Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic haematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial

Based on previous preclinical and clinical data which revealed treosulfan a promising alternative conditioning agent prior to allogeneic haematopoietic stem cell transplantation, a prospective, multicentre phase II protocol was conducted to assess the safety and efficacy of treosulfan-based conditioning in MDS patients. Eleven centres from 4 countries participated. In total, 45 patients with a median age of 50 years (range: 22 - 63 years) were included. Of the donors 33% were matched related and 67% unrelated (MUD). Thirteen per cent of the patients had received AML-like induction therapy and 7% lowdose chemotherapy. The IPSS risk groups were: 7% "low", 44% "Int-1", 31% "Int-2" and 18% "high". At study entry 44% of the patients had 5% or more blasts in the bone marrow. Treosulfan (14 g/[m.sup.2], 2 hour infusion) was administered on days -6 to -4 and fludarabine (30 mg/[m.sup.2], 0.5 hour infusion) on days -6 to -2. GvHD prophylaxis consisted of ciclosporine-A and a short course of MTX as well as ATG-Fresenius® (10 mg/[m.sup.2] i.v., days -4 to -2) in case of MUD. The graft was PBPC in 89% and BM in 11%. This final analysis is based on a median follow-up of 25.7 (range: 12.2 - 41.4) months. The median times to neutrophil (> 0.5 x [10.sup.9]/l) and platelet (> 20 x [10.sup.9]/l) engraftment were 18 and 17 days, respectively. The cumulative incidence (CI) of complete donor chimerism was 73% on day +28 and 93% on day +100. The frequencies of adverse events CTC grade III/IV (exceeding 5%) occurring during 28 days post-transplantation were 80% for CTC category "infection"; 22% "gastrointestinal"; 9% "pulmonary/ upper respiratory" and 7% "neurology". Frequencies for grade III/IV hyperbilirubinaemia, mucositis/stomatitis and seizures were 13%, 0% and 0%, respectively. There were two cases of mild VOD which resolved before day +20 after the transplantation. The CI of grade II - IV aGvHD was 24% and that of grade III - IV 16%. The CI of cGvHD at 2 years was 59% and that of extensive cGvHD 28%. The CI of non-relapse mortality was 9% at 100 days and 17% at 2 years, and that of relapse/progression 16% at 2 years. Accordingly, the KaplanMeier estimates of OS and DFS at 2 years were 71% and 67%. These final phase II data confirm favourable safety and efficacy of the treosulfan-based conditioning therapy in MDS patients. Overall, promising survival results in this MDS patient population give a reasonable base for comparative allogeneic transplantation trials.