多发性骨髓瘤的造血干细胞移植.ppt

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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 al.Cance

2、r.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 data not available,Haroussea

3、u et al.ASH/ASCO symposium during ASH 2008Rajkumar et al.ASCO 2008(Abstract 8504);ASH 2008(joint ASH/ASCO symposium),Lokhorst et al.Haematologica 2008;93:124127Sonneveld et al.ASH 2008(Abstract 653);IMW(Abstract 152)Cavo et al.ASH 2008(Abstract 158);IMW 2009(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

4、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

5、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 mobili

6、zation 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 Haematology Hammersmith Hospital Imperial College Healthcare NHS Trust,London,UK,Bone Ma

7、rrow 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 number of CD34tcells/kg collected overall,on the first apheresis day,a

8、nd 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 standardMelphalan+Busulphan.may be superiorMelphalan+Bortezomib70%VGPR(35%CR)(1mg/m2 D-6-3+1+4)Melphalan+Bortezom

9、ib53%VGPR(1.3mg/m2 D-1 or+1),BU and CY as conditioning regimen for autologous transplant in patientswith 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 Tra

10、nsplantation(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 myeloma patients treated with the BU/CY regimen and ASCT(n79),from day 0 of ASCT.Thin lines in

11、dicate 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 patients treated with the BU/CY regimen and ASCT carried out upfront,that is,in first remission(n62,continu

12、ous 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 351,A Phase Study of Double Autotransplantation Incorporating Bortezomib-Thalidomide-Dexamethasone(VTD)or Thali

13、domide-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 Network GIMEMA,Italy,Study Design,.,REGISTRATION,

14、Thalidomide+DexT 100-200 mg po days1-21/D 40mg days 1,2,4,5,8,9,11,12q21x3 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 1,8,1522q35/T 100mg po days1-35/D 320mg per

15、 cycleQ35,B x 2 cycles,MaintenanceDex,Patient Characteristics,.,9,Best Response,.,PFS in High-risk Cytogenetics*,*t(4;14)del(17p),Br J Haematol,2008,140:625634.,Mel 干细胞回输 G-CSFV V V V,-6-3-2 0+1+4+7,V=万珂 2 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

16、=4050%）,Rousselet al.Hematology 2006;91(suppl.1),p98.EHA 2006,abs 0233#,Consolidation with Bortezomib+Thalidomide+Dex,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

17、因移植,Overall and event-free survival are not improved 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,Bronno van der Holt,et al.Erasmus Medical Cent

18、er Rotterdam(Erasmus MC)and UniversityMedical Center Utrecht(UMCU)for the Dutch-Belgian Hemato-OncologyCooperative 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

19、.006,Causes of Treatment Failure,Cumulative Incidence of Relapse,Years,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,AdvangtagesStem cells Non-contaminated No damageGVM effect,DisadvantagesTrx related mortality 20%40%Age&Donor availablity 10

20、%candidates,High mortality with conventional allohas favored 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-非清髓移植,Allogenic Hematopoietic Stem-cell Transplantation With Reduced-

21、intensity Conditioning in Patients With Refractory 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 Transplantati

22、on,Chaim Sheba Medical Center,Tel-Hashomer,IsraelDepartment of Bone Marrow 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 HospitalUni

23、versity of Turin tUniversity of Udine,Udine,N Engl J Med 2007;356:1110-20.,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 re

24、gimens may explain these discrepant results.,异基因移植的优势,Allogeneic Bone Marrow Transplantation for Multiple Myeloma,Associated with high complete response ratesDurable molecular remissions are noted in some patientsTwo advantages which may reduce the risk of relapse after allogeneic transplant compare

25、d with autologous transplant are:infusion of a tumor free stem cell product graft versus myeloma effectHigh 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

26、 of residual disease after allogeneic 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 CD4+DLIN=12,Pre DLI Maximal Response Current status

27、9-persistent or 6 CR 5 CR-1 RelapseProgressive 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 surviv

28、al 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.,mSMART2.0:Classification of Active MM,3 year

29、s 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 hypodiploidPCLI3%,All others including:Hyperdiploid t(11:14)t(6:14),High-Risk Intermediate-Risk Standard-Risk,mSMART2.0:Treatment of Active MM,High-Risk Intermediate-Risk Standard-Risk,No

30、vel approachesNew drugs”TT3 like”approachfor p53 deletion?,Bortezomib based combinationHDM+/-consolidationLenalidomide maintenanceTargeted therapy,Regimen 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,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。,