Chronicleukemia

1CategoryofChronicleukemia

ChronicMyelocyticLeukemia(CML)ChronicLeukemia ChronicLymphocyticLeukemia(CLL)2ChronicMyelocyticleukemia

3CMLChronicmyelogenousleukemia(CML)isapluripotentialstemcelldiseasecharacterizedbyanemia,extremebloodgranulocytosisandgranulocyticimmaturity,basophilia,oftenthrombocytosis,andsplenomegaly.OneimportantlandmarkinthestudyofCMLwasthediscoveryofthePhiladelphia(Ph)chromosomein1960.Anotherwasthecharacterizationinthe1980softheBCR–ABLchimericgeneandassociatedoncoprotein.45NEnglJMed.2004;351:657-67,Weissman’slabHematopoieticstemcells6ChronicMyelocyticleukemiaClonalstemcelldisorderOverproductiongranulocyticcellsMarkedsplenomegalyVeryhighWBC7Incidence

1~1.5/100,000Peakage:50yearsoldMale:female3:28Incidence9ReviewofCMLCMLpathophysiologyt(9;22)(q34;q11)BCR-ABLoncoprotein,p210increasedtyrosinekinaseactivity(酪氨酸激酶)10PhchromosomeBCR-ABL(激活的酪氨酸激酶)BCRABLCMLPhiladephia（Ph）CML11ClinicalFeaturesSymptomsFatigueAnorexiaWeightlossFeverAbdominalpain12ClinicalFeaturesSignsSplenomegalyHepatomegalyLymphadenopathySternaltendernessPurpura13

LabFindingsPeripheralBlood

WBCelevated,>20x109/LBasophilandEosinophilincreasedAnemia:mildPlatelet:normalorelevatedImmaturegranulocytesindifferentstageBlastcell:1~3%14ChronicLeukemia----Peripheralblood

15

LabFindingsBoneMarrow

HyperplasiaImmaturegranulocytesofdifferentstagesBlasts<10%NAPslightpositiveornegativeBasophilandEosinophilelevated16BoneMarrow

ChronicLeukemia Normal17CytogeneticsandMolecularBiologyPh1chromosome----t(9;22)----95%ofCMLbcr/ablfusiongeneP210protein(tyrosinekinase)ImportantroleinpathogenesisofCMLTargetoftreatment18Chromosome9Chromosome22ABLBCR5’3’1b1aa2a3a115’3’e1e1’e2’e6e14e19m-bcrM-bcrμ-bcre1a2e13a2e14a2e19a2p190bcr-ablp210bcr-ablp230bcr-ablThePhiladelphiaChromosome19BCR-ABL20CMLBCR/ABL21

Clinicalmanifestations:splenomegalyPeripheralbloodBonemarrowexaminationPh’ChromosomepositiveBCR/ABLfusiongeneDiagnosis22

Reactive CML Leukocytosisinfection + +or-splenomegaly -or+ +++NAP +++ -Ph1 - +Basophilia N ↑ leukocyte moremature immatureDifferentialDiagnosis23StagesofCMLChronicPhaseAcceleratedPhaseAcuteTransformation(BlasticPhase)2425AcceleratedphaseSymptomsandsigns:Fever,nightsweating,weightlossRapidlyenlargedspleenBonepainAggravatinganemiaandbleedingPoorresponsetotreatment26AcceleratedphaseLaboratoryFindings:Blastinpeipheralorbonemarrow>10%Peripheralbasophil>20%PlateletcountdecreaseorincreaseCytogeneticevolutionDifficulttocontrolWBCMarrowreticulinorcollagenfibrosis27BlasticPhaseTerminalstageofCMLSimilartoacuteleukemiainclinic,includingextramedullaryinfiltrationMostcasestransformintoAML

28BlasticPhaseLaboratoryFindings:Peripheral:blast+promyelocyte>30%BM:myeloblast+promyelocyte>30%BM:blast+procyte20%CytogeneticclonalevolutionExtramedullaryblasticchloroma29TreatmentOptionsinCMLHydroxyurea,BusulfanSCT(±DLI)IFN-(ara-C)ImatinibNewagentssencondTKIOthers30TreatmentofCML

Hydroxyurea:InhibitribonucleotidereductaseDose:0.5~3g/daySideeffects:nausea,skinrashBusulfan:

4~6mg/daySideeffects:severandprolongedmarrowaplasia,pulmonaryfibrosis,hypoadrenalism31TreatmentofCMLSmalldoseAra-C:15~30mg/m2.dInterferon-:2~5million/m2.dx6~12monthsAntiproliferativeagentEarlychronicphase32TreatmentofCMLAllogeneictransplantationAllo-BMTAllo-PBSCTHLA-matchedsiblingAge:<50yearsLong-termdisease-freesurvival:50%33TreatmentofCMLImatinib(Gleevec,伊馬替尼):targettobcr/ablprotreinIfblasticphasehappenstreatasacuteleukemia3435TreatmentofCMLGleevec(Imatinib,signaltransductioninhibitor)InhibitionofbindingsiteforATPtotheAblkinaseInhibitBCR-ABLtyrosinekinaseactivitySpecificityforAbl,PDGF-R,c-kittyrosinekinase36Y=TyrosineP=PhosphateBcr-AblATPSubstrateGleevecBcr-AblSubstratePPPPStructureandMechanismofActionofImatinibMesylate(Gleevec)CH3SO3HOClass:Phenylaminopyrimidines,589.7mwImatinib

mesylate37TreatmentofCMLGleevecstudyinnewly-diagnosedCMLDoses:400mg/d3months:cytogeneticresponse76%vsIFN3%to24%;complete36%vsIFN2%to5%6months:CCR50%38TreatmentofCMLGleevecside-effectsMyelosuppression(骨髓抑制)Nausea,vomiting,diarrheaEdemaRashes,musclecramps(痛性痙攣),boneandjointachesRareseizures(癲癇)orliverdysfunction3940DirectContactF317T315F359

