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白白 血血 病病 LeukemiaSIRRUNRUNSHAWHOSPITALHUANGJINWENRudolfVirchow,whonamed“leukemia”in1845AlfredVelpeauwhofirstdiscrepted“leukemia”in1827白血病的分类AcuteChronicMyeloid originLymphoid originAcute Myeloid Leukemia(AML)Acute Lymphoblastic Leukemia(ALL)Chronic Myelogenous Leukemia(CML)Chronic Lymphocytic Leukemia(CLL)白血病各亚型分布图(2001)Total Reported Cases=31,500SourcesfromLeukemia,Lyphoma,MyelomaFacts2001CLL=ChronicLymphocyticALL=AcuteLymphocyticCML=ChronicMylogenousAML=AcuteMylogenousAcuteMyeloidLeukemia概述Concepts,biologyEpidemiologyClinicalandlaboratorymanifestationsDiagnosisManagementandprognosis造血干细胞分化及白血病起源示意图NeutrophilsEosinophilsBasophilsMonocytesPlateletsRed cellsMyeloidprogenitorLymphoidprogenitorB-lymphocytesB-lymphocytesT-lymphocytesPlasmacellsnaveALLALLAMLAMLdifferentiation blockenhancedproliferationAcuteLeukemia+Gain of function mutations of tyrosine kinaseseg.FLT3,c-KIT，N-and K-RAS mutations BCR-ABL TEL-PDGFbRLoss of function of transcription factors needed for differentiation eg.AML1-ETO CBFb-SMMHC PML-RARa白血病起源学的两种模式FAB(1976)分类M0-UndifferentiatedAMLM1-AMLwithoutmaturationM2-AMLwithmaturationM3-AcutePromyelocyticLeukemiaM4-AcuteMeylomonocyticLeukemiaM5-AcuteMonocyticLeukemiaM6-Erythroleukemia(DiGuglielmos)M7-MegakaryoblasticLeukemiaWHO 分类AMLwithrecurrentcytogenictranslocationsAMLwithmulti-lineagedysplasiaAMLandmyelodysplasia,therapyrelatedAML,nototherwisecategorizedFAB 与 WHO 分类的异同点FABcriteriaMorphologyCytochemistryWHOcriteriaMorphologyImmunophenotypingGeneticfeaturesKaryotypingMoleculartestingClinicalfeaturesandhistory临床表现Symptomsdueto:marrowfailuretissueinfiltrationleukostasisconstitutionalsymptomsothers(DIC)usuallyshortdurationofsymptoms骨髓功能衰减Neutropenia:infections,sepsisAnemia:fatigue,pallorThrombocytopenia:bleeding组织或器官浸润Enlargementofliver,spleen,lymphnodesGumhypertrophyBonepainotherorgans:CNS,skin,testis,etc。并发症并发症HyperleukocytosisandLeukostasisCNSLeukemiaOcularinvolvementTumorlysissyndrome/HyperuricemiaInfections/NecrotizingenterocolitisPregnancy过去史过去史Apriorhematologicdisorderoramalignancy.Cardiacdisease,renalfunction,etc.Transfusionhistoryorpregnancies.Possibledrugallergies.Infectionhistories.Mensesinpremenopausalwomen.体格检查体格检查FeverSkinEyesOropharynxOrganomegalySternaltenderness牙龈增生ABC髓样肉瘤NEJM 1998诊 断实验室检查实验室检查CBCwithWBCdifferential.Coagulationstudies.Aminotransferases,alkalinephosphatase,bilirubin,LDH,etcCreatinine,electrolytes,uricacid,glucoseCalcium,phosphorus外周血涂片外周血涂片骨髓抽吸及活检示意图骨髓抽吸及活检示意图骨髓抽吸及活检并发症BleedingLocalinfectionNeuropathy,osteomyelitis,needlebreakageCardiactamponade,pulmonaryemboli,pulmonaryinfection,boneerosion/thining正常骨髓象白血病骨髓象Acute Promyelocytic LeukemiaAcute myeloid leukemia with maturationAuerrodsinAMLFAB诊断及其分类流程 组化急淋AML急单POX-分化差的原始细胞-+-+分化好的原始细胞分化好的原始细胞 +PAS+成块或颗粒状-或+，弥漫-或+呈弥漫性性淡红色或颗粒状NSE-+不被NaF抑制+能被NaF抑制NAP增加减少或-正常或增加白血病细胞组织化学染色WHO诊断及其分类流程Morphology/EnzymecytochemicalstainsImmunophenotyping/flowcytometryCytogeneticanalysisMoleculargeneticanalysisorFluorescenceinsituhybrization(FISH)类型类型 染色体改变染色体改变 基因改变基因改变M2 t(8;21)(q22;q22)AML1/ETOM3 t(15;17)(q22;q21)PML/RAR,RAR /PMLM4Eo inv/del(16)(q22)CBFB/MYH11M5 t/del(11)(q23)MLL/ENLAMLAML常见的染色体和基因特异改变常见的染色体和基因特异改变t(8:21)RUNX1-RUNX1T1(previously AML1-ETO)WHO：Aml诊断标准Blast20%ofANCoftheBMaspirate，orBlasts20%ofperipheralbloodt(8;21),inv(16),ort(15;17)，orMyeloidsarcoma.MyeloidorigindemonstratedbyeitherAuerrods,cytochemical,orimmunophenotypingClinicalfeaturesWHO：AML 分类AML with recurrent cytogenetic translocationsAMLwitht(8;21)APLwitht(15;17)AMLwithinv(16)ort(16;16)AMLwith11q23MLLabnormalitiesAML with multilineage dysplasiaWithpriorMDS,WithoutpriorMDSAML with myelodysplastic syndrome,therapy relatedAlkylatingagentrelated,Epipodophyllotoxinrelated,OthertypesAML not otherwise categorizedAMLminimallydifferentiatedAMLwithoutmaturationAMLwithmaturationAcutemyelomonocyticleukemiaAcutemonocyticleukemiaAcuteerythroidleukemia,AcutemegakaryocyticleukemiaAcutebasophilicleukemia,Acutepanmyelosiswithmyelofibrosis其它检查及操作其它检查及操作CXR(chestx-ray)EKG(electrocardiogram)EF(cardiacejectionfraction)LumbarpunctureHBV，HerpessimplexandCMVserologyInsertionofHickmancentralcatheterorPICCline.ConsultationpriortochemotherapyHLAtypingofthepatientandsiblingsDentalconsultation核磁共振核磁共振治疗原则Combinationchemotherapy#firstgoaliscompleteremission#furtherTreatmentstopreventrelapseComplicationsSupportivemedicalcare#transfusions,antibiotics,nutritionPsychosocialsupport#patientandfamilyAML诱导缓解方案 Drugs Dosing Comments Cytarabine plusdaunorubicin Cytarabine:100 to 300 mg/m2 daily as a continuous infusion for 7 days;Daunorubicin:60-90 mg/m2 intravenous push on each of the first 3 days of treatmentStandard 7+3 induction regimen resulting in approximately 60 to 80 percent remission rate and acceptable toxicity in patients under 60 years old HDAC plusdaunorubicinCytarabine:1 to 3 g/m2 twice daily for a total of 12 doses;Daunorubicin:45 mg/m2 intravenous push for 3 days following cytarabineYields a 90 percent remission rate;however,substantial toxicity precludes postremission therapy in a high proportion of patientsCytarabine plus idarubicinCytarabine:100-200 mg/m2 daily as a continuous infusion for 7 days;Idarubicin:12-13 mg/m2 IV push on each of first 3 days of treatmentHas produced a greater remission rate(88 versus 70 percent)than cytarabine/daunorubicin in younger patients;appears superior to daunorubicin in patients with hyperleukocytosis;overall survival not clearly superior to standard regimen造血干细胞移植术permits“rescue”fromotherwiseexcessivelytoxictreatmentadditionaladvantageofgraft-vs-leukemiaeffectinallogeneictransplantstrade-offforallogeneictransplantation:greateranti-leukemiceffectbutmoretoxic完全缓解定义完全缓解定义ANC1.0X103/dL,Plt100X103/dL,andindependencefromRBCtransfusion.AnormalmaturationofallcellularcomponentsinbonemarrowBlastcells5%inthebonemarrowNonclustersorcollectionsofblastcellsinBMbiopsy.Extramedullaryleukemiamustbeabsent.The absence of a previously detected clonalcytogeneticabnormality,etc.