內(nèi)科學(xué)教學(xué)課件：Leukemia

LeukemiaIntroductionDefinition

History

1827Velpeal

withhisblood"likegruel”1845Benett

，Edinburg,England.with"colorandconsistencyoftheirblood";

Virchow，Berlin,Germany

introducedleukemiafromGreekmeaning"whiteblood"IntroductionDefinition

Leukemia

isagroupofclonalmalignantdeseasesdevelopedformhematopoieticstemcellorprogenitorcell.thatleadtoSuppressionofnormalhematopoiesis

Infiltrationsinoutsideofbonemarrow

Introduction

Classification

AcuteLeukemiaAcutelymphocyticLeukemia（ALL）

AcutemyelogenousLeukemiaorAcutenon-lymphocyticLeukemia（AML，ANLL）

ChronicLeukemiaChronicGranulocyticLeukemia（CGL，CML）

ChroniclymphocyticLeukemia（CLL）LeukemiauncommoninclinicIntroductionIncidenceThetotalmorbidity:2.67/100thousandshigherthanthechancetowinalottery(1/400thousands)男：女=1.8：1IntroductionPrognosis

100%012345YEARBMTCHEMOEtiologyandPathogenesisVirus

ATLVHTLV-IHTLV-IIHTLV-IIIChemicalsubstance

Bemzenepoisoning

Ionizingradiation

IntroductionswellNationalCancerInstitute(NCI)

researcherRobertGalloreportsisolationofanAIDSvirushecallsHTLV-IIIEtiologyandPathogenesisVirus

ATLVHTLV-IHTLV-IIHTLV-IIIChemicalsubstance

Benzenepoisoning

Ionizingradiation

IntroductionIntroductionPathogenesisNormalStemcellBlastcellLeukemicstemcellmutationProgenitorcellsIntroduction1)thosethatconferaproliferativeorandsurvival

KITFLT3↑，NF-1↓2)thosethatimpairhematopoieticdifferentiationandconferpropertiesofself-renewal

RUNX1-ETO,CBFB-SMMHC,TEL-RONX1fusionsmutation

IntroductionPropertiesofLSC:

self-renewal,quiescent,proliferation,multi-potentiality?,differentiationdamaged.Immunophenotype

ofLSC:

AMLCD34+CD38-CD71-CD90-CD117+CD123+,HLA-DR-;

CMLCD34+CD38-AcuteLeukemiaAcuteLeukemiaDefinitioncharacterizedbyahuge(massive)accumulationofblastcells.theinfiltrationoftheseblastcellsresultin：

1）suppressionofnormalhematopoiesisleadtoanemia,infection,bleeding2）clinicmanifestationrelatedtoinvolvementoforgansoutsideBMAcuteLeukemiaClassification：

1976MorphologicClassifyingbyInternationalFABcooperativegroup，

1980MIC，Morphology,Immunology,Cytogenetics

2001WHOAcuteLeukemiaFABclassificationALL：

L1:lymphoblastcellsaresmall,usually<12umindiameter.withscantycytoplasmandinconspicuous(indistinctive)nucleoli.morecommoninchildren(approximately85%ofchildrencasesofAL).Prognosisisbetter.AcuteLeukemia

ALL

L2:lymphoblastsarelargerinsize(>12um),havemoreprominentnucleoliandabundantcytoplasm.morecommoninadult,worseinprognosisAcuteLeukemia

ALLL3:

identicalmorphologicallytoBurkitt’slymphoma.havemanifestdeeplyblue(basophilia)cytoplasmandprominentvacuolationAcuteLeukemiaAML

M0Acutemyeloblasticleukemia,minimaldifferentiatedM1Acutemyeloblasticleukemia,withoutmaturationM2Acutemyeloblasticleukemia,withmaturationM3Acutepromyelocyticleukemia,hypergranularM3vAcutepromyelocyticleukemia,variant,microgranularM4AcutemyelomonocyticleukemiaM4e0AcutemyelomonocyticleukemiawitheosinophiliaM5aAcutemonoblasticleukemia,poorlydifferentiatedM5bAcutemonoblasticleukemia,differentiatedM6AcuteerythroleukemiaM7Acutemegakaryoblasticleukemia

