Reduced-intensity Conditioning Transplantation

Transcription

1 Reduced-intensity Conditioning Transplantation Current Role and Future Prospect He Huang M.D., Ph.D. Bone Marrow Transplantation Center The First Affiliated Hospital Zhejiang University School of Medicine, China

2 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

3 Effect of HSCT High-dose chemotherapy and graft-versusleukemia (GVL) effect. Decrease recurrence rate Long-term disease-free-survival transplantation related mortality GVHD <50-55 years

4 Reduced-intensity Conditioning (RIC) Regimens usually involve a combination of a purine analog (primarily fludarabine) with an alkylating agent (usually melphalan or busulfan). Regimens are generally considered to include less than 16 mg/kg busulfan or less than 10 Gy total body irradiation (TBI). Blood 2004;104:

5 TBI RIC-HSCT: Regimens TBI + Flu TBI + ATG Bu + Flu + ATG Bu + Flu + alemtuzumab Flu + melphalan Flu + melphalan + alemtuzumab Flu + CTX Cisplatin + Flu + CTX

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7 RIC for Allo-HSCT The immune system plays a major role in controlling and curing certain malignancies. Reduced-intensity Conditioning directed to selectively target the immune system. leading to donor cell engraftment. without causing significant damage to other organs as seen with the myeloablative regimens. Older and weak patients can receive allo-hsct.

8 Full T-cell chimerism (%) RIC-HSCT is safe and effective Engraftment Seattle Group: 322 patients Conditioning Regimen: TBI or TBI + Flu Only 21 patients experienced graft rejection Months from transplantation J Clin Oncol 2005;23:

9 RIC-HSCT is safe and effective Immunologic Recovery Seattle Group Conditioning Regimen: RIC: TBI + Flu Myeloablative: High-dose chemo- +/- TBI Absolute CMV TH cell number after transplantation Time after HSCT RIC Myeloablative P value D < D < D RIC-HSCT may be improved immune reconstitution early post-hst. Experimental Hematology 2003;

10 The current role of RIC-HSCT Allogeneic Transplants Registered with the CIBMTR, ,000 9,000 8,000 Reduced Intensity Conditioning Traditional 7,000 6,000 5,000 4,000 3,000 2,000 1,

11 The current role of RIC-HSCT EBMT Activity Survey on HSCT in Europe RIC Transplant,

12 EBMT Activity Survey on HSCT in 2007 Donor and Source Source Donor BM PB CB Total Allogeneic Total HLA-id sib HLA-nid sib Twin Unrelated Autologous Total *No. of patients receiving first transplants only in /03/2008

13 EBMT Activity Survey on HSCT in 2007 General Information Allo-SCT Auto-SCT Total Cord Blood Transplants Reduced Intensity Conditioning Transplants Pts. receiving Donor Lymphocyte Infusion Pts. receiving Mesenchymal Stem Cell Pts. receiving Hematopoietic Stem Cell for nonhematopoietic use Cardiovascular Neurological Tissue repair /03/2008

14 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

15 AML in older patients More often antecedent hematologic disorder Less proliferative Lower white blood cell count lower percentage of marrow blasts expression of pglycoprotein in AML blasts unfavorable cytogenetic profile Low CR rate, short survival

16 AML in older patients A ECOG research: 348 patients, older than 55 years. Median overall survival is 6.7 months. Best Pract Res Clin Haematol 2008;21(4):

17 RIC-HSCT for AML A research from Israel group 112 consecutive patients met eligibility criteria: myeloablative conditioning(45) noneligible patients: RIC (67) Conditioning Regimen: Myeloablative: BuCy RIC : busulfan 6.4 mg/kg (FB2) or 12.8 mg/kg (FB4) Leukemia 2006;20:

18 RIC-HSCT for AML Group BuCy FB4 FB2 P value Patients Median age 42(22-58) 51(18-64) 57(18-70) OS (2 y) 50(34-66) 49(24-74) 47(30-65) NS DFS(2 y) 45(29-60) 49(25-72) 43(24-62) NS Relapse(2 y) 33(21-51) 43(25-74) 49(34-72) NS NRM (2 y) 22(13-39) 8(2-31) 8(2-23) 0.05 RIC vs myeloablative: older patients, less NRM, similar survival. Leukemia 2006;20:

19 RIC-HSCT for AML: CR Status A Germany research. 122 patients, Median age: 57.5 years. 51 in CR1, 39 in CR2, 32 in advanced. Conditioning Regimen: 2 Gy TBI ± fludarabine 30 mg/m2/d, from days 4 to 2. Persistent, progressive, or relapsed malignancies in the absence of GvHD: rapid discontinuation of systemic immunosuppression. relapse/disease progression or persistent mixed chimerism: DLI. Best Pract Res Clin Haematol 2008;21(4):

20 RIC-HSCT for AML: CR Status Survival at 3 years was 46% for the 51 patients transplanted in first remission (CR1), 42% for the 39 patients transplanted in second remission (CR2), and approximately 18% for those transplanted with more active disease. Best Pract Res Clin Haematol 2008;21(4):

21 RIC-HSCT for AML: cgvhd RIC HSCT: low dose chemotherapy and GVL effect. GVHD accompany with GVL effect. GVHD = long survival? A research from Barcelona group 93 patients, median age: 53 years Conditioning Regimen: fludarabine (150 mg/m2) and oral busulfan (8 to 10 mg/kg).

22 RIC-HSCT for AML: cgvhd OS With cgvhd P<0.001 Without cgvhd relapse Without cgvhd P<0.01 With cgvhd The development of chronic GVHD after transplant improves survival by reducing relapse. J Clin Oncol 2008;26:

23 RIC vs chemo: Cohort Studies Better understand the impact of transplantation Identifying patients at the time of diagnosis A recent study: 95 patients with AML in first remission Median age: 52 years Had an HLA-matched sibling : donor group Did not have HLA-matched sibling : : no donor group Conditioning Regimen: fludarabine, busulfan and ATG

24 RIC vs chemo: Cohort Studies DFS OS P=0.003 P=0.003 If a matched related donor is identified, RIC-allo-SCT should be proposed because it represents a valid and potentially curative option for AML patients not eligible for standard myeloablative allo-sct.

25 RIC-HSCT for AML: Cord Blood Not every patient has a HLA-match donor A Minnesota group compared the Unrelated umbilical cord blood (UCB) an HLA matched related donor (MRD) 90 patients older than 55 years Conditioning Regimen: TBI(200 cgy) Flu + CTX Flu + busulfan 88% received two UCB units to optimize cell dose 93% received 1-2 HLA mismatched UCB grafts Biol Blood Marrow Transplant 2008;14(3):

26 RIC-HSCT for AML: Cord Blood Engraftment Grade 2-4 agvhd P=0.05 P=0.2 cgvhd DFS P=0.02 P=0.98 Biol Blood Marrow Transplant 2008;14(3):

27 RIC-HSCT for AML: Cord Blood Graft type had no impact on TRM or survival. Supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have a MRD.

28 RIC-HSCT for AML: Summary Older patients have poor Prognosis. RIC-HSCT provide a similar survival rate compare with myeloablative HSCT, better than chemotherapy. Better survival Require a Complete Remission. Umbilical cord blood could be an alternative graft source.

29 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

30 ALL in older patients Older patients have poor Prognosis(ECOG group). Rowe et al, 2005

31 RIC-HSCT for ALL The toxicity of the conditioning regimen has been virtually removed Relies almost entirely on harnessing the graftversus-leukemia effect Becoming established in AML The experience in ALL is far more limited.

