CMML診治進(jìn)展江蘇省人民醫(yī)院血液科洪鳴1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContentsDefinitionWHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)DefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)DiagnosisClinicalmanifestationsignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegalyMPN-typeMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMorphology(PB)PBmonocytesusuallyrangefrom2to5×109/L,butmayexceed80×109/L.Dysgranulopoiesisispresentinmostcases.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurmonocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)dysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocyteswithabnormallylobatednuclei(inupto80%ofpatients)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.ImmunophenotypeThePBandBMcellsusuallyexpressCD33andCD13,withvariableexpressionofCD14,CD68,CD64.AnincreasedpercentageofCD34+cellshasbeenassociatedwithearlytransformationtoacuteleukemia.Occasionally,overexpressionofCD56,aberrantexpressionofCD2,anddecreasedexpressionofHLA-DR,CD13,CD15,andCD36maybeobserved.Histopathologymonocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)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%)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.SomaticmutationsDiseaseprogressionMyelomonocyticClonalproliferationLessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcasesSRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutMeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2012Oct11;120(15):3080-8.PersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/LLessthan20%blastsinPBandBMAtleastoneofthefollowing(a)Dysplasiainoneormorecelllines(b)Anacquiredclonalcytogeneticabnormalityormoleculargeneticabnormalitypresentinhematopoieticcells(c)Noevidenceofothercausesofmonocytosis(infection,inflammationormalignancy)CMML-1:blast(includingpromonocytes)<5%inPBand<10%inBMCMML-2:blastsfrom5%~19%inPBand10%~19%inBMorAuerrodsarepresentirrespectiveofblastcount

RiskstratificationRiskstratificationIPSSforsurvivalinMDSoriginallyproposedincluded126patientswithCMML.“Proliferative-typeCMML”(WBC>12×109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.Hb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcellsRiskmodelsubgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45NewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)ScoreLevelsofrisklowInt-1Int-2highTherapeuticoptionsTherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantationCytotoxicchemotherapyWatteletal.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:12monthsWelltoleratedHypomethylatingagentsAribietal.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:12monthsAllogeneicstemcelltransplantation

(retrospectiveregistryfromlargetransplantcenters)EGBMT283patients245patients(93%)successfullyengrafted.III/IVacuteGVHD:85/258(30%)chronicGVHD:58/102(57%)NRM(nonrelapsemortality):37%Eissaetal.BiolBloodMarrowTransplant2011;17:908–915.85patientsbetween1986and2008attheirinstitutionIII/IVacuteGVHD:21/81(26%)chronicGVHD:37(4