异基因造血干细胞移植治疗多发性骨髓瘤课件

Allogeneichaematopoieticcelltransplantationformultiple

myelomaAllogeneichaematopoieticcell1TheallogeneictransplanthastheadvantageovertheautologoustransplantThegraftdoesnotcontaintumorcellsandthepotentialforagraftversusmyeloma(GvM)effectTheallogeneictransplanthas2Bonemarrowtransplantationinthreepatientswithmultiplemyeloma

GahrtonG,RingdénO,LönnqvistB,LindquistR,LjungmanP.ActaMedScand1986;219(5):523-7.瑞典卡罗林斯卡医学院1983MyeloablativeconditioningBonemarrowtransplantationin3ThreepatientswithmultiplemyelomareceivedbonemarrowgraftsfromHLA-identicalsiblingdonorsOneofthepatients,withIgAkappamyeloma,refractorytoalkeran-prednisonetherapy,iswellandstillwithoutsignofdisease26monthsposttransplantationAsecondpatientwithBence-Joneskappamyelomaiswell,andskeletalpainandBence-Jonesproteinuriahasdisappeared2monthsaftertransplantation.AthirdpatientwithIgG-lambdamyelomadiedofeffusivepericarditisshortlyaftertransplantation.

ActaMedScand1986;219(5):523-7Threepatientswithmultiplem4Conclusion

BonemarrowtransplantationmaybeindicatedinaselectivegroupofpatientswithmultiplemyelomaActaMedScand1986;219(5):523-7ConclusionBonemarrowtransp5异基因造血干细胞移植治疗多发性骨髓瘤课件6

Outof690allogeneticmatchedsiblingdonortransplantsforMM344wereperformedduringtheperiod1983-93(allwithBM)[group1]356during1994-98(223withBMgroup2and133withPBgroup3)Outof690allogeneticmatche7异基因造血干细胞移植治疗多发性骨髓瘤课件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异基因造血干细胞移植治疗多发性骨髓瘤课件25duringtheyears1983to1994189myelomapatientswhounderwentallo-BMTwithanHLA-identicalsiblingdonorwerecomparedretrospectivelywithanequalnumberofpatientswhoreceivedasingleautologousbonemarroworbloodstemcellgraftAndtheASCTpatientsweretransplantedfrom1986to1994duringtheyears1983to199426异基因造血干细胞移植治疗多发性骨髓瘤课件27conclusionTheoverallsurvivalwassignificantlybetterforASCTthanforallo-BMT,withamediansurvivalof34monthsand18months,respectively(P=.001),Themainreasonforthepoorersurvivalinallo-BMTpatientswashigherTRM(41%v13%forASCT,P=.0001),whichwasnotcompensatedforbyalowerrateofrelapseandprogression异基因造血干细胞移植治疗多发性骨髓瘤课件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异基因造血干细胞移植治疗多发性骨髓瘤课件321998~2003Wereporttheoutcomeof229patientswhoreceivedanallograftformyelomawithreduced-intensityconditioning(RIC)regimensfrom33centerswithintheEBMT.1998~200333异基因造血干细胞移植治疗多发性骨髓瘤课件34异基因造血干细胞移植治疗多发性骨髓瘤课件35异基因造血干细胞移植治疗多发性骨髓瘤课件36异基因造血干细胞移植治疗多发性骨髓瘤课件37异基因造血干细胞移植治疗多发性骨髓瘤课件38异基因造血干细胞移植治疗多发性骨髓瘤课件39异基因造血干细胞移植治疗多发性骨髓瘤课件40异基因造血干细胞移植治疗多发性骨髓瘤课件41异基因造血干细胞移植治疗多发性骨髓瘤课件42异基因造血干细胞移植治疗多发性骨髓瘤课件43异基因造血干细胞移植治疗多发性骨髓瘤课件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异基因造血干细胞移植治疗多发性骨髓瘤课件46RICvsMACRICvsMAC47异基因造血干细胞移植治疗多发性骨髓瘤课件48Datawereavailableonatotalof516patientsfrom103centers:320patientswithRICand196withMAC.betweenJanuary1,1998,toDecember31,2002Themedianfollow-upwas28monthsDatawereavailableonatotal49异基因造血干细胞移植治疗多发性骨髓瘤课件50异基因造血干细胞移植治疗多发性骨髓瘤课件51异基因造血干细胞移植治疗多发性骨髓瘤课件52异基因造血干细胞移植治疗多发性骨髓瘤课件53异基因造血干细胞移植治疗多发性骨髓瘤课件54异基因造血干细胞移植治疗多发性骨髓瘤课件55异基因造血干细胞移植治疗多发性骨髓瘤课件56异基因造血干细胞移植治疗多发性骨髓瘤课件57conclusionRICwasassociatedwithareductioninTRM

