多發(fā)性骨髓瘤的造血干細(xì)胞移植課件

1、多發(fā)性骨髓瘤的造血干細(xì)胞移植 首都醫(yī)科大學(xué)附屬北京朝陽醫(yī)院北京市多發(fā)性骨髓瘤醫(yī)療研究中心多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植為什么要移植？多發(fā)性骨髓瘤的造血干細(xì)胞移植為什么要移植？多發(fā)性骨髓瘤的造血干細(xì)胞移植不同時間段內(nèi)多發(fā)性骨髓瘤主要年齡組患者的10年生存率Brenner et al;Blood 2008;111:2521-2526多發(fā)性骨髓瘤的造血干細(xì)胞移植不同時間段內(nèi)多發(fā)性骨髓瘤主要年齡組患者的10年生存率BreP10 -5 P=0.07 EFS CR vs nCR or PR nCR vs PR OS CR vs nCR CR vs PR

2、 nCR vs PR P=0.01 P10 -6 P=0.04 月數(shù) 月數(shù)CR, n=278 nCR, n=124 PR, n=280 PD, n=25 Lahuerta et al. JCO 2008;26:5775-5782 緩解程度與長生存密切相關(guān)無事件生存率%總生存率%多發(fā)性骨髓瘤的造血干細(xì)胞移植P10 -5 EFS OS P=0.01 Barlogie B, et al. Cancer. 2008;113:355359. . 持久CR是長生存的最重要因素生存率0 1 2 3 4 5 6 SUS-CR: 獲得并維持CR狀態(tài) NON-CR: 從未獲得CR狀態(tài) LOS-CR: 獲得但失去C

3、R狀態(tài) 年數(shù) 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后反應(yīng)，%CR16 vs 9*15 vs 4*VGPR 54 vs 37*59 vs 47*PR 80 vs 7792 vs 77*具有顯著性差異*對于IFM2005/01，首次移植后的反應(yīng)率表示為總體反應(yīng)率，包含第二次移植反映率。 VGPR的反應(yīng)率在VD組為68%

4、，VAD組為47%；CR/nCR在VD組為39.5%，VAD組為22.5%。1.Harousseau JL, et al. JCO 2010 in press. 2. Sonneveld P, et al. IMW 2009:abstract 152.多發(fā)性骨髓瘤的造血干細(xì)胞移植以硼替佐米為基礎(chǔ)的誘導(dǎo)方案IFM2005-01HOVON-G移植的時機目前傾向于作為鞏固治療在疾病早期進(jìn)行，避免在疾病復(fù)發(fā)時一般情況差、腎功能不全、年齡增加、過多骨骼破壞以及發(fā)生MDS的高風(fēng)險。 多發(fā)性骨髓瘤的造血干細(xì)胞移植移植的時機目前傾向于作為鞏固治療在疾病早期進(jìn)行，避免在疾病復(fù)病人的年齡多限定在65歲以下，但也有

5、超出該年齡病人的報道。腎功能不全不是移植的禁忌癥，一般可將馬法蘭的劑量調(diào)整至140mg/m2;如病人有低蛋白血癥，可將馬法蘭的劑量進(jìn)一步調(diào)整至70-100mg/m2。 多發(fā)性骨髓瘤的造血干細(xì)胞移植病人的年齡多限定在65歲以下，但也有超出該年齡病人的報道。多Kumar et al ASH2009 (Abstr 956）VRD5Stem CollectionR12mASCT at relapseVRD3復(fù)發(fā)前和復(fù)發(fā)后進(jìn)行ASCT療效相同IFM-DFCL2009ASCT 在復(fù)發(fā)前還是在復(fù)發(fā)后進(jìn)行？ VRD3Stem CollectionASCTVRD2R12m多發(fā)性骨髓瘤的造血干細(xì)胞移植Kumar

6、et al ASH2009 (Abstr 956小結(jié)患者的生存與緩解程度有關(guān)化療可以提高緩解率及緩解程度二次移植優(yōu)于單次移植新藥的應(yīng)用可以進(jìn)一步提高療效早期與晚期移植的療效相似多發(fā)性骨髓瘤的造血干細(xì)胞移植小結(jié)患者的生存與緩解程度有關(guān)多發(fā)性骨髓瘤的造血干細(xì)胞移植 干細(xì)胞動員的問題多發(fā)性骨髓瘤的造血干細(xì)胞移植 干細(xì)胞動員的問題多發(fā)性骨髓瘤的造血干細(xì)胞移植High rate of stem cell mobilization failure after thalidomide and oral cyclophosphamide induction therapy for multiple myelo

