内科学 白血病(英文)

LEUKEMIA

18/12/2009Female,age47years,wasadmittedtohospitalforfeelingweakandsubcutaneousbleedingfor1week.Bloodtest:WBC54×109/L,HGB72g/L,PLT15×109/L.Bonemarrowaspiration:blasts42%,MPO(-),CD19(+),CD20(+)Question:1.What’stheinitialdiagnosisofthispatientandtheevidences?2.What’stheprincipleoftreatment?Case28/12/2009CONTENTSDEFINITION

CLASSIFICATIONETIOLOGYMANIFESTATIONSLABORATORYEVALUATIONDIAGNOSISTREATMENT38/12/2009Origin:HematopoieticsystemLevel:MalignantclonaldiseaseofstemcellNature:MalignancyWhatisleukemia?48ConceptofleukemiaLeukemiaistheresultofthetumor(malignant)proliferationofhematopoieticstemcells.Leukemiaisamalignantblooddisorder(notsolidtumor).Leukemiaischaracterizedbytheaccumulationof（immature）blastcellsinthebonemarrowandblood,whitebloodcells(leukocytes)areusuallyinvolved.

58/12/20091.Maturityoftheleukemiacells2.Kindsofcells3.ThenumberofWBC4.FABclassification5.MICMclassification(WHO)

TheClassification68AccordingtothematurityoftheleukemiacellsAcuteRapidgrowthofimmaturebloodcellsMostlyinchildren,youngadultsNeedsimmediatetreatmentChronicExcessivebuildupofmorematurebloodcellsMostlyinolderpatientsMonitoringbeforetreatment78/12/2009RelationshipbetweenALandCLAcuteLeukemiaChronicLeukemia88/12/2009AcuteLymphocytic/LymphoblasticLeukemia(ALL): mostcommontypeinyoungchildren; alsoaffectsadults,>65AcuteMyelogenous/MyeloidLeukemia(AML) morecommoninadultsthaninchildren.ChronicLymphocyticleukemia(CLL) mostoftenaffectsadultsovertheageof55ChronicMyelogenousleukemia(CML) occursmainlyinadultsLymphoid Affectslymphocytesand plasmacellsLymphocyticleukemia MyeloidAffectseosinophils, neutrophils,basophilsMyelogenousleukemiaAccordingtocellkinds98/12/2009Leukocytosis：WBC>10×109/L(LeukocyteLeukemia

)Non-leukocytosis：WBC＜1×109/L(Non-leukocyteLeukemia

)AccordingtothenumberofWBC108/12/2009In1976,sevenhematologyexpertscomefromFrance,America,Britain(Franch-American-British)proposedtheclassificationofacuteLeukemiainParis,thenamendedmanytimes.

AML(ANLL)ALLWhatisFABcategory

?118M0MinimallydifferentiatedAMLM1AMLwithoutmaturationM2AMLwithmaturationM3Acutepromyelocyticleukemia(APL)

M4Acutemyelomonocyticleukemia(AMML)M5Acutemonocyticleukemia(AMoL)M6Erythroleukemia(EL)M7Acutemegakaryoblasticleukemia(AMeL)TheFABcategoryofAML(ANLL)128M0MinimallydifferentiatedAMLM1AMLwithoutmaturationM2AMLwithmaturationM3Acutepromyelocyticleukemia(APL)

138/12/2009M4Acutemyelomonocyticleukemia(AMML)M5Acutemonocyticleukemia(AMoL)148/12/2009M6Erythroleukemia(EL)M7Acutemegakaryoblasticleukemia(AMeL)158/12/2009Myelomono168/12/2009TheFABcategoryofALLL1L2L3178

MorphologyImmunology

Cytogenetics

MolecularbiologyMICMclassification188WHOClassificationofAMLAMLwithrecurrentcytogenictranslocationsAMLwithmulti-lineagedysplasiaAMLandmyelodysplasia,therapyrelatedAML,nototherwisecategorized198/12/2009WHOClassificationofLymphoproliferativeSyndromesPrecursorBLymphoblasticLeukemia/Lymphoma(ALL/LBL)--ALLinchildren(80-85%ofchildhoodALL);LBLinyoungadultsandrare;FABL1orL2blastmorphologyPrecursorTALL/LBL--15%ofchildhoodALLand25%ofadultALLBurkittLeukemia/Lymphoma(FABL3)208/12/2009VirusIonizingRadiationChemicalsanddrugsGeneticOtherblooddisease

Etiology?218Virus

HTLV-1

DNA

HostDNAReversetranscriptaseIntegration228IonizingRadiationAtombombHighdoseXradiation238ChemicalsandDrugsBenzeneAlkylatingagents:Therapy-relatedLeukemia

