多发性骨髓瘤的造血干细胞移植.ppt

为什么要移植 不同时间段内多发性骨髓瘤主要年龄组患者的10年生存率 Brenneretal Blood2008 111 2521 2526 P 10 5P 0 07 EFSCRvsnCRorPRnCRvsPR OSCRvsnCRCRvsPRnCRvsPR P 0 01P 10 6P 0 04 Lahuertaetal JCO2008 26 5775 5782 缓解程度与长生存密切相关 无事件生存率 总生存率 BarlogieB etal Cancer 2008 113 355 359 持久CR是长生存的最重要因素 0123456 SUS CR 获得并维持CR状态NON CR 从未获得CR状态LOS CR 获得但失去CR状态 年数 100 80 60 40 20 0 BarlogieB etal Cancer 2008 113 355 359 P value avsb 0 0001 bvsc 0 0001 avsc 0 0001 a b c 以新药为基础的诱导方案的疗效 诱导方案 ASCT能进一步提高新药诱导后的疗效 Post transplantdatanotavailable Harousseauetal ASH ASCOsymposiumduringASH2008Rajkumaretal ASCO2008 Abstract8504 ASH2008 jointASH ASCOsymposium Lokhorstetal Haematologica2008 93 124 127Sonneveldetal ASH2008 Abstract653 IMW Abstract152 Cavoetal ASH2008 Abstract158 IMW2009 Abstract451 新药诱导治疗和ASCT的作用是互补的 而不是作为二选一的治疗手段 以硼替佐米为基础的诱导方案 具有显著性差异 对于IFM2005 01 首次移植后的反应率表示为总体反应率 包含第二次移植反映率 VGPR的反应率在VD组为68 VAD组为47 CR nCR在VD组为39 5 VAD组为22 5 1 HarousseauJL etal JCO2010inpress 2 SonneveldP etal IMW2009 abstract152 移植的时机目前倾向于作为巩固治疗在疾病早期进行 避免在疾病复发时一般情况差 肾功能不全 年龄增加 过多骨骼破坏以及发生MDS的高风险 病人的年龄多限定在65岁以下 但也有超出该年龄病人的报道 肾功能不全不是移植的禁忌症 一般可将马法兰的剂量调整至140mg m2 如病人有低蛋白血症 可将马法兰的剂量进一步调整至70 100mg m2 KumaretalASH2009 Abstr956 复发前和复发后进行ASCT疗效相同 IFM DFCL2009 ASCT在复发前还是在复发后进行 VRD 3 StemCollection ASCT VRD 2 R 12m 小结 患者的生存与缓解程度有关化疗可以提高缓解率及缓解程度二次移植优于单次移植新药的应用可以进一步提高疗效早期与晚期移植的疗效相似 干细胞动员的问题 HighrateofstemcellmobilizationfailureafterthalidomideandoralcyclophosphamideinductiontherapyformultiplemyelomaHWAuner LMazzarella LCook RSzydlo FSaltarelli JPavlu MBua CGiles JFApperleyandARahemtullaDepartmentofHaematologyHammersmithHospitalImperialCollegeHealthcareNHSTrust London UK BoneMarrowTransplantation 2010 1 4 epub Figure1InductiontherapywithCYandthalidomidewithdexamethasone CTD impairsthestemcellcollectionyieldandincreasesthenumberofapheresisproceduresrequired a BarsshowthemediannumberofCD34tcells kgcollectedoverall onthefirstapheresisday andperapheresisprocedure b BarsshowthepercentageofpatientsundergoingX2apheresisprocedures 预处理 Howtoimprovetheefficacyofconditionregimens Melphalan200mg m2 thegoldstandardMelphalan Busulphan maybesuperiorMelphalan Bortezomib 70 VGPR 35 CR 1mg m2D 6 3 1 4 Melphalan Bortezomib 53 VGPR 1 3mg m2D 1or 1 BUandCYasconditioningregimenforautologoustransplantinpatientswithmultiplemyelomaGTalamo DFClaxton DWDougherty CWEhmann JSivik JJDrabickandWRybkaBoneMarrowTransplantProgram PennStateMiltonSHersheyCancerInstitute Hershey PA USA BoneMarrowTransplantation 2009 44 157 161 Figure1OSofmultiplemyelomapatientstreatedwiththeBU CYregimenandASCT n79 fromday0ofASCT Thinlinesindicatethe95 confidenceinterval Figure2PFSofmultiplemyelomapatientstreatedwiththeBU CYregimenandASCT n79 fromday0ofASCT Thinlinesindicatethe95 confidenceinterval Figure3PFSofmultiplemyelomapatientstreatedwithoral n13 continuousline vsi v BU n66 dottedline fromday0ofASCT Figure4OSofmultiplemyelomapatientstreatedwiththeBU CYregimenandASCTcarriedout upfront thatis infirstremission n62 continuousline vsASCTcarriedoutas salvagetherapy thatis ondiseaseprogression relapse n17 dottedline SurvivaliscalculatedfromthetimeofMMdiagnosis 移植后的巩固与维持治疗 2009ASHAbstract351 APhase StudyofDoubleAutotransplantationIncorporatingBortezomib Thalidomide Dexamethasone VTD orThalidomide Dexamethasone TD forMultipleMyeloma SuperiorClinicalOutcomeswithVTDComparedtoTDMicheleCabvo PaolaTacchetti FrancescaPatriarca etal sergnoliInstituteofHematology BolognaUniversitySchoolofMedicine Bologna ItalyItalianMyelomaNetworkGIMEMA Italy StudyDesign REGISTRATION Thalidomide DexT100 200mgpodays1 21 D40mgdays1 2 4 5 8 9 11 12q21x3cycles Bortezomib t DB1 3mg days1 4 8 11 Q21x3cycles DoubleASCTMelphalan200mg TDConsolidationT100mgpodays1 35 D320mgpercycleq35x2cycles VTDConsolidationB1 3mg days1 8 1522q35 