Comparison of Outcomes after Reduced-Intensity Versus Myeloablative Stem Cell Transplantation in 128 Patients with Acute Myeloid Leukemia: A Single-Center Analysis.
Authors: Ohara Fusako , Fukuda Takahiro , Kato Ruri , Yamasaki Satoshi , Kim Sung-Won , Mori Shin-ichiro , Tanosaki Ryuji , Heike Yuji , Makimoto Atsushi , Tobinai Kensei , Takaue Yoichi 
Published: October 2019

Abstract
Background: It is still unclear whether the intensity of the conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) affects the overall outcome of patients with acute myeloid leukemia (AML).
Patients and Methods: We retrospectively surveyed the data of 128 patients with AML who received HCT between Jan, 2000, and Mar, 2005. Cytogenetic risk groups based on the SWOG classification were favorable (n=19), intermediate (52), unfavorable (41), and unknown (16) risks. Disease status was CR1 (n=31), ≥CR2 (36), relapse (33), primary refractory (24) and untreated (4). Regimens with myeloablative conditioning (n=71) included cyclophosphamide with 12 Gy TBI (n=48) or busulfan (23), and those with reduced-intensity conditioning (RIC, n=57) included 8 mg/kg of busulfan plus 180 mg/m2 of fludarabine or 0.66 mg/kg of cladribine with or without 2–4 Gy TBI. The patients received bone marrow (n=55), G-CSF-mobilized PBSC (62) or cord blood (11) from either an HLA-matched relative (n=46), a mismatched relative (18) or an unrelated volunteer (64). For GVHD prophylaxis in the myeloablative group, 83% of the patients received cyclosporine (CyA) plus methotrexate (MTX), while the RIC group received CyA with (44%) or without (54%) MTX. The median follow-up of surviving patients was 1,347 days (423–2,282).
Results: Patients who received RIC were older than those who received a myeloablative regimen (median age, 55 vs 37 years). The engraftment rates (95% vs 93%) and cumulative incidence of grade II-IV acute GVHD (39% vs 38%) were comparable between the two groups, but the incidence of grade III-IV acute GVHD was higher in the RIC group (21% vs 10%). The 3-year overall survival (OS) according to pre-transplant disease status was 58% in CR1, 53% in ≥CR2, 18% in relapse, and 25% in primary refractory. The 3-year OS according to cytogenetic risk groups was 63% in favorable, 42% in intermediate, 26% in unfavorable, and 35% in unknown risk. The 3-year OS of patients who received grafts from an HLA-matched relative was 52%, and this was 31% in those who received grafts from an alternative donor (unrelated or HLA-mismatched related donor). The 3-year OS and relapse rate were essentially comparable between the two groups, i.e. 33% and 35% for the RIC group and 44% and 47% for the myeloablative group, respectively. Unexpectedly, the 3-year non-relapse mortality (NRM) was higher in the RIC group (52% vs 28%). In a multivariate analysis, pre-transplant non-remission disease status (HR: 3.0 [95% CI, 1.9–5.0] p<0.0001) and transplantation from an alternative donor (HR: 2.4 [95% CI, 1.4–4.2] p=0.0006) were associated with poor OS. The intensity of the conditioning regimen was not a risk factor for poor OS.
Conclusions: Our data showed that OS and relapse rate were comparable between the RIC and myeloablative groups, although the RIC group was predominantly composed of older patients. In contrast to our expectation, our data showed higher NRM after RIC, which might be due to a higher incidence of grade III-IV acute GVHD in this group as a result of the intentional induction of a graft-versus-leukemia effect by the rapid tapering of immunosuppresion. To improve survival, GVHD prophylaxis should be optimized in older patients undergoing HCT with a RIC regimen.