Bimolane,Bimine

248GeneticFactorsCongenitaldiseasehaveahigherincidence.Identicaltwin---20%Non-Identical

twin---5timeshigherthanordinarypeople.258MyeloproliferativeDiseaseChronicmyeloidleukemia(CML)Polycythemiavera(PV)Primarythrombocythemia(PT)Myelofibrosis(MF)Myelodysplasticsyndrome(MDS)Paroxysmalnocturnalhemoglobinuria(PNH)LymphomaormyelomaFromotherblooddisorders268/12/2009Mechanism

MalignantblooddisordersRadiation,chemicals,virus,genetics&otherblooddisordersChromosometranslocationFusiongeneformationFusionproteinMalignantbiologicbehaviors278/12/2009NormalstemorprogenitorcellMaturebloodcellsMutationsLeukemicstemcellsLeukemiablastpopulationNormaldevelopmentblockedModelforDevelopmentofLeukemia288/12/2009FourClinicalManifestations3.Anemia1.Fever4.Infiltration2.Hemorrhage298Leukopenia,especiallyneutropeniaorabnormalfunctionofneutropil.Developmentobstaclesofthelymphaticsystem,declinedcellularimmunefunction.Bonemarrow(Hematopoiesis)isinhibitedbyanti-leukemiadrugsHormone,asoneofcompositionofchemotherapyreducesimmunity.Bleedingandcombinationofhiddeninfectiousdisease,suchasanalfissure,cholecystitis,etcInfiltrationofleukemiacellsCausesoffeverInfectionandInfiltration308CausesofbleedingThequalityandquantityofplateletareabnormal,BPC<50×109/Leasilybleeding.Infiltrationdamagetothevesselwallandcausesleukocyteembolization.Reductionofclottingfactors.DIC(ANLL-M3)318AplasiaofRBCduetotheinhibitionofnormalhematopoiesisbyleukemiacellAcuteorchronicbleedingorhemolyticanemiaChemotherapy-inducedbonemarrowsuppressionmegaloblasticanemiaCausesofanemia328Hepatomegaly,splenomegaly,lymphadenopathy,sternaltendernessSpecialinfiltrationareaChloromas:skin,orbit(granulocyticsarcoma)Painlessenlargementoftesticle(ALL)CNSinvolvement,paraplegia

(ALL,M4,M5)Gingivitis

(M4,M5)

Infiltration338/12/2009LaboratoryEvaluation348/12/2009MICMTypingDiagnosisMICMMorphologyImmunologyCytogeneticsMolecular358/12/2009AnemiaWBCfrom<1×109/L(nonleukemoid)to>100×109/L(hyperleukocytosis),blastsarepresentPlatelets:normalearlyanddecreasedlately

NormalhumanbloodWhiteCellRedCellPlateletBloodwithleukemiaBlastsRedCellPlateletWhiteCellBloodroutinetest368/12/2009BoneMarrowCellularity:hypercellularmarrowGranulocyte/erythrocyte:significantlydecrease.Blasts≥20%.Erythropoiesis↓，Megakaryocytopoiesis↓Staining378/12/2009StainingofthreeblastsTypesALLAMLAMoLWrightStainNuclear/Cytoplasmic>111or<1ChromatinCoarseparticlesSand-likeFinemeshNucleolus

1-22-53-5

Auerrods-+++HistochemicalStainPOXperoxidase-+~++,rough－～+,finePASPeriodicacid-Schiff’sreaction+,rough--NSEnon-specificesterase-±++388Auerrods

398/12/2009POX:primarygranulesofgranulocyticcells408/12/2009PAS:erythroleukemia

418/12/2009NSE:monocyticcellswhicharediffuselypositive

428/12/2009ImmunologyExaminationM1~M5MPO,CD13,CD14,CD15,CD33,CD117ALL-BCD79a,CyCD22,CD19,CD20ALL-TCD3,CD2,CD5,CD4,CD8,CD7438/12/2009CytogeneticsAbnormalitieswithintheleukemicclone:thePhiladelphiachromosome(Ph)---theproductofatranslocationbetweenchromosomes9and22,isoneofthediagnosiscriteriaofCML,andalsoconfersaverypoorprognosisincasesofALL.448/12/2009MolecularBiologyPML-RAR-t(15,17)BCR/ABL–t(9,22)AML1-ETOFLT3(fms-liketyrosinekinase3)–ITD(Internaltandemduplications)458/12/2009RiskStatus

