第六篇+第九章+白血病

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第六篇血液系统疾病第九章白血病(Leukemia)周剑峰学时数：3学时 讲授目的和要求1.掌握急、慢性白血病的临床表现，实验室检查及诊断标准，治疗原则2.熟悉急性白血病FAB分型，联合化疗的原则，完全缓解的概念 讲授主要内容概述病因和发病机制临床表现实验室检查诊断标准鉴别诊断治疗 Erythrocytes:transportoxygenNeutrophilBasophilEosinophilMonocytes/MacrophageDefenseagainstinfectionPlatelets:MediatebloodclottingT-lymphocytes:antigenpresentingB-lymphocytesPlasmacell:Sourceofantibodies PluripotentialstemcellsMyeloidstemcellsLymphoidstemcellsUnipotentialprogenitorcellsImmaturehematopoieticcellsmaturehematopoieticcells Hematopoiesiscomposesoftheoptionsofcommitmenttodifferentlineagesandtheprogressivestagesofmaturationatwhichpartialorcompletearrestcanoccur,resultsinthewidearrayofmalignantdisease-LeukemiaStemcellProgenitorcellImmaturecellMaturecell AccumulationofmutationsofDNAwithinapluripotentialstemcellorveryearlyprogenitorcellgivesrisetoleukemicstemcellsNormalstemcellLeukemicstemcell Etiology&PathogenesisEnvironmentalfactorsAcquireddiseasesLesionstotheDNAClonalexpansion Alotofenvironmentalfactorshasbeenreportedtocauseleukemia.However,onlyfourofthemarefirmlyestablishedcausalagents.Theyare:IrradiationexposureChronicbenzeneexposureChemotherapeuticagentsLeukemiavirusinfectionEnvironmentalfactorscauseleukemia Inheritedsyndromessuchasataxia-telangiectasia,downsyndromepredisposetosubsequentdevelopmentofleukemia.Usually,thesekindsofsyndromessharethecommonfeaturesthattheyallhavehereticdefectsintheirgenomegavebytheirparentsInheritedsyndromespredisposetoleukemia AcquireddiseasepredisposetoleukemiaLeukemiamayalsodevelopfromtheprogressionofotherclonaldisordersofhematopoieticstemcells.Ploycythemiavera,idiopathicmyelofibrosis,etc LeukemiaClassificationThereareatleastdozensofvarietiesofleukemia.Theyareclassifiedbyhowquicklyitprogresses.Acuteleukemiaisfast-growingandcanoverrunthebodywithinafewweeksormonths.ByContrast,chronicleukemiaisslow-growingandprogressivelyworsenoveryears AcuteversuschronicleukemiaAcute:thebloodcellsofacuteleukemiaremaininanimmaturestate,sotheyreproduceandaccumulateveryrapidly.Therefore,theyneedtreatmentimmediately,otherwisethediseasemaybefatalwithinfewmonthsChronic:inChronicleukemia,thebloodcellseventuallymature,orpartiallymature.Buttheyarenot“normal”.Theyremaininthebloodmuchlongerthannormalbloodcellsandtheycannotactfunctionalcellswell MyelogenousversuslymphocyticleukemiaIftheleukemiccellsarisefrommyeloidpluripotentialstemcells:myeloidleukemiaIftheleukemiccellsarisefromlymphocyticpluripotentialstemcells:lymphocyticleukemia ClinicalmanifestationsLeukemichematopoiesisNormalhematopoiesismarrowfailureInfiltration MarrowfailureAnemia(lossoferythocytes):fatigues,pallorweakness,reducedexercisetoleranceFeverandinfection(Poorinfectionfighters)Abnormalbleeding(lossofplatelets) InfiltrationsOraltissue:swollenpainful,andbleedinggumsSplenomegalyandhepatomegalyLymphnodeenlargementBoneorjointpainCNS-headaches,seizures,weakness,blurredvisionandvomiting BloodtestfindingsAnemiaisaconstantfeature.Nucleatedredcellsorimmatureredbloodcellmaybepresent.Thrombocytopeniaisnearlyalwayspresentatthetimeofdiagnosis.Thetotalleukocytecountscanbehigh,normalorlow.Immaturehematopoieticcellsarealmostpresentintheblood MarrowfindingsNormalbonemarrowAMLmarrow Cytogeneticfindings Diagnosis&ClassificationOthernewlydevelopedmethods Morphology:thebonemarrowcellsareevaluatedaccordingtotheirsize,shape,andcontentofgranulesandthentheyareclassifiedwithrespectedtomaturityCytochemistrystaining:identificationofthechemicalcomponentsofcellsisconductedtodistinguishdifferenttypesofleukemia.Cytochemistryoftenusespecialcoloreddyes