異基因造血干細胞移植治療多發(fā)性骨髓瘤課件

Allogeneichaematopoieticcelltransplantationformultiple

myelomaAllogeneichaematopoieticcell1TheallogeneictransplanthastheadvantageovertheautologoustransplantThegraftdoesnotcontaintumorcellsandthepotentialforagraftversusmyeloma(GvM)effectTheallogeneictransplanthas2Bonemarrowtransplantationinthreepatientswithmultiplemyeloma

GahrtonG,RingdénO,L?nnqvistB,LindquistR,LjungmanP.ActaMedScand1986;219(5):523-7.瑞典卡羅林斯卡醫(yī)學院1983MyeloablativeconditioningBonemarrowtransplantationin3ThreepatientswithmultiplemyelomareceivedbonemarrowgraftsfromHLA-identicalsiblingdonorsOneofthepatients,withIgAkappamyeloma,refractorytoalkeran-prednisonetherapy,iswellandstillwithoutsignofdisease26monthsposttransplantationAsecondpatientwithBence-Joneskappamyelomaiswell,andskeletalpainandBence-Jonesproteinuriahasdisappeared2monthsaftertransplantation.AthirdpatientwithIgG-lambdamyelomadiedofeffusivepericarditisshortlyaftertransplantation.

ActaMedScand1986;219(5):523-7Threepatientswithmultiplem4Conclusion

BonemarrowtransplantationmaybeindicatedinaselectivegroupofpatientswithmultiplemyelomaActaMedScand1986;219(5):523-7ConclusionBonemarrowtransp5異基因造血干細胞移植治療多發(fā)性骨髓瘤課件6

Outof690allogeneticmatchedsiblingdonortransplantsforMM344wereperformedduringtheperiod1983-93(allwithBM)[group1]356during1994-98(223withBMgroup2and133withPBgroup3)Outof690allogeneticmatche7異基因造血干細胞移植治療多發(fā)性骨髓瘤課件8

themedianageattransplantationofpatientsingroup1was43years(range21-62)Ingroup2,44years(range18_57)andingroup3,46years(range25_60)themedianageattransplanta9

TBI+CYtendedtobemorecommonlyusedingroup1(37%)and2(39%)thaningroup3(27%)Melphalancontainingregimestendedtobemorelyusedingroup3MelphalanorBusulphan+CYrarely

ConditiongregimeTBI+CYtendedtobemorecom10EngraftmentEngraftment11GVHDGVHD12Treatment–relatedmortalityTreatment–relatedmortality13Treatment–relatedmortalityTreatment–relatedmortality14Relapserate

Relapserate15Relapserate

Relapserate16SurvivalSurvival17SurvivalSurvival18Progression–freesurvival

PFSwassignificantlybetterforgroup2thanforgroup1(P＜0.0001)Withnosignificantlydifferencebetweengroup2and3Progression–freesurvivalPFS19Causeofdeath

75%ingroup1,36%ingroup2,33%ingroup3GVHDFungalARDSOrganfailureCauseofdeath75%ingroup120Causeofdeath

thestudyshowsthattheimprovementisentirelyaresultofalowerTRMduringthelatest5-yearsperiodaGVHDhasnochangedduringthisperoidTherewassignificantdifferenceindeathscausedbyIPandbacterialandfungalinfectionCauseofdeaththestudyshow21ConditioningregimeTBI+MelphalanhasnotprevirousbeenShowntobesuperiortoTBI+CYinthisstudyConditioningregimeTBI+Melph22conclusion

Survival30~60%Treatment–relatedmortality30%conclusionSurvival23MyeloablativeallogeneicversusautologoustransplantationMyeloablativeallogeneic24異基因造血干細胞移植治療多發(fā)性骨髓瘤課件25duringtheyears1983to1994189myelomapatientswhounderwentallo-BMTwithanHLA-identicalsiblingdonorwerecomparedretrospectivelywithanequalnumberofpatientswhoreceivedasingleautologousbonemarroworbloodstemcellgraftAndtheASCTpatientsweretransplantedfrom1986to1994duringtheyears1983to199426異基因造血干細胞移植治療多發(fā)性骨髓瘤課件27conclusionTheoverallsurvivalwassignificantlybetterforASCTthanforallo-BMT,withamediansurvivalof34monthsand18months,respectively(P=.001),Themainreasonforthepoorersurvivalinallo-BMTpatientswashigherTRM(41%v13%forASCT,P=.0001),whichwasnotcompensatedforbyalowerrateofrelapseandprogression異基因造血干細胞移植治療多發(fā)性骨髓瘤課件28