RISKSTATUSCYTOGENETICSMOLECULARABNORMALITIESBetter-riskinv(16)t(8;21)t(16;16)NormalcytogeneticswithisolatedNPM1mutationIntermediate-riskNormal+8onlyt(9;11)onlyOtherabnormalitiesnotlistedwithbetter-riskandpoor-riskcytogeneticsandmolecularmutationsc-KITinpatientswitht(8;21)orinv(16)Poor-riskComplex(≥3abnormalities)-5-75q-7qAbnormalitiesof11q23,excludingt(9;11)inv(3)t(3;3)t(6;9)t(9;22)NormalcytogeneticswithisolatedFLT3-ITDmutations468/12/2009DiagnosisThenormalbloodcell↓andleukemiacell↑areshownbyclinicalsigns,symptoms,laboratoryfeaturesandspecialexaminations.Blastmorethan20%innonerythrocyticcells(NEC)ofbonemarrowsmearMICM478/12/2009DifferentialDiagnosisMyelodysplasticsyndrome(MDS)Refractoryanemiaorpancytopenia;BM:dysplasia,blasts<20%LeukemoidreactionMatureleukocytesproliferationwouldplayamainrole,

LAP(NeutrophilalkalinePhosphatase)↑,ifprogenitorincreases,onlyshortlyontimeCML:matureprogenitors↑E↑、B↑,NAP=0,ph'(＋),BCR-ABL(+)Stomatitis,Infectiousmononucleosis,ITP,AA,Agranulocytopenia

Noblast

inbonemarrow488/12/2009TherapeuticPrinciple

Symptomaticandsupportivetreatment(proctect,antibiotics)

Chemotherapy(early,combineddrugs)

HSCT(Hematopoieticstemcelltransplantation)498/12/2009Emergencytreatmentof

Hyperleukocytosis

WBC>100×109/LLeukapheresisHydrationChemotherapyBloodCellPheresisNotinAML-M3508/12/2009Enviromentalprotection;Etiologicalinvestigation＋drugsensitivitytest;EmpiricalAntibiotics;TargetedAntibioticsThepreventionandcontrolofInfection518G-CSF(granulocytecolony-stimulatingfactor)

GM-CSF(granulocyte-macrophageCSF)High-dose

gammaglobulin

OthersRegulateimmunity,promotehematopoiesis

528BloodTransfusionAnemia<80g/LtransfuseRBCsuspensionPlatelet<50×109/Lwithoutbleeding--observation

withbleeding–transfuseplatelet<20×109/Lwithorwithoutbleeding--transfuseplatelet538ProphylaxisandTreatmentofHyperuricemiaAntiemeticNutritionalsupportReducethecomplicationsofchemotherapyPsychotherapy548/12/2009whyearly?Theoverhyperplasia&infiltrationcouldbringthedifficultyontherapyTumorlysisLeukemiacellenterintotheareaprotectedbyblood-brainbarrier

Couldmakeanti-infection,supportivetreatmentandchemotherapytobedoneatsametimeifnecessaryPrinciple:early,combine,full,interval,bystages558/12/2009CombineUsecombinationregimenofchemicaldrugswith

differentaction,typingandtoxicitytoincreasecurativeeffectanddecreasetoxicity

Principle:early,combine,full,interval,bystages568/12/2009FullthedrugshouldworkinallperiodofcellcyclethedosageshouldbefullTheregimenwouldbeusedrepeatedly

KillingthecellsinallperiodofcellcyclerepeatedlycouldmakeG0→cycle&controlthesourceofrelapse（minimalresidualdisease,

MRD)Principle:

early,combine,full,interval,bystages578/12/2009Interval:for3~4weeksbeforenexttherapyPrinciple:early,combine,full,interval,bystagesLeukemiaCellNormalCellOnsetThegreaterpartofcellsisnotinG0periodHyperplasiaisinhibitedEasilykilledbychemotherapyInG0periodornot?DoublingTimeLongShortRecoverinintervalNoteasytorecoverEasytorecover588/12/2009

Bystages:ToreduceMRDstepbystep;keeptheDFSforlongtimePrinciple:early,combine,full,interval,bystagesInductionPhaseConsolidationMaintenance1011～1012106～8104（MRD）PreventCNSleukemia6cycles3～5years598/12/20091.InductionPhaseProliferationisoutofcontrol：TokilltumorcellsApoptosisisinhibited:ToinduceapoptosisDifferentiationofHSCisblocked：ToInducedifferentiation608/12/2009Objective:CR(completeremission)

Noanemia,fever,hemorrhageandinfiltrationPB：ANC>1×109/L，Hb>100g/L，PLT>100×109/L

BM:blasts<5%PR:atleast50%decreaseofblasts;NR:lessthen50%decreaseofblastsorineffective618/12/2009InductiontreatmentofAML(1

courseof

induction)

DA3+7（CRrate55~80%）DNR30~45mg/m2ivd1-3Ara-C100~200mg/m2ivd1-7Anthracyclines:daunorubicin,idarubicinAntimetabolites:

cytarabine(Ara-C)628/12/2009InductiontreatmentofAML-M3(Acutepromyelocyticleukemia)

