多发性骨髓瘤的造血干细胞移植.ppt

1、多发性骨髓瘤的造血干细胞移植 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, et a

2、l. 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 d

3、ata 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 200

4、9 (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、

5、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。,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

6、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,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 Hammers

7、mith Hospital Imperial 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

8、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.,预 处 理,How to improve the efficacy of condition regimens,Melphalan 200mg/m2.the gold standard Melphalan+Busulphan.may

9、 be superior 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 myeloma G Talamo, DF Claxton, DW Dougherty, CW Ehmann, J Sivik, JJ Drabick and W Rybka Bone Mar

10、row Transplant Program, 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 P

11、FS 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 mult

12、iple 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.,移植后的巩固与维持治疗

13、,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. sergno

14、li Institute of Hematology, 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 AS

15、CT 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,Patient Characteristics,.,9,Best Response,.,PFS in High-risk Cytogenetics*,*t (4;14) del (17

16、p),Br J Haematol,2008,140:625634.,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 Borte

17、zomib+Thalidomide+Dex,Patients(n=40) with CR or VGPR following ASCT Treatments: 4 consolidation cycles of Btz-Thal-Dex Results: -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

18、 following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study Christine M. Segeren, Pieter Sonneveld, Bronno van der Holt, et al. Erasmus Medical Center Rotterdam (Erasmus MC) and University Medical Center Utrecht (UMCU) for the Du

19、tch-Belgian Hemato-Oncology 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,Year

20、s,Cumulative Incidence,0,2,4,6,8,10,12,0.0,0.2,0.4,0.6,0.8,1.0,Autologous,Allogeneic,p=0.02,Allogeneic SCT,Advangtages Stem cells Non-contaminated No damage GVM effect,Disadvantages Trx related mortality 20%40% Age cGVHD: 35%70% 356:1110-20.,Non-myeloablative Transplantation,Auto-allo RIC vs Tandem

21、Auto,3 studies(IFM, PETHEMA, HOVON).No benefit 2 studies(GIMEMA, EBMT)significant benefit (EFS, OS) #Differences in patients characteristics, GVHD prophylaxis, 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. Autol

22、ogous 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.,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) Cytog