影响影响AMLAML预后的因素预后的因素Favorable FactorsUnfavorable factorsAge60Karnovskyscore60percentKarnovskyscore60percentCD34-negativephenotypeCD34-positivephenotypeMDR1-negativephenotypeMDR1-positivephenotypeHypocellularLeukemiaPriormyelodysplasticsyndrome,myeloproliferativeorhematologicdisorder,chemotherapy,orradiationtherapyNormalkaryotypeinv(16)t(8;21)t(15;17)Trisomy8Complexkaryotypicabnormalities，t(6;9)Absenceofchangesinchromosomes5or7Changesinchromosomes5or7(eg,trisomy,deletions,etc)FLT3genemutationsabsentFLT3genemutationspresent细胞遗传学分类Cytogenetic risk group#Induction successOverall survivalFavorablet(8;21)inv(16)ort(16;16)t(8;21)inv(16)ort(16;16)del(9q)*AdverseComplexkaryotype(ie,3abnormalities)inv(3)ort(3;3)abn(12p)Complexkaryotype(ie,3abnormalities)inv(3)ort(3;3)t(6;9)t(6;11)-7+8(soleabnormality)+8with1otherabnormality*t(11;19)(q23;p13.1)#Patientswitht(15;17)andt(9;22)wereexcludedfromthisanalysis.Theintermediateriskgroupincluded:normalkaryotype;-Y;del(5q);lossof7q;t(9;11);+11;del(11q);abn(12p);+13;del(20q);and+21.细胞遗传学分类与总体生存率细胞遗传学分类与总体生存率年龄对AML生存及化疗疗效的影响OS according to age irrespective of managementBlood2009;113:4179.Copyright2009AmericanSocietyofHematologypatientswithdenovoAML,fitforintensivetreatment细胞核型及治疗选择KaryotypeCompleteremission rateRemission durationTreatment approacht(8;21)(q22,q22)HighLongStandardinductionwithananthracycline.IntensiveconsolidationchemotherapywiththreerepetitivecoursesofHDACinv(16)(p13q22)ort(16;16)(p13;q22)HighIntermediatetolongStandardinductionwithananthracycline.IntensiveconsolidationchemotherapywiththreerepetitivecoursesofHDACt(15;17)(q22;q11-12)HighIntermediatetolongAll-transretinoicacidtogetherwithananthracycline.Arsenictrioxidetotreatrelapse.t(9;11)(p22;q23)HighIntermediateStandardinductionandintensiveconsolidationwithHiDAC.ReserveHCTforsecondremissionformostt(9;11)patients.del(5q),+13,+8,-7,inv3,del(12p),t(9;22),othert(11q23),orcomplexbnormalitiesLowShortNew induction regiments,including use of growth factors during or after chemotherapy,or modulators of drug resistance.Perform HCT in first CR.AcuteLymphoblasticLeukemia白血病，还是淋巴瘤Lymphoma(LBL)diagnosed,withamasslesion,or/and25percentbonemarrowblasts.WHO 分类PrecursorBCell(Acute)LymphoblasticLeukemiaPrecursorTCell(Acute)LymphoblasticLeukemia ALLALL骨髓象骨髓象L1：原始和幼淋细胞以小细胞原始和幼淋细胞以小细胞 为主为主L2：原始和幼淋细胞以大细胞为主原始和幼淋细胞以大细胞为主L3：原始和幼淋细胞以大细胞为主，原始和幼淋细胞以大细胞为主，大小较一致，细胞内有明显空大小较一致，细胞内有明显空 