骨髓增生异常综合征

Myelodysplasticsyndromes(MDS)骨髓增生异常综合征,ChenYun,MD,PhD陈昀ProfessorofShandongUniversityJinanCentralHospitalE-mail:yunchen,Content,Definition（定义）History（历史）Etiology（流行病学）Classifications（分类）Pathogenesis（发病机理）Diagnosisanddifferentialdiagnosis（诊断）Treatment（治疗）,Definition,Myelodysplasticsyndrome(MDS)isaclonaldisordercharacterizedbyineffectivehematopoiesis,whichledtoeitherfatalcytopebiasoracutemyelogenousleukemias(AML)克隆性疾病、无效造血、致命性血细胞减少症或急性髓细胞白血病演变PathogeneticallyrelatedtoabouthalfofAMLcases,especiallyinolderpatients常见于老年人ClinicalfeaturesofMDS,areusuallypresentedbybonemarrowfailure通常表现为骨髓衰竭PeripheralbloodcytopeniasincombinationwithahypercellularbonemarrowexhibitingdysplasticchangesarethehallmarksofMDS.,History,1941,BomfordandRhoadsRefractoryanemia(RA)1953,BlockProgressiontoleukemia(PL)1956,BjrkmanRefractoryanemiawithringedsideroblats(RARS)1970,DreyfusRefractoryanemiawithexcessblats(RAEB)1974,MiescherChronicmyelomonocyticleukemia(CMML)1976,FABcooperativegroup-thedefinitionofMyelodysplaticsyndrome(MDS)1982,FABcooperativegroup-thediagnosisandclassificationofMDS1987,BennerMorphological,Immunogical,andCytogeneticclassificationofMDS2000,WorldHealthOrganization(WHO)MDSiscategorizedtomyeloidmalignances,Etiology,TheincidencecurvesforpopulationsatriskforAMLandMDSaresimilarinshape,withMDSexceedingAMLandwithapotentialincreaseforbothwithadvancingage.SimilartoAML,thesexdistributionofMDSisapproximatelyequaluntilage60,afterwhichasubstantialmalepredominancedevelops.MDS-relatedAML,asubtypeofAML,mirrorstheincidenceofAML,includingtheprogressivemalepredominancethatdevelopswithadvancingagebeyond60years.,Classification-FAB,In1982,theFrench-American-British(FAB)CooperativeGroupclassifiedfivesubtitlesofMDSRefractoryanemia(RA)Refractoryanemiawithexcessofblasts(RAEB)Refractoryanemiawithexcessofblastsintransformation(RAEB-T)Refractoryanemiawithringedsideroblasts(RARS)Chronicmyelomonocyticleukemia(CMML),Classification-WHO,TheclassificationbasedonmorphologiccriteriawasrevisedresultinginWHOclassification,whichprovidesmorehomogenousMDScategoriesbuteliminatesthe“RAEB-T”category.Thebetterprognosisofpatientswithanisolatedcytogeneticaberrationat5qwasidentifiedas5q-Patientswith10%BMblastshaveashortermediansurvivalandahighertransformationratetoAMLascomparedtothosewith10%blasts,RAEBisdividedintotwosubgroups,RAEB-1andRAEB-2,dependingonthenumberofblastsinBMandPB.Inadditiontothenumberofblastcells,thepresenceofAuerrobscanbepredictiveforRAEB-2.,Classification-WHO,ComparisonofFABandWHOclassificationsofMDS,InternationalPrognosticScoringSystem(IPSS),Theinitialchromosomalaberration,theageofpatients,andthenumberandseverityofthecytopeniaareimportanttoevaluatetheprognosisofMDSassummarizedinIPSS.ThemediansurvivalofMDSpatientsaccordingtothisclassificationrangesfrom6yearsforlow-riskto6monthsforhigh-riskpatients.Therefore,theimplicationofthisscoringsysteminanyclinicaltrialevaluatingtreatmentoptionsinMDSisnowastandardrequirement.,InternationalPrognosticScoringSystemforRiskAssessmentinPrimaryMDS,