T100mgpodays1 35 D320mgpercycleQ35 Bx2cycles MaintenanceDex PatientCharacteristics 9 BestResponse PFSinHigh riskCytogenetics t 4 14 del 17p BrJHaematol 2008 140 625 634 Mel干细胞回输G CSFVVVV 6 3 20 1 4 7 V 万珂1 0 1 3mg m2Mel 马法兰200mg m2 万珂 马法兰用于ASCT预处理的研究 缓解率CR 31 VGPR 46 CR VGPR 77 历史对照 常规HDM预处理 ASCT后的CR VGPR 40 50 Rousseletal Hematology2006 91 suppl 1 p98 EHA2006 abs0233 ConsolidationwithBortezomib Thalidomide Dex Patients n 40 withCRorVGPRfollowingASCTTreatments 4consolidationcyclesofBtz Thal DexResults 36 convertedfromVGPRtoCR Sixpatients 15 achievedMolecularRemission 清髓性异基因移植 Overallandevent freesurvivalarenotimprovedbytheuseofmyeloablativetherapyfollowingintensifiedchemotherapyinpreviouslyuntreatedpatientswithmultiplemyeloma aprospectiverandomizedphase3studyChristineM Segeren PieterSonneveld BronnovanderHolt etal ErasmusMedicalCenterRotterdam ErasmusMC andUniversityMedicalCenterUtrecht UMCU fortheDutch BelgianHemato OncologyCooperativeStudyGroup HOVON TheNetherlands BLOOD 2003 101 6 2144 51 TTP OS MyeloablativeBMT OverallSurvival Years Proportion 0 2 4 6 8 10 12 0 0 0 2 0 4 0 6 0 8 1 0 Allogeneic Autologous p 0 006 CausesofTreatmentFailure CumulativeIncidenceofRelapse Years CumulativeIncidence 0 2 4 6 8 10 12 0 0 0 2 0 4 0 6 0 8 1 0 Autologous Allogeneic p 0 02 AllogeneicSCT AdvangtagesStemcellsNon contaminatedNodamageGVMeffect DisadvantagesTrxrelatedmortality 20 40 Age Donoravailablity10 candidates Highmortalitywithconventionalallo hasfavoredtheReducedIntensityConditioningregimens RIC ButtheTRMisstill10 20 cGVHD 35 70 morerelapses extramedullary toovercomerelapses TandemAuto Allo program 序贯自体 非清髓移植 AllogenicHematopoieticStem cellTransplantationWithReduced intensityConditioninginPatientsWithRefractoryandRecurrentMultipleMyelomaLong TermFollow UpAvichaiShimoni IzharHardan FrancisAyuk GeorgiaSchilling DjordeAtanackovic WolfgangZeller RonitYerushalmi AxelRolfZander NicolausKroger andArnonNaglerDepartmentofBoneMarrowTransplantation ChaimShebaMedicalCenter Tel Hashomer IsraelDepartmentofBoneMarrowTransplantation UniversityHospitalHamburg Hamburg Germany Cancer 2010 epub os PFS AComparisonofAllograftingwithAutograftingforNewlyDiagnosedMyelomaBrunoB RottaM PatriarcaF etal SanGiovanniBattistaHospitalUniversityofTurintUniversityofUdine Udine NEnglJMed2007 356 1110 20 Non myeloablativeTransplantation Auto alloRICvsTandemAuto 3studies IFM PETHEMA HOVON Nobenefit2studies GIMEMA EBMT significantbenefit EFS OS Differencesinpatientscharacteristics GVHDprophylaxis conditioningregimensmayexplainthesediscrepantresults 异基因移植的优势 AllogeneicBoneMarrowTransplantationforMultipleMyeloma AssociatedwithhighcompleteresponseratesDurablemolecularremissionsarenotedinsomepatientsTwoadvantageswhichmayreducetheriskofrelapseafterallogeneictransplantcomparedwithautologoustransplantare infusionofatumorfreestemcellproductgraftversusmyelomaeffectHighdoseconventionalallogeneictransplantationisassociatedwithahightreatmentrelatedmortality upto50 insomestudies EvidenceforaGraftversusMyeloma GVM Effect DelayeddisappearanceofresidualdiseaseafterallogeneicBMTinsomepatientsDecreasedrateofrelapseafterallogeneicBMTcomparedwithautologousBMT40 80 overallresponserateinpatientswithrelapsedmultiplemyelomaafterdonorlymphocyteinfusion ResponsetoCD4 DLIN 12 PreDLIMaximalResponseCurrentstatus9 persistentor6CR5CR 1RelapseProgressivedisease3PR2relapse3 CR 2CR 1relapse 浆细胞白细胞的移植 Primaryplasmacellleukemiaandautologousstemcelltransplantation haematologica 2010 95 5 804 9 Primaryplasmacellleukemia PCL lessthan5 ofmalignantPCD Ithasapoorprognosis mediansurvivalof8 12months Autologousstemcelltransplantationmayimprovesurvival Aretrospectiveanalysis EuropeanGroupforBloodandMarrowTransplantation 272patientsPCLand20844withMMundergoingfirsta