多发性骨髓瘤的造血干细胞移植

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1、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 首都医科大学附属北京朝阳医院首都医科大学附属北京朝阳医院首都医科大学附属北京朝阳医院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北京市多发性骨髓瘤医疗研究中心北京市多发性骨髓瘤医疗研究中心北京市多发性骨髓瘤医疗研究中心为什么要移植？为什么要移植？不同时间段内多发性骨髓瘤不同时间段内多发性骨髓瘤不同时间段内多发性骨髓瘤不同时间段内多发性骨髓瘤主要年龄组患者的主要年龄组患者的主要年龄组患者的主要年龄组患者的1010年生存率年生存率年生存率年生存率Brenner et al;Blood 2008;111:2521-2526P P

2、1010 -5-5 P P=0.07 =0.07 EFS EFS CR vs nCR or CR vs nCR or PR PR nCR vs PR nCR vs PR OSOS CR vs nCR CR vs nCR CR vs PR CR vs PR nCR vs PR nCR vs PR P P=0.01 =0.01 P P10 10 -6-6 P P=0.04 =0.04 月数月数月数月数 月数月数月数月数CR, n=278 nCR, n=124 PR, n=280 PD, CR, n=278 nCR, n=124 PR, n=280 PD, n=25 n=25 LahuertaLah

3、uerta et al et al. . JCO JCO 2008;26:5775-5782 2008;26:5775-5782 缓解程度与长生存密切相关无无事事件件生生存存率率%总总生生存存率率%Barlogie B, et al. Cancer. 2008;113:355359. . 持久持久CRCR是长生存的最重要因素是长生存的最重要因素生存率生存率0 1 2 3 4 5 0 1 2 3 4 5 6 6 SUS-CR:SUS-CR: 获获得并得并得并得并维维持持持持CRCR状状状状态态 NON-CR:NON-CR: 从未从未从未从未获获得得得得CRCR状状状状态态 LOS-CR:LOS-

4、CR: 获获得但失去得但失去得但失去得但失去CRCR状状状状态态 年数年数 100% 100% 80%80%60%60%40%40%20%20%0%0%Barlogie B, et al. Cancer. 2008;113:355359. . P-value: a vs b0.0001, b vs c 0.0001, a vs c VGPR VGPR 38 38 vsvs 15 15* *33 33 vsvs 12* 12*PR PR 78.5 78.5 vsvs 63* 63*80 80 vsvs 64* 64*ASCTASCT后反应，后反应，后反应，后反应，%CRCR16 16 vsvs

5、9* 9*15 15 vsvs 4* 4*VGPR VGPR 54 54 vsvs 37* 37*59 59 vsvs 47* 47*PR PR 80 80 vsvs 77 7792 92 vsvs 77* 77*具有显著性差异具有显著性差异*对于对于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。，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的反应率在的反应率在VD组为组为68%，VAD组为组为47%；CR/nCR在在VD组为组为39.5%，VAD组为组为22.5%。1.Harousseau JL, et al. JCO 2010 in

6、 press. 2. Sonneveld P, et al. IMW 2009:abstract 152.n n移植的时机移植的时机移植的时机移植的时机目前倾向于作为巩固治疗在目前倾向于作为巩固治疗在目前倾向于作为巩固治疗在目前倾向于作为巩固治疗在疾病早期疾病早期疾病早期疾病早期进行进行进行进行，避免在疾病复发时一般情况差、肾功能不，避免在疾病复发时一般情况差、肾功能不，避免在疾病复发时一般情况差、肾功能不，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全、年龄增加、过多骨骼破坏以及发生全、年龄增加、过多骨骼破坏以及发生全、年龄增加、过多骨骼破坏以及发生MDSMDSMD

7、SMDS的高风的高风的高风的高风险。险。险。险。 n n病人的年龄多限定在病人的年龄多限定在病人的年龄多限定在病人的年龄多限定在6565岁以下，但也有超出岁以下，但也有超出岁以下，但也有超出岁以下，但也有超出该年龄病人的报道。该年龄病人的报道。该年龄病人的报道。该年龄病人的报道。n n肾功能不全肾功能不全肾功能不全肾功能不全不是移植的禁忌症，一般可将马法不是移植的禁忌症，一般可将马法不是移植的禁忌症，一般可将马法不是移植的禁忌症，一般可将马法兰的剂量调整至兰的剂量调整至兰的剂量调整至兰的剂量调整至140mg/m140mg/m2 2; ; ; ;如病人有如病人有如病人有如病人有低蛋低蛋低蛋低蛋白

