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现在是1页\一共有42页\编辑于星期三现在是2页\一共有42页\编辑于星期三现在是3页\一共有42页\编辑于星期三1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContents现在是4页\一共有42页\编辑于星期三Definition现在是5页\一共有42页\编辑于星期三WHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)现在是6页\一共有42页\编辑于星期三DefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)现在是7页\一共有42页\编辑于星期三Diagnosis现在是8页\一共有42页\编辑于星期三ClinicalmanifestationMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMPN-typesignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegaly现在是9页\一共有42页\编辑于星期三

Morphology(PB)PBmonocytesusuallyrangefrom2to5×109/L,butmayexceed80×109/L.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Dysgranulopoiesisispresentinmostcases.现在是10页\一共有42页\编辑于星期三

Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurdysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocytes

withabnormallylobatednuclei(inupto80%ofpatients)monocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)现在是11页\一共有42页\编辑于星期三Monocytosiswithmorphologicallynormalmonocytes(PB)MonocyteswithnuclearandCytoplasmicabnormalities(PB)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.现在是12页\一共有42页\编辑于星期三

ImmunophenotypeThePBandBMcellsusuallyexpressCD33andCD13,withvariableexpressionofCD14,CD68,CD64.AnincreasedpercentageofCD34+cellshasbeenassociatedwithearlytransformationtoacuteleukemia.Occasionally,overexpressionofCD56,aberrantexpressionofCD2,anddecreasedexpressionofHLA-DR,CD13,CD15,andCD36maybeobserved.现在是13页\一共有42页\编辑于星期三

grnulocyticproliferationanincreaseinerythroidprecursorsmildtomoderateincreaseintheamountofreticulinfibres(30%)Histopathology现在是14页\一共有42页\编辑于星期三

Immunohistochemistryontissuesectionsthemostreliablemarkers:CD168R,CD163

monocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)relativelyinsensitiveascomparedwithcytochemistryorflowcytometry现在是15页\一共有42页\编辑于星期三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%)现在是16页\一共有42页\编辑于星期三Chromosomalabnormalities现在是17页\一共有42页\编辑于星期三

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.现在是18页\一共有42页\编辑于星期三MyelomonocyticClonalproliferationDiseaseprogressionSomaticmutations现在是19页\一共有42页\编辑于星期三Spliceosomalmutations

Yoshida,etal.Frequentpathwaymutationsofsplicingmachineryinmyelodysplasia.Nature2011;478(7367):64-9.Lessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcases现在是20页\一共有42页\编辑于星期三SRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutSRSF2mutwerecorrelatedwithhigherage,lesspronouncedanemiaandanormalkaryotype.SRSF2mutandEZH2mutweremutuallyexclusivebutassociatedwithTET2mut.SRSF2

Pro95HishadafavorableimpactonOSintheRUNX1mutsubcohort.MeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2012Oct11;120(15):3080-8.现在是21页\一共有42页\编辑于星期三

WHOdiagnosticcriteriaforCMMLPersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/L现在是22页\一共有42页\编辑于星期三

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

现在是23页\一共有42页\编辑于星期三现在是24页\一共有42页\编辑于星期三现在是25页\一共有42页\编辑于星期三Diagnosticwork-up现在是26页\一共有42页\编辑于星期三现在是27页\一共有42页\编辑于星期三Riskstratification现在是28页\一共有42页\编辑于星期三

RiskstratificationIPSSforsurvivalinMDSoriginallyproposedincluded126patientswithCMML.“Proliferative-typeCMML”(WBC>12×109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.现在是29页\一共有42页\编辑于星期三Riskstratification

MDAPS(M.D.AndersonPrognosticScore)

现在是30页\一共有42页\编辑于星期三Onepointforeachofthefollowing

variablesHb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcells现在是31页\一共有42页\编辑于星期三subgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel现在是32页\一共有42页\编辑于星期三NewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)现在是33页\一共有42页\编辑于星期三Score现在是34页\一共有42页\编辑于星期三lowInt-1Int-2highLevelsofrisk现在是35页\一共有42页\编辑于星期三Therapeuticoptions现在是36页\一共有42页\编辑于星期三TherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantation现在是37页\一共有42页\编辑于星期三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现在是38页\一共有42页\编辑于星期三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现在是39页\一共有42页\编辑于星期三Allogeneicstemcelltransplantation

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