IPSSGroupsandOutcomes,MorphologicfeaturesofMDS,AvarietyofmorphologicabnormalitiesofallthreehematoloieticlinesarefoundinbloodandmarrowinMDS.Inperipheralblood,commonfindingsinredcellsaremacrocyticordimorphic(macrocyticandnormocytic)populations,basophilicstippling,andnucleatedredbloodcells.GranulocytesmayhavePelger-Huetmorphology,hepersegmentation,hypogranulation,andimmatureforms.Plateletsmaybelarge,agranular,orvacuolated.Inmarrow,additionalerythroidchangesaremegaloblastoidchanges(nucleocytoplasmicasynchrony),irregularnuclearshapes,bi-ormultinucleation,ringedandabnormalsiderob;asts,PASpositivity,andinternuclearbridging(INB).AdditionalgranulocyticchangesincludemegaloblastoidorblockedmaturationandlossofMPOreactivity.Megakaryocytesmaybesmallwothsingleormultiplesmallnuclei,largerandmonolobate,orlargewithlarge,hyperchromatic,irregularnuclei.Immaturecellsinperipheralbloodmayshowmostofthesamefeaturesasmarrowcells.,Dysplasia,Hypogranulation,Multinuclearity,Negativeforneutrophilmyeloperoxidase,MorphologicfeaturesofMDS,Refractoryanemia(marrowclotsection)Hyperproliferation,Refractoryanemia(marrowsmear)Ineffectiveerythropoiesis,RefractoryanemiaWithringedsideroblasts(ironstaining),MorphologicfeaturesofMDS,RefractoryanemiaWithexcessblasts(RAEB-1)Marrowblasts59%,Refractoryanemiawithexcessblasts(RAEB-2)Marrowblasts1019%,Transformation(Progression)toleukemiaMarrowblasts20%,ApplicationofimmunophenotypingtoMDS,Inadditionaltoacquiredmorphologicfunctional,cytogenetic,andproductionabnormalities,marrowcellsinMDSfrequentlydemonstrateaberrantpatternsofdifferentiationantigenexpressionandlineage-aberrantantigenexpression.Flowcytometry(FCM)inMDSusingapanelofantibodiessimilartothoseforALhasdemonstratedaberrantdifferentiationpatternsinbothmyeloidanderythroidprecursorsandlineage-aberrantantigenexpressioninmyeloidprecursorsinalargepercentageofcases.ThisapproachmayprovideadditionalinformationtoconfirmdiagnosisofMDSindifficultcasesandmaypossiblycontributetosubclassificationofMDS.However,evaluationofbothmyeloidanderythroidlineagesforthispurposerequiresuseofalargepanelofantigens,andthisapproachhasnotyetgainedwidespreadclinicaluse.Ifvalidateandsimplifiedwithimprovementsinflowtechnology,itmaybecomeavaluableadjunctfordiagnosisandsubclassificationofMDS.,CytogeneticandmolecularalterationsinMDS,ThecytogeneticchangesfoundinMDSarenotunique.Bothstructuralandnumericalcytogeneticchangesmayoccur.ThemostfrequentchromosomalabnormalitiesinMDSinvolveddeletionsofchromosomes5,7,11,12,and20and/ortrisomy8.Theincidenceofchromosomalabnormalitiesisabout30%50%inprimaryMDSand80%inmutagen-relatedMDS.Thelatteroftenhascomplexchangesthatfrequentlyinvolvedeletionsofchromosomes5and/or7orthelongarmsofthesechromosomes.,Relativepercentageofvariouscytogeneticabnormalitiesindenovomyelodysplasticsyndrome(MDS).,CytogeneticandmolecularalterationsinMDS,TranslocationsarerareinMDS.MDS-relatedchromosomaldeletionssuggestthattumorsuppressorgenesorDNArepairgenesarealteredinthisgroupofdisease.Usuallythesechangesrequiretwohits:mutationofthetargetgeneandlossofthesecondallelethroughoneofseveralgeneticeventsincludingdeletion,duplication,orrecombination.,FISHfor5qdeletion,位于5q31上的红色信号只有一个，表示5q31缺失。