多發(fā)性骨髓瘤的造血干細胞移植

1、為什么要移植？,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,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,Lahuerta et al. JC

2、O 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%,Barlogie B, et al. Cancer. 2008;113:355–359. .,持久CR是長生存的最重要因素,0 1 2 3 4 5

3、 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CR狀態(tài),年數(shù),100% 80%60%40%20%0%,Barlogie B, et al. Cancer. 2008;113:355–359. .,P-value: a vs b<0.0001, b vs c <0.0

4、001, a vs c <0.0001,a,b,c,以新藥為基礎(chǔ)的誘導(dǎo)方案的療效,誘導(dǎo)方案,ASCT能進一步提高新藥誘導(dǎo)后的療效,*Post-transplant data not available,Harousseau et al. ASH/ASCO symposium during ASH 2008Rajkumar et al. ASCO 2008 (Abstract 8504); ASH

5、2008 (joint ASH/ASCO symposium),Lokhorst et al. Haematologica 2008;93:124–127Sonneveld et al. ASH 2008 (Abstract 653); IMW (Abstract 152) Cavo et al. ASH 2008 (Abstract 158); IMW 2009 (Abstract 451),新藥誘導(dǎo)治療和ASCT的作用是互補的,

6、 而不是作為二選一的治療手段,,,,,,,,,以硼替佐米為基礎(chǔ)的誘導(dǎo)方案,,*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%，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

7、 2009:[abstract 152].,移植的時機目前傾向于作為鞏固治療在疾病早期進行，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。,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。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一步調(diào)整至70-100mg/m2。,,Kumar et al ASH2009 (Abstr

8、 956）,復(fù)發(fā)前和復(fù)發(fā)后進行ASCT療效相同,IFM-DFCL2009,ASCT 在復(fù)發(fā)前還是在復(fù)發(fā)后進行？,VRD×3,,,,,Stem Collection,ASCT,VRD×2,R×12m,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)用可以進一步提高療效早期與晚期移植的療效相似,干細胞動員的問題,High rate of stem cell

9、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 RahemtullaDep

10、artment of Haematology Hammersmith Hospital Imperial College Healthcare NHS Trust, London, UK,Bone Marrow Transplantation (2010), 1–4,epub,,Figure 1 Induction therapy with CY and thalidomide with dexamethasone (CTD) im

11、pairs 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.

12、 (b) Bars show the percentage of patients undergoing X2 apheresis procedures.,,,,,預(yù) 處 理,How to improve the efficacy of condition regimens,Melphalan 200mg/m2…..the gold standardMelphalan+Busulphan….may be superiorMe

13、lphalan+Bortezomib…70%≧VGPR(35%CR) (1mg/m2 D-6 -3 +1 +4)Melphalan+Bortezomib…53%≧VGPR (1.3mg/m2 D-1 or +1),BU and CY as conditioning regimen for autologous transplant in patien

14、tswith 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, USA,Bone Marrow Trans

15、plantation (2009) 44, 157–161,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

16、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 (n

17、66, 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 ‘sa

18、lvage therapy’, that is, on disease progression/relapse (n17, dotted line). Survival is calculated from the time of MM diagnosis.,,,,,,移植后的鞏固與維持治療,2009 ASH Abstract 351,A Phase Ⅲ Study of Double Autotransplantation Inc

19、orporating Bortezomib- Thalidomide- Dexamethasone (VTD) or Thalidomide- Dexamethasone (TD) for Multiple Myeloma: Superior Clinical Outcomes with VTD Compared to TDMichele Cabvo, Paola Tacchetti, Francesca Patriarca, e

20、t al.sergnoli Institute of Hematology, Bologna University School of Medicine, Bologna, ItalyItalian Myeloma Network GIMEMA, Italy,Study Design,.,REGISTRATION,,,Thalidomide +DexT 100-200 mg po days1-21/D 40mg days 1

21、,2,4,5,8,9,11,12q21x3 cycles,Bortezomib + t + DB 1.3 mg/㎡ days 1,4,8,11,Q21x3 cycles,Double ASCTMelphalan 200 mg/㎡,TD ConsolidationT 100mg po days 1-35/D320mg per cycle q35x2cycles,VTD ConsolidationB 1.3mg/㎡ days

