Reduced Intensity Compared to High Dose Conditioning for Allotransplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Comparative Clinical Analysis.

Abstract

We evaluated the comparative safety and efficacy of stem cell transplantation using reduced intensity (RI) vs myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Thirty two patients [18 males, median age 54 (range 19–69)] underwent a RI HSCT from January 2000- September 2003, and these were compared to 187 patients [93 males, median age 39 (range 18.4–60.3)] who received MA transplants between January 1990 – September 2003. Disease status in the 2 groups was similar, (AML in CR1: RI 38% vs MA 38%; CR2: 22% vs 15%; AML relapse: 13% vs 20% and MDS 28% vs 27%). Patients were eligible for RI if age >55 with HLA matched sibling donor (Sib) or >45 with unrelated bone marrow (BM) or umbilical cord blood (UCB) donor; extensive previous therapy including previous transplant or major co-morbidity. RI donors were Sib (n=17, 53%), unrelated UCB (n=14, 44%), or unrelated BM (n=1). MA donors were Sib (n=176, 94%) and UCB (n=11, 6 %), p<0.01. RI conditioning included an alkylator (busulfan (Bu) or cyclophosphamide (Cy), a nucleoside analogue (fludarabine or cladribine) and 200 cGy total body irradiation (TBI), while MA conditioning was Cy/TBI (1320 cGy) (n=177) or Bu/Cy (n=10). Median follow up is 1.7 years in RI recipients and 4.2 years in MA. Neutrophil engraftment was more rapid in the RI group (median =11.5 days vs 21 days) with 3% and 6% graft failure respectively in the RI and MA groups. The cumulative incidence of Grade III–IV acute graft versus host disease (GVHD) was 22%±14% in RI vs 12±4% after MA HSCT. The cumulative incidence of relapse or disease progression at 1 year was 31% after RI vs 22% after MA HSCT (p=0.06). Disease free survival (DFS) at 1 year was 31± 16% in RI and 37%± 7% in the MA group (p=0.14). Multivariate regression analysis showed that neither conditioning intensity (NST RR=1.4, p=0.14) nor donor choice (UCB RR 0.9, p=0.63) significantly altered DFS. More failures (relapse or death) followed transplant for AML in relapse (RR=1.5, p=0.05), recipient seropositive for CMV (RR1.4, p=0.03) and development of Grade III/IV GVHD (RR 1.9, p<0.01), with MDS having an outcome similar to AML in remission (RR 1.2,p=0.28). These data suggest that allografts for AML or MDS using RI conditioning, even for older patients or using unrelated UCB can yield satisfactory outcomes and extended DFS. Advances in GVHD management and new approaches for patients in relapse are needed to improve these outcomes.