conclusionHowever,inpatientsaliveat1yearposttransplant,therewasatrendforbetterlong-termsurvival(P=.O9)andsignificantlybetterprogression-freesurvival(P=.02)forallo-BMTascomparedwithASCTWeconcludethatthemediansurvivalissuperiorforASCTHowever,allo-BMThasalowerrelapserate,whichresultsinasimilarlong-termoutcomeforbothapproaches,butalongerfollow-upisneededtoassessthefinaloutcomeconclusion29

Reduced-intensityconditioningallogeneictransplantationReduced-intensitycondition30TheAllo-RICwasintroducedinanattempttodecreasethetransplant-relatedtoxicitywhileretainingthebeneficialGvMeffect1998beginclinicalstudyTheAllo-RICwasintroducedin31異基因造血干細胞移植治療多發(fā)性骨髓瘤課件321998~2003Wereporttheoutcomeof229patientswhoreceivedanallograftformyelomawithreduced-intensityconditioning(RIC)regimensfrom33centerswithintheEBMT.1998~200333異基因造血干細胞移植治療多發(fā)性骨髓瘤課件34異基因造血干細胞移植治療多發(fā)性骨髓瘤課件35異基因造血干細胞移植治療多發(fā)性骨髓瘤課件36異基因造血干細胞移植治療多發(fā)性骨髓瘤課件37異基因造血干細胞移植治療多發(fā)性骨髓瘤課件38異基因造血干細胞移植治療多發(fā)性骨髓瘤課件39異基因造血干細胞移植治療多發(fā)性骨髓瘤課件40異基因造血干細胞移植治療多發(fā)性骨髓瘤課件41異基因造血干細胞移植治療多發(fā)性骨髓瘤課件42異基因造血干細胞移植治療多發(fā)性骨髓瘤課件43異基因造血干細胞移植治療多發(fā)性骨髓瘤課件44Withamedianfollow-upof28months,115patientsarealive(range,1-53months)Theestimatedoverallsurvivalat3yearsis40.6%(CI,33%-49%)Thetreatment-relatedmortalitiesatday100,1year,and2yearswere10%,22%,and26%,respectively.Thecumulativeprobabilityoftheprogression-freesurvivalwas21.3%(CI,15%-29%)at3yearsWithamedianfollow-upof2845ConclusionWhileRICisfeasible,heavilypretreatedpatientsandpatientswithprogressivediseasedonotbenefit異基因造血干細胞移植治療多發(fā)性骨髓瘤課件46RICvsMACRICvsMAC47異基因造血干細胞移植治療多發(fā)性骨髓瘤課件48Datawereavailableonatotalof516patientsfrom103centers:320patientswithRICand196withMAC.betweenJanuary1,1998,toDecember31,2002Themedianfollow-upwas28monthsDatawereavailableonatotal49異基因造血干細胞移植治療多發(fā)性骨髓瘤課件50異基因造血干細胞移植治療多發(fā)性骨髓瘤課件51異基因造血干細胞移植治療多發(fā)性骨髓瘤課件52異基因造血干細胞移植治療多發(fā)性骨髓瘤課件53異基因造血干細胞移植治療多發(fā)性骨髓瘤課件54異基因造血干細胞移植治療多發(fā)性骨髓瘤課件55異基因造血干細胞移植治療多發(fā)性骨髓瘤課件56異基因造血干細胞移植治療多發(fā)性骨髓瘤課件57conclusionRICwasassociatedwithareductioninTRM

butthiswasoffsetbyanincreaseinrelapserisktheconditioningintensitydidnotimpactonoverallsurvivalorretainsignificanceforPFSThesedatasuggestthatthereisacontinuingneedtoinvestigatedoseintensityintheconditioningformyelomaallografts.conclusion58Tandemautologous/Allo-RICtransplantation異基因造血干細胞移植治療多發(fā)性骨髓瘤課件59Autologoushematopoieticcelltransplantation(HCT)followedbynonmyeloablativeallogeneicHCT(auto/alloHCT)providescytoreductionandgraft-versus-myelomaeffects.Autologoushematopoieticce60弗雷德哈欽森癌癥研究中心弗雷德哈欽森癌癥研究中心61