butthiswasoffsetbyanincreaseinrelapserisktheconditioningintensitydidnotimpactonoverallsurvivalorretainsignificanceforPFSThesedatasuggestthatthereisacontinuingneedtoinvestigatedoseintensityintheconditioningformyelomaallografts.conclusion58Tandemautologous/Allo-RICtransplantation异基因造血干细胞移植治疗多发性骨髓瘤课件59Autologoushematopoieticcelltransplantation(HCT)followedbynonmyeloablativeallogeneicHCT(auto/alloHCT)providescytoreductionandgraft-versus-myelomaeffects.Autologoushematopoieticce60弗雷德哈钦森癌症研究中心弗雷德哈钦森癌症研究中心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异基因造血干细胞移植治疗多发性骨髓瘤课件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.异基因造血干细胞移植治疗多发性骨髓瘤课件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研究所佩奥利-Calmettes，马赛，法国

研究所佩奥利-Calmettes，马赛，法国77

Thiswasaretrospectivestudyfrom3centers37patientstreatedbetweenNovember2003andMarch2007Thiswasaretrospectivestud78异基因造血干细胞移植治疗多发性骨髓瘤课件79异基因造血干细胞移植治疗多发性骨髓瘤课件80异基因造血干细胞移植治疗多发性骨髓瘤课件81conclusionbortezomibisasafeandefficientoptionformyelomapatientsafterRIC-allo-SCT.conclusion82

DoubleautologousVersustandemauto/Allo-RICtransplantationDoubleautologous83圣乔凡尼巴蒂斯塔大学医院，都灵，意大利圣乔凡尼巴蒂斯塔大学医院，都灵，意大利84异基因造血干细胞移植治疗多发性骨髓瘤课件85异基因造血干细胞移植治疗多发性骨髓瘤课件86

Methods

AllpatientswereinitiallytreatedwithVADfollowedbymelphalanandautologousstem-cellrescueMethods87PatientswithanHLA-identicalsiblingthenreceivednonmyeloablativetotal-bodyirradiationandstemcellsfromthesibling.PatientswithoutanHLA-identicalsiblingreceivedtwoconsecutivemyeloablativedosesofmelphalan,eachofwhichwasfollowedbyautologousstem-cellrescue.Theprimaryendpointswereoverallsurvivalandevent-freesurvival.PatientswithanHLA-identical88异基因造血干细胞移植治疗多发性骨髓瘤课件89异基因造血干细胞移植治疗多发性骨髓瘤课件90异基因造血干细胞移植治疗多发性骨髓瘤课件91ConclusionsAmongpatientswithnewlydiagnosedmyeloma,survivalinrecipientsofahematopoieticstem-cellautograftfollowedbyastem-cellallograftfromanHLA-identicalsiblingissuperiortothatinrecipientsoftandemstem-cellautografts.Conclusions92UNSOLVEDQUESTIONSINALLOGENEICTRANSPLANTATIONWhichisthebestallogeneictransplantationapproach?WhoarethepatientsmostlikelytobenefitfromAllo-RIC?HowtoimprovetheresultsofAllo-RIC?UNSOLVEDQUESTIONSINALLOGEN93Allogeneichaematopoieticcelltransplantationformultiple

myelomaAllogeneichaematopoieticcell94TheallogeneictransplanthastheadvantageovertheautologoustransplantThegraftdoesnotcontaintumorcellsandthepotentialforagraftversusmyeloma(GvM)effectTheallogeneictransplanthas95Bonemarrowtransplantationinthreepatientswithmultiplemyeloma

GahrtonG,RingdénO,LönnqvistB,LindquistR,LjungmanP.ActaMedScand1986;219(5):523-7.瑞典卡罗林斯卡医学院1983MyeloablativeconditioningBonemarrowtransplantationin96ThreepatientswithmultiplemyelomareceivedbonemarrowgraftsfromHLA-identicalsiblingdonorsOneofthepatients,withIgAkappamyeloma,refractorytoalkeran-prednisonetherapy,iswellandstillwithoutsignofdisease26monthsposttransplantationAsecondpatientwithBence-Joneskappamyelomaiswell,andskeletalpainandBence-Jonesproteinuriahasdisappeared2monthsaftertransplantation.AthirdpatientwithIgG-lambdamyelomadiedofeffusivepericarditisshortlyaftertransplantation.