ATRA:30~60mg,P.OCR>80%,Av30daysAs2O3:10mg,iv.gttCRabout90%,28~70daysNocross-resistancewithATRA638/12/2009RAreceptorPMLPMLPMLRARaRARaSUMO-1PML-RARaPathogenicityprotein

APLCellDifferentiationApoptosisATRAAll-transretinoicacidAs2o3arsenictrioxideInduceddifferentiationandapoptosis648/12/2009InductiontreatmentofALL(1

induction)

VDLP(vincristine,daunorubicin,prednisone,L-asparaginase)VCR1.4mg/m2ivd1,8,15,22DNR30~45mg/m2ivd1-3,15-17PDN40~60mg/m2pod1-28L-ASP6000u/m2

ivd19-28658/12/2009

UseainductionregimenforsixcyclesUsedifferentregimenalternatelyforsixcycles2.ConsolidationRegimen668/12/2009

Clinicalmanifestations&diagnosisofCNSleukemia

Clinicalexamination

IntracranialhypertensionThesignsofmeningesstimulatedthesignsofnervesinjuryCSF(cerebrospinalfluid)examination

Presure>200mmH20,sugar,protein(>40mg/dl),WBC>10/mm3Couldfind

leukemiacells

678/12/2009

ThepreventionandtreatmentofCNSL

Prevention：

MTX5－10mgorAra-CIntrathecalinjection8times,High-dosechemotherapy.

Treatment：Intrathecalinjection,q.d.,untilthesymptomsdisappear,CSFnormal.Fractionateradiotherapyforhead,spinalcord.High-dosechemotherapy.

Clinicalmanifestations&diagnosisofCNSleukemia

MTX(methotrexate):folicacidantagonists688/12/2009Treatmentwithextendedintervalusingdifferentinductionregimenalternatelyfor3~5yInintervaltime,patientswithALLtakeCTX,6-MP,6-TG&MTX,P.ONomaintenance

therapyunlessleukemiarelapse,protectthecapacityofbodyimmunity,improvequalityoflifeCTX(cyclophosphamide),6-MP(mercaptopurine),6-TG(thioguanine)3.MaintenanceRemission698/12/2009

Gastrointestinalevents:DNR,Ara-C;

Bonemarrowsuppression:DNR,Ara-C;

CardiacEffects:DNR---600mg/m2

(550-800mg/m2);

NS:VCR,Ara-C;Others:Hormone(bloodpressure,bloodsugar,infection);L-ASP(Allergy,coagulopathy,pancreatitis)

Thetoxicityofthedrugs708/12/2009WhatisHSCT？AfterCR,patientsreceiveconditioningregimens:high-dosechemotherapyandTBI(totalbodyirradiation)tokillthemaximumnumberofresidualleukemiacells,andcauseseriousbonemarrowsuppression,thenimmediatelytransplantdonorstemcellsofmatchedHLAtype.Thereasontochooseallogeneictransplantationisthattheimmune-mediatedgraft-versus-leukemiaeffectofthetransplantedcellsreducestheriskofrelapseconsiderablyandimprovesrelapse-freesurvival.ThealloSCTadvantageobviouslyhastobecautiouslybalancedagainsttheincreasedriskofdeathandmorbiditythatistypicallyconnectedwithalloSCT.718/12/2009ChronicMyelogenousLeukemia(CML)

ClonalproliferativedisorderofpluripotentstemcellConsistentlyassociatedwiththePhchromosomeandBCR-ABLfusiongeneAbout15~25%ofleukemia25~60years,slightlymoreinmenthanwomenChronicPhaseAcceleratedPhase

BlastPhaseAbout3years1～2yearsSixmonths

728/12/2009Geneticsfactors:

Chromosometranslocate,formatethePhiladelphiachromosome

BCR-ABLFusiongene8.5KbmRNA(b3a2orb2a2)210Kdprotein(P210)

Mechanism—PhChromosome738/12/2009SymptomsarevagueandnonspecificSplenomegaly,90%;sternaltenderness

PeripheralBlood:WBC10～1000×109/LGranulocytesatallstagesarepresent,

LAP=0BMproliferate,Granulopoiesisisdominantblast<10%,B&EandErythropoiesismegakaryocytopeoiesisandreticulinfibrosisPh1(+),BCR-ABL(+)Diagnosis748/12/2009CMLbyStagesChronicphaseaccelerativephaseblastphaseAsymptomaticAnemia,hemorrhageLikeacuteleukemiaSplenomegalySplenomegalyBlast>20%EosinophiliaBasophiliccell>20%Basophl