P-loop4.M2445.G2506.Q2527.Y2538.E255Activationloop9.M35110.E35511.V37912.L38713.H396ResistancetoImatinibThroughMutations41

ImatinibBcr-AblMutationBcr-Abl非依賴性機制Amplification/overexpression擴增/過度表達Ablkinasesmutation激酶結構域突變Bcr-Abl-Independent非依賴性Bcr-Abl-Dependent依賴性vonBubnoffetal.Leukemia.2003;17:829.MechanismsofResistancetoImatinib

42伊馬替尼(STI571)達沙替尼(BMS-354825)300x結合活化構像多靶點(SRC)DasatinibissecondgenerationtyrosinekinaseinhibitorNNNHNCH3NHNONCH31x結合非活化構像

分子結構也伊馬替尼無相關性4344ChronicLymphocyticLeukemia

(CLL)

45Definition:Chroniclymphocyticleukemia(CLL)isaneoplasticdiseasecharacterizedbytheaccumulationofsmall,mature-appearinglymphocytesintheblood,marrow,andlymphoidtissues.Patientswerenotedtohavemild-to-moderatesplenicenlargement,lymphadenopathy,andlargenumbersofsmallagranularcellsinthebloodthatresembledthosefoundinenlargedlymphnodes.MostoftheCLLcellsareBcellorigin.46Incidence:Age:usually>50Male:Female=2-3:1CLL47SymptomsSlowonsetAnemiaFatiguelossweightfrequentlyinfectionAutoimmunehemolyticanemiaClinicalManifestation48SignsEnlargementoflymphnodesHepatomegalySplenomegalyClinicalManifestation49LaboratoryFeaturesPeripheralblood:

WBC>10x109/LAbsolutelymphocyte5x109/LAnemia-----inlatestagePlatelet-----decreaseinlatestage50LaboratoryFeaturesBM:HyperplasiaLymphocyte40%,mainlymatureImmunologicmarkersB-cell:CD5.CD19.CD20.CD22.CD23.HLA-DR.sIgdimT-cell:CD2.CD3.CD4/CD8positive;CD5negative/positive51LaboratoryFeaturesNormalimmunoglobulin:decreased

Autoimmuneantibody:Coombs’(+)Cytogeneticchanges:+12,14q+,inv(14)52DiagnosisPeripheral:lymphocyte5x109/LpersistantlyBoneMarrow:lymphocyte

40%LymphocytesusuallyidentifiedasmonoclonalBcellorigin(CD19,CD20,CD22,CD23,ect)53B-LineageLeukemiaAcuteLymphoblasticLeukemiaMorphologyImmunophenotypeMolecularStatus54B-LineageLeukemiaChronicLymphocyticLeukemiaMorphologyImmunophenotypeMolecularStatus55DifferentialdiagnosisInfectioncauses:bacterial,viralProlymphocyticleukemiaLeukemicphaseofnon-HodgkinlymphomaHairycellleukemia56Differentialdiagnosis57BinetclinicalstagingforCLL

stageClinicalfeaturesatdiagnosismediansurvival(years)ABloodandmarrowlymphocytosis<3areasofpalpableadenopathy12BLymphocytosis,

3areasofadenopathy9CSameasstageB,plusanemiaand/orthrombocytopenia758CLLprognosticfactorsLymphocyteSerumB2-MGCD38expressionIgVHmutatedorunmutatedZAP-70overexpressionCytogeneticchangep53mutatedand/orsecondaryp53abnormalgene59IgVHmutatedandCD38expressedYearsfromdiagnosisDamleetal.Blood.1999;94:1840.CD38-midsurvive>20年CD38+midsurvive~10年201816141210864201009080706050403020100survive(%)survive(%)100908070605040302010020181614121086420CD38CD3830%CD3830%P=0.0001IgVHMutatedUnmutatedP=0.000160ZAP-70expressCrespoMetal.NEnglJMed.2003;348:1764-1775.024681012141604812162024283236YearsafterdiagnosisYearsafterdiagnosisRiskofdiseaseSurvive1009080706050403020100100908070605040302010020%ZAP-70+細胞<20%ZAP-70+細胞20%ZAP-70+細胞<20%ZAP-70+細胞P=0.009P=0.01cases%cases%61GeneticabnormalitiesassociatedwithprogressionandpoorprognosisinCLL11q23deletionsYoungerage(20%ofcases)LymphadenopathyShortsurvivalTrisomy12CLL/PL(15%ofcases)DiseaseprogressionHighproliferationrateAbnormal17p21CLL/PL(p53mutations/delet