32 RIC-HSCT for ALL: Early trial A retrospective studies from Japan From 2000 to 2003, 33 patients Age range from 17 to 68, median patients in CR1, 6 patients in CR2 Conditioning Regimen: Flu based 2y DFS and OS was 18.6% and 29.7% Cumulative incidence of progression at 3 years was 50.9%. Cumulative incidence of nonprogression mortality at 3 years was 30.4%. Hamaki T et al, Bone Marrow Transplant. 2005

33 RIC-HSCT for ALL: Early trial CR1 others CR2 Hamaki T et al, Bone Marrow Transplant. 2005

34 RIC-HSCT for ALL: CR1 97 adult patients with ALL from the EBMT Registry Median age: 38 years 28 patients in CR1, 37 patients were Ph+ Conditioning Regimen: low dose TBI + ATG Patients 2y OS 2y DFS TRM All(n=97) 31% 21% 28% CR1(n=28) 52% 42% 18% Mohty M et al, Haematologica. 2008

35 RIC-HSCT for ALL: CR1 A retrospective studies from Minnesota 22 adult patients, median age: 49 (24-68) 12 in CR1, 14 were Ph+ Conditioning Regimen: Flu + CTX Patients 3y OS(%) TRM(%) All(n=22) CR1 (n=12) 81 8 CR2 or advanced(n=10) Bachanova V et al, Blood. 2009

36 A CIBMTR Analyisis RIC group RIC Vs MA in ALL 92 patients median age: 45y Conditioning Regimen: Bu + melphalan MA group 1421 patients median age: 28y Conditioning Regimen: BuCy or TBI based Other major potential prognostic factors were similar in the two groups. Marks et al, ASH 2009 abstract-872

37 RIC Vs MA in ALL RIC MA P value age < agvhd(100d,%) cgvhd(3y,%) Relapse(3y,% ) OS(3y, %) TRM(3y, %) The only difference between RIC and MA group is age. Marks et al, ASH 2009 abstract-872

38 RIC-HSCT for ALL: Summary Older patients have poor prognosis. The experience in ALL is far more limited than AML. Patients underwent HSCT in CR1 had a better prognosis. Similar OS, TRM and relapse rate compare with MA-HSCT.

39 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

40 CML: the Imatinib Period On 7 November 2001, imatinib was licensed for CML. CR rate was more than 90% Long time survival was more than 80% Allo-HSCT was not recommend as a first-line therapy in NCCN guideline. Imatinib: CR rate Imatinib: DFS

41 CML: allo-hsct? Data from EMBT

42 CML: Asia and Western CML in the far east Younger patients: median age: 40 vs 60 Longer time for imatinib gene mutation: resistance Economics

43 RIC-HSCT for CML in our Group A clinical research in our group From June 2005 to October 2007, 28 consecutive patients with Ph + CML in CP1. median age of 26 years (range, years). median interval from diagnosis to transplant was 8 months (range, 4 28 months). Imatinib was administered at a dose of 400 mg/day for 3 6 months before transplantation. Leukemia 2009;23(6): ; Int J Hematol 2009;89(4):

44 RIC-HSCT for CML in our Group Conditioning regimen: intravenous Flu 30mg/m 2 /day (from day 10 to 5) oral Bu 4 mg/kg (n=4) or intravenous Bu 3.2 mg/kg (n=24) (from day 6 to 5) ATG Fresenius 5 mg/kg/day (from day 4 to 1) Prevent agvhd: cyclosporin (CsA), mycophenolate mofetil (MMF) and short-term methotrexate. Imatinib was administered mg/day after transplantation to treat relapsed disease or graft failure. Leukemia 2009;23(6): ; Int J Hematol 2009;89(4):

45 RIC-HSCT for CML in our Group Engraftment: 26 cases (92.9%) Grade I II agvhd: 7 cases (26.9%) None of grade III IV agvhd Limited cgvhd: 10 cases (40%) Extensive cgvhd: 2 cases (8%) At a median follow-up of 23 months: overall non-relapse mortality was 14.3% overall survivalwas 82.1% Leukemia 2009;23(6): ; Int J Hematol 2009;89(4):

