leukemia1LeukemiaDefinition:Agroupofmalignantclonalmalignantdiseaseofhematopoietictissue.Blockageofcelldifferentationindifferentstages.Accumulationofleukemiccellsinbonemarrow orotherorgans.Impairedproductionofnormalbloodcells.2ProgenitorcellStemcell3Normobalst原紅Basophilicnormoblast早幼紅Polychromaticnormoblast中幼紅Ortho-chromaticnormoblast晚幼紅4Myeloblast原粒Promyelocyte早幼粒Myelocyte中幼粒Metamyelocyte晚幼粒bandcell桿狀核Segmentedcell分葉核5Monoblast原單Promonocyte幼單核Monocyte單核6Lymphoblast原淋Prolymphocyte幼淋Lymphocyte成熟淋Lymphocyte成熟淋7Megakaryoblast原巨核Promegakaryocyte幼巨核Granularmegakaryocyte顆粒巨核Platelate-formingmegakaryocyte產(chǎn)板巨核89CategoryofLeukemia

AcuteLymphoblasticLeukemia(ALL)AcuteLeukemia AcuteMyeloidLeukemia(AML) ChronicMyeloidLeukemia(CML)ChronicLeukemia ChronicLymphocyticLeukemia(CLL)10Acutemyelogenousleukemia(AML)Acutemyelogenousleukemia(AML)isaclonalmalignantdiseaseofhematopoietictissuesthatischaracterizedbyaccumulationofabnormalleukemicblastcells,principallyinthemarrowandimpairedproductionofnormalbloodcells.Thus,theleukemiccellinfiltrationinmarrowisaccompanied,nearlyinvariably,byanemiaandthrombocytopenia.Theabsoluteneutrophilcountmaybelowornormal,dependingonthetotalwhitecellcount.11IncidenceofAMLIncidenceRatesbyRaceRace/EthnicityMaleFemaleAllRaces4.3per100,000men3.0per100,000womenWhite4.5per100,000men3.1per100,000womenBlack3.5per100,000men2.8per100,000womenAsian/PacificIslander3.5per100,000men2.8per100,000womenAmericanIndian/AlaskaNativea2.5per100,000men3.1per100,000womenHispanicb3.5per100,000men2.7per100,000womenAgeadjustedincidence3.6per100,000.

Medianageatdiagnosis:66years.

LifetimeriskofadiagnosisofAML:0.39%ofpeoplebornnow.

NationalCancerInstitute.SEERStatSheets:AcuteMyeloidLeukemia.

/statfacts/html/amyl.html12AgedistributionofAML13AgedistributionofALL14IncidenceofLeukemiaInChina:AcuteLeukemia>ChronicLeukemiaAdult:AML>ALLChildren:ALL>AML15EtiologyofLeukemiaVirus:HTLV-I,HTLV-II,EBIonizingRadiation:AtomicbombexposureChemicalAgents:Benzene;cytotoxicdrugschloramphenicol(氯霉素);phenylbutazone(保泰松).HereditaryFactors:Downsyndrome,21trisomy(三體)16ACUTE LEUKEMIA17FABclassificationofALLL1:smalllymphoblastictypeL2:largelymphoblastictypeL3:largelymphoblastictypewithprominentcytoplasmicvacuolization18

AcuteLymphocyticleukemia(L1)

Theblastcellshaveahighnucleocytoplasmicratio,lackvisiblenucleoliandarerelativesmall.19AcuteLymphocyticLeukemia(L2)

Theblastcellsaremainlylargeandhaveoneortwoprominentnucleoli,whichrangeinsizefromsmalltolarge.20AcuteLymphocyticLeukemia

(L3)

