Phase II Prospective Multicentre Study Testing The Efficacy and Safety Of a Clofarabine (Clo), I.v. Busulfan (Bu) and Antithymocyte Globulins (ATG)-Based Reduced-Intensity Conditioning Regimen (RIC) Before Allogeneic Stem Cell Transplantation (allo-SCT) For High-Risk Myelodysplastic Syndrome Or Acute Leukemia: The Cloric Trial

Clofarabine (Clo) is a purine analogue which was developed to overcome limitations and to incorporate the favorable pharmakokinetic properties of fludarabine and cladribine. This agent has also a significant antileukemic activity. Thus, can one exploit both the antileukemic and immunosuppressive effects of Clo for further improving outcome after RIC allo-SCT for patients with high-risk myelodysplastic syndrome (MDS) or acute leukemia. Here we report the results of a prospective multicentre trial testing the use of Clo in replacement of fludarabine in combination with i.v. Busulfan (Bu) and ATG in 30 patients with high-risk MDS/acute leukemia (clinicaltrials no. NCT00863148).

Thirty patients (male n=18, female n=12) from 6 centres were included in this study between October 2009 and August 2012. Sixteen patients were diagnosed with high-risk MDS (n=5) or acute myeloid leukemia (AML, n=11), while 13 patients had high-risk acute lymphoblastic leukemia (ALL, Ph+ n= 2, Ph- n=11) and 1 patient a biphenotypic leukemia. All patients were in first (AML/MDS, n= 10; ALL/biphenotypic n=10) or second (AML n= 3; ALL n= 4) complete remission, or in stable disease (MDS n=3) at time of transplant. Median age at transplant was 58.8 years (range: 20.5-64.5). The median interval between diagnosis and transplant was 6 months (range: 3.8-124). Karnofsky’s performans status at transplant was: 100% (n=19); 90% (n=6); and 80% (n=4).The RIC regimen consisted of: i.v. Clo 30 mg/m²/day for 4 days (day-8 to day-5), i.v. Bu 3.2 mg/Kg/day for 2 days (day-4 and day-3) and ATG (Thymoglobuline) 2.5 mg/kg/day for 2 days (day -2 and day-1). All patients received G-CSF-mobilized PBSCs and cyclosporine alone for GVHD prophylaxis, irrespective of the type of donor (sibling donors n=14; 10/10 MUD, n=16). For the purpose of this study, the single case of binephotypic leukemia was considered as ALL for comparison between AML/MDS and ALL patients. The primary endpoint of the trial was the assessment of leukemia-free survival (LFS) at one year after allo-SCT.

Engraftment was observed in all patients (100%). Median time for neutrophils (>500 /µL) and platelets (>50.000/µL) recovery was 18 (range: 14-26) and 12 (range: 0-23) days, respectively. With a median follow-up of 23 months (range: 12-37), the 1-year and 2-year overall survival (OS), leukemia-free survivals (LFS), relapse incidence (RI) and non relapse mortality (NRM) rates were 63±9% and 58+-10%, 57±9% and 53+-9%, 40±9% and 44+-9%, and 3.3±3% and 3.3±3%, respectively. Thirteen patients relapsed (43%) at a median time of 3.5 months (range: 2.3-13.1) after allo-SCT. Overall, 13 patients died, with the cause of death being relapse in 11 and GVHD in 2 (including one after donor lymphocyte injection).

1-year and 2-year OS were significantly higher for AML/MDS patients compared to ALL patients (75±10% vs 50±13%, and 75±10% vs 37±14%, p=0.04). There were trends for higher 1-year and 2-year LFS (69±12% vs 43±13%, and 69±12% vs 34±13%, p=0.08) and lower RI (57±14% vs 25±11%, and 66±14% vs 25±11%, p=0.05) for AML/MDS patients compared to ALL patients. Finally, 1-year and 2-year NRM were similar between both groups (AML/MDS: 6±6% vs 0%, p=0.36).

This phase 2 prospective multicentre trial shows that a Clo-i.v. Bu-ATG RIC regimen prior to allo-SCT in high-risk MDS/leukemia is feasible allowing for full engraftment and very low toxicity. Disease control appears to be satisfactorily, especially in AML/MDS, warranting a prospective comparison with other widely used fludarabine-based RIC regimens (e.g. Fludarabine, i.v. Bu, ATG versus Clo, i.v. Bu, ATG).

Genzyme/Sanofi provided clofarabine and financial support for the study.

No relevant conflicts of interest to declare.