ActaMedScand1986;219(5):523-7Threepatientswithmultiplem97Conclusion

BonemarrowtransplantationmaybeindicatedinaselectivegroupofpatientswithmultiplemyelomaActaMedScand1986;219(5):523-7ConclusionBonemarrowtransp98异基因造血干细胞移植治疗多发性骨髓瘤课件99

Outof690allogeneticmatchedsiblingdonortransplantsforMM344wereperformedduringtheperiod1983-93(allwithBM)[group1]356during1994-98(223withBMgroup2and133withPBgroup3)Outof690allogeneticmatche100异基因造血干细胞移植治疗多发性骨髓瘤课件101

themedianageattransplantationofpatientsingroup1was43years(range21-62)Ingroup2,44years(range18_57)andingroup3,46years(range25_60)themedianageattransplanta102

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

ConditiongregimeTBI+CYtendedtobemorecom103EngraftmentEngraftment104GVHDGVHD105Treatment–relatedmortalityTreatment–relatedmortality106Treatment–relatedmortalityTreatment–relatedmortality107Relapserate

Relapserate108Relapserate

Relapserate109SurvivalSurvival110SurvivalSurvival111Progression–freesurvival

PFSwassignificantlybetterforgroup2thanforgroup1(P＜0.0001)Withnosignificantlydifferencebetweengroup2and3Progression–freesurvivalPFS112Causeofdeath

75%ingroup1,36%ingroup2,33%ingroup3GVHDFungalARDSOrganfailureCauseofdeath75%ingroup1113Causeofdeath

thestudyshowsthattheimprovementisentirelyaresultofalowerTRMduringthelatest5-yearsperiodaGVHDhasnochangedduringthisperoidTherewassignificantdifferenceindeathscausedbyIPandbacterialandfungalinfectionCauseofdeaththestudyshow114ConditioningregimeTBI+MelphalanhasnotprevirousbeenShowntobesuperiortoTBI+CYinthisstudyConditioningregimeTBI+Melph115conclusion

Survival30~60%Treatment–relatedmortality30%conclusionSurvival116MyeloablativeallogeneicversusautologoustransplantationMyeloablativeallogeneic117异基因造血干细胞移植治疗多发性骨髓瘤课件118duringtheyears1983to1994189myelomapatientswhounderwentallo-BMTwithanHLA-identicalsiblingdonorwerecomparedretrospectivelywithanequalnumberofpatientswhoreceivedasingleautologousbonemarroworbloodstemcellgraftAndtheASCTpatientsweretransplantedfrom1986to1994duringtheyears1983to1994119异基因造血干细胞移植治疗多发性骨髓瘤课件120conclusionTheoverallsurvivalwassignificantlybetterforASCTthanforallo-BMT,withamediansurvivalof34monthsand18months,respectively(P=.001),Themainreasonforthepoorersurvivalinallo-BMTpatientswashigherTRM(41%v13%forASCT,P=.0001),whichwasnotcompensatedforbyalowerrateofrelapseandprogression异基因造血干细胞移植治疗多发性骨髓瘤课件121

conclusionHowever,inpatientsaliveat1yearposttransplant,therewasatrendforbetterlong-termsurvival(P=.O9)andsignificantlybetterprogression-freesurvival(P=.02)forallo-BMTascomparedwithASCTWeconcludethatthemediansurvivalissuperiorforASCTHowever,allo-BMThasalowerrelapserate,whichresultsinasimilarlong-termoutcomeforbothapproaches,butalongerfollow-upisneededtoassessthefinaloutcomeconclusion122

Reduced-intensityconditioningallogeneictransplantationReduced-intensitycondition123TheAllo-RICwasintroducedinanattempttodecreasethetransplant-relatedtoxicitywhileretainingthebeneficialGvMeffect1998beginclinicalstudyTheAllo-RICwasintroducedin124异基因造血干细胞移植治疗多发性骨髓瘤课件1251998~2003Wereporttheoutcomeof229patientswhoreceivedanallograftformyelomawithreduced-intensityconditioning(RIC)regimensfrom33centerswithintheEBMT.1998~2003126异基因造血干细胞移植治疗多发性骨髓瘤课件127异基因造血干细胞移植治疗多发性骨髓瘤课件128异基因造血干细胞移植治疗多发性骨髓瘤课件129异基因造血干细胞移植治疗多发性骨髓瘤课件130异基因造血干细胞移植治疗多发性骨髓瘤课件131异基因造血干细胞移植治疗多发性骨髓瘤课件132异基因造血干细胞移植治疗多发性骨髓瘤课件133异基因造血干细胞移植治疗多发性骨髓瘤课件134异基因造血干细胞移植治疗多发性骨髓瘤课件135异基因造血干细胞移植治疗多发性骨髓瘤课件136异基因造血干细胞移植治疗多发性骨髓瘤课件137Withamedianfollow-upof28months,115patientsarealive(range,1-53months)Theestimatedoverallsurvivalat3yearsis40.6%(CI,33%-49%)Thetreatment-relatedmortalitiesatday100,1year,and2yearswere10%,22%,and26%,respectively.Thecumulativeprobabilityoftheprogression-freesurvivalwas21.3%(CI,15%-29%)at3yearsWithamedianfollow-upof28138ConclusionWhileRICisfeasible,heavilypretreatedpatientsandpatientswithprogressivediseasedonotbenefit异基因造血干细胞移植治疗多发性骨髓瘤课件139RICvsMACRICvsMAC140异基因造血干细胞移植治疗多发性骨髓瘤课件141Datawereavailableonatotalof516patientsfrom103centers:320patientswithRICand196withMAC.betweenJanuary1,1998,toDecember31,2002Themedianfollow-upwas28monthsDatawereavailableonatotal142异基因造血干细胞移植治疗多发性骨髓瘤课件143异基因造血干细胞移植治疗多发性骨髓瘤课件144异基因造血干细胞移植治疗多发性骨髓瘤课件145异基因造血干细胞移植治疗多发性骨髓瘤课件146异基因造血干细胞移植治疗多发性骨髓瘤课件147异基因造血干细胞移植治疗多发性骨髓瘤课件148异基因造血干细胞移植治疗多发性骨髓瘤课件149异基因造血干细胞移植治疗多发性骨髓瘤课件150conclusionRICwasassociatedwithareductioninTRM