Theblastcellshaveprominentcytoplasmicbasophiliaandareheavilyvacuolated

21FABclassificationofAMLM0:AcuteMyelocyticleukemiawithminimallydifferentiationM1:AcuteMyeloblasticLeukemia(withoutmaturation)M2:AcuteMyeloblasticLeukemia(withmaturation,M2a,M2b)M3:AcutePromyelocyticLeukemia(M3a,M3b)M4:AcuteMyelomonocyticLeukemia(M4a,M4b,M4c,M4EO)M5:AcuteMonocyticLeukemia(M5a,M5b)M6:AcuteErythroleukemiaM7:AcuteMegakaryoblasticLeukemia22FABM0type.BlastcellswithnoevidentfeaturesofdifferentiationandwithnegativereactionsforSudanblackBandmyeloperoxidase.Onimmunophenotypicanalysis,allBandTmarkerswerenegativebuttherewasexpressionofCD13,CD33.andCD34.FABM1type.BlastcellsaresmalltomediuminsizewithahighnucleocytoplasmicratioandoneofthemcontainsanAuerrod.SudanblackBandperoxidasereactionswerepositive.Peripheralbloodfilm.Auerrod23FABM2type.ThereisdifferentiationtopromyelocytesandthereisoneneutrophilandablastcellcontaininganAuerrod.Bonemarrowfilm.FABM3type.Blastcellsareinaminority,thedominantcellbeingahypergranularpromyelocytes,somewithbundlesofAuerrods.BonemarrowfilmAuerrods24FABM4category.Therearesomeblastsshowinggranulocyticdifferentiationandothersshowingmonocyticdifferentiation.Granulocyticdifferentiationismoreobviousinthebonemarrow(left)andmonocyticintheperipheralblood(right).Bonemarrowandperipheralfilm.FABM4category,witheosinophilicdifferentiation.ThiscategoryofAMLisoftenreferredtoasM4EOAML.Therearematureeosinophilsandeosinophilprecursors.Thelatterhavelargepro-eosinophilicgranules,whichhavebasophilicstainingcharacteristics.Bonemarrowfilm.leftright25FABM5acategory.Theblastsarelargewithabundantcytoplasm.Theyshowlittlesignsofdifferentiation,butonecellhasanindentednucleus.Nucleoliarelargeandprominent.Sometimestherearefineazurophilic(嗜苯胺藍(lán)顆粒)granules.Bonemarrowfilm.FABM5bcategory.Monocyticdifferentiationisapparent.Bonemarrowfilm.26FABM6showingerythropoiesisthatisdysplasticandgrosslymegaloblastic(巨幼紅細(xì)胞);thereisanexcessofproerythroblastsbutalsoofimmaturegranulocytes,includingblastcells.Bonemarrowfilm.FABM7category.Bonemarrowtrephinebiopsyshowsblastcells(left)andincreasedreticulindeposition(right).2728FlowchartshowinghowtheWHOhierarchicalclassificationisapplied.29AML的WHO分型

伴有再現(xiàn)性遺傳學(xué)異常的AML伴有t(8;21)(q22;q22)(AML1/ETO)的AML伴有inv(16)(p13q22)或t(16;16)(p13;q22)(CBF/MYH11)和異常骨髓嗜酸細(xì)胞的AML伴有t(15;17)(q22;q12)(PML/RAR)的APL伴有11q23(MLL)異常的AML伴有多系病態(tài)造血的AML由MDS或MDS/MPD發(fā)展而來的AML無先前的MDS或MDS/MPD病史但二系或三系病態(tài)造血細(xì)胞50%治療相關(guān)性AML和MDSt-AML和t-MDS烷化劑或放療所致的AML/MDSDNA柘撲異構(gòu)酶抑制劑所致的AML/MDS一些可能為ALL無法按上述分型的白血病NOC-AML急性微分化白血病急性未分化白血病急性部分分化的白血病急性粒單細(xì)胞白血病急性單核細(xì)胞白血病急性紅血病急性紅白血病和純紅血病急性巨核細(xì)胞白血病急性嗜堿細(xì)胞白血病急性全髓細(xì)胞增生伴骨髓纖維化髓系肉瘤305-year12%5-year40%5-year61%31ClinicalFeatures

Anemia----pallor,weaknessFever----mainlyduetoinfection(G-bacilli)

Bleeding----skin,nasal,gum,intracranial(顱內(nèi))Infiltration----organsandtissues32CausesofAnemiaDecreasedproductionoferythrocytesShortenedredbloodcellsurvivaltimeHemorrahagePost-chemotherapy33CausesofinfectionReducednormalgranulocytesinnumberImpairedfunctionofgranulocytesWeakenedcellularimmunityPost-chemotherapyeffects34CausesofBleedingQuantityandqualityofplateletPerivascularinfiltrationofleukemiccellsCoagulationabnormalities(凝血異常)DIC:releaseoftissuefactor-likeprocoagulants(促凝物質(zhì))fromgranuleswithintheleukemiccells35Leukemiainfiltration

