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1、Allogeneic haematopoietic cell transplantation for multiple myeloma,The allogeneic transplant has the advantage over the autologous transplant The graft does not contain tumor cells and the potential for a graft versus myeloma (GvM) effect,Bone marrow transplantation in three patients with multiple
2、myeloma Gahrton G, Ringdn O, Lnnqvist B, Lindquist R, Ljungman P.,Acta Med Scand 1986;219(5):523-7.,瑞典卡罗林斯卡医学院 1983,Myeloablative conditioning,Three patients with multiple myeloma received bone marrow grafts from HLA-identical sibling donors One of the patients, with IgA kappa myeloma, refractory to
3、 alkeran-prednisone therapy, is well and still without sign of disease 26 months post transplantation A second patient with Bence-Jones kappa myeloma is well, and skeletal pain and Bence-Jones proteinuria has disappeared 2 months after transplantation. A third patient with IgG-lambda myeloma died of
4、 effusive pericarditis shortly after transplantation.,Acta Med Scand 1986;219(5):523-7,Conclusion,Bone marrow transplantation may be indicated in a selective group of patients with multiple myeloma,Acta Med Scand 1986;219(5):523-7,Out of 690 allogenetic matched sibling donor transplants for MM 344 w
5、ere performed during the period 1983-93(all with BM ) group 1 356 during 1994-98 (223 with BM group 2 and 133 with PB group 3),the median age at transplantation of patients in group 1 was 43 years (range 21-62) In group 2 ,44 years (range 18_57) and in group 3, 46 years (range 25_60),TBI+CY tended t
6、o be more commonly used in group 1(37%) and 2 (39%) than in group 3 (27%) Melphalan containing regimes tended to be morely used in group 3 Melphalan or Busulphan + CY rarely,Conditiong regime,Engraftment,GVHD,Treatment related mortality,Treatment related mortality,Relapse rate,Relapse rate,Survival,
7、Survival,Progression free survival,PFS was significantly better for group 2than for group 1(P0.0001) With no significantly difference between group 2 and 3,Cause of death,75% in group 1,36% in group 2 ,33 % in group 3 GVHD Fungal ARDS Organ failure,Cause of death,the study shows that the improvement
8、 is entirely a result of a lower TRM during the latest 5-years period aGVHD has no changed during this peroid There was significant difference in deaths caused by IP and bacterial and fungalinfection,Conditioning regime,TBI+Melphalan has not previrous been Shown to be superior to TBI+CY in this stud
9、y,conclusion,Survival 3060% Treatment related mortality 30%,Myeloablative allogeneic versus autologous transplantation,during the years 1983 to 1994 189 myeloma patients who underwent allo-BMT with an HLA-identical sibling donor were compared retrospectively with an equal number of patients who rece
10、ived a single autologous bone marrow or blood stem cell graft And the ASCT patients were transplanted from 1986 to 1994,conclusion The overall survival was significantly better for ASCT than for allo-BMT, with a median survival of 34 months and 18 months, respectively (P = .001), The main reason for
11、 the poorer survival in allo-BMT patients was higher TRM (41% v 13% for ASCT, P = .0001), which was not compensated for by a lower rate of relapse and progression,conclusion However, in patients alive at 1 year posttransplant, there was a trend for better long-term survival (P = .O9) and significant
12、ly better progression-free survival (P = .02) for allo-BMT as compared with ASCT We conclude that the median survival is superior for ASCT However, allo-BMT has a lower relapse rate, which results in a similar long-term outcome for both approaches, but a longer follow-up is needed to assess the fina
13、l outcome,Reduced-intensity conditioning allogeneic transplantation,The Allo-RIC was introduced in an attempt to decrease the transplant-related toxicity while retaining the beneficial GvM effect 1998 begin clinical study,19982003 We report the outcome of 229 patients who received an allograft for m
14、yeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the EBMT.,With a median follow-up of 28 months, 115 patients are alive(range, 1-53 months) The estimated overall survival at 3 years is 40.6% (CI, 33%-49%) The treatment-related mortalities at day 100, 1 year,and 2 year