AcuteLeukemia

M0

minimaldifferentiated

CD33,CD13+AcuteLeukemiaM1myeloblast≥90%AcuteLeukemiaM2myeloblast30~89%AcuteLeukemia

M3

Acutepromyelocyticleukemia

AcuteLeukemia

M3

Acutepromyelocyticleukemia

microgranlularAcuteLeukemiaM4

Blast≥30%Monocyte>20%CD14+

AcuteLeukemiaM5

Monoblast+Promonocyte≥30%CD14+AcuteLeukemiaM6Acuteerythroleukemia

immatureerythrocyte>50%blast≥30%AcuteLeukemia

M7

megablast≥30%CD41+,CD61+,CD42+AcuteLeukemia

干細(xì)胞（M0）

M1M4M5M6M7myeloblastmonoblasterythroblast

MKblastsM2

M3promyeloctePROmonocyte早幼紅

AcuteLeukemiaFABclassificationissimpleandconvenient,buthavesomeshortage:

（1）Itcannotavoidmisdiagnosissinceitrelyontheexperienceinmorphologyofobserver

（2）Itcannotidentifythethefurthercelllinetheleukemiccellsoriginedfrom.

（3）ItcannotdistinguishM0、L2、M7、biphenotypicleukemias,mixedlineageleukemiasAcuteLeukemiaWHO2001ACUTEMYELOIDLEUKAEMIASAcutemyeloidleukaemiaswithrecurrentcytogeneticabnormalitiesAMLwitht(8;21)(q22;q22),(AML1/ETO)9896/3AMLwithinv(16)(p13q22)ort(16;16)(p13;q22),(CBF/MYH11)9871/3Acutepromyelocyticleukaemia(AMLwitht(15;17)(q22;q12),(PML/RAR)andvariants)9866/3AMLwith11q23(MLL)abnormalitieAcuteLeukemiaAcutemyeloidleukaemiawithmultilineagedysplasia9895/3withpriormyelodysplasticsyndromewithoutpriormyelodysplasticsyndromeAcutemyeloidleukaemiaandmyelodysplasticsyndrome,therapyrelated9920/3AlkylatingagentrelatedTopoisomeraseIIinhibitor-relatedAcuteLeukemiaAcutemyeloidleukaemianototherwisecategorisedAcutemyeloidleukaemia,minimallydifferentiated9872/3Acutemyeloidleukaemiawithoutmaturation9873/3Acutemyeloidleukaemiawithmaturation9874/3Acutemyelomonocyticleukaemia9867/3Acutemonoblasticandmonocyticleukaemia9891/3Acuteerythroidleukaemia9840/3Acutemegakaryoblasticleukaemia9910/3Acutebasophilicleukaemia9870/3Acutepanmyelosiswithmyelofibrosis9931/3Myeloidsarcoma9930/3AcuteleukaemiaofambiguouslineageAcuteLeukemiaClinicManifestation

manifestationrelatedtopancytopenia

（1）Infection

1）generalfeature：

2）infectionsite：

3）Infectivepathogens：associatedwithgranulocytopeniaanddefectinimmunesystem.1）generalfeature：①feverT>38.5○C；②thelocalimflammationismild；③progressrapidly，andeasytospread；④increasedopportunisticorganismsinfection.2）infectionsite：respiratorytract（nasalcavity,oralcavity,throat,lung），digestivetract（esophagus,GI,analareas），skinetc.oralcandidiasispneumonia;dysphagia(difficulttoswallow);esophagealcandidiasis,perirectalabscesses3）Infectivepathogens：Gram-negativeandpositivebacteriaaremajorpathogensofinfectionincluding—E.coli,Pseuduomonas-aeruginosa,klebsiellapneumoniae，Staphylococcus