Lymphadenopathy,Hepatomegaly,Splenomegaly:especiallyinALLBone(sternumtenderness，胸骨壓痛)andJointChloroma（綠色瘤）:AMLOralCavityandSkin:guminfiltrationfrequentlyseeninM4,M5CentralNerveSystemLeukemia(CNS-L):mainlyinALLTesticular(睪丸)Leukemia:mainlyinALL36guminfiltrationskinbleedingandinfiltration37LabFindings:PeripheralBlood

WBC-----5.0to50.0x109/L<1.0x109/Lor>100x109/LLeukemiccellsoftencanbeseenAleukemictype:WBCdecreasedwithoutleukemiccellsAnemia-----RBCcountandHbdecreasePlateletCount-----decreased38

AcuteLeukemia----PeripheralBlood

39LabFindings:PeripheralBlood

SubtypeaccordingtoperipheralbloodLeukemictype:

WBCincreasedwithleukemiccellsSubleukemictype:

WBCnormalrangewithleukemiccellsAleukemictype:

WBCdecreasedwithoutleukemiccells40LabFindings:BoneMarrow

GeneralAspects:HyperplasiaLeukemiccellsexcessivelyproliferationInhibitingothercelllinesLeukemiccells>20%41BoneMarrow

Acuteleukemia Normal42BonemarrowAML43BonemarrowofAPL44Renjihospital

ClinicalandmolecularcharacteristicsofAPL

45Bonemarrowofacutemonocyticleukemia46BonemarrowofALL47CytochemistryofleukemiccellsALLAMLAMoLPOX-+++-~+PAS+clumporgranular-/+diffused-/+diffusedNSENAP-↑-/+NotinhibitbyNaF↓/-++InhibitedbyNaFN/↑48

CytochemicalstainPOX

NSEPAS49POXofAPLSEofAPL50ImmunologicMarkers

LineageAntigen

B-cellCD19,CD20,CD21,CD22,HLA-DRT-cellCD1,CD2,CD3,CD4,CD5,CD7,CD8MyeloidCD13,CD14,CD15,CD33,CD4151ImmunologicMarkers

M1M2M3M4M5M6M7CD13+++++--CD33+++++--CD14-±-++--CD41------+52ImmunologicMarkers

LineageAntigenErythroidGlycophorinAMegakaryocyticCD41,CD42b,CD6153CytogeneticsandMolecularBiologyAMLM3t(15;17)(q22;q21)PML/RARRAR/PMLM4EOivn(16)(q22)CBFB/MYH11M2t(8;21)(q22;q22)AML1/ETOM5t/del(11)(q23)MLL/ENL

54PMLRARaPML-RARaRARa-PML15171517

CytogeneticsandMolecularBiologyofAPL55RISKSTATUSBASEDONCYTOGENETICSANDMOLECULARMUTATIONS56Distributionofcommoncytogeneticabnormalitiesinpatientsagedlessthanormorethan60.

57TheDFSandOSofcytogeneticchangesinAMLBetter-riskIntermediate-riskPoor-riskBetter-risk1Intermediate-riskPoor-risk58CytogeneticsandMolecularBiologyALLt(9;22)(q34;q11)BCR/ABLALL-L2t(1;19);t(4;11)ALL-L3t(8;14)(q24;q32)MYC/IgH

59RenatoBassanetal,2004,OncologyHematology60MICMCategoryM----morphologyI----immunologyC----cytogeneticsM----molecularbiology61LabFindings:Others

Hyperuricemia(高尿酸血癥)----tumorcelllysisLactateDehydrogenase(LDH)increaseActivityoflysozyme(溶菌酶)increase, commoninM4orM5DIC:morecommoninAMLthanALL,especiallyinM3(APL)62LabfindingsCellularmorphologyBloodroutinebiochemistryimmunologyGenemutations：C-KIT、FLT3-ITD、NPM1、CEBPACytogeneticMolecularfeatures(PML/RARα、AML1/ETO、CBFb/MYH11、MLL)2．Labfindings63DiagnosiccriteriaClinicalmanifestationPeripheralbloodchangesAnemiaThrombocytopeniaLeukemiccellsBonemarrowexaminationleukemiccells>20%64DifferentialdiagnosisMyelodysplasticsyndromes(MDS)LeukemoidreactionAplasticanemia65Jamesw,etal.Blood,2002,100(7):229266ManagementGeneralmanagement:SupportivecarestreatingofongoinginfectionsandpreventingChemotherapy,usuallycombinedremedyProphylacticandtreatmentofextramedullaryleukemiaImmunotherapyBMT67ChemotherapyGOALS:AchieveCompleteRemmission(CR);ProlongDiseaseFreeSurvival(DFS);Curethedisease68PrinciplesofChemotherapySelectionofdrugsandprotocolsDrugsfocusingondifferentcellcyclesDrugsworkingcorporatelyNoseveroverlapoftoxicity69Anti-LeukemiaDrugs:

Killers:makingtheleukemiccellsdead---mostofthedrugsweuseInducerofdifferentiation:leadingtheblaststomatureones---ATRAPromotorofApotosis:leadingleukemiccellsto“naturaldeath”---As2O370StrategyofChemotherapyTherapeuticperiodandintermittentperiodRemissionInductionTherapyPost-RemissionTherapy71TreatmentInductionConsolidationmaintenance72Treatmentstrategy73ALL:RemissionInduction

DVPRegimen:Daunomycin(D)45mg/m2/d,D1-3(15-17)orIdarubicin(ID)8-12mg/m2/d,D1-3(15-17)Vincristine(V)1.4mg/m2/d,D1,8,15,22Prednisone(P)40mg/m2/d,D1-28CRrate: adult----80~90%74NCCNGuidelineforAML75AML:Remissioninduction

DARegimen:

Daunomycin(D)60-90mg/m2/d,D1-3

orIdarubicin(ID)8-12mg/m2/d,D1-3Ara-C(A)150mg/m2

/d,D1-7HARegimen:Harringtonin(H)3-4mg/d,D1-3Ara-C(A)150mg/m2/d,D1-7CRrate:65-85%76PostremissiontherapyAccordingtocytogeneticsandmolecularabnormalitiesBetter–riskorintermediate-risk(nodonor)HD-AraC2.0g/m2,q12h,d1,d2,d3Intermediate-risk:Allo-PBSCTPoor-risk:Allo-PBCST7778Acutepromyelocyticleukemia(APL))DiagnosisBM:cellularmorphologyCytogenetics:t(15;17)Molecularfeature:PML-RAROthers:t(11;17)→PLZF—RARα,NuMA–RARαt(5;17)→NPM—RARαAML-M3a79CytogeneticsandmolecularfeaturesofAPLcytogeneticsIncidenceinAPLFusiongeneClinicalfeaturest(15;17)(q22;q21)>95%PML-RARaATRA

sensitiveRARa-PMLArsenic

sensitivet(11;17)(q23;q21)0.8%PLZF-RARaATRAnosensitiveRARa-PLZFArsenic

resistancet(11;17)(q13;q21)rareNuMA-RARaATRAsensitivet(5;17)(q35;q21)<0.5%NPM-RARaATRAsensitiveRARa-NPMder(17)rareSTAT5b-RARa?ATRA

sensitive80InductiontherapyWBC>10X109/L(highrisk)ATRA:25mg/m2/d,d1-CRIDA:8mg/m2/d,d2,4,6,8;orDNR:45-60mg/m2/d,d1-3±Ara-CATO0.16mg/kg/d,d1-CRWBC<10X109/L(lowrisk)ATRA+IDA

orDNR+ATO81ConsolidationtherapyLowriskATRA:25mg/m2/d,d1-d14IDA:8mg/m2/d,orDNR60mg/m2/dx3dHighriskATRA+IDA8mg/m2/d,orDNR60mg/m2/dx3d+Ara-C150mg/m2/dx7d.ATRA+HHT2mg/m2/dx3d+Ara-C1.0g/m2q12hx3d.(1course)2courses2courses82MaintenancetherapyLowriskATRA:20mg/m2/dx14d.(onemonths)ATO:0.16mg/kg/dx14d，interval14d,0.16mg/kg/dx14d(thesecondandthirdmonths)

5cycles83MaintenancetherapyHighriskATRA:20mg/m2/dx14d.(onemonths)ATO:0.16mg/kg/dx14d，interval14d,0.16mg/kg/dx14d(thesecondandthirdmonths)MTX15mg/m2/wx4w6-MP50mg/m2/dx28d（thefourthmonths）

5cycles84DualMechanismofAs2O385ATRAandATOcombinationProcNatlAcadSciUSA.2004;101:5328-5335.

8687APLtherapy

PrimaryAPLATRA+As2O3+ChemotherapyHCR

CTX2~3courses