,探针：1、EGR1（红色），定位：5q31；2、D5S23，D5S721（绿色），定位：5p15,位于5q33上的红色信号只有1个，表示5q33缺失。,探针：1、CSF1R（红色），定位：5q33；2、D5S23，D5S721（绿色），定位：5p15,Pathogenesis,TheunderlyingcausesofprimaryMDSarestillbeingdefined.AproposalformultisteppathogenesisofMDSisshown.Afterinitialdamageoftheprogenitorcellbyatoxinorspontaneousmutation,severaladditionallaterationsmayaffectthesecellsprovidingthemwithagrowthadvantage.Thesealterationscaninfluenceexpressionofcellcycle-relatedgenes,transceiptionfactorsaswellastumorsuppressorgenes.,Pathogenesis,EnhancedintramedullaryapoptosismaycontributetotheineffectivehematopoiesisinMDS.Theactivityofthecaspases1and3wasfoundtobeincreasesinbonemarrowcellsfrompatientswithlow-riskMDS.EarlyMDSwasdescribedtobeassociatedwithanelevatedrationofapoptosistoproliferation,butthemechanismsforthisfindingarenotyetestablished.Recently,microarrayanalysescanprovidesufficientdatatodetectgenesorgenepatternsthatassociatedwithMDS,forexample,hypermethylation.TheapproachmayhaveastrongimpactonthefurtherclassificationandriskdefinitionofMDS.,MultisteppathogenesisinMDS,Outcomeandprognosticfactors,TheevaluationofdiseaseriskandoutcomeofpatientswithMDSisoneofthemostcriticalpoints.TheintroductionofIPSScoulddemonstrateforthefirsttimethatmultipleparametersincludingchromosomalchanges,bonemarrowblastcells,andthenumberofcytopeniasarerequiredtopredictforthesurvivalandtransformationratetoAML.InpatientswithIPSSloworintermediate-1risk,thedisordercanbestableforyearswithoutworseningofanemiaorsymptoms.Themediansurvivalisabout6years.Insuchpatients,ironoverloadedisacommonprobleminpolytransfusedpatientsleadingtosecondaryhemosiderosisandsometimestohemochromatosis.Thesurvivaltimeisconsiderablyshorterforpatientswithincreasedblastsinthebonemarrow.,Outcomeandprognosticfactors,Besidestheapplicationofclassicalmorphologicalandcytogeneticaltechniques,theintroductionofmutationalandepigenetic(DNA-methylation)analysisofkeygenes(egFILT3,CHK2,p14ARF,p15INK4b,p16INK4a)involvedintothecellcycleprovidedevidencefortheriskevaluationinMDS.Furthermore,ithasbeenrecentlyshownthatgeneexpressionprofilingofhematopoieticstemcellsodpatientswithMDScandistinguishbetweenlow-andhigh-riskpatientswithhighaccuracy.TheknowledgeabouttheriskclassificationofMDSattimeofinitialdiagnosiscouldresultinmoreindividuletreatmentstrategiesinpatientswithMDS.,DifferentialDiagnosis,TheclinicaldiagnosisoftypicalMDSaccordingtoFABcriteriaisoftenstraightfowardandpresentsnodifficulty.Whilethediagnosismaybesuspectedonthebasisofthehistoryandtheperipheralbloodfindings,morphologicalexaminationofBMisessentialtoestablishthediagnosis.Exclusionofhypoplastic/aplasticanemiamaybedifficultinhypocellularMDS.Rarely,disorderswithhypoplastichematopoiesis,forexample,amegakaryocyticthrombocytopenia,chronicneutropenia,andaplasticanemiacanevolveintoacuteleukemiaandmustbedistinguishedfromMDS.Inthesecases,chromosomalabnormalitiesmaybehelpfultoverifyMDS.,DifferentialDiagnosis,SerumvitaminB12andfolatelevelsareoftenmeasuredtoexcludethesevitamindeficiencies.Inyoungerpatients,congenitaldyserythropoieticanemiasandpureredcellanemiamustbeconsidered,thelattercanbeassociatedwithMDS.Sideroblasticchangesmayalsobecausedbydrugs(chloramphenicol,tuberculostaticagents,penicillamine),oralcohol,andoccupationaltoxins(lead,benzene),orbeassociatedwithnonmalignantdisorders(renalorhepaticfailure,connectivetissuedisease).,DifferentialDiagnosis,IndividualsinfectedwithhumanimmunodeficiencyviruscanhavemorphologicalfeaturesofMDSintheirbonemorrowandtheyhavetobedistinguishedfromprimaryMDS.Disordersthatresultinperipheraldestructionofthematurecells(immunephenomena,infectiousagents,mechanicalhemolysis,hypersplenism)mustbeexcluded.ThedistinctionbetweenCMMLandchronicmyelogenousleukemia(CML)cansometimespresentdiagnosticdifficulties.Cytogenetic(Philadelphiachromosome)andmolecular(bcr-abl-translocation)studieswillhelpinsuchcases.Ontheotherhand,thedistinctionbetweenosteomyelofibrosisandMDSwithaccompanyingmyelofibrosiscanbedifficult.,TreatmentStrategies,PatientswithMDSaremainlyolderpatientssufferingfromaccompanyingdiseases.Therefore,variousstrategieshavebeenusedtotreatpatientswithMDS.Ratherthanofferacurativetherapeuticoption(whichisallogeneichematopoieticcelltransplantation),themaintherapeuticgoalinpatientswithMDSistoimprovethehematopoiesisandensuretheage-relatedqualityoflife.,TreatmentStrategiesforLow-riskMDS,Low-intensitytherapies,definedastreatmentscapableofpermittinganoutpatientmanagement,areoftendirectedatpatientswithlow-riskMDS(IPSSlowandintermediate-1).Usingsuchstrategies,thegoalistoimprovehematopoiesisandtominimizethenumberofredbloodcelltransfusions.Suchstrategiesarenotnecessarilyassociatedwithimprovedoverallsurvivalorprogression-freesurvival.,TreatmentStrategiesforHigh-riskMDS,Patientswithhigh-riskMDS(IPSSintermediate-2andhigh)haveaneedtoreceivehigh-intensitytherapies(aggressiveantileukemicchemotherapyand/orhematopoieticcelltransplantation)toeliminatetheexpandedclonalcellsandtoinducehematologicalresponses.AsaresultofthehighmedianageofpatientswithMDS,onlyaboutone-thirdofhigh-riskMDSpatientscanenterintensivecytotoxictreatment.Forpatientsnotqualifyingforintensivetherapy,theapplicationofexperimentaltreatmenttosuppress,differentiate,oreradicatethemalignantcloneareunderinvestigation.,NewaspectsintreatmentofMDS,DemethylatingagentsImmunosuppressiveagentsDifferentiation-inducingtherapyAntiangiogenicagentsFutureexperimentalapproaches,Demethylatingagents,Manygeneshaveregionsintheirpromoter(CpGislands)thatcanbemethylatedatthe5positionofcytosine,whichsilencesexpressionofthesegenes.Theoretically,demethylationofmethylatedgenesthatareimportantindifferentiationand/orapoptosiscouldhaveclinicalapplications.,Demethylatingagents,Initialpilottrialswithlow-doseAzacitidineandlow-doseDecitabineprovidedencouragingresultsthatwereconfirmedinmulticenterstudies.TheresultsofamulticenterphaseIItrialwithlow-doseintravenousDecitabine(45mg/m2for3daysevery6weeks)werereportedfor66mostlyelderlypatientswithadvanced(24%Int-1,38%Int-2,38%high-risk)MDS.Theoverallhematologicresponseratewas49%,whichincludedaresponseof64%forhigh-riskindividuals.CytogeneticremissionfollowingtreatmentwithDecitabinehavebeennotedin31%ofpatientswithanabnormalkaryotype,and38%withcomplexkaryotypeand/orchromosome7abnormalities.,Immunosuppressiveagents,Antithymocyteglobulin(ATG)ATGhasbeensuccessfullyinthetreatmentofsevereaplasticanemia.Inalargestudy,42transfusion-dependentMDSpatientsreceivedATG(40mg/kg/dayfor4days).RBCtransfusionindependenceoccurredin16individuals,andplateletsincreasedin14ofthem.ThreeindividualswithRAhadacompleteremission.Theresponseratewas64%inthelow-riskindividualsand33%inthosewithhigh-riskMDS.CyclosporinA(CSA)CSAcanbeeffectiveinimprovinganemiainautoimmunedisorders.SeveralsmallstudiesusedCSAforMDSpatientswithvariableresults.ApredictivemarkerforagoodresponsemaybetheexpressionoftheJLA-DRB1*1501allele.,Differentiation-inducingtherapy,Arsenictrioxide(As2O3)ArsenictrioxidehasbeenusedtherapeuticallyforatleastamillenniuminChina.ItwasemployedinthemiddleofthelastcenturyintheWesterncountriesfortreatmentofchronicmyelogenousleukemia(CML).Mostrecently,ithasproducedverygoodresponseinacutepromyelocyticleukemia(APL).ClinicalstudiestoevaluateArsenictrioxideinMDSareunderway.,Antiangiogenicagents,ThebonemarrowofindividualswithMDScontainsanabnormallyhighnumberofbloodvessels.Thishasencouragedtheinvestigationofinhibitorsofangiogenesissuchasthalidomide,lenalidomide,andinhibitorsofvascularendothelialgrowthfactors(VEGF)forindividualswitheitherAMLorMDS.Thalidomidewasinitiallydevelopedtousedastoantireactionofpregnancy,butitwasfoundtohaveactivityinthetreatmentofpatientswithmultiplemyeloma.UsingthisdrugeitheraloneorincombinationwithTopotecan,Pentoxifyllin,resultedin3040%ofMDSpatientsshowingahematopoieticresponse,usuallyanimprovederythropoiesis.,Intensivecytotoxictreatment,Atthepresenttime,long-termbenefitforindividualswithMDScanbeachievedonlybyeradicationoftheabnormalcloneandrestorationofnormalhematopiesis.Asaconsequenceoftheimprovedsupportivecareinpatientsreceivingintensivecytotoxictreatment,duringthelastyearstheremissionratewhichisachievedinyoungerpatientswithhigh-riskMDSiscomparablewiththoseknownfrompatientswithdenovoAML.However,datafromEORTCandMDAndersonCancerCenter,neitherthechemotherapynorthetransplantationcouldshowaclearbenefitforthosepatients.,Intensivecytotoxictreatment,ThedecisionwhetheraggressivetreatmentmaybeofbenefitforanindividualshouldincludestratificationaccordingtotheirriskfactorsusingtheIPSS.Also,theuseofhematopoieticgrowthfactorspermitsmorepatientstoreceiveintensivecytotoxictreatment.Nevertheless,thedurationofremissionsareassociatedwithrestorationofpolyclonalhemopoiesis,andtheachievementofapartialremissionafterinductiontherapymaybeofclinicalbenefitforhigh-riskpatients.,OveralltreatmentapproachinMDS,ThetreatmentdecisionshouldtakeintoconsiderationDiseaseriskaccordingtoIPSSAgeofthepatientsPerformancestatusofthepatientsBasedontheseresults,andkeepinginmindthemediansurvivaldeterminedbyIPSS(low-risk,5.7years;intermediaterisk,1.23.5years;high-risk,0.5years),fourpossibletreatmentstrategiesareasfollows,ForyoungerpatientswhoarecandidateofHCT,Individualsuptothe(biological)ageofapproximately5560yearsarecandidateforallogeneictransplantationfromHLA-matched(siblingorunrelated)donor.Thepatientsshouldbecarefullyinformedabouttherisksoftheallogeneichematopoieticcelltransplantationincludinginformingaboutthenecessary,sometimeslong-termprophylaxisagainstgraft-versus-hostdisease.Thealternativetreatmentoptionsshouldbementionedindetail.,Forpatientswithlow-orInt-1risk,Patientswithloworintermeidate-1riskMDSwhohavenoHLA-identicaldonororareolderthan60yearswithgoodclinicalperformanceshouldreceiveeithersupportivecareorwhennecessaryatrialoferythropoietin.Fornon-respondertoerythropoietin,thecombinationtherapyoferythropoietinwithG-CSFmaybeeffective.Alternatively,immunosuppressivetherapyshouldbeconsidered.Astheirdiseaseprogresses,varioustherapiesmightbeevaluatedinthecontextofongoingclinicalstudies.,ForpatientswithInt-2orhighrisk,Patientswithintermediate-2orhighriskMDS,olderthan60yearsandhaveagoodclinicalperformance,arecandidatesforintensivecytotoxictherapy,followedbyconsolidationtherapyandperhapsautologoustransplantation.,Elderpatientsorwithpoorperformance,Individualswhoareelderand/orinpoorclinicalconditionshouldreceivesupportivecareandifpossibleanddesiredbythepatientsinvestigational,outpatient-basedtherapy(egdemethylatingdrugsorthalidomide).,Summary,MDSisheterogenous,fromrefractoryanemiatoprogressiontoAML.Themediansurvivalisverydifferent.Recentlydevelopmentinunderstandingoftheunderlyingpathogenesisandtheclassificationdependedontheoutcomeofthediseasehasalreadyimprovedsomeofthepatients.IndividualizationoftherapeuticstrategiesisveryimportantbothforprolongingthesurvivalandimprovingthequalityoflifeforpatientswithMDS.,Thankyouforyourattention.,Myelodysplasticsyndromes(MDS),GuoNongjian,MD,PhDProfessorofShandongUniversityJinanCentralHospitalE-mail:gnjian2002,Content,DefinitionHistoryEtiologyClassificationsPathogenesisDiagnosisanddifferentialdiagnosisTreatment,Definition,Myelodysplasticsyndrome(MDS)isaclonaldisordercharacterizedbyineffectivehematopoiesis,whichledtoeitherfatalcytopebiasoracutemyelogenousleukemias(AML)PathogeneticallyrelatedtoabouthalfofAMLcases,especiallyinolderpatientsClinicalfeaturesofMDS,areusuallypresentedbybonemarrowfailurePeripheralbloodcytopeniasincombinationwithahypercellularbonemarrowexhibitingdysplasticchangesarethehallmarkofMDS.,History,1941,BomfordandRhoadsRefractoryanemia(RA)1953,BlockProgressiontoleukemia(PL)1956,BjrkmanRefractoryanemiawithringedsideroblats(RARS)1970,DreyfusRefractoryanemiawithexcessblats(RAEB)1974,MiescherChronicmyelomonocyticleukemia(CMML)1976,FABcooperativegroup-thedefinitionofMyelodysplaticsyndrome(MDS)1982,FABcooperativegroup-thediagnosisandclassificationofMDS1987,BennerMorphological,Immunogical,andCytogene