007:727-736MinimalDiagnosticCriteriainMDS

Cont’d...(C)

Co-criteria(forpatientsfulfilling‘A’butnot‘B”):

Typicalclinicalfeatures,macrocytictransfusion-dependentanemia.典型臨床特征，輸血依賴大細(xì)胞貧血AbnormalphenotypeofBMcellsindicativeofamonoclonalpopulationdeterminedbyflowcytometry單克隆表型-流式Molecular:MonoclonalcellpopulationinHUMARAassay,genechipprofiling,orpointmutationanalysis(e.g.RASmutations)單克隆表型-基因異常Markedlyandpersistentlyreducedcolony-formationofBMor/andcirculatingprogenitorcells(CFU-assay)骨髓集落培養(yǎng)減低ValentP,etal.LeukemiaResearch2007:727-736MDS治療原則治療方案設(shè)計要求個體化、分層personalization

stratification;支持、對癥治療仍是主要措施（Bestsupportivecare)：

紅細(xì)胞、血小板輸注，CSFs,EPO

抗感染

去鐵治療FDA批準(zhǔn)的藥物（3個）：

去甲基化藥物:-阿扎胞苷（5-azacytidine2004）-地西他濱（decitabine,2006;中國2009）來那度胺（lenalidomide，2005）：del(5q)首選造血干細(xì)胞移植HypomethylatingCytosineAnalogues地西他賓FDA2006阿扎胞苷FDA2004地西他濱（Decitabine，Dacogen)15-30mg/m2(10-50mg)intravenouslydaily3-5days/cycle.DecitabinePharmacology

MechanismofActionDecitabineisanS-phasespecificagentAntineoplasticactivityattributedtoInhibitionofcellproliferationathigherdosesincorporationintoDNAblockingofDNAsynthesiscytotoxicitynonreversiblecovalentlinkingwithDNAmethyltransferaseInductionofhypomethylationatlowerdosespromotingcelldifferentiationre-expressionoftumorsuppressorgenesstimulationofimmunemechanismssuppressionoftumorgrowthHypomethylatorsvsIntensiveChemoRxinMDSwith10-30%Blasts330pts:93(28%)RxwithHMAand237(72%)withchemoRx

MVA:worsesurvivalwithchemoRxParameterHMAIntensiveChemoRxpvalue%CR+CRp4260.01MedianRem.dur.(mos)14.714.7%8-wkmortality1013medianOS(mos)18.814.6.32Nazha.Blood122:abst2788:2013來那度胺(Lenalidomide,瑞復(fù)美)AntiangiogenicImmunomodulatoryimidedrugs(IMiDs)5q-syndrome10mg/dayorallyMultiplemyelomaThalidomide（沙利度胺、反應(yīng)停）developedbyGermanpharmaceuticalcompanyGrünenthalsoldfrom1957to1961topregnantwomen,asanantiemetictocombatmorningsicknessandasanaidtohelpthemsleepapproximately10,000childrenwerebornwithseveremalformities,includingphocomelia（SealBaby)1991Dr.GillaKaplanatRockefellerUniversityshowedthatthalidomideworkedinleprosybyinhibitingtumornecrosisfactoralpha其它治療選擇免疫抑制劑：ATG,CsA,Dexamethasone小劑量化療：Low-dosecytarabine；DA亞砷酸ATRAAmifostine阿米福汀(氨磷汀)Clinicaltrials預(yù)后PrognosticmodelsIPSSIPSS-RWPSSOthers:GlobalMDACCmodel;MDACClowerriskmodel;Impactofcomorbidities發(fā)病機(jī)制及分子治療細(xì)胞遺傳學(xué)異常分子遺傳學(xué)（基因結(jié)構(gòu)）異常表觀遺傳學(xué)調(diào)控紊亂Nybakken&Bagg.JournalofMolecularDiagnostics,2014;16:145-158CytogeneticfindingsinMDSDistributionofrecurrentmutationsand

karyotypicabnormalitiesinMDSMutationallandscapeinMDSHaferlachetal.Leukemia2013Targetedsequencingofalimitednumberofgenescandetectmutationsin80%to90%ofMDSpatients;themostcommonlymutatedgenesinMDSareSF3B1,TET2,SRSF2,ASXL1,DNMT3A,RUNX1,U2AF1,TP53,andEZH2MutationsofTP53&SF3B1TP53mutationisassociatedwithaggressivediseaseinMDSingeneralandappearstopredictpoorerresponsetolenalidomideinpatientswithdel(5q).WithregardtoMDSwithringsideroblasts(MDS-RS),recurrentmutationsinthespliceosomegeneSF3B1arefrequentinMDSandareassociatedwiththepresenceofringsideroblasts.So,ifanSF3B1mutationisidentified,adiagnosisofMDS-RSmaybemadeifringsideroblastscompriseasfewas5%ofnucleatederythroidcellsImpactofmutationofp53orDNMT3AonsurvivalofMDSptsw/HSC表觀遺傳學(xué)調(diào)控異常epigenetics不涉及基因一級結(jié)構(gòu)改變的表達(dá)調(diào)控機(jī)制，即基因DNA序列不發(fā)生改變的情況下，基因的表達(dá)水平與功能發(fā)生改變，并產(chǎn)生可遺傳的表型三大特征：DNA序列本身不變、可遺傳、可逆性Regulationoftransc