aureus，pneumonococcus。Fungus（candida,aspergillus,cryptococcus）infectionstakemorethan10~20%.Viraus,mycoplasmacanalsobepathogensofinfection.AcuteLeukemia（2）Anemia

earlyofonsetdevelopeprogressivelyAcuteLeukemia（3）Bleeding

mainlycausedbythrombocytopenia,butalsorelatedtodysfunctionofbloodvesselthatassociatedwithinfectionsandanemia.petechialecchymosisAcuteLeukemiamanifestationscausedbyinvolvementoforgansoutsideBM

1）PeripheralWBC：

2）Enlargementofliver,spleen,andlymphonode:3）Infiltrationoforalmucousandgum:4）Infiltrationofskin:

sweetEvectionnoduleAcuteLeukemia5）CNS-L

commoninALL(50%),only5~7%inAML

Manyareasymptomatic.presentwithintracranialhypertension顱內(nèi)高壓、stiff-neck頸強(qiáng)直、papilledema視乳頭水腫、nervouslesion第VI對(duì)cranialnervelesion.CNS-Lcanbediagnosedbydetermineofcerebrospinalfluidcytology.

6）Involvementofotherorgans:

Bonepainiscommon.eyes,lung,pleura,heart,pericardium,kidneycanalsobeinvolvement.AcuteLeukemiaLeukostasis

Thehighnumber(>50000/mm3speciallyM5)ofcirculatingbastcellsincreasebloodviscosityandisassociatedwithsmallvesselleukoblasticemboli,resultinginleukostasis.AcuteLeukemiamanifestatoinsrelatedtometabolicabnormality：

hyperuricemia

hypercalcinemia

其他：

tumorlysissyndromeischaracterizedbytherapiddevelopmentofhyperuricemia,hyperkalemia,hyperphosphatemiaandhypocalcemiaetc.AcuteLeukemiaLaboratoryFindingsBloodRoutineExamination

1）WBCcount2）leukemiccellscanbefoundin90%patientsAcuteLeukemia

BoneMarrowAspiration

1）Cellularity.foundin90%patients.2）Leukemiccells≥30%nonerythroidcells3）Auerrods(spindle-shaped)canonlybefoundinAMLAuerrodsAcuteLeukemiaCytochemicalStain

Lymphoblastmyeloblastmonoblast

peroxydase-+~+++~+nonspecificesterase-~++

PAS(periodicaicd-Schiff)：++-~+

AcuteLeukemiaperoxydaseStain

AcuteLeukemiaImmunophenotypicMarkersinAL

CD3CD7CD10CD19CD34CD13CD14CD33CD41,61GlyACD2CD20CD22CD15B-CELL--+++++------T-CELL++++--+------M0----++++M1~4-----+++++++---M6-------=--++M7----+---++++++-ImmunophenotypicclassificationofALLTypeCriteriaFeaturesB>=2makers:D19,CD79a,CD22Pro-BNomoreHighWBC,CNS-L,MLL,poorCommonAdditionalCD10+LowWBC,TEL/AML1,favorablePre-BAdditionalcyIgM+HighWBC,E2A/PBX1,favorable(intensivechemotherapy)MatureBΚ+,λ+,mIgM+Commonextramedullary,favorable(intensivechemotherapy)TcyCD3+/mCD3+Pro-TCD7+Pre-TCD2+/CD5+/CD8+Cortical-TCD1a+Mature-TmCD3+,CD1a-AcuteLeukemiaCytogenetics