22、 1,8,1522q35/T 100mg po days1-35/D 320mg per cycleQ35, B x 2 cycles,MaintenanceDex,,,,,,,Patient Characteristics,.,9,,Best Response,.,PFS in High-risk Cytogenetics*,*t (4;14) ± del (17p),Br J Haematol,2008,140:6

23、25–634.,,,,,Mel 干細胞回輸 G-CSFV V V V,,,,,,-6 -3 -2 0 +1 +4 +7,,,,V= 萬珂 1.0-1.3mg/m2 Mel = 馬法蘭 200mg/m2,萬珂-馬法蘭用于ASCT預(yù)處理的研究,緩解率CR

24、 = 31% !，VGPR = 46% CR+VGPR=77% （歷史對照：常規(guī)HDM預(yù)處理，ASCT后的CR+VGPR=40~50%）,Rousselet al. Hematology 2006;91 (suppl .1),p98.EHA 2006,abs 0233#,Consolidation with Bortezomib+Thalidomide+Dex,Patients(n=40) with CR or VGPR follo

25、wing ASCTTreatments: 4 consolidation cycles of Btz-Thal-DexResults: --36% converted from VGPR to CR --Six patients(15%) achieved Molecular Remission,清髓性異基因移植,Overall and event-free survival are not i

26、mproved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 studyChristine M. Segeren, Pieter Sonneveld, Bron

27、no van der Holt, et al.Erasmus Medical Center Rotterdam (Erasmus MC) and UniversityMedical Center Utrecht (UMCU) for the Dutch-Belgian Hemato-OncologyCooperative Study Group (HOVON), The Netherlands,BLOOD, 2003 , 10

28、1( 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,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

29、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

30、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Allogeneic,Autologous,p=0.006,,Causes of Treatment Failure,Cumulative Incidence of Relapse,,Years,Cumulative Incidence,0

31、,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 cells Non-contaminated No damageGVM effect,DisadvantagesTrx related mortality &g

32、t; 20%~40%Age&Donor availablity 10% candidates,High mortality with conventional allo…h(huán)as favored the Reduced Intensity Conditioning regimens (RIC) …But the TRM is still 10%~20%; cGVHD: 35%~70% & more r

33、elapses (extramedullary) … to overcome relapses: “Tandem Auto-Allo” program,序貫自體-非清髓移植,Allogenic Hematopoietic Stem-cell Transplantation With Reduced-intensity Conditioning in Patients With Refractory and Recurrent Multi

34、ple 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

35、 Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, IsraelDepartment of Bone Marrow Transplantation,University Hospital Hamburg, Hamburg, Germany,Cancer,2010,epub,os,PFS,,,,,A Comparison of Allograf

36、ting with Autografting for Newly Diagnosed MyelomaBruno B, Rotta M, Patriarca F, et al.San Giovanni Battista HospitalUniversity of Turin tUniversity of Udine, Udine,N Engl J Med 2007;356:1110-20.,,,Non-myeloablati

37、ve 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, & co

38、nditioning regimens may explain these discrepant results.,異基因移植的優(yōu)勢,Allogeneic Bone Marrow Transplantation for Multiple Myeloma,Associated with high complete response ratesDurable molecular remissions are noted in some p

39、atientsTwo 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 effectHigh dose convent

40、ional 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 allogene

41、ic BMT in some 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,Response to C

42、D4+ DLIN=12,Pre DLI Maximal Response Current status9-persistent or 6 CR 5 CR-1 RelapseProgressive disease 3 PR

43、 2 relapse3-CR - 2 CR-1 relapse,,,,漿細胞白細胞的移植,Primary plasma cell leukemia and autologous stem cell transplantation,haematologica | 2010;

44、 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 anal

45、ysis(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

46、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 hypodi

47、ploidPCLI≥3%,All others including: Hyperdiploid t(11:14) t(6:14),High-Risk Intermediate-Risk Standard-Risk,mSMART2.0: Treatment of Active MM,High-Risk

48、 Intermediate-Risk Standard-Risk,Novel approachesNew drugs”TT3 like” approachfor p53 deletion?,Bortezomib based combinationHDM+/-consolidationLenalidomide maintenanceTargeted

49、 therapy,Regimen whichprovides a high ORRand which minimizes early toxicity HDM could be delayed in patients achieving CRLenalidomide maintenance,新型藥物作為誘導(dǎo)治療用于適合移植者,VTD,RVD,干細胞采集高劑量的美法侖干細胞回輸,CY=環(huán)磷酰胺；Rd=來那度胺