Reduced Toxicity Conditioning with Treosulfan and Fludarabine in Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes: Results of an International Prospective Phase II Trial.
Authors: Ruutu Tapani , Volin Liisa , Beelen Dietrich W. , Trenschel Rudolf , Finke Juergen , Schnitzler Marc , Holowiecki Jerzy , Giebel Sebastian , Uharek Lutz , Blau I. Wolfgang , Stelljes Matthias , Kienast Joachim , Larsson Kajsa , Zander Axel R. , Gramatzki Martin , Repp Roland , Einsele Hermann , Stuhler Gernot , Freund Mathias , Casper Jochen 
Published: October 2019

Recent preclinical and clinical data have revealed treosulfan a promising alternative conditioning agent for allogeneic hematopoietic stem cell transplantation. After previous dose-finding studies in high-risk patients suffering from various hematological malignancies this prospective, multicenter phase II trial was carried out to assess the safety and efficacy of treosulfan-based conditioning in MDS patients. Eleven centers from four countries participated. Forty-five patients (24 females, 21 males) with a median age of 50 years (range 22 – 63 years) were included. In 33 % of the transplantations the donor was related (MRD), in 67 % unrelated (MUD). Forty-seven per cent of the patients had received some kind of treatment before the transplantation, including 13 % given AML-like induction therapy. The IPSS risk groups were: 7 % “low”, 44 % “Int-1”, 31 % “Int-2” and 18 % “high”. At the time of transplantation 44 % of the patients had 5 % or more blasts in the bone marrow. In total, 9 % of all patients were considered non-eligible to standard conditioning therapy because of comorbidity or age. Treosulfan (14 g/m2, 2 hour infusion) was administered on days -6 to -4 and fludarabine (30 mg/m2, 30 min infusion) on days -6 to -2. The graft was peripheral blood stem cells in 89 % and bone marrow in 11 % of the transplantations. GvHD prophylaxis consisted of ciclosporine-A and a short course of MTX as well as ATG-Fresenius® (10 mg/m2 i.v., days -4 to -2) in case of MUD. This analysis is based on a median follow-up of 15 months (range 3.3 – 35.8 months). The conditional cumulative incidence (CI) of neutrophil (> 0.5 x 109/l), leukocyte (>1 x 109/l) and platelet (> 20 x 109/l) engraftment reached 91 %, 93 % and 89 % on day +28 and 98%, 98 % and 91 % overall, respectively. The median time to engraftment was 18, 17 and 17 days, respectively (G-CSF treatment was not recommended in the protocol). The CI of complete donor chimerism increased from 73 % (day +28) to 93 % (day +100). The frequencies (exceeding 5 %) of adverse events CTC grade III/IV with at least possible relatedness to the study drug and occurring during 28 days post-transplantation were 13 % for CTC category “gastrointestinal” and 24 % for “infection”. Frequencies for grade III/IV hyperbilirubinemia, mucositis/stomatitis and seizures were low (13 %, 2 % and 0 %, respectively). There were two cases of mild VOD which resolved before day +20 after the transplantation. The CI of grade II - IV acute GvHD was 24 % and that of grade III-IV 16 %. The CI of chronic GvHD at 1 year was 45 % and that of extensive cGvHD 25 %. The CI of non-relapse mortality was 9 % at 100 days and 15 % at 1 year, and that of relapse/progression 14 % at 1 year. The Kaplan-Meier estimates of OS and DFS at 1 year were 80 % and 71 %. These interim phase II data confirm promising safety and efficacy of this alternative treosulfan-based conditioning therapy in MDS patients, as previously reported for AML and CML patients by others. Final survival data with 1-year follow-up for all living patients will be available in September 2008. These encouraging results give a base for future trials comparing treosulfan/fludarabine conditioning with conventional conditioning regimens.