類型染色體基因

M3t（15；17）PML-RARaCMLt（9；22）ALLt（9；22）ABL-BCRM2t(8;21)AML1-ETOM4EOinv/del(16)CBFB-MYH11L3t(8;14)MYCIgHM5t/del(11)MLL-ENLRiskgroupsinAMLaccordingtoCytogeneticsRiskgroupKaryotypicFeatureFavorableT(8;21);inv(16)/t(16;16);t(15;17)IntermediateMormal;-Y,del(7q);del(9q);t(9;11);del(11q);+8,+11,+13,+21,adverseComplexkaryotype;inv(3)/t(3;3);-7;t(6;9);t(6;11);t(11;19);-5;del(5q)ImpactofkaryotypeonoutcomeinyoungeradultswithAML.OverallsurvivalisshownforadultswithAML(medianage43years,range16–59)treatedinsuccessiveMedicalResearchCouncil/NationalCancerResearchInstitutetrials(MRCAML10,AML12,AML15).GrimwadeD,andHillsRKHematology2009;2009:385-395ImpactofkaryotypeonoutcomeinyoungeradultswithAML.OverallsurvivalisshownforadultswithAML(medianage43years,range16–59)treatedinsuccessiveMedicalResearchCouncil/NationalCancerResearchInstitutetrials(MRCAML10,AML12,AML15).GrimwadeD,andHillsRKHematology2009;2009:385-395?2009byAmericanSocietyofHematologyStratificationbasedoncytogeneticandmolecularentities

RiskgroupCytogeneticMolecularEntitiesFavorablet(15;17)

t(8;21)

inv(16)/t(16;16)PML-RARA;RUNX1-RUNX1T1;

CBFB-MYH11

IntermediateNormal

Othernon-complexEntitiesnotclassifiedasfavorableoradverseadverseabn(3q)

-5/del(5q)

-7

complex[≥5unrelabn]

ExcludingthosewithfavorablechangesFLT3-ITD;EVI-1

AcuteLeukemiaAMLwitht（15；17）AcuteLeukemiaCMLt（9；22）AcuteLeukemiaDiagnosisanddifferentialdiagnosis

Diagnosis

approachtodiagnosis

Ifabnormalitybefoundinbloodroutinetest,speciallypancytopeniaandimmaturecells,thebonemarrowaspirationandbiopsymustbedone

establishthediagnosis

blastcells≥30%(FAB),or≥20%(WHO,2003)

classificationwouldbecorrectly

AcuteLeukemiaDifferentialDiagnosisInfact,blastcells≥30%nevercanbeseeninanyotherdiseaseexcept

AcuteLeukemia.AplasticAnemia,Infectiousmonocytosis,Infectiouslymphocytosisetc.AcuteLeukemiaTherapy1865LissauertreatedCMLwithFowlerliquidwithAsinit.FarbertreatedALLinchildrenwithMTX(methotrexate)AcuteLeukemia1956Thomas,afirstmantreatedleukemiawithbonemarrowtransplantationAcuteLeukemia

Therapeuticprinciple

longtermsurvival

BMT確診InductiontherapyCRPBSCT

按難治AL處理treatasrefractoryleukemiachemotheray復(fù)發(fā)relapseNRAcuteLeukemiaSupportcarehighWBC

WBC>10,000/㎜3oraladministrationofallopurinolWBC>50,000/㎜3

InfectionnofeverT<101OF，prophylacticoraladministrationHavefeverT>101OF,broadspectrumantibiotics(egImipenen)musbeused.Ifpneumoniahasbeenconfirmedortemperaturecannotdecreasedinthreedaysandbloodbacterialcultureisnegative,amphotericinBwouldbeusedempirically.AcuteLeukemiaBleedingplatelettransfusion:nosignsofbleedingbutPLT<10000/㎜3signsofbleeding,PLT<50000/㎜3AcuteLeukemiaChemotherapy化學(xué)治療：

ChemotherapeuticProtocolinALL化療方案：

(1).VPandVDP,VDLP(2)HighdoseAra-C(HDAC)Highdosemethotrexate

（HDMTX）AcuteLeukemiaChemotherapeuticprotocolsinAML

youngadultAPLnon-APLATRA+anthracyclineDA3+7AS2O3

inv16ort(8;21)中差

SCT