8、血症白血症白血症白血症，可将马法兰的剂量进一步调整至，可将马法兰的剂量进一步调整至，可将马法兰的剂量进一步调整至，可将马法兰的剂量进一步调整至70-70-100mg/m100mg/m2 2。 Kumar et al ASH2009 (Abstr 956） ）VRD5Stem CollectionR12mASCT at relapseVRD3复发前和复发后进行复发前和复发后进行ASCTASCT疗效相同疗效相同IFM-DFCL2009ASCT 在复发前还是在复发后进行？ n nVRD3VRD3Stem CollectionASCTVRD2R12m小结小结n n患者的生存与缓解程度有关患者的生存与缓

9、解程度有关患者的生存与缓解程度有关患者的生存与缓解程度有关n n化疗可以提高缓解率及缓解程度化疗可以提高缓解率及缓解程度化疗可以提高缓解率及缓解程度化疗可以提高缓解率及缓解程度n n二次移植优于单次移植二次移植优于单次移植二次移植优于单次移植二次移植优于单次移植n n新药的应用可以进一步提高疗效新药的应用可以进一步提高疗效新药的应用可以进一步提高疗效新药的应用可以进一步提高疗效n n早期与晚期移植的疗效相似早期与晚期移植的疗效相似早期与晚期移植的疗效相似早期与晚期移植的疗效相似 干细胞动员的问题干细胞动员的问题High rate of stem cell mobilization failur

10、e 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 Haematology Hammersmith Hospital Imperial College Healthcare NHS Trust, London, UKBone Marrow

11、 Transplantation (2010), 14,epubFigure 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

12、, and per apheresis procedure. (b) Bars show the percentage of patients undergoing X2 apheresis procedures.预预 处处 理理How to improve the efficacy of condition regimensn nMelphalan 200mg/m2.the gold standardMelphalan 200mg/m2.the gold standardn nMelphalan+BusulphanMelphalan+Busulphan.may be superior.may

13、 be superiorn nMelphalan+BortezomibMelphalan+Bortezomib70%70%VGPR(35%CR)VGPR(35%CR) (1mg/m2 D-6 -3 +1 +4) (1mg/m2 D-6 -3 +1 +4)n nMelphalan+BortezomibMelphalan+Bortezomib53%53%VGPRVGPR (1.3mg/m2 D-1 or +1) (1.3mg/m2 D-1 or +1)BU and CY as conditioning regimen for autologous transplant in patientswit

14、h multiple myelomaG Talamo, DF Claxton, DW Dougherty, CW Ehmann, J Sivik, JJ Drabick and W RybkaBone Marrow Transplant Program, Penn State Milton S Hershey Cancer Institute, Hershey, PA, USABone Marrow Transplantation (2009) 44, 157161Figure 1 OS of multiple myeloma patients treated with the BU/CY r

15、egimen 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 intervalFigure 3 PFS of multiple myeloma patients treated wit

16、h 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 progre

17、ssion/relapse (n17, dotted line). Survival is calculated from the time of MM diagnosis.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 351A Phase A Phase Study of Double Study of Double AutotransplantationAutotransplantation Incorporating Incorporating BortezomibBortezomib- Thalidomide- - Thalidomide- Dexam

18、ethasoneDexamethasone (VTD) or Thalidomide- (VTD) or Thalidomide- DexamethasoneDexamethasone (TD) for (TD) for Multiple Myeloma: Superior Clinical Multiple Myeloma: Superior Clinical Outcomes with VTD Compared to TDOutcomes with VTD Compared to TDMichele Michele CabvoCabvo, Paola , Paola TacchettiTa

19、cchetti, Francesca , Francesca PatriarcaPatriarca, et al., et al.sergnolisergnoli Institute of Hematology, Bologna University School of Institute of Hematology, Bologna University School of Medicine, Bologna, ItalyMedicine, Bologna, ItalyItalian Myeloma Network GIMEMA, ItalyItalian Myeloma Network G

20、IMEMA, ItalyStudy Design. .REGISTRATIONThalidomide +DexT 100-200 mg po days1-21/D 40mg days 1,2,4,5,8,9,11,12q21x3 cyclesBortezomib + t + DB 1.3 mg/ days 1,4,8,11,Q21x3 cyclesDouble ASCTMelphalan 200 mg/TD ConsolidationT 100mg po days 1-35/D320mg per cycle q35x2cyclesVTD ConsolidationB 1.3mg/ days 1

