慢性粒单核细胞白血病诊治进展课件

CMML诊治进展江苏省人民医院血液科洪鸣1精选pptCMML诊治进展江苏省人民医院血液科洪鸣1精选ppt2精选ppt2精选ppt3精选ppt3精选ppt1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContents4精选ppt1Definition2Diagnosis3RDefinition5精选pptDefinition5精选pptWHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)6精选pptWHOClassificationofMDS/MPNDefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)7精选pptDefinitionAclonalhematopoieDiagnosis8精选pptDiagnosis8精选pptClinicalmanifestationMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMPN-typesignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegaly9精选pptClinicalmanifestationMDS-type

Morphology(PB)PBmonocytesusuallyrangefrom2to5

×109/L,butmayexceed80

×109/L.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Dysgranulopoiesisispresentinmostcases.10精选pptMorphology(PB)PBmonocytes

Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurdysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocytes

withabnormallylobatednuclei(inupto80%ofpatients)monocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)11精选pptMorphology(BM)hypercellularMonocytosiswithmorphologicallynormalmonocytes(PB)MonocyteswithnuclearandCytoplasmicabnormalities(PB)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.12精选pptMonocytosiswithmorphological

ImmunophenotypeThePBandBMcellsusuallyexpressCD33andCD13,withvariableexpressionofCD14,CD68,CD64.AnincreasedpercentageofCD34+cellshasbeenassociatedwithearlytransformationtoacuteleukemia.Occasionally,overexpressionofCD56,aberrantexpressionofCD2,anddecreasedexpressionofHLA-DR,CD13,CD15,andCD36maybeobserved.13精选pptImmunophenotypeThePBandBM

grnulocyticproliferationanincreaseinerythroidprecursorsmildtomoderateincreaseintheamountofreticulinfibres(30%)Histopathology14精选pptgrnulocyticproliferationmi

Immunohistochemistryontissuesectionsthemostreliablemarkers:CD168R,CD163

monocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)relativelyinsensitiveascomparedwithcytochemistryorflowcytometry15精选pptImmunohistochemistryontissChromosomalabnormalities

NospecificcytogeneticalterationshavebeenidentifiedinpatientswithCMML.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%)16精选pptChromosomalabnormalitiesNosChromosomalabnormalities

17精选pptChromosomalabnormalities17精选

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):375-383.18精选pptChromosomalabnormalitiesMyelomonocyticClonalproliferationDiseaseprogressionSomaticmutations19精选pptMyelomonocyticDiseaseSomaticmSpliceosomalmutations

Yoshida,etal.Frequentpathwaymutationsofsplicingmachineryinmyelodysplasia.Nature2011;478(7367):64-9.Lessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcases20精选pptSpliceosomalmutationsYoshidaSRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutSRSF2mutwerecorrelatedwithhigherage,lesspronouncedanemiaandanormalkaryotype.SRSF2mutandEZH2mutweremutuallyexclusivebutassociatedwithTET2mut.SRSF2

Pro95HishadafavorableimpactonOSintheRUNX1mutsubcohort.MeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2012Oct11;120(15):3080-8.21精选pptSRSF2mutationsinCMML129/275

WHOdiagnosticcriteriaforCMML

PersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/L22精选pptWHOdiagnosticcriteriafor

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

23精选pptLessthan20%blastsinPBa24精选ppt24精选ppt25精选ppt25精选pptDiagnosticwork-up26精选pptDiagnosticwork-up26精选ppt27精选ppt27精选pptRiskstratification28精选pptRiskstratification28精选ppt

RiskstratificationIPSSforsurvivalinMDSoriginallyproposedincluded126patientswithCMML.“Proliferative-typeCMML”(WBC>12×109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.29精选pptRiskstratificationIPSSforRiskstratification

MDAPS(M.D.AndersonPrognosticScore)

30精选pptRiskstratification

MDAPS(M.Onepointforeachofthefollowing

variablesHb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcells31精选pptOnepointforeachofthefollsubgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel32精选pptsubgroupsscoreMediansurvivallNewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)33精选pptNewMDSmodelappliedinCMMLScore34精选pptScore34精选pptlowInt-1Int-2highLevelsofrisk35精选pptlowInt-1Int-2highLevelsofrisTherapeuticoptions36精选pptTherapeuticoptions36精选pptTherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantation37精选pptTherapeuticoptionsBestsupporCytotoxicchemotherapyWatteletal.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:12monthsWelltolerated38精选pptCytotoxicchemotherapyWatteleHypomethylatingagentsAribietal.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:12months39精选pptHypomethylatingagentsAribietAllogeneicstemcelltransplantation

(retrospectiveregistryfromlargetransplantcenters)EGBMT283patients245patients(93%)successfullyengrafted.III/IVacuteGVHD:85/258(30%)chronicGVHD:58/102(57%)NRM(nonrelapsemortality):37%Eissaetal.BiolBloodMarrowTransplant2011;17:908–915.85patientsbetween1986and2008attheirinstitutionIII/IVacu