PatientinclusioncriteriaforthisanalysiswerestageIIorIIIMMatdiagnosisavailablehumanleukocyteantigen(HLA)–identicalsiblingdonorprogrammedsequentialtreatmentwithconventionalautologousHCTfollowedbynonmyeloablativeauto/alloHCTnopriorautologousHCT.Patientinclusioncriteria62

105patientswithMMfulfillingthosecriteriaweresequentiallyenrolledat10centerson4FHCRC-coordinatedmultiinstitutionalprotocolsfromAugust1998toAugust2005PatientsproceededtoallogeneicHCT40to180daysafterautografting105patientswithMMfulfill63

AutologousHCT.(G-CSF)mobilizedperipheralbloodmononuclearcells(G-PBMC)wereharvestedbyleukapheresisaftertreatmentwithcyclophosphamide3to4g/m2(day1)andG-CSF10g/kgsubcutaneously(fromday3throughcollection)AutologousHCT.64

AutologousHCT38patientsreceivedadditionalpaclitaxel(250mg/m2perday,day2),and25receivedadditionaletoposide(200mg/m2perday;days1,2,3)anddexamethasone(10mg/dayorally;days1,2,3,4)TwopatientsreceivedG-CSFalone.AutologousHCT65

AutologousHCTNotreatmentforMMwasgivenbetweenautologousandallogeneicHCTAutologousHCT66

AllogeneicHCT

AfterrecoveryfromautologousHCT102patientsproceededtoallotransplantation.DonorswereHLA-identicalsiblingsAllogeneicHCT67

Nonmyeloablativeconditioningconsistedinallpatientsof2Gytotalbodyirradiation(TBI)at7cGy/minbylinearacceleratororcobaltonday027patientsreceivedadditionalfludarabine(30mg/m2)ondays4,3,and2Nonmyeloablativeconditioning68異基因造血干細胞移植治療多發(fā)性骨髓瘤課件69N%N%70

EngraftmentAll102allograftedpatientshadsustainedengraftment.Onday28,mediansof90%,95%,and95%ofperipheralbloodTcells,granulocytes,andnucleatedmarrowcells,respectively,wereofdonororigin.Thisincreasedtomediansof96%to100%onday84Engraftment71GVHD43patients(42%)developedgrades2to4acuteGVHDatamedianof42(range,8-107)days74patients(74%)developedchronicextensiveGVHDatamedianof167(range,90-830)daysaftertransplantation.異基因造血干細胞移植治療多發(fā)性骨髓瘤課件72

NRMNRMwas1%atday100and11%,14%,and18%at1,2,and5yearsafterallografting,respectivelyGVHDandinfectionswereresponsiblefor18of19nonrelapserelateddeaths.NRM73

Overallandprogression-freesurvivalsAfteramedianfollow-upof6.3yearsafterallografting(range2-9)60of102(59%)patientssurvivedand33of102(32%)areinremissionFive-yearestimatedOSandPFSwere64%and36%,respectivelyOverallandprogression-free74

conclusionauto/allo-RICHCTisatreatmentoptionforpatientswithadvancedstageMMTheadditionofnovelagents(eg,thalidomide,bortezomib,andlenalidomide)asinductionorpostgraftingtherapy,actingwithGVMeffectsagainstdisease-specificantigens,mightfurtherimprovetheoutcome.conclusion75improvetheoutcomeThalidomide/lenalidomidedexamethasoneBortezomibimprovetheoutcome76研究所佩奧利-Calmettes，馬賽，法國

研究所佩奧利-Calmettes，馬賽，法國77

Thiswasaretrospectivestudyfrom3centers37patientstreatedbetweenNovember2003andMarch2007Thiswasaretrospectivestud78異基因造血干細胞移植治療多發(fā)性骨髓瘤課件79異基因造血干細胞移植治療多發(fā)性骨髓瘤課件80異基因造血干細胞移植治療多發(fā)性骨髓瘤課件81conclusionbortezomibisasafeandefficientoptionformyelomapatientsafterRIC-allo-SCT.conclusion82

DoubleautologousVersustandemauto/Allo-RICtransplantationDoubleautologous83圣喬凡尼巴蒂斯塔大學醫(yī)院，都靈，意大