Low-dose clofarabine in combination with a standard remission induction in patients aged 18-60 years