慢性粒單核細(xì)胞白血病診治進(jìn)展演示文稿

慢性粒單核細(xì)胞白血病診治進(jìn)展演示文稿當(dāng)前1頁，總共42頁。當(dāng)前2頁，總共42頁。當(dāng)前3頁，總共42頁。1Definition2Diagnosis3Riskstratification4TherapeuticoptionsContents當(dāng)前4頁，總共42頁。Definition當(dāng)前5頁，總共42頁。WHOClassificationofMDS/MPN1CMML2AtipicalCML,BCR-ABL1negative3JMML4MDS/MPN,U(RARS-T,refractoryanemiawithringedsideroblastsassociatedwiththrombocytosis)當(dāng)前6頁，總共42頁。DefinitionAclonalhematopoieticstemcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(>1×109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHOclassificationofmyeloidneoplasms)當(dāng)前7頁，總共42頁。Diagnosis當(dāng)前8頁，總共42頁。ClinicalmanifestationMDS-typeFatigueanddyspneaduetoanemiasusceptibilitytoinfectionsrarelybleedingMPN-typesignificantweightlossdrenchingnighsweatsleftupperquadrantpainfromsignificantsplenomegaly當(dāng)前9頁，總共42頁。

Morphology(PB)PBmonocytesusuallyrangefrom2to5×109/L,butmayexceed80×109/L.Themonocytesgenerallyaremature,butcanexhibitabnormalgranulationorunusualnuclearlobationorchromatinpatten.(abnormalmonocytes)Dysgranulopoiesisispresentinmostcases.當(dāng)前10頁，總共42頁。

Morphology(BM)hypercellular

inover75%ofcasesnormalcellularandhypocellularalsooccurdysgranulopoiesis,dyderythropoiesis,micromegakaryocytesandmegakaryocytes

withabnormallylobatednuclei(inupto80%ofpatients)monocyticproliferationcanbedifficulttoappreciate(cytochemistryandimmunohistochemistry)當(dāng)前11頁，總共42頁。Monocytosiswithmorphologicallynormalmonocytes(PB)MonocyteswithnuclearandCytoplasmicabnormalities(PB)CMML-1(BM)CMML-2(BM)RepresentativeperipheralbloodandBMsmearsdistinctionbetweenpromonocytesandabnormalmonocytesmaybeproblematicPromonocytestypicallyhavealight-graycytoplasmwithafewlilac-coloredgranulesandastipplednuclearchromatin.Abnormalmonocyteshavedenserchromatin,nuclearconvolutionsandfoldsandamoregreyishcytoplasm.當(dāng)前12頁，總共42頁。

ImmunophenotypeThePBandBMcellsusuallyexpressCD33andCD13,withvariableexpressionofCD14,CD68,CD64.AnincreasedpercentageofCD34+cellshasbeenassociatedwithearlytransformationtoacuteleukemia.Occasionally,overexpressionofCD56,aberrantexpressionofCD2,anddecreasedexpressionofHLA-DR,CD13,CD15,andCD36maybeobserved.當(dāng)前13頁，總共42頁。

grnulocyticproliferationanincreaseinerythroidprecursorsmildtomoderateincreaseintheamountofreticulinfibres(30%)Histopathology當(dāng)前14頁，總共42頁。

Immunohistochemistryontissuesectionsthemostreliablemarkers:CD168R,CD163

monocyticcells:lysozym(+)CAE(-)granulocyticcells:lysozym(+)CAE(+)relativelyinsensitiveascomparedwithcytochemistryorflowcytometry當(dāng)前15頁，總共42頁。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%)當(dāng)前16頁，總共42頁。Chromosomalabnormalities當(dāng)前17頁，總共42頁。

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.當(dāng)前18頁，總共42頁。MyelomonocyticClonalproliferationDiseaseprogressionSomaticmutations當(dāng)前19頁，總共42頁。Spliceosomalmutations

Yoshida,etal.Frequentpathwaymutationsofsplicingmachineryinmyelodysplasia.Nature2011;478(7367):64-9.Lessconspicuouslybutsignificantly,SRSF2mutationsweremorefrequentinCMMLcases當(dāng)前20頁，總共42頁。SRSF2mutationsinCMML(anewdiagnosticmarker?)129/275(47%)hadSRSF2mutSRSF2mutwerecorrelatedwithhigherage,lesspronouncedanemiaandanormalkaryotype.SRSF2mutandEZH2mutweremutuallyexclusivebutassociatedwithTET2mut.SRSF2

Pro95HishadafavorableimpactonOSintheRUNX1mutsubcohort.MeggendorferM,etal.SRSF2mutationsin275caseswithchronicmyelomonocyticleukemia(CMML).Blood.2012Oct11;120(15):3080-8.當(dāng)前21頁，總共42頁。

WHOdiagnosticcriteriaforCMMLPersistentperipheralbloodmonocytosisPhchromosomeorBCR-ABL1ArrangementofPDGFRAorPDGFRB(speciallyexcludedincaseswitheosinophilia)＞3months＞1×109/L當(dāng)前22頁，總共42頁。

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

當(dāng)前23頁，總共42頁。當(dāng)前24頁，總共42頁。當(dāng)前25頁，總共42頁。Diagnosticwork-up當(dāng)前26頁，總共42頁。當(dāng)前27頁，總共42頁。Riskstratification當(dāng)前28頁，總共42頁。

RiskstratificationIPSSforsurvivalinMDSoriginallyproposedincluded126patientswithCMML.“Proliferative-typeCMML”(WBC>12×109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.當(dāng)前29頁，總共42頁。Riskstratification

MDAPS(M.D.AndersonPrognosticScore)

當(dāng)前30頁，總共42頁。Onepointforeachofthefollowing

variablesHb＜

120g/LALC＞2.5×109/L

PBIMC＞0%BMblasts≥10%ALC:absolutelympcytecountIMC:immaturemyeloidcells當(dāng)前31頁，總共42頁。subgroupsscoreMediansurvival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel當(dāng)前32頁，總共42頁。NewMDSmodelappliedinCMMLwithleukocytosis(WBC＞12×109/L)當(dāng)前33頁，總共42頁。Score當(dāng)前34頁，總共42頁。lowInt-1Int-2highLevelsofrisk當(dāng)前35頁，總共42頁。Therapeuticoptions當(dāng)前36頁，總共42頁。TherapeuticoptionsBestsupportivecareHypomethylatingagents(azacitidineanddecitabine)CytotoxicchemotherapyAllogeneicstemcelltransplantation當(dāng)前37頁，總共42頁。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當(dāng)前38頁，總共42頁。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當(dāng)前39頁，總共42頁。Allogeneicstemcelltransplantation

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