Prospective Multicenter Phase II Study of Myeloablative Conditioning Consisted of Intravenous Busulfan and Fludarabine +/- Total Body Irradiation for Older Patients (55 years and older): Final Analysis of the JSCT FB09 Study

Aim: Multicenter phase II study has been conducted to investigate whether myeloablative dose of intravenous busulfan (ivBu) can be used for elderly recipients. Method: This study started in September 2009, and 32 centers participated (Trial identifier: UMIN000002426). Patients aged from 55 to 70 with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who were planned for allo-SCT (bone marrow (BM), peripheral blood (PB), and cord blood (CB)) were enrolled. Pretransplant conditioining consisted of 30 mg/m2 of fludarabine (Flu) for 6 days (total 180 mg/m2) and 3.2 mg/kg of ivBu for 4 days (divided by 4 daily, total 12.8 mg/kg) with or without total body irradiation depending on type of donor cells. Calcineurine inhibitors + methotrexate for BM or PB recipients, and tacrolimus + mycophenolate mofetil were used for CB recipients. Result: Thirty-eight patients were enrolled. Median age was 60 (55-68), 22 male and 16 female, 31 AML and 7 MDS were included. Donors were 8 matched and 2 1-Ag/allele-mismatched related BM/PB, 8 matched and 4 1-Ag/allele-mismatched unrelated BM, and 16 CB (≤2-Ag-mismatched). There was 1 whose total dose of ivBu was reduced (11.2 mg/kg) due to neurotoxicity (grade III). Thirty-five achieved neutrophil recovery (median day 17 (range, 11-45)). There was 1 who died from NRM early before engraftment (CB recipient, day 27) due to cerebral hemorrhage, and were 2 who failed to engraft (both CB recipients, one due to early relapse, and the other due to rejection). There were 2 VOD/SOS observed. Cumulative incidences of grade II-IV and III-IV acute GVHD were 37% and 16%, respectively. With respect to donor type, no grade III-IV acute GVHD was observed in transplants from matched related donors. Cumulative incidence of total chronic GVHD was 38%. Up to 24 months post-transplant, there were 11 relapse, and 7 non-relapse mortality. Cumulative incidences of non-relapse mortality and relapse at 2-year post-transplant were 21% and 31%, respectively. Overall and event-free survivals were estimated to be 58 % and 53 % at 2 year post-transplant. Conclusions: Myeloablative conditioning using Flu/ivBu12.8 mg/kg +/- TBI was well tolerated with acceptable low toxicities and was sufficient to allow donor cell-engraftment post allo-SCT for elderly patients with AML or MDS. Given the promising results of OS and PFS, phase II studies in much larger scale are now under investigation.