7、maHW 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 Transplantation (2010), 14,epub多發(fā)性骨髓瘤的造血干細(xì)胞移植High rate of stem cell mobiliz多發(fā)性骨髓瘤

8、的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植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

9、apheresis procedure. (b) Bars show the percentage of patients undergoing X2 apheresis procedures.多發(fā)性骨髓瘤的造血干細(xì)胞移植Figure 1 Induction therapy wit多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植預(yù) 處 理多發(fā)性骨髓瘤的造血干細(xì)胞移植預(yù) 處 理多發(fā)性骨髓瘤的造血干細(xì)胞移植How to improve the efficacy of condition regimensMelphalan 200mg/m2.the gold standardMelphala

10、n+Busulphan.may be superiorMelphalan+Bortezomib70%VGPR(35%CR) (1mg/m2 D-6 -3 +1 +4)Melphalan+Bortezomib53%VGPR (1.3mg/m2 D-1 or +1)多發(fā)性骨髓瘤的造血干細(xì)胞移植How to improve the efficacy ofBU and CY as conditioning regimen for autologous transplant in patientswith multiple myelomaG Talamo, DF Claxton, DW Doughert

11、y, 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, 157161多發(fā)性骨髓瘤的造血干細(xì)胞移植BU and CY as conditioning regi多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植Figure 1 OS of multiple myeloma patients tre

12、ated 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 intervalFigure 3 PFS of multiple myeloma

13、 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

14、is, on disease progression/relapse (n17, dotted line). Survival is calculated from the time of MM diagnosis.多發(fā)性骨髓瘤的造血干細(xì)胞移植Figure 1 OS of multiple myelom移植后的鞏固與維持治療多發(fā)性骨髓瘤的造血干細(xì)胞移植移植后的鞏固與維持治療多發(fā)性骨髓瘤的造血干細(xì)胞移植2009 ASH Abstract 351A Phase Study of Double Autotransplantation Incorporating Bortezomib- Thalido

15、mide- 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 Hematology, Bologna University School of Medicine, Bologna, ItalyItalian Myeloma Netwo

16、rk GIMEMA, Italy多發(fā)性骨髓瘤的造血干細(xì)胞移植2009 ASH Abstract 351A Phase Study 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 cycl

17、e q35x2cyclesVTD ConsolidationB 1.3mg/ days 1,8,1522q35/T 100mg po days1-35/D 320mg per cycleQ35, B x 2 cyclesMaintenanceDex多發(fā)性骨髓瘤的造血干細(xì)胞移植Study Design.REGISTRATIONThaliPatient Characteristics.VTD(n=241)TD(n=239)Age (years)56.336.8855.867.41Stage ISS(%) +107(44)134(56)107(45)132(55)2-MG (mg/L)3.812.4

18、83.832.14Albumin (g/dL)3.830.644.173.97Creatinine (mg/dL)1.010.301.010.31Hb (g/dL)11.101.9111.241.96Plts (X10 /L)243.6989.06235.8678.04BMPC meanSD(%)52.4223.1952.7824.15Genetic abnormalities(by FISH in 93% of pts)Del(13q) pos (%) del(13q) alonet(4:14) pos (%)del (17p) pos (%)473018746262089多發(fā)性骨髓瘤的造血

19、干細(xì)胞移植Patient Characteristics.VTD(n=Best Response.VTD(%)TD(%)PCR57.2031.070.0001CR+ nCR69.9151.230.0001VGPR87.7172.26 20%40%Age&Donor availablity 10% candidatesHigh mortality with conventional allohas favored the Reduced Intensity Conditioning regimens (RIC) But the TRM is still 10%20%; cGVHD: 35%70%

20、 & more relapses (extramedullary) to overcome relapses: “Tandem Auto-Allo” program多發(fā)性骨髓瘤的造血干細(xì)胞移植Allogeneic SCT Advang序貫自體-非清髓移植多發(fā)性骨髓瘤的造血干細(xì)胞移植序貫自體-非清髓移植多發(fā)性骨髓瘤的造血干細(xì)胞移植Allogenic Hematopoietic Stem-cell Transplantation With Reduced-intensity Conditioning in Patients With Refractory and Recurrent Multipl

21、e 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-Hashomer, IsraelDepartment

