Clofarabine/Busulfan-Based Reduced Intensity Conditioning Regimens Provides Very Good Survivals in Patients Allografted in Remission for Acute Myeloid Leukemia: A Retrospective Study on Behalf of the SFGM-TC

Introduction: Clofarabine/busulfan based reduced conditioning regimens (RIC) have been developed recently with the hope to improve outcomes in older patients allografted for myeloid malignancies. Indeed, clofarabine, a second generation purine analogue, has been proved to have higher anti-leukemic myeloid activity compared to fludarabine, a drug extensively used as part of RIC for allogeneic stem cell transplantation (allo-SCT). However, larger studies are needed to confirm these results.

Method: This was a retrospective study including all patients who received a clofarabine/busulfan based RIC allo-SCT for myeloid malignancies and reported within the SFGM-TC registry. Data were obtained through PROMISE, an internet-based system shared by all European transplantation centers. All patients gave informed consent allowing to collect their personal data from this data base.

RIC regimen consisted of clofarabine 30 mg/m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and one or two days of rabbit antithymocyte globulin (A1 or A2). CloB2A2 have been used first as a conditioning platform while some centers have used CloB2A1 since 2014 in order to try to decrease relapse and improve the results of the CloB2A2 patients.

The primary objective of the study was to report the main outcomes of the whole cohort at 2 years: overall survival (OS), disease free survival (DFS), relapse incidence (RI), non-relapse mortality (NRM) and GVHD and Relapse-free survival (GRFS). Secondary objectives were to identify prognostic factors and to compare outcomes between CloB2A2 (n=43)/CloB2A1 (n=41) cases.

Results: Between January 2008 and December 2016, 84 patients (males n=47, median age 61.6 years) met the inclusion criteria. The majority of patients had acute myeloid leukemia (AML, n=63) while 21 cases had myelodysplastic or myeloproliferative syndrome. Sixty-one patients were in complete remission (CR) at time of transplant (CR1 n=49. CR2, n=12), including 55 AML cases (CR1 n=43; CR2 n=12). All patients but one (bone marrow graft) received peripheral blood stem cell as graft source. All patients received matched donors (sibling n=34; unrelated n=50). There were no significant differences in term of characteristics between CloB2A2 (n=43, median follow-up 39 months) and CloB2A1 (n=41, median follow-up 21 months) patients, except the median age of the cohort which was higher in the latter group (65 vs 61 years, p=0.02) and, as expected, the median year of transplant (2013 vs 2015, p<0.001). All patients engrafted except one CLOB2A1 case.

With a median follow up of 31 months (range: 5.7-74.1) for patients alive, 2-year OS, DFS, RI, NRM and GRFS were 64.5% (53.8-75.2); 57.2% (46.2-68.2); 27.7% (18.2-37.9); 15.1% (8.2-23.9) and 43.6% (32.5-54.7), respectively, for the whole cohort. Considering AML in remission, 2-year OS, DFS, RI, NRM and GRFS were 74.2% (62-86.5); 66.8% (53.6-79.9); 23.4% (12.7-36); 9.8% (3.5-19.9) and 50.9% (36.9-64.9), respectively.

2-year outcomes were similar between CloB2A1 and CloB2A2 sub-groups: OS 61.2% (43.8-78.6) vs 65.1% (50.9-79.4), p=0.93; DFS 60.8% (44.9-76.6) vs 54.7% (39.6-69.7), p=0.93; RI 28.8% (15.1-44) vs 26.3% (14-40.3), p=0.51; NRM 10.5% (3.2-22.7) vs 19% (8.8-32.2), p=0.55; GRFS 45% (27.9-62) vs 41.7% (27-56.5), p=0.96. Comparable outcomes were also observed when considering only AML patients in CR. However, a trend for lower NRM within the CloB2A1 subgroup was observed (4.2% (0.3-18.1) vs 16% (4.8-33), p= 0.14).

In multivariate analysis, active disease at transplant was the only factor adversely impacting 2 years outcomes.

Conclusion: CloB2A2/A1 RIC regimens provides very good results for AML patients allografted in CR. CloB2A1 should be retained as a RIC platform for these patients. Our results have to be confirmed prospectively.