Allogeneic Stem Cell Transplantation for MDS and sAML Following Reduced Intensity Conditioning and Preemptive Donor Lymphocyte Transfusion.

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) are diseases of the hematopoietic stem cell that are potentially curable by allogeneic stem cells transplantation (ASCT). MDS and sAML are most frequent in elderly patients with significant co-morbidity. Here we report our results with reduced intensity conditioning regimen and preemptive donor lymphocyte transfusions that have been successful in patients with advanced and refractory AML. Sixty seven patients were treated for MDS and 90 patients for sAML. The FLAMSA regimen consisted of a 4 day course of chemotherapy (Ara-C 2g/m², Fludarabin 30 mg/m², and amsacrin 100 mg/m²) followed by 3 days rest and reduced intensity conditioning with 4 Gy total body irradiation (TBI), cyclophosphamide (CY) +/− antithymocyte globulin (ATG). Overall survival at 10 years was 50% for MDS and 26% for sAML (p=0.014, log rank). In the MDS group most patients had preleukemic forms (IPSS 3 and 4). Survival at 5 years was 58% with FLAMSA, 44% with myeloablative conditioning with TBI and 67% with Busulfan (BUS). Non-relapse mortality at 5 years was 41% with FLAMSA, 20% for BUS and 50% for TBI. The relapse or progression rate was 0% for FLAMSA, 24 % for BUS and TBI respectively. In sAML the 5 year survival was 17% for FLAMSA, 57 % for BUS and 30% for TBI. Non-relapse mortality was 60% for FLAMSA, 36% for BUS and 66% for TBI, whereas the relapse rate was 62% for FLAMSA, 12.5 % for BUS and 37% for TBI (p=0.04). In multivariate analysis adjusted for disease, conditioning treatment and source of stem cells – marrow vs. mobilized blood – differences were not significant and the only significant prognostic factor was age less than 30 years (p=0.003). Therefore patients of the age of 60 years and older with AML were treated with FLAMSA containing BUS (8mg/kg in two days) instead of 4 Gy TBI. The overall survival at 2 years was 64%, 61% with FLAMSA-TBI and 70% with FLAMSA-BUS. The non-relapse mortality was 9% for FLAMSA-BUS and 37% for FLAMSA-TBI; the relapse rate was 25% at 2 years. At day 120 patients received donor lymphocytes (DLT) in 3 escalating doses from 1 × 10⁶/kg, 5 × 10⁶/kg on day 150 and 1 × 10⁷/kg on day 180, if they had no GVHD, infection or relapse. Preemptive DLT appear to prevent relapse when compared to a historical control and contemporary patients not given DLT. We conclude from these data that MDS/sAML may have a different biology in young patients, and that in the elderly we can optimize the treatment with FLAMSA-BUS as a dose reduced regimen and preemptive immunotherapy for maintenance of remission.