CloB2A2 Reduced-Intensity Conditioning (RIC) Regimen Prior to Allogeneic Stem Cell Transplantation Provides Significant Better Survival Compared to FB2A2 RIC Regimen in Adults with Acute Myeloid Leukemia (AML): A Study on Behalf of the SFGM-TC

Purpose: The FB2A2 (fludarabine, intermediate doses of busulfan and ATG) reduced-intensity conditioning (RIC) regimen is considered as a standard RIC regimen in many centers worldwide. Recently, we have reported the prospective good results of a clofarabine-busulfan containing RIC regimen (CloB2A2) in adults with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission (CR) at time of transplant (Chevallier et al, Haematologica, 2014). Thus, this regimen may prove to be superior to the FB2A2 regimen in patients with AML/MDS.

Patients and Methods:

The aim of this study was to compare outcomes between adult AML/MDS patients who have received, between 2009 and 2015, in 26 French centers, either a FB2A2 RIC regimen (n=170, male 61%, median age: 58 years, AML 86%, CR1 79%) or the CloB2A2 RIC regimen (n=39, including the 16 cases treated within the prospective trial mentioned above, male 62%, median age: 61 years, AML 62%, CR1 64%). The FB2A2 and CloB2A2 regimens consisted of either 30 mg/m²/day Fludarabine for 5 days or 30mg/m²/day Clofarabine for 4 or 5 days, each combined with 3.2 mg/kg/day Busulfan for 2 days and 2.5 mg/kg/day Anti-thymocyte globulin (ATG, Thymoglobuline) for 2 days. As GVHD prophylaxis, cyclosporine (CsA) alone was used in case of related donor in both groups, and for the 16 CloB2A2 patients treated within the prospective trial, while CsA+ MMF were used in case of unrelated donors. The two groups were not statistically different in term of gender, median age and performans status at transplant, median white blood count at diagnosis, median time between diagnosis and transplant, type of donors or cytogenetics for AML patients. Conversely, there were more AML patients (86% vs 62%, p=0.0004) and more patients in CR1 (79% vs 64%, p=0.04) in the FB2A2 group. Also, CloB2A2 patients were transplanted more recently (median year of transplant: 2014 vs 2011, p<0.0001).

Results: All patients engrafted, except one in the FB2A2 group. Median time of neutrophils recovery was similar between both groups (FB2A2: 17 days vs CloB2A2: 18 days, p=0.10). With a median follow-up of 28 and 14 months in the FB2A2 and the CloB2A2 groups, respectively, 2-year overall survival (OS) were 59% (51.4-66.7) for the former vs 77% (62.8-91.1) for the latter, p=0.07, 2-year leukemia-free survival (LFS) were 52.7% (44.9-60.4) vs 64% (48.1-79.9), p=0.23, 2-year relapse incidence were 31.1% (24.2-38.4) vs 27.5% (14-42.9), p=0.58, 2-year non relapse mortality were 16.2% (5.8-31.3) vs 8.5% (2.1-20.7), p=0.26 and 2-year chronic GVHD were 13.8% (8.3-20.5) vs 23.9% (8.1-44.2), p=0.12. Incidences of grade 2-4 or grade 3-4 acute GVHD were similar between both groups: FB2A2 22% vs CloB2A2 23%, p=0.86,and 8% vs 3%, p= 0.31. In multivariate analysis, FB2A2 RIC regimen was significantly associated with lower OS and LFS (HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and HR: 2.32; 95%CI: 1.12-4.79, p=0.02) contrary to CR1 status which was associated with significant higher survivals (HR: 0.48; 95%CI: 0.28-0.83, p=0.008 and HR: 0.42; 95%CI: 0.25-0.70, p=0.001). MDS (HR: 1.88; 95%CI: 1.03-3.43, p=0.03) and higher WBC at diagnosis (>median) (HR: 1.76; 95%CI: 1.10-2.82, p=0.01) were also significantly associated with lower LFS. However, when considering AML and MDS patients separately, benefit of CLOB2A2 RIC regimen appears to be restricted to AML patients (2-year OS FB2A2: 58.1% vs CloB2A2: 80.2%; HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and 2-year LFS FB2A2: 53.6%, vs CloB2A2: 76.9%; HR: 2.32; 95%CI: 1.12-4.79, p=0.02).

Conclusion: Thisretrospective comparison suggests thattheCloB2A2 RIC regimen can likely provide a higher survival compared to the use of a FB2A2 RIC regimen for AML patients. A prospective phase 3 randomized study is warranted.