慢性粒单核细胞白血病诊治进展

CMML诊治进展江苏省人民医院血液科洪鸣第1页第2页第3页1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContents第4页Definition第5页WHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)第6页DefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)第7页Diagnosis第8页ClinicalmanifestationMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMPN-typesignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegaly第9页

Morphology(PB)PBmonocytesusuallyrangefrom2to5

×109/L,butmayexceed80

×109/L.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Dysgranulopoiesisispresentinmostcases.第10页

Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurdysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocytes

withabnormallylobatednuclei(inupto80%ofpatients)monocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)第11页Monocytosiswithmorphologicallynormalmonocytes(PB)MonocyteswithnuclearandCytoplasmicabnormalities(PB)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.第12页

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

grnulocyticproliferationanincreaseinerythroidprecursorsmildtomoderateincreaseintheamountofreticulinfibres(30%)Histopathology第14页

Immunohistochemistryontissuesectionsthemostreliablemarkers:CD168R,CD163

monocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)relativelyinsensitiveascomparedwithcytochemistryorflowcytometry第15页Chromosomalabnormalities

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%)第16页Chromosomalabnormalities

第17页

Chromosomalabnormalities

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

Cytogeneticriskstratificationinchronicmyelomonocyticleukemia.

Haematologica.2023;96(3):375-383.第18页MyelomonocyticClonalproliferationDiseaseprogressionSomaticmutations第19页Spliceosomalmutations

Yoshida,etal.Frequentpathwaymutationsofsplicingmachineryinmyelodysplasia.Nature2023;478(7367):64-9.Lessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcases第20页SRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutSRSF2mutwerecorrelatedwithhigherage,lesspronouncedanemiaandanormalkaryotype.SRSF2mutandEZH2mutweremutuallyexclusivebutassociatedwithTET2mut.SRSF2

Pro95HishadafavorableimpactonOSintheRUNX1mutsubcohort.MeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2023Oct11;120(15):3080-8.第21页

WHOdiagnosticcriteriaforCMML

PersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/L第22页

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

第23页第24页第25页Diagnosticwork-up第26页第27页Riskstratification第28页

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

MDAPS(M.D.AndersonPrognosticScore)

第30页Onepointforeachofthefollowing

variablesHb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcells第31页subgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel第32页NewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)第33页Score第34页lowInt-1Int-2highLevelsofrisk第35页Therapeuticoptions第36页TherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantation第37页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.Cancer2023;107:1525–1529.9-nitro-campothecin,atadoseof2mg/m2orallydailyfor5daysaweekin32patientsCR:11%PR:16%OS:12monthsWelltolerated第38页HypomethylatingagentsAribietal.Cancer2023;109:713–717.decitabineatasametotaldoseof100mg/m2percoursein3differentschedulesin19patientsCR:58%PR:0%HI:11%OS:19monthsWijermansetal.LeukRes2023;32:587–591.decitabineadministeredas15mg/m2over4hrIV3timesaday(totaldoseof135mg/m2percourse)in31patientsCR:10%PR:16%HI:19%OS:15monthsCostaetal.Cancer2023;117:2690–2696.azacitidine75mg/m2/dayfor7daysor100mg/m2/dayfor5days,every4weeksin38patients.CR:11%PR:3%HI:25%OS:12months第39页Allogeneicstemcelltransplantation

(retrospectiveregistryfromlargetransplantcenters)EGBMT283patients245patients(93%)successfullyengrafted.III/IVacuteGVHD:85/258(30%)chronicGVHD:58/102(57%)NRM(nonrelapsemortality):37%Eissaetal.BiolBloodMarrowTransplant2023;17:908–915.85