22、of Bone Marrow Transplantation,University Hospital Hamburg, Hamburg, GermanyCancer,2010,epub多發(fā)性骨髓瘤的造血干細(xì)胞移植Allogenic Hematopoietic Stem-cosPFS多發(fā)性骨髓瘤的造血干細(xì)胞移植osPFS多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植A Comparison of Allografting with Autograf

23、ting for Newly Diagnosed MyelomaBruno B, Rotta M, Patriarca F, et al.San Giovanni Battista HospitalUniversity of Turin tUniversity of Udine, UdineN Engl J Med 2007;356:1110-20.多發(fā)性骨髓瘤的造血干細(xì)胞移植A Comparison of Allografting w多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干

24、細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植Non-myeloablative TransplantationAuthorConditioningregimenGVHD regimenN(URD)PriorAutoTRM %CR%Gr 2-4 aGVHD %ChronicGVHD %OS % (yrs)KrogerMel100/Flu/ATGCSA/MTX17 (8(2)KrogerMel100-140/Flu/ATGCSA/MTX21 (21)92440381274 (2)MohtyBu/Flu/ATGCSAMTX41 (NR)017243641

25、62 (2)PeggsTBI/Flu/AlemtuzumabCSA/MMF20 (8)0151025NR71 (2)MaloneyTBI-2Gy/FluCSA/MMF54 (0)542257456069 (4)GerullTBI-2Gy/FluCSA/MMF52 (20)01727377041 (1.5)HoepfnerTBI-2Gy/FluCSA/MMF19 (6)032NR37NR50 (2)MaTBI-3Gy/FluCSA/MMF10 (0)00306040100 (1)GalimbertiTBI-2Gy/Flu; Flu/CyCSA/MMF20 (0)202035253058 (2)E

26、inseleTBI-2Gy/Flu/CyCSA/MMF/ATG22 (15)02327383226 (2)LeeTBI-2Gy/Flu/ Mel100CSA45 (12)123864581336 (3)GiraltMel/FluFK/MTX22 (9)04132462730 (2)Perez-SimonMel/FluCSA/MTX29 (NR)102128415160 (2)多發(fā)性骨髓瘤的造血干細(xì)胞移植Non-myeloablative TransplantatAuto-allo RIC vs Tandem Auto3 studies(IFM, PETHEMA, HOVON).No benef

27、it2 studies(GIMEMA, EBMT)significant benefit (EFS, OS)#Differences in patients characteristics, GVHD prophylaxis, & conditioning regimens may explain these discrepant results.多發(fā)性骨髓瘤的造血干細(xì)胞移植Auto-allo RIC vs Tandem Auto3 異基因移植的優(yōu)勢多發(fā)性骨髓瘤的造血干細(xì)胞移植異基因移植的優(yōu)勢多發(fā)性骨髓瘤的造血干細(xì)胞移植Allogeneic Bone Marrow Transplantatio

28、n for Multiple MyelomaAssociated with high complete response ratesDurable molecular remissions are noted in some patientsTwo 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 mye

29、loma effectHigh dose conventional allogeneic transplantation is associated with a high treatment related mortality, up to 50% in some studies多發(fā)性骨髓瘤的造血干細(xì)胞移植Allogeneic Bone Marrow TransplEvidence for a Graft versus Myeloma (GVM) EffectDelayed disappearance of residual disease after allogeneic BMT in s

30、ome patientsDecreased rate of relapse after allogeneic BMT compared with autologous BMT40%-80% overall response rate in patients with relapsed multiple myeloma after donor lymphocyte infusion多發(fā)性骨髓瘤的造血干細(xì)胞移植Evidence for a Graft versus MResponse to CD4+ DLIN=12Pre DLI Maximal Response Current status9-p

31、ersistent or 6 CR 5 CR-1 RelapseProgressive disease 3 PR 2 relapse3-CR - 2 CR-1 relapse多發(fā)性骨髓瘤的造血干細(xì)胞移植Response to CD4+ DLIN=12Pre D漿細(xì)胞白細(xì)胞的移植多發(fā)性骨髓瘤的造血干細(xì)胞移植漿細(xì)胞白細(xì)胞的移植多發(fā)性骨髓瘤的造血干細(xì)胞移植Primary plasma cell leukemia and autologous stem cell transplantationhaematologica | 2010; 95(5):804-9Primary plasma cell le

32、ukemia(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. 多發(fā)性骨髓瘤的造血干細(xì)胞移植Primary plasma cell leukemia a多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造血干細(xì)胞移植多發(fā)性骨髓瘤的造