15、s were 10%, 22%, and 26%, respectively. The cumulative probability of the progression-free survival was 21.3% (CI, 15%-29%) at 3years,Conclusion While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit,RIC vs MAC,Data were available on a total of 516 pa
16、tients from 103 centers: 320 patients with RIC and 196 with MAC. between January 1, 1998, to December 31, 2002 The median follow-up was 28 months,conclusion RIC was associated with a reduction in TRM but this was offset by an increase in relapse risk the conditioning intensity did not impact on over
17、all survival or retain significance for PFS These data suggest that there is a continuing need to investigate dose intensity in the conditioning for myeloma allografts.,Tandem autologous/Allo-RIC transplantation,Autologous hematopoietic cell transplantation(HCT) followed by nonmyeloablative allogene
18、ic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects.,弗雷德哈钦森癌症研究中心,Patient inclusion criteria for this analysis were stage II or III MM at diagnosis available human leukocyte antigen (HLA)identical sibling donor programmed sequential treatment with conventional autologous HC
19、T followed by nonmyeloablative auto/alloHCT no prior autologous HCT.,105 patients with MM fulfilling those criteria were sequentially enrolled at 10 centers on 4 FHCRC-coordinated multiinstitutional protocols from August 1998 to August 2005 Patients proceeded to allogeneic HCT 40 to 180 days after a
20、utografting,Autologous HCT. (G-CSF) mobilized peripheral blood mononuclear cells (G-PBMC) were harvested by leukapheresis after treatment with cyclophosphamide 3 to 4 g/m2 (day 1) and G-CSF 10 g/kg subcutaneously (from day 3 through collection),Autologous HCT 38 patients received additional paclitax
21、el (250 mg/m2 per day, day 2), and 25 received additional etoposide (200 mg/m2 per day; days 1, 2, 3) and dexamethasone (10 mg/day orally; days 1, 2,3, 4) Two patients received G-CSF alone.,Autologous HCT No treatment for MM was given between autologous and allogeneic HCT,Allogeneic HCT After recove
22、ry from autologous HCT 102 patientsproceeded to allotransplantation. Donors were HLA-identical siblings,Nonmyeloablative conditioning consisted in all patients of 2 Gy total body irradiation (TBI) at 7 cGy/min by linear accelerator or cobalt on day 0 27 patients received additional fludarabine (30 m
23、g/m2) on days 4, 3, and 2,N,%,Engraftment All 102 allografted patients had sustained engraftment. On day 28, medians of 90%, 95%, and 95% of peripheral blood T cells, granulocytes, and nucleated marrow cells,respectively, were of donor origin. This increased to medians of 96% to 100% on day 84,GVHD
24、43 patients (42%) developed grades 2 to 4 acute GVHD at a median of 42 (range, 8-107) days 74 patients (74%) developed chronic extensive GVHD at a median of 167 (range, 90-830) days after transplantation.,NRM NRM was 1% at day 100 and 11%, 14%, and 18% at 1, 2, and 5 years after allografting, respec
25、tively GVHD and infections were responsible for 18 of 19 non relapse related deaths.,Overall and progression-free survivals After a median follow-up of 6.3 years after allografting (range 2-9) 60 of 102 (59%)patients survived and 33 of 102 (32%) are in remission Five-year estimated OS and PFS were 6
26、4% and 36%,respectively,conclusion auto/allo-RIC HCT is a treatment option for patients with advanced stage MM The addition of novel agents (eg,thalidomide, bortezomib, and lenalidomide) as induction or postgrafting therapy, acting with GVM effects against disease-specific antigens, might further im
27、prove the outcome.,improve the outcome Thalidomide/lenalidomide dexamethasone Bortezomib,研究所佩奥利- Calmettes，马赛，法国,This was a retrospective study from 3 centers 37 patients treated between November 2003 and March 2007,conclusion bortezomib is a safe and efficient option for myeloma patients after RIC-
28、allo-SCT.,Double autologous Versus tandem auto/Allo-RIC transplantation,圣乔凡尼巴蒂斯塔大学医院，都灵，意大利,Methods All patients were initially treated with VAD followed by melphalan and autologous stem-cell rescue,Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem
29、 cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival.,Conclusions Among patients with newly diagnos
30、ed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts.,UNSOLVED QUESTIONS IN ALLOGENEIC TRANSPLANTATION Which is the best allogeneic transplantation approach? Who are the patients most likely to benefit from Allo-RIC? How to improve the results of Allo-RIC?,