21、,8,1522q35/T 100mg po days1-35/D 320mg per cycleQ35, B x 2 cyclesMaintenanceDexPatient Characteristics. .VTD(nVTD(n=241)=241)TD(nTD(n=239)=239)Age (years)Age (years)56.336.8856.336.8855.867.4155.867.41Stage ISS(%) Stage ISS(%) +107(44)107(44)134(56)134(56)107(45)107(45)132(55)132(55)2 2-MG (mg/L)-MG

22、 (mg/L)3.812.483.812.483.832.143.832.14Albumin (Albumin (g/dLg/dL) )3.830.643.830.644.173.974.173.97CreatinineCreatinine (mg/ (mg/dLdL) )1.010.301.010.301.010.311.010.31HbHb ( (g/dLg/dL) )11.101.9111.101.9111.241.9611.241.96PltsPlts (X10 /L) (X10 /L)243.6989.06243.6989.06235.8678.04235.8678.04BMPC B

23、MPC meanSDmeanSD(%)(%)52.4223.1952.4223.1952.7824.1552.7824.15Genetic Genetic abnormalities(byabnormalities(by FISH in FISH in 93% of pts)93% of pts)Del(13q) pos (%) del(13q) aloneDel(13q) pos (%) del(13q) alonet(4:14) pos (%)t(4:14) pos (%)del (17p) pos (%)del (17p) pos (%)4730473018187 74626462620

24、208 89Best Response. .VTD(%)VTD(%)TD(%)TD(%)P PCRCR57.2057.2031.0731.070.00010.0001CR+ CR+ nCRnCR69.9169.9151.2351.230.00010.0001VGPRVGPR87.7187.7172.2672.260.0001 20%40% 20%40%n nAge&DonorAge&Donor availablityavailablity 10% candidates 10% candidatesHigh mortality with conventional allohas favored

25、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序贯自体序贯自体-非清髓移植非清髓移植Allogenic Hematopoietic Stem-cell Transplantation With Reduced-intensity Conditioning in Patients With Refr

26、actory and Recurrent Multiple MyelomaLong-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

27、-Hashomer, IsraelDepartment of Bone Marrow Transplantation,University Hospital Hamburg, Hamburg, GermanyCancer,2010,epubosPFSA Comparison of Allografting with Autografting for Newly Diagnosed MyelomaBruno B, Rotta M, Patriarca F, et al.San Giovanni Battista HospitalUniversity of Turin tUniversity of

28、 Udine, UdineN Engl J Med 2007;356:1110-20.Non-myeloablative TransplantationAuthorAuthorConditioningConditioningregimenregimenGVHD GVHD regimenregimenNN(URD)(URD)PriorPriorAutoAuto TRMTRM % %CRCR%GrGr 2-4 2-4 aGVHDaGVHD %ChroniChronic cGVHD GVHD %OS % OS % (yrs)(yrs)KrogerKrogerMel100/Flu/ATGMel100/

29、Flu/ATGCSA/MTXCSA/MTX17 (8)17 (8)17171818737338387 774 (2)74 (2)KrogerKrogerMel100-Mel100-140/Flu/ATG140/Flu/ATGCSA/MTXCSA/MTX21 21 (2(21)1)9 9242440403838121274 (2)74 (2)MohtyMohtyBu/Flu/ATGBu/Flu/ATGCSACSA MTXMTX41 41 (N(NR)R)0 0171724243636414162 (2)62 (2)PeggsPeggsTBI/Flu/TBI/Flu/AlemtuzumAlemtu

30、zumababCSA/MMFCSA/MMF20 (8)20 (8)0 0151510102525NRNR71 (2)71 (2)MaloneyMaloneyTBI-2Gy/FluTBI-2Gy/FluCSA/MMFCSA/MMF54 (0)54 (0)5454222257574545606069 (4)69 (4)GerullGerullTBI-2Gy/FluTBI-2Gy/FluCSA/MMFCSA/MMF52 52 (2(20)0)0 0171727273737707041 41 ( (1.1.5 5) )HoepfnerHoepfnerTBI-2Gy/FluTBI-2Gy/FluCSA/

31、MMFCSA/MMF19 (6)19 (6)0 03232NRNR3737NRNR50 (2)50 (2)MaMaTBI-3Gy/FluTBI-3Gy/FluCSA/MMFCSA/MMF10 (0)10 (0)0 00 0303060604040100 100 ( (1 1) )GalimbertiGalimbertiTBI-2Gy/Flu; TBI-2Gy/Flu; Flu/CyFlu/CyCSA/MMFCSA/MMF20 (0)20 (0)2020202035352525303058 (2)58 (2)EinseleEinseleTBI-2Gy/Flu/CyTBI-2Gy/Flu/CyCS