46 RIC-HSCT for CML in our Group plateau phase? Leukemia 2009;23(6): ; Int J Hematol 2009;89(4):

47 RIC-HSCT for CML in our Group Cause of death interstitial pneumonia bronchiolitis obliterans Intracranial extramedullary relapse DLI-aGVHD Leukemia 2009;23(6): ; Int J Hematol 2009;89(4):

48 RIC-HSCT for CML: Summary Imatinib changed the place of HSCT. Difference between Asia and western. Imatinib plus RIC-HSCT could be a safe and effective therapy choice for young CML patients.

49 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

50 Allo-HSCT in MM Advantages Stem cells: no contaminated and no damage (chemo) GVM effects Disadvantages TRM (20-40%) Age and donor availability (only 10% candidates)

51 IFM study Auto/RIC vs tandem Auto Blood 2006;107:

52 Auto/RIC vs tandem Auto Blood 2006;107:

53 Auto/RIC vs tandem Auto OS Blood 2006;107:

54 Auto/RIC vs tandem Auto A retrospective study from PETHEMA study received 6 cycles of VBMCP or VBAD Failing to achieve CR or ncr after first auto-hsct Conditioning regimen: Flu + melphalan Blood 2008;112:

55 Auto/RIC vs tandem Auto group RIC Auto P value TRM 16% 5% 0.08 DFS Not reached 31months 0.08 OS Not reached 58months 0.9 RIC: plateau? RIC DFS auto OS auto Blood 2008;112:

56 Auto/RIC vs tandem Auto A EBMT cohort study 358 myeloma patients from 26 European centres with an HLA-identical sibling: allocated to the ASCT-RIC-arm (n=107) without a matched sibling donor: ASCT (n=251) Conditioning regimen Auto: melphalan 200 mg/m 2 RIC: ludarabine 30 mg/m 2 x 3 plus TBI 2 Gy gahrton, ASH 2009 abst 52

57 Auto/RIC vs tandem Auto RIC group vs auto group(auto + tandem Auto) group RIC auto P value Relapse(5y,%) <0.05 PFS (5y,%) <0.05 OS (5y,%) >0.05 RIC group vs tandem Auto group RIC auto P value CR rate(%) Relapse(5y,%) <0.05 PFS (5y,%) <0.05 OS (5y,%) >0.05 gahrton, ASH 2009 abst 52

58 RIC-HSCT for MM: Summary Studies have different conclusions. Difference in patient characteristics, GVHD prophylaxis, conditioning regimens may explain these discrepant results. Not the upfront choice. Yes in high-risk patient. Should go to transplantation with low tumor burden.

59 Contents Introduction RIC-HSCT for AML RIC-HSCT for ALL RIC-HSCT for CML RIC-HSCT for MM Future prospect

60 RIC-HSCT: A better future Lower TRM Conditioning regimen anti-infection immunosuppressive agents More candidates Up to 70 years or older? Young patients?

61 Unresolved issues in RIC-HSCT Role of T-cell depletion on relapse and overall survival. Impact of minimal residual disease status at the time of transplantation on relapse risk. Optimal dose and duration of post transplant immunosuppression. Role of donor lymphocyte infusion in patients with isolated mixed T-cell chimerism in the first 12 months post transplant. Bone Marrow Transplant 2008;41:

62 Outcome of nonmyeloablative vs myeloablative allo-hsct for patients older than 50 years Dana Farber Cancer Institute Figure. Comparison of the causes of treatment failure for patients over the age of 50 receiving either nonmyeloablative or myeloablative transplants. Blood. 2005;105:1810.

63 Conclusions RIC-HSCT: based on GVL effect, for older and weak patients RIC-HSCT provide a similar survival rate compare with myeloablative HSCT. Better survival require a complete remission How can improve outcome due to decrease relapse after transplantation

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