1、多发性骨髓瘤的造血干细胞移植陈文明首都医科大学附属北京朝阳医院 北京市多发性骨髓瘤医疗研究中心,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,P10 -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 P10 -6 P=0.04,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 %,Barlogie B, e
2、t al. Cancer. 2008;113:355359. .,持久CR是长生存的最重要因素,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 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-transplant da
3、ta not available,Harousseau et al. ASH/ASCO symposium during ASH 2008 Rajkumar et al. ASCO 2008 (Abstract 8504); ASH 2008 (joint ASH/ASCO symposium),Lokhorst et al. Haematologica 2008;93:124127 Sonneveld et al. ASH 2008 (Abstract 653); IMW (Abstract 152) Cavo et al. ASH 2008 (Abstract 158); IMW 2009
4、 (Abstract 451),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.Harousseau JL, et al. JCO 2010 in press. 2. Sonneveld P, et al. IMW 2009:abstract 152.,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
5、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。,Kumar et al ASH2009 (Abstr 956）,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,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
6、疗效早期与晚期移植的疗效相似,干细胞动员的问题,High rate of stem cell mobilization failure after thalidomide and oral cyclophosphamide induction therapy for multiple myelomaHW Auner, L Mazzarella, L Cook, R Szydlo, F Saltarelli, J Pavlu, M Bua, C Giles, JF Apperley and A RahemtullaDepartment of HaematologyHammersmith Hosp
7、italImperial College Healthcare NHS Trust, London, UK,Bone Marrow Transplantation (2010), 14,epub,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 num
8、ber 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.,预 处 理,How to improve the efficacy of condition regimens,Melphalan 200mg/m2the gold standardMelphalan+Busulphan.may be superior
9、Melphalan+Bortezomib70%VGPR(35%CR)(1mg/m2 D-6 -3 +1 +4)Melphalan+Bortezomib53%VGPR(1.3mg/m2 D-1 or +1),BU and CY as conditioning regimen for autologous transplant in patients with multiple myelomaG Talamo, DF Claxton, DW Dougherty, CW Ehmann, J Sivik, JJ Drabick and W RybkaBone Marrow Transplant Pro
10、gram, Penn State Milton S Hershey Cancer Institute, Hershey, PA, USA,Bone Marrow Transplantation (2009) 44, 157161,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 mye
11、loma 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 patie
12、nts 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.,移植后的巩固与维持治疗,2009 ASH Abstract
13、 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 TDMichele Cabvo, Paola Tacchetti, Francesca Patriarca, et al.sergnoli Institute of Hema
14、tology, Bologna University School of Medicine, Bologna, Italy Italian Myeloma Network GIMEMA, Italy,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/
15、,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,Patient Characteristics,.,9,Best Response,.,PFS in High-risk Cytogenetics*,*t (4;14) del (17p),Br J Haematol,200
16、8,140:625634.,Mel 干细胞回输 G-CSF V V V V,-6 -3 -2 0 +1 +4 +7,V= 万珂 1.0-1.3mg/m2 Mel = 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=4050%）,Rousselet al. Hematology 2006;91 (suppl .1),p98.EHA 2006,abs 0233#,Consolidation with Bortezomib+Thalidomide+De
17、x,Patients(n=40) with CR or VGPR following ASCTTreatments: 4 consolidation cycles of Btz-Thal-DexResults:-36% converted from VGPR to CR -Six patients(15%) achieved Molecular Remission,清髓性异基因移植,Overall and event-free survival are not improved by the use of myeloablative therapy following intensified
18、chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 studyChristine M. Segeren, Pieter Sonneveld, Bronno van der Holt, et al.Erasmus Medical Center Rotterdam (Erasmus MC) and University Medical Center Utrecht (UMCU) for the Dutch-Belgian Hemato-Oncolo
19、gy Cooperative Study Group (HOVON), The Netherlands,BLOOD, 2003 , 101( 6):2144-51,TTP,OS,Myeloablative BMT,Overall Survival,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,Causes of Treatment Failure,Cumulative Incidence of Relapse,Years,Cumulative Incidence,0,
20、2,4,6,8,10,12,0.0,0.2,0.4,0.6,0.8,1.0,Autologous,Allogeneic,p=0.02,Allogeneic SCT,AdvangtagesStem cellsNon-contaminatedNo damageGVM effect,DisadvantagesTrx related mortality 20%40%Age&Donor availablity10% candidates,High mortality with conventional allohas favored the Reduced Intensity Conditioning
21、regimens (RIC) But the TRM is still 10%20%; cGVHD: 35%70% & more relapses (extramedullary) to overcome relapses: “Tandem Auto-Allo” program,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
22、-Term Follow-UpAvichai Shimoni, Izhar Hardan, Francis Ayuk, Georgia Schilling, Djorde Atanackovic, Wolfgang Zeller, Ronit Yerushalmi, Axel Rolf Zander, Nicolaus Kroger, and Arnon NaglerDepartment of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel Department of Bone Marr
23、ow Transplantation, University Hospital Hamburg, Hamburg, Germany,Cancer,2010,epub,os,PFS,A Comparison of Allografting with Autografting for Newly Diagnosed MyelomaBruno B, Rotta M, Patriarca F, et al.San Giovanni Battista Hospital University of TurintUniversity of Udine, Udine,N Engl J Med 2007;356
24、:1110-20.,Non-myeloablative Transplantation,Auto-allo RIC vs Tandem Auto,3 studies(IFM, PETHEMA, HOVON)No benefit2 studies(GIMEMA, EBMT)significant benefit (EFS, OS)#Differences in patients characteristics, GVHD prophylaxis, & conditioning regimens may explain these discrepant results.,异基因移植的优势,Allo
25、geneic 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 fr
26、ee stem cell productgraft versus myeloma effect High dose conventional allogeneic transplantation is associated with a high treatment related mortality, up to 50% in some studies,Evidence for a Graft versus Myeloma (GVM) Effect,Delayed disappearance of residual disease after allogeneic BMT in some p
27、atientsDecreased rate of relapse after allogeneic BMT compared with autologous BMT40%-80% overall response rate in patients with relapsed multiple myeloma after donor lymphocyte infusion,Response to CD4+ DLI N=12,Pre DLI Maximal Response Current status9-persistent or 6 CR 5 CR-1 Relapse Progressive
28、disease 3 PR 2 relapse3-CR - 2 CR-1 relapse,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 cel
29、l 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.,mSMART2.0: Classification of Active MM,3 years 5 years 7-10 years,FISHDel 17Pt(1
30、4:16)t(14:20)GEPHigh risksignature,FISHt(4:14)Cytogeneticdeletion 13 orhypodiploidPCLI3%,All others including:Hyperdiploidt(11:14)t(6:14),High-Risk Intermediate-Risk Standard-Risk,mSMART2.0: Treatment of Active MM,High-Risk Intermediate-Risk Standard-Risk,Novel approachesNew drugs”TT3 like” approach
31、 for p53 deletion?,Bortezomib based combinationHDM+/-consolidationLenalidomidemaintenanceTargeted therapy,Regimen which provides a high ORR and which minimizes early toxicity HDM could be delayed in patients achieving CRLenalidomidemaintenance,新型药物作为诱导治疗用于适合移植者,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,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。,
