Feasibility of Cyclosporine and Short-Term Methotrexate for Graft-Vs.-Host disease Prophylaxis in T-Cell-Replete, Reduced-Intensity Allogeneic Bone Marrow Transplantation From Unrelated Donors.

Abstract 4347

Optimal graft-vs.-host disease (GVHD) prophylaxis in T-cell-replete, reduced-intensity allogeneic stem cell transplantation from an unrelated donor (u-RIST) has not been established yet. Tacrolimus-based acute GVHD prophylaxis has been widely used in allogeneic stem cell transplantation from unrelated donors. In addition, T-cell-depletion conditioning regimen containing anti-thymocyte globulin (ATG), or alemtuzumab with/without 2-4 Gy total body irradiation (TBI) has been reportedly applied in u-RIST. However, in-vivo T cell depletion using ATG or alemtuzumab may cause increased risk of infection or relapse after transplantation. TBI may also possibly cause increased incidence of GVHD via tissue damage. Here we report the feasibility of using cyclosporine and short-term methotrexate for GVHD prophylaxis in u-RIST. The conditioning regimen consisted of fludarabine and busulfan (Flu+Bu) without T-cell depletion, such as ATG or alemtuzumab, and without TBI for u-RIST in patients who received prior chemotherapy.

In this study, we retrospectively analyzed 30 consecutive patients with hematologic malignancies (median age: 53; range: 22 to 69 years; AML: 11; ALL: 9; MDS: 2; NHL: 5; ATL/L: 3) who received unrelated-donor bone marrow transplantation from HLA 6/6 (A, B, DRB1), either allele-matched (n = 24 patients), one DRB1 allele-mismatched (n = 5 patients), or one A allele-mismatched (n=1) donor at our institution between September 2002 and June 2009. All patients received at least one cycle of prior chemotherapy (median cycle: 6; range: 1 to 19). Of these, 15 patients (50%) were at high risk of relapse. For all, acute GVHD prophylaxis consisted of cyclosporine and short-term methotrexate (day 1: 10mg/m²; day 3 and 5: 7 mg/m²). The reduced intensity conditioning consisted of fludarabine 180mg/m² and oral busulfan 8 mg/kg for 12 patients; the other 18 patients' conditioning consisted of fludarabine 180 mg/m² and intravenous busulfan 8mg/kg.

Neutrophil and platelet engraftments were achieved in 100% (30/30) and 93% (28/30) of patients, respectively. The median times for neutrophil and platelet engraftments were 16 days (range: 12 to 26 days) and 24.5 days (range: 18 to 291 days), respectively. In patients receiving oral and intravenous busulfan for conditioning, the achievement rates of complete T-cell chimerism by day 100 were 75% (9/12) and 100% (18/18), respectively (p = 0.03). The median period of follow-up was 280 days (range: 34∼1987). During the follow-up our observational periods, 19 patients were alive and 11 patients died of relapse (n = 8) or transplant-related mortality (n = 3). The cumulative incidences of acute GVHD of grade II to IV and III to IV at day 100 were 40% and 17%, respectively. Extensive type of chronic GVHD was 30% in 23 evaluable patients. The 2-year overall survival (OS) and event-free survival rates were 58% (low/standard risk group: 78%; high risk group: 43%; p = 0.04) and 52% (low/standard risk group: 72%; high risk group: 33%; p = 0.01), respectively. In multivariate analysis, grade III to IV acute GVHD and disease status at high relapse were significantly associated with worse OS (p = 0.03 and 0.008, respectively). Day 100 and 2-year TRM were 3% and 10%, respectively. Cyclosporine and short-term methotrexate for GVHD prophylaxis without T-cell deplete-conditioning allowed acceptable incidence of GVHD even in u-RIST. Additionally, only Flu+Bu conditioning for uRIST ensured high rate of complete T-cell chimerism especially in patients receiving intravenous busulfan. Our results suggested that we might be required to determine optimal conditioning and GVHD prophylaxis regimens based on patient characteristics, including a history of prior chemotherapy.