慢性粒单核细胞白血病诊治进展演示文稿

慢性粒单核细胞白血病诊治进展演示文稿当前第1页\共有42页\编于星期五\9点当前第2页\共有42页\编于星期五\9点当前第3页\共有42页\编于星期五\9点1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContents当前第4页\共有42页\编于星期五\9点Definition当前第5页\共有42页\编于星期五\9点WHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)当前第6页\共有42页\编于星期五\9点DefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)当前第7页\共有42页\编于星期五\9点Diagnosis当前第8页\共有42页\编于星期五\9点ClinicalmanifestationMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMPN-typesignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegaly当前第9页\共有42页\编于星期五\9点

Morphology(PB)PBmonocytesusuallyrangefrom2to5×109/L,butmayexceed80×109/L.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Dysgranulopoiesisispresentinmostcases.当前第10页\共有42页\编于星期五\9点

Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurdysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocytes

withabnormallylobatednuclei(inupto80%ofpatients)monocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)当前第11页\共有42页\编于星期五\9点Monocytosiswithmorphologicallynormalmonocytes(PB)MonocyteswithnuclearandCytoplasmicabnormalities(PB)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.当前第12页\共有42页\编于星期五\9点

ImmunophenotypeThePBandBMcellsusuallyexpressCD33andCD13,withvariableexpressionofCD14,CD68,CD64.AnincreasedpercentageofCD34+cellshasbeenassociatedwithearlytransformationtoacuteleukemia.Occasionally,overexpressionofCD56,aberrantexpressionofCD2,anddecreasedexpressionofHLA-DR,CD13,CD15,andCD36maybeobserved.当前第13页\共有42页\编于星期五\9点

grnulocyticproliferationanincreaseinerythroidprecursorsmildtomoderateincreaseintheamountofreticulinfibres(30%)Histopathology当前第14页\共有42页\编于星期五\9点

Immunohistochemistryontissuesectionsthemostreliablemarkers:CD168R,CD163

monocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)relativelyinsensitiveascomparedwithcytochemistryorflowcytometry当前第15页\共有42页\编于星期五\9点ChromosomalabnormalitiesNospecificcytogeneticalterationshavebeenidentifiedinpatientswithCMML.Someofthemorefrequentlyreportedrecurringabnormalitiesinclude:Monosomy7(3.9–8.5%)Trisomy8(4.1–7.8%)complexkaryotypeinvolving≥3abnormalities(4.4–6.3%)trisomy21(1–2%)isochromosome17(1–2%)deletion5q(1.5%)deletion20q(0.7–1%)当前第16页\共有42页\编于星期五\9点Chromosomalabnormalities当前第17页\共有42页\编于星期五\9点

Chromosomalabnormalities

110/414(27%)patientshadcytogeneticabnormalitiesMultivariableanalysisSurvivalandProgressiontoAMLLow-risk:normalor-YasasingleanomalyOSat5years:35%Intermediate-risk:allotherabnormalitiesOSat5years:26%high-risk:trisomy8orabnormalitiesofchromosome7orcomplexkaryotypeOSat5years:4%SuchE,CerveraJ,CostaD,etal.

Cytogeneticriskstratificationinchronicmyelomonocyticleukemia.

Haematologica.2011;96(3):375-383.当前第18页\共有42页\编于星期五\9点MyelomonocyticClonalproliferationDiseaseprogressionSomaticmutations当前第19页\共有42页\编于星期五\9点Spliceosomalmutations

Yoshida,etal.Frequentpathwaymutationsofsplicingmachineryinmyelodysplasia.Nature2011;478(7367):64-9.Lessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcases当前第20页\共有42页\编于星期五\9点SRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutSRSF2mutwerecorrelatedwithhigherage,lesspronouncedanemiaandanormalkaryotype.SRSF2mutandEZH2mutweremutuallyexclusivebutassociatedwithTET2mut.SRSF2

Pro95HishadafavorableimpactonOSintheRUNX1mutsubcohort.MeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2012Oct11;120(15):3080-8.当前第21页\共有42页\编于星期五\9点

WHOdiagnosticcriteriaforCMMLPersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/L当前第22页\共有42页\编于星期五\9点

Lessthan20%blastsinPBandBMAtleastoneofthefollowing(a)Dysplasiainoneormorecelllines(b)Anacquiredclonalcytogeneticabnormalityormoleculargeneticabnormalitypresentinhematopoieticcells(c)Noevidenceofothercausesofmonocytosis(infection,inflammationormalignancy)CMML-1:blast(includingpromonocytes)<5%inPBand<10%inBMCMML-2:blastsfrom5%~19%inPBand10%~19%inBMorAuerrodsarepresentirrespectiveofblastcount

当前第23页\共有42页\编于星期五\9点当前第24页\共有42页\编于星期五\9点当前第25页\共有42页\编于星期五\9点Diagnosticwork-up当前第26页\共有42页\编于星期五\9点当前第27页\共有42页\编于星期五\9点Riskstratification当前第28页\共有42页\编于星期五\9点

RiskstratificationIPSSforsurvivalinMDSoriginallyproposedincluded126patientswithCMML.“Proliferative-typeCMML”(WBC>12×109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.当前第29页\共有42页\编于星期五\9点Riskstratification

MDAPS(M.D.AndersonPrognosticScore)

当前第30页\共有42页\编于星期五\9点Onepointforeachofthefollowing

variablesHb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcells当前第31页\共有42页\编于星期五\9点subgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel当前第32页\共有42页\编于星期五\9点NewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)当前第33页\共有42页\编于星期五\9点Score当前第34页\共有42页\编于星期五\9点lowInt-1Int-2highLevelsofrisk当前第35页\共有42页\编于星期五\9点Therapeuticoptions当前第36页\共有42页\编于星期五\9点TherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantation当前第37页\共有42页\编于星期五\9点CytotoxicchemotherapyWatteletal.Blood1996;88:2480–2487.1,000mg/dayoforalhydroxyureato150mg/weekoforaletoposidein105patientsRR:60%vs36%OS:20monthsvs9monthsBeranetal.JClinOncol1999;17:2819–2830topotecanatadoseof1.25mg/m2asacontinuousinfusionandcytarabine1.0g/m2over2hr,bothfor5days,27patientsCR:44%OS:9.4monthsInductionmortality:7%Quintas-Cardamaetal.Cancer2006;107:1525–1529.9-nitro-campothecin,atadoseof2mg/m2orallydailyfor5daysaweekin32patientsCR:11%PR:16%OS:12monthsWelltolerated当前第38页\共有42页\编于星期五\9点HypomethylatingagentsAribietal.Cancer2007;109:713–717.decitabineatasametotaldoseof100mg/m2percoursein3differentschedulesin19patientsCR:58%PR:0%HI:11%OS:19monthsWijermansetal.LeukRes2008;32:587–591.decitabineadministeredas15mg/m2over4hrIV3timesaday(totaldoseof135mg/m2percourse)in31patientsCR:10%PR:16%HI:19%OS:15monthsCostaetal.Cancer2011;117:2690–2696.azacitidine75mg/m2/dayfor7daysor100mg/m2/dayfor5days,every4weeksin38patients.CR:11%PR:3%HI:25%OS:12months当前第39页\共有42页\编于星期五\9点Allogeneicstemcelltransplantation

(retrospectiveregistryfromlargetransplantcenters)EGBMT283patients245patients(93%)successfullyengrafted.III/IVacuteGVHD:85/258(30%)chronicGVHD:58/102(57%)NRM(nonrelapsemortality):37%Eissaetal.