butthiswasoffsetbyanincreaseinrelapserisktheconditioningintensitydidnotimpactonoverallsurvivalorretainsignificanceforPFSThesedatasuggestthatthereisacontinuingneedtoinvestigatedoseintensityintheconditioningformyelomaallografts.conclusion151Tandemautologous/Allo-RICtransplantation异基因造血干细胞移植治疗多发性骨髓瘤课件152Autologoushematopoieticcelltransplantation(HCT)followedbynonmyeloablativeallogeneicHCT(auto/alloHCT)providescytoreductionandgraft-versus-myelomaeffects.Autologoushematopoieticce153弗雷德哈钦森癌症研究中心弗雷德哈钦森癌症研究中心154

PatientinclusioncriteriaforthisanalysiswerestageIIorIIIMMatdiagnosisavailablehumanleukocyteantigen(HLA)–identicalsiblingdonorprogrammedsequentialtreatmentwithconventionalautologousHCTfollowedbynonmyeloablativeauto/alloHCTnopriorautologousHCT.Patientinclusioncriteria155

105patientswithMMfulfillingthosecriteriaweresequentiallyenrolledat10centerson4FHCRC-coordinatedmultiinstitutionalprotocolsfromAugust1998toAugust2005PatientsproceededtoallogeneicHCT40to180daysafterautografting105patientswithMMfulfill156

AutologousHCT.(G-CSF)mobilizedperipheralbloodmononuclearcells(G-PBMC)wereharvestedbyleukapheresisaftertreatmentwithcyclophosphamide3to4g/m2(day1)andG-CSF10g/kgsubcutaneously(fromday3throughcollection)AutologousHCT.157

AutologousHCT38patientsreceivedadditionalpaclitaxel(250mg/m2perday,day2),and25receivedadditionaletoposide(200mg/m2perday;days1,2,3)anddexamethasone(10mg/dayorally;days1,2,3,4)TwopatientsreceivedG-CSFalone.AutologousHCT158

AutologousHCTNotreatmentforMMwasgivenbetweenautologousandallogeneicHCTAutologousHCT159

AllogeneicHCT

AfterrecoveryfromautologousHCT102patientsproceededtoallotransplantation.DonorswereHLA-identicalsiblingsAllogeneicHCT160

Nonmyeloablativeconditioningconsistedinallpatientsof2Gytotalbodyirradiation(TBI)at7cGy/minbylinearacceleratororcobaltonday027patientsreceivedadditionalfludarabine(30mg/m2)ondays4,3,and2Nonmyeloablativeconditioning161异基因造血干细胞移植治疗多发性骨髓瘤课件162N%N%163

EngraftmentAll102allograftedpatientshadsustainedengraftment.Onday28,mediansof90%,95%,and95%ofperipheralbloodTcells,granulocytes,andnucleatedmarrowcells,respectively,wereofdonororigin.Thisincreasedtomediansof96%to100%onday84Engraftment164GVHD43patients(42%)developedgrades2to4acuteGVHDatamedianof42(range,8-107)days74patients(74%)developedchronicextensiveGVHDatamedianof167(range,90-830)daysaftertransplantation.异基因造血干细胞移植治疗多发性骨髓瘤课件165

NRMNRMwas1%atday100and11%,14%,and18%at1,2,and5yearsafterallografting,respectivelyGVHDandinfectionswereresponsiblefor18of19nonrelapserelateddeaths.NRM166

Overallandprogression-f