AcuteleukemiaAMLALLM0:undifferentiatedAMLM1:Myeloblasticleukemia(withoutmaturation)M2:Myeloblasticleukemia(withmaturation)M3:promyelocyticleukemiaM4:MyelomonocyticleukemiaM5:MonocyticleukemiaM6:ErythroleukemiaM7:MegkaryoblasticleukemiaL1:MatureappearinglymphoblastsL2:ImmatureandvariouslyshapedlymphoblastsL3:Lymphoblastsarelargeanduniform P142(CDtables)AlotofCDprovidescluesforthediagnosis FlowCytometryImmunohistochemistry ImmnuophenotypingpanelusedinSt.JudeChildren’sresearchhospitalU.S.A.CD13CD33CD19CytoCD79aCD7CytoCD3AML----B-ALL----T-ALL----Byusingthismethodofanalysis,onecanmakeafirmdiagnosisin99%ofcases 免疫表型分型方案T细胞B细胞（4%）B细胞前体CD7（敏感），cCD3（特异）CD19(敏感),cCD79a(特异)成熟T细胞（18%）前T细胞（6%）前B-细胞（9%）早期前-B细胞（52%）前-前-B细胞（11%）sIg,sIg Inserttable90%ofthecaseswithleukemiahavenon-randomizedtranslocation P118typesoftranslocationsCMLAML-M2AML-M3AML-M4AMLAML-M4E0 Othernewdevelopedmethods DifferentialDiagnosisPseudoleukemiaMyelodysplasticsyndromeNonleukemicpancytopenia TreatmentSupportivecaresandpreparationofthepatientsAntileukemictherapyTherapyofthecentralnervoussystemStemcelltransplantation AnemiaHemorrhageInfection HematologicalsupportTransfusionofPlateletsTransfusionofpackedredcellsTransfusionsofgranulocytesTransfusionsofIgG InfectioncontrolSpecialprecautions:protectiveisolationEliminationofcontaminatedfoodsOralanddigestivesystemcareBroadspectrumantibioticsGM-CSFadministration AntileukemictherapyChemotherapytokillleukemiacellsusingstronganti-cancerdrugs TreatmentphasesInductiontherapy:theaimistobringaboutremission,thatisleukemiccellsarenolongerfoundinthebonemarrowandtherecoveryofnormalhematopoiesisPost-remissiontherapy:toeliminateanyleukemiacellspotentialhidinginthebody SpecialsubtypesAcutepromyelocyticLeukemia(APL):becauseofthesmallparticles(procoagulants)insidetheAPLcell,DICarecommonlyseeninthistypeofAML NormalAPLGenesessentialfordifferentiationareshutdownbythefusionproteinsPML-RARalpha Differentiationagents(all-transretinoicacid,arsenictrioxide) Hyperleukecytosis:causeabatchofcomplicationsandshouldbetreatedusingleukapheresis(exchangingtransfusion)orpreinductiontreatmentpriortointensivechemotherapy Acuteleukemiaover60yearsofageislessresponsivetochemotherapyStandardtwo-drugstherapycanbeused.CR30%Intoleranttostandardtherapy.Low-doseofAra-Ccanbeusedfor14-28days TherapyoftheCNSleukemiaTheCNSisafrequentsanctuarysiteforleukemiccellsbecausemostofthechemotherapydrugsarenotabletoreachtheCNS.SometypesofacuteleukemiahavetendencytobewithCNSleukemiasuchasAML(M4,M5),ALL IntrathecalchemotherapyCranialirradiation StemcelltransplantationsThemainpurposeofBMTandPBSCTincancertreatmentistomakeitpossibleforpatientstoreceiveveryhighdosesofchemotherapyand/orradiationtherapy.Inaddition,re-establishednormalhematopoiesisandimmunesystembythehealthystemcellsfightagainstleukemiaeffectively.Soitchangethevisioninthemedicalhistorythatleukemiaisincurablemalignancies ThreetypesoftransplantationperformedAllogeneictransplantation(HLA-matchedindividualdonors)Syngeneictransplantation:identicaltwinsAutologoustransplantation:patientsreceivetheirownstemcells ClinicalresultsofstemcelltransplantationAMLALLCMLFive-yearsdiseasefreesurvivalrateTransplantationChemotherapy Chronicmyelogenousleukemia(CML) Futuredirections 复习思考题1.慢性粒细胞白血病与类白血病反应的鉴别要点？2.白血病完全缓解的标准？为何要进行巩固、强化化疗？3.骨髓增生异常综合征的分型、临床表现、与急性白血病的关系？