32、A/MMF/ATGCSA/MMF/ATG22 22 (1(15)5)0 0232327273838323226 (2)26 (2)LeeLeeTBI-2Gy/Flu/ TBI-2Gy/Flu/ Mel100Mel100CSACSA45 45 (1(12)2)1212383864645858131336 (3)36 (3)GiraltGiraltMel/FluMel/FluFK/MTXFK/MTX22 (9)22 (9)0 0414132324646272730 (2)30 (2)Perez-Perez-SimonSimonMel/FluMel/FluCSA/MTXCSA/MTX29 29 (N

33、(NR)R)1010212128284141515160 (2)60 (2)Auto-allo RIC vs Tandem Auton n3 3 studies(IFMstudies(IFM, PETHEMA, HOVON).No benefit, PETHEMA, HOVON).No benefitn n2 2 studies(GIMEMAstudies(GIMEMA, EBMT)significant benefit , EBMT)significant benefit (EFS, OS)(EFS, OS)#Differences in patients characteristics,

34、GVHD #Differences in patients characteristics, GVHD prophylaxis, & conditioning regimens may explain prophylaxis, & conditioning regimens may explain these discrepant results.these discrepant results.异基因移植的优势异基因移植的优势Allogeneic Bone Marrow Transplantation for Multiple Myeloman nAssociated with Associ

35、ated with high complete response rateshigh complete response ratesn nDurable molecular remissionsDurable molecular remissions are noted in are noted in some patientssome patientsn nTwo advantages which may reduce the risk of Two advantages which may reduce the risk of relapse after allogeneic transp

36、lant compared relapse after allogeneic transplant compared with autologous transplant are:with autologous transplant are: infusion of a tumor free stem cell productinfusion of a tumor free stem cell product graft versus myeloma effect graft versus myeloma effectn nHigh dose conventional allogeneic H

37、igh dose conventional allogeneic transplantation is associated with a transplantation is associated with a high high treatment related mortalitytreatment related mortality, up to 50% in some , up to 50% in some studiesstudiesEvidence for a Graft versus Myeloma (GVM) Effectn nDelayed disappearance of

38、 residual diseaseDelayed disappearance of residual disease after after allogeneic BMT in some patientsallogeneic BMT in some patientsn nDecreased rate of relapseDecreased rate of relapse after allogeneic BMT after allogeneic BMT compared with autologous BMTcompared with autologous BMTn n40%-80% over

39、all response rate in patients with 40%-80% overall response rate in patients with relapsed multiple myeloma after relapsed multiple myeloma after donor lymphocyte donor lymphocyte infusioninfusionResponse to CD4+ DLIN=12Pre DLI Maximal Response Current status9-persistent or 6 CR 5 CR-1 RelapseProgre

40、ssive disease 3 PR 2 relapse3-CR - 2 CR-1 relapse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 transplantationhaematologica | 2010; 95(5):804-9Primary plasma cell leukemia(PCL): less than 5% of malignant PCD. It has a poor prognosis, median survival of 8-12 months. Autologo

41、us 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 yearsFISH

42、 Del 17P t(14:16) t(14:20)GEP High risk signatureFISH t(4:14)Cytogenetic deletion 13 or hypodiploidPCLI3%All others including: Hyperdiploid t(11:14) t(6:14) High-Risk Intermediate-Risk Standard-RiskmSMART2.0: Treatment of Active MMHigh-Risk Intermediate-Risk Standard-RiskNovel approachesNew drugs”TT

43、3 like” approachfor p53 deletion?Bortezomib based combinationHDM+/-consolidationLenalidomide maintenanceTargeted therapyRegimen whichprovides a high ORRand which minimizes early toxicity HDM could be delayed in patients achieving CRLenalidomide maintenance新型药物作为诱导治疗用于适合移植者新型药物作为诱导治疗用于适合移植者硼替佐米硼替佐米Ve

44、l+DexPADVCD雷利度胺雷利度胺RDRdRAD沙利度胺沙利度胺Thal+DexTADCTD常规常规VADIDCY+DexVTDRVD干细胞采集干细胞采集高剂量的美法仑高剂量的美法仑干细胞回输干细胞回输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结 论论1 造血干细胞移植是治疗造血干细胞移植是治疗MM有效手段之一；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；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诱导治疗中加入新药，大部分病人可能不需要二次移植；二次移植；4 清髓性移植有可能清除微小残留病；但移植相清髓性移植有可能清除微小残留病；但移植相关死亡率高；关死亡率高；5 NST可降低可降低TRM,但疗效有限；但疗效有限；6 移植后用新药维持治疗，可能提高疗效。移植后用新药维持治疗，可能提高疗效。