Allogeneic Stem Cell Transplantation after Conditioning with Treosulfan, Etoposide and Cyclophosphamide for Patients with Acute Lymphoblastic Leukemia (ALL) Not Eligible for TBI-Containing Regimens: A Phase II-Study on Behalf of the German ALL Study Group (GMALL) and the German Cooperative Transplant Study Group

Total-body-irradiation (TBI) based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with acute lymphoblastic leukemia (ALL). Within a multi-center prospective phase II study we have investigated the toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide, and cyclophosphamide in patients with ALL. Inclusion criteria were complete remission, non-eligibility for TBI or patient’s wish to avoid TBI. Between July 2007 and August 2010, 50 patients with a median age of 46.5 years were enrolled at ten German centers. 74% of the patients were in 1. CR and 26% 2. or higher CR.The conditioning regimen consisted of treosulfan (12 g/m²) given intravenously on three consecutive days (-7, -6, and -5) plus etoposide (30 mg/kg BW) infused on day -4, and cyclophosphamide (60 mg/kg BW) intra­venously on day -3 and -2. GvHD prophylaxis consisted of ATG-Fresenius (Fresenius Biotech, Gräfelfing, Germany), 20 mg/kg on day -3, -2, and -1 for unrelated donors, and optional for matched related donors. All patients received cyclosporine A and short course methotrexate (days 1, 3 and 6). Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. Primary graft-failure was observed in three patients. The toxicity was moderate including VOD in four patients. Acute graft-versus-host disease (GvHD) grade II - IV and grade III/IV was noted in 53 % and 14 %, respectively. Chronic GvHD at one year was seen in 41 %, which was extensive in 14 %. After a median follow-up of 24 months, the cumulative incidence of non-relapse mortality (NRM) at one year was 8 %, and of relapse 36 % and 51 % at one and two years, respectively. Patients in first complete remission showed a 12-months relapse-rate of 23 % compared to 69 % in patients beyond first complete remission. After 24 months, the respective rates were 34 % compared to 92 %. The estimated 2-year disease-free and overall survival was 36 % and 48 %, respectively. Patients in first complete remission experienced a median DFS of 25.7 months versus 8.9 months in patients beyond first complete remission. The 12- and 24-months DFS-rates were 69 % and 50 %, respectively, compared to 23 % and 0 %, respectively. Overall, we conclude that a conditioning regimen containing treosulfan, etoposide, and cyclophosphamide resulted in a low NRM , but a high risk of relapse in 2. or higher complete remission. This regimen might represents an alternative therapy for patients with ALL in 1.complete remission who need allogeneic stem cell transplantation but are not eligible for total-body irradiation. (registered under NCT00682305)