Sequential Regimen of Clofarabine, Cytarabine and Reduced Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) in Primary Treatment Failure

Introduction. The prognosis of AML in primary treatment failure remains very poor. Salvage allo-SCT might be a potential therapeutic option in this setting. However, the limited feasibility of standard myeloablative conditioning (MAC) allo-SCT in these patients, lead to the development of the so-called “sequential” transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and transplant conditioning within the same procedure - ). With this background, we conducted a phase 2 prospective trial to test the feasibility of a novel “sequential” approach, using busulfan and clofarabine.

Study objective. This phase 2 prospective multicenter trial (ClinicalTRials.gov Identifier: NCT01188174) aimed to assess the efficacy (survival) and safety of a new “sequential“ conditioning regimen based on Clofarabine 30 mg/m²/d for 5 days, aracytine 1g/m²/d for 5 days and after a 3 days rest, cyclophosphamide 60 mg/Kg/d for 1 day, IV Busulfan 3.2 mg/Kg/d for 2 days and ATG (Thymoglobuline*) 2.5mg/Kg/d for 2 days in AML patients in primary induction failure (i.e. persistent leukemia after 2 courses of induction chemotherapy or persisting bone marrow hypoplasia following induction chemotherapy). For GVHD prophylaxis, patients received cyclosporine alone in case of a family donor, and cyclosporine+mycophenolate mofetil in case of an HLA-matched unrelated donor (MUD: 10/10 or 9/10).

Patients and transplant characteristics. Between 2010 and 2013, a total of 24 patients were included. The median age of patients at time of allo-SCT was 47 (range, 20–55) years. At time of conditioning, all patients were confirmed having AML in primary induction failure. Karyotype was intermediate in 9 patients (38%) and adverse in 13 patients (54%), no patients had favorable karyotype and karyotype was missing in 2 patients (8%). Seven patients (29%) had secondary AML. The donor was an HLA-identical sibling donor in 15 cases (62%) and an HLA MUD in 9 cases (38%). Per protocol performance status was comprehensively assessed at time of inclusion. The Karnofsky score was 50%, 60%, 70%, 80%, 90%, and 100% in 2 (8%), 1 (4%), 2 (8%), 6 (25%), 8 (33%) and 5 (21%) patients, respectively.

Results. ANC>500/μL was achieved at a median of 15 (range, 13–30) days after allo-SCT. The cumulative incidence of disease progression (RI) was 46% (95%CI, 25–64%) at one year and 59% (95%CI, 36–76%) at 2 years; while the cumulative incidence of NRM was 8% (95%CI, 1–24%) at one year and 13% (95%CI, 3–30%) at 2 years. The Kaplan-Meier estimate of overall (OS) was 54% (95%CI, 34–74%) at one year and 37% (95%CI, 17–56%) at 2 years. The Kaplan-Meier estimates of leukemia-free survival (LFS) were 46% (95%CI, 26–66%) at one year and 28% (95%CI, 9–46%) at 2 years.

Conclusions. Results from this phase 2 prospective multicenter trial validated the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen. Such sequential regimen appeared to be safe with a 8% NRM at one year in high risk patients, and exhibits an efficient disease control both in very high risk refractory AML with a LFS of 46% at 1 year, warranting further investigations as part of phase 3 trials.