Improved Outcome With T-Cell–Depleted Bone Marrow Transplantation for Acute Leukemia

Summary:One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n ‫؍‬ 45) or without anti-thymocyte globulin (ATG) (n ‫؍‬ 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (Ͼ1 ؋ 10 9 /l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (Ͼ20 ؋ 10 9 /l) 24 and 19 days (P ‫؍‬ 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P ‫؍‬ 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P ‫؍‬ 0.002). Chronic GVHD was seen in 36% and 67% (P ‫؍‬ 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors. Allogeneic stem cell transplantation from HLA-identical siblings for patients suffering from acute or chronic myeloid leukemia has become a curative treatment option. Transplant-related mortality as the cause of death is approximately 30%, and most deaths are related directly or indirectly to acute or chronic graft-versus-host disease (GVHD). Allogeneic stem cell transplantation from HLAidentical siblings with an unmanipulated graft resulted in an incidence of acute GVHD of approximately 30 to 60%. 1 Several investigators have shown that removal of T cells from the graft by ex vivo T cell depletion resulted in a dramatic decrease in GVHD. However, it became rapidly apparent that T cell depletion resulted in a high incidence of graft failure and an increased risk of leukemia relapse. [2][3][4][5][6] Partial or selective depletion of different subpopulations of T cells, or T cell depletion with T cell add-back has been investigated and resulted either in enhanced graft failure or increased risk of GVHD after T cell add-back. [7][8][9] Other forms of T cell depletion including T cell depletion with monoclonal antibodies either in vivo or ex vivo have been investigated extensively, resulting in a decrease of GVHD, but a relatively high incidence of graft failure has been observed. 10,11 By adding monoclonal anti-52 antibodies to the conditioning regimen to deplete residual host T cells, the problem of graft failure has been partly overcome. 12 Another strategy of in vivo T cell depletion is the use of anti-thymocyte globulin as part of the conditioning regimen. We and others have recently shown that ATG as part of the preparative regimen in unrelated stem cell tran...

Section: Discussionmentioning

confidence: 95%

Section: Engraftment and Graft Failurementioning

confidence: 99%

mentioning

confidence: 99%

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In vivo T cell depletion with pretransplant anti-thymocyte globulin reduces graft-versus-host disease without increasing relapse in good risk myeloid leukemia patients after stem cell transplantation from matched related donors

Kröger¹,

Zabelina²,

Krüger³

et al. 2002

“…[3][4][5] This method is currently used worldwide 6 and, despite the requirement for allo-HSCT, is an important strategy for patients with an unfavorable prognosis who fail to find a donor with concordant MHC characteristics. However, unlike conventional allogeneic transplantation, this method requires a powerful, well-designed conditioning regimen, and high-efficiency T-cell depletion (TCD) of the donor.…”

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confidence: 99%

Haplotype mismatched transplantation using high doses of peripheral blood CD34+ cells together with stratified conditioning regimens for high-risk adult acute myeloid leukemia patients: a pilot study in a single Korean institution

Kim

et al. 2005

Summary:A total of 11 high-risk Korean acute myeloid leukemia (AML) patients received stem cell transplantation from human leukocyte antigen (HLA) haploidentical donors. Specifically, for eight patients with 2-3 mismatched antigens and bidirectional vectors, we used a newly designed conditioning regimen that consists of total body irradiation, busulfex, ATG, and fludarabine. The median number of CD34 þ cells infused was 15.4 Â 10 6 /kg (range, 8-21.2). These patients received neither graftversus-host disease (GvHD) prophylaxis nor post transplantation G-CSF. All of the patients who were followed up for a median of 6 months (range, 17 days-28 months) showed stable primary engraftment and had no acute GvHD or transplant-related mortality for 100 days post transplant. Three patients with high-risk or refractory disease eventually died in relapse, even with GvH-directed NK alloreactivity. However, the patients in complete remission (CR), with the exception of one patient who is alive at 18 months EFS, died at 4, 6, and 8 months post transplantation due to infections that were associated with delayed immune recovery. Our findings suggest that haploidentical transplantation represents a feasible treatment for patients with high-risk AML in CR, provided that a plan for the enhancement of immune recovery is implemented. Bone Marrow Transplantation (2005) 35, 959-964.

“…Immunosuppressive drugs, such as cytarabine and thiotepa, may facilitate engraftment as well. 35,36 It would be ideal to avoid irradiation altogether for these young patients, due to effects upon growth, organ development, and increased risk of secondary cancers. 37,38 Although chemotherapy-only regimens appear successful in achieving engraftment in SAA patients receiving MSD, irradiation may be necessary for URD or partially matched related donor recipients.…”

Section: Discussionmentioning

confidence: 99%

Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion

Bunin

Aplenc

Iannone

et al. 2005

Summary:Both increased graft rejection and increased graft vs host disease (GVHD) remain obstacles to success for unrelated donor (URD) BMT for patients with SAA. Partial T cell depletion (PTCD) may decrease the risk of severe GVHD, while still maintaining sufficient donor T lymphocytes to ensure engraftment. We report on 12 patients with SAA who underwent PTCD URD BMT. All patients had failed medical therapy or relapsed following initial responses, and were transfusion dependent. The median age was 6 years, and there were five males. Donors were matched for four patients, and mismatched for eight. All patients received total body irradiation with either Ara-C or thiotepa and cyclophosphamide. PTCD was accomplished using monoclonal antibody T10B9 or OKT3 and complement. All patients engrafted, with a median time of 18 days to ANC 4500. Only one patient had greater than grade II acute GVHD; two patients had limited and one patient extensive chronic GVHD. Nine patients are alive and transfusion independent at a median months post BMT. Three patients died from infection or renal failure. This series suggests that an aggressive immunosuppressive conditioning regimen with PTCD results in successful engraftment and minimal GVHD in pediatric patients with SAA, even with HLA mismatched donors.