,单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,多发性骨髓瘤的造血干细胞移植,多发性骨髓瘤的造血干细胞移植,为什么要移植？,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,Brenner et al;Blood 2008;111:2521-2526,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Bre,P,10,-5,P,=0.07,EFS,CR vs nCR or PR,nCR vs PR,OS,CR vs nCR,CR vs PR,nCR vs PR,P,=0.01,P,10,-6,P,=0.04,月数,月数,CR, n=278 nCR, n=124 PR, n=280 PD, n=25,Lahuerta,et al,.,JCO,2008;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,%,P10 -5 EFS OS P=0.01,Barlogie B, et al.,Cancer. 2008;113:355359.,.,持久,CR,是长生存的最重要因素,生存率,0 1 2 3 4 5 6,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%,Barlogie B, et al.,Cancer. 2008;113:355359.,.,P-,value: a vs b0.0001,b vs c 0.0001,a vs c VGPR,38 vs 15,*,33 vs 12*,PR,78.5 vs 63*,80 vs 64*,ASCT,后反应，,%,CR,16 vs 9*,15 vs 4*,VGPR,54 vs 37*,59 vs 47*,PR,80 vs 77,92 vs 77*,*,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.Harousseau JL, et al. JCO 2010 in press. 2. Sonneveld P, et al. IMW 2009:abstract 152.,以硼替佐米为基础的诱导方案IFM2005-01HOVON-G,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。,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,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/m,2,;,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/m,2,。,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。,Kumar et al ASH2009 (Abstr 956,）,VRD5,Stem Collection,R12m,ASCT at relapse,VRD3,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？,VRD3,Stem Collection,ASCT,VRD2,R12m,Kumar et al ASH2009 (Abstr 956,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,小结患者的生存与缓解程度有关,干细胞动员的问题,干细胞动员的问题,High rate of stem cell mobilization failure after thalidomide and oral cyclophosphamide induction therapy for multiple myeloma,HW Auner, L Mazzarella, L Cook, R Szydlo, F Saltarelli,J Pavlu, M Bua, C Giles, JF Apperley and A Rahemtulla,Department of Haematology,Hammersmith Hospital,Imperial College Healthcare NHS Trust, London, UK,Bone Marrow Transplantation (2010), 14,epub,High rate of stem cell mobiliz,多发性骨髓瘤的造血干细胞移植课件,Figure 1 Induction therapy with CY and thalidomide with dexamethasone (CTD) impairs the stem cell collection yield and increases the number of apheresis procedures required. (a) Bars show the median number of CD34tcells/kg collected overall, on the first apheresis day, and per apheresis procedure. (b) Bars show the percentage of patients undergoing X2 apheresis procedures.,Figure 1 Induction therapy wit,多发性骨髓瘤的造血干细胞移植课件,预 处 理,预 处 理,How to improve the efficacy of condition regimens,Melphalan 200mg/m2,.the gold standard,Melphalan+Busulphan,.may be superior,Melphalan+Bortezomib,70%VGPR(35%CR),(1mg/m2 D-6 -3 +1 +4),Melphalan+Bortezomib,53%VGPR,(1.3mg/m2 D-1 or +1),How to improve the efficacy of,BU and CY as conditioning regimen for autologous transplant in patients,with multiple myeloma,G Talamo, DF Claxton, DW Dougherty, CW Ehmann,J Sivik, JJ Drabick and W Rybka,Bone Marrow Transplant Program, Penn State Milton S Hershey Cancer Institute, Hershey, PA, USA,Bone Marrow Transplantation (2009) 44, 157161,BU and CY as conditioning regi,多发性骨髓瘤的造血干细胞移植课件,Figure 1 OS of multiple myeloma patients treated with the BU/CY regimen and ASCT (n79), from day 0 of ASCT. Thin lines indicate the 95% confidence interval.,Figure 2 PFS of multiple myeloma patients treated with the BU/CY regimen and ASCT (n79), from day 0 of ASCT. Thin lines indicate the 95% confidence interval,Figure 3 PFS of multiple myeloma patients treated with oral (n13, continuous line) vs i.v. BU (n66, dotted line), from day 0 of ASCT.,Figure 4 OS of multiple myeloma patients treated with the BU/CY regimen and ASCT carried out upfront, that is, in first remission (n62, continuous line), vs ASCT carried out as salvage therapy, that is, on disease progression/relapse (n17, dotted line). Survival is calculated from the time of MM diagnosis.,Figure 1 OS of multiple myelom,移植后的巩固与维持治疗,移植后的巩固与维持治疗,2009 ASH Abstract 351,A Phase Study of Double Autotransplantation Incorporating Bortezomib- Thalidomide- Dexamethasone (VTD) or Thalidomide- Dexamethasone (TD) for Multiple Myeloma: Superior Clinical Outcomes with VTD Compared to TD,Michele Cabvo, Paola Tacchetti, Francesca Patriarca, et al.,sergnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy,Italian Myeloma Network GIMEMA, Italy,2009 ASH Abstract 351A Phase ,Study Design,.,REGISTRATION,Thalidomide +Dex,T 100-200 mg po days,1-21/D 40mg days 1,2,4,5,8,9,11,12q21x3 cycles,Bortezomib + t + D,B 1.3 mg/ days 1,4,8,11,Q21x3 cycles,Double ASCT,Melphalan 200 mg/,TD Consolidation,T 100mg po days 1-35/D,320mg per cycle q35x2,cycles,VTD Consolidation,B 1.3mg/ days 1,8,15,22q35/T 100mg po days,1-35/D 320mg per cycle,Q35, B x 2 cycles,Maintenance,Dex,Study Design.REGISTRATIONThali,Patient Characteristics,.,VTD(n=241),TD(n=239),Age (years),56.336.88,55.867.41,Stage ISS(%) ,+,107(44),134(56),107(45),132(55),2,-MG (mg/L),3.812.48,3.832.14,Albumin (g/dL),3.830.64,4.173.97,Creatinine (mg/dL),1.010.30,1.010.31,Hb (g/dL),11.101.91,11.241.96,Plts (X10 /L),243.6989.06,235.8678.04,BMPC meanSD(%),52.4223.19,52.7824.15,Genetic abnormalities(by FISH in 93% of pts),Del(13q) pos (%) del(13q) alone,t(4:14) pos (%),del (17p) pos (%),4730,18,7,4626,20,8,9,Patient Characteristics.VTD(n=,Best Response,.,VTD(%),TD(%),P,CR,57.20,31.07,0.0001,CR+ nCR,69.91,51.23,0.0001,VGPR,87.71,72.26, 20%40%,Age&Donor availablity,10% candidates,High mortality with conventional allohas favored the,Reduced Intensity Conditioning regimens (RIC) ,But the TRM is still 10%20%; cGVHD: 35%70% & more relapses (extramedullary), to overcome relapses: “Tandem Auto-Allo” program,Allogeneic SCT Advang,序贯自体,-,非清髓移植,序贯自体-非清髓移植,Allogenic Hematopoietic Stem-cell Transplantation With Reduced-intensity Conditioning in Patients With Refractory and Recurrent Multiple Myeloma,Long-Term Follow-Up,Avichai Shimoni, Izhar Hardan, Francis Ayuk, Georgia Schilling, Djorde Atanackovic, Wolfgang Zeller, Ronit Yerushalmi, Axel Rolf Zander, Nicolaus Kroger,and Arnon Nagler,Department of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel,Department of Bone Marrow Transplantation,University Hospital Hamburg, Hamburg, Germany,Cancer,2010,epub,Allogenic Hematopoietic Stem-c,os,PFS,osPFS,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,A Comparison of Allografting with Autografting for Newly Diagnosed Myeloma,Bruno B, Rotta M, Patriarca F, et al.,San Giovanni Battista Hospital,University of Turin,tUniversity of Udine, Udine,N Engl J Med 2007;356:1110-20.,A Comparison of Allografting w,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,Non-myeloablative Transplantation,Author,Conditioning,regimen,GVHD regimen,N,(URD),Prior,Auto,TRM,%,CR,%,Gr 2-4 aGVHD %,Chronic,GVHD %,OS %,(yrs),Kroger,Mel100/Flu/ATG,CSA/MTX,17 (8),17,18,73,38,7,74 (2),Kroger,Mel100-140/Flu/ATG,CSA/MTX,21 (21),9,24,40,38,12,74 (2),Mohty,Bu/Flu/ATG,CSA,MTX,41 (NR),0,17,24,36,41,62 (2),Peggs,TBI/Flu/Alemtuzumab,CSA/MMF,20 (8),0,15,10,25,NR,71 (2),Maloney,TBI-2Gy/Flu,CSA/MMF,54 (0),54,22,57,45,60,69 (4),Gerull,TBI-2Gy/Flu,CSA/MMF,52 (20),0,17,27,37,70,41 (1.5),Hoepfner,TBI-2Gy/Flu,CSA/MMF,19 (6),0,32,NR,37,NR,50 (2),Ma,TBI-3Gy/Flu,CSA/MMF,10 (0),0,0,30,60,40,100 (1),Galimberti,TBI-2Gy/Flu; Flu/Cy,CSA/MMF,20 (0),20,20,35,25,30,58 (2),Einsele,TBI-2Gy/Flu/Cy,CSA/MMF/ATG,22 (15),0,23,27,38,32,26 (2),Lee,TBI-2Gy/Flu/ Mel100,CSA,45 (12),12,38,64,58,13,36 (3),Giralt,Mel/Flu,FK/MTX,22 (9),0,41,32,46,27,30 (2),Perez-Simon,Mel/Flu,CSA/MTX,29 (NR),10,21,28,41,51,60 (2),Non-myeloablative Transplantat,Auto-allo RIC vs Tandem Auto,3 studies(IFM, PETHEMA, HOVON).No benefit,2 studies(GIMEMA, EBMT),significant benefit (EFS, OS),#Differences in patients characteristics, GVHD prophylaxis, & conditioning regimens may explain these discrepant results.,Auto-allo RIC vs Tandem Auto3,异基因移植的优势,异基因移植的优势,Allogeneic Bone Marrow Transplantation for Multiple Myeloma,Associated with,high complete response rates,Durable molecular remissions,are noted in some patients,Two advantages which may reduce the risk of relapse after allogeneic transplant compared with autologous transplant are:,infusion of a tumor free stem cell product,graft versus myeloma effect,High dose conventional allogeneic transplantation is associated with a,high treatment related mortality, up to 50% in some studies,Allogeneic Bone Marrow Transpl,Evidence for a Graft versus Myeloma (GVM) Effect,Delayed disappearance of residual disease,after allogeneic BMT in some patients,Decreased rate of relapse,after allogeneic BMT compared with autologous BMT,40%-80% overall response rate in patients with relapsed multiple myeloma after,donor lymphocyte infusion,Evidence for a Graft versus M,Response to CD4+ DLI,N=12,Pre DLI Maximal Response Current status,9-persistent or 6 CR 5 CR-1 Relapse,Progressive disease 3 PR 2 relapse,3-CR - 2 CR-1 relapse,Response to CD4+ DLIN=12Pre D,浆细胞白细胞的移植,浆细胞白细胞的移植,Primary plasma cell leukemia and,autologous stem cell transplantation,haematologica | 2010; 95(5):804-9,Primary plasma cell leukemia(PCL): less than 5% of malignant PCD.,It has a poor prognosis, median survival of 8-12 months.,Autologous stem cell transplantation may improve survival.,A retrospective analysis(European Group for Blood and Marrow Transplantation):,272 patients PCL and 20844 with MM undergoing first autologous transplantation between 1980 and 2006.,Primary plasma cell leukemia a,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,多发性骨髓瘤的造血干细胞移植课件,mSMART2.0: Classification of Active MM,3 years 5 years 7-10 years,FISH,Del 17P,t(14:16),t(14:20),GEP,High risk,signature,FISH,t(4:14),Cytogenetic,deletion 13 or,hypodiploid,PCLI,3%,All others including:,Hyperdiploid,t(11:14),t(6:14),High-Risk Intermediate-Risk Standard-Risk,mSMART2.0: Classification of A,mSMART2.0: Treatment of Active MM,High-Risk Intermediate-Risk Standard-Risk,Novel approaches,New drugs,”TT3 like” approach,for p53 deletion?,Bortezomib based,combination,HDM+/-consolidation,Lenalidomide,maintenance,Targeted therapy,Regimen which,provides a high ORR,and which minimizes,early toxicity,HDM could be,delayed in patients,achieving CR,Lenalidomide,maintenance,mSMART2.0: Treatment of Active,新型药物作为诱导治疗用于适合移植者,硼替佐米,Vel+Dex,PAD,VCD,雷利度胺,RD,Rd,RAD,沙利度胺,Thal+Dex,TAD,CTD,常规,VAD,ID,CY+Dex,VTD,RVD,干细胞采集,高剂量的美法仑,干细胞回输,CY=,环磷酰胺；,Rd=,来那度胺,+,低剂量地塞米松；,RD=,雷利度胺,+,标准剂量地塞米松,新型药物作为诱导治疗用于适合移植者硼替佐米Vel+Dex雷利,结 论,1,造血干细胞移植是治疗,MM,有效手段之一；,2,移植优于单纯化疗；二次移植优于单次移植；,3,诱导治疗中加入新药，大部分病人可能不需要二次移植；,4,清髓性移植有可能清除微小残留病；但移植相关死亡率高；,5 NST,可降低,TRM,但疗效有限；,6,移植后用新药维持治疗，可能提高疗效。,结 论,