泡，胞浆嗜碱性，染色深泡，胞浆嗜碱性，染色深.ALL与AML的鉴别诊断MPO(myeloperoxidase)neg.TdTpos.ALL与AML基因谱的表达B细胞分化抗原的表达EarlyprecursorB(pro-B-ALL)：membraneCD19+,CD79a+,andcytoplasmicCD22+CommonALL：CD10+Latepre-BALL：CD20+,cytoplasmicmuheavychain.Earlyorpro-T：CD2,CD7,CD38andcytoplasmicCD3(30percent)Commonthymocyte：CD1a,sCD3,CD4/CD8doublepositive(50percent)Latethymocyte：CD4orCD8singlepositive(20percent)T细胞分化抗原的表达细胞遗传学及基因学Thet(9;22)andt(v;11q23)areoftenassociatedwithapro-Bimmunophenotypeandapoorprognosist(12;21)andhyperdiploidyareassociatedwithagoodprognosis.TCRbetaorgamma&IgHmaynotbelineage-specific临床表现WhataredifferentmanifestationsofALLfromAMLWhataredifferentcomplicationsbetweenALLandAML成人成人PhPh+ALLALL 的治疗的治疗InductionChemo:ABCR-ABLtyrosinekinaseinhibitor(TKI)pluscombinationchemoreg.ConsolidationChemo:Allo-trans.orTKI+Chemo,MaintenanceTxTKIFollowup:ConventionalchemoregimensAllohematopoieticstemcelltransplantation成人成人PhPh ALLALL 的治疗的治疗ALL 常规化疗方案Generalconsiderations:DAU,CTX,Pred,L-asp+CNSprophylaxisCancerandLeukemiaGroupB(CALGBstudy8811or9111)ALLregimenLarsonRAetal,Blood.1995;85(8):2025-37StandardoraugmentedBerlin-Frankfurt-Munster(BFM)hasbeenusedbytheChildrenCancerGroupforchildrenandadolescentsStockWetal,Blood.2008;112(5):1646-54HyperfractionatedCTX,VCR,DOX,andDXM(Hyper-CVAD)alternatingwithhigh-doseMTXandARA-CKantarjianHMetal,JClinOncol.2000;18(3):547-61FrenchGRAALL-2003regimenforyoungeradultsHuguetFetal,JClinOncol.2009;27(6):911-8CR1后异基因移植生存率汇总表*patients who receive post-remission therapy may expect five-year survival rates of 40 to 60 percentChronicMyelogenousLeukemiaCML vs AML的外周血象Myeloid cell CML AML normalblastsqqpromyelocytesqmyelocytesqmetamyelocytes qbandsqneutrophilsq#q临床表现AtriphasicorbiphasicclinicalcourseAsymptomatic,suspectedfromroutinebloodtestsSymptomatic,fatigue,malaise,weightloss,excessivesweating,abdominalfullness,bleedingepisodes,Abdominalpain/discomfortAcutegoutyarthritis,splenomagely,lowsternumtenderness,etc.白细胞淤滞AccumulationofblastsinmicrocirculationwithimpairedperfusionLungs:hypoxemia,pulmonaryinfiltratesCNS:strokeonlyseenwithWBC50 x109/LCMLCML骨髓象和外周血象骨髓象和外周血象费城染色体费城染色体FISH：t(9;21)positive nucleiCMLCML诊断要点诊断要点NeutrophilicleukocytosiswithcirculatingimmaturecellsofthegranulocyteseriesNAPSplenomegaly,BasophiliaPh+chromosome,BCR-ABLfusionmRNA,orbcr-ablproteinCMLCML加速期诊断标准加速期诊断标准CMLCML急变期诊断标准急变期诊断标准Blasts20percentinperipheralbloodorinbonemarrowLargefociorclustersofblastsonthebonemarrowbiopsyExtramedullaryblasticinfiltratesCMLCML急变骨髓象急变骨髓象慢性期骨髓细胞形态慢性期骨髓细胞形态急变期骨髓细胞形态急变期骨髓细胞形态CML 慢性期治疗建议Tyrosinekinaseinhibitor(TKI)(Grade 1A).Allogeneichematopoieticcelltransplantation(HCT)maybeareasonablealternativeinrarecircumstancesThesecondgenerationTKIsimprovedclinicalbenefitoverimatinibImatinibisnottoleratedorthegoalnotbeenachievedorlost,therapyshouldbealteredOverall survival of CMLOverall survival of CMLChelseaIcanseeyourhalo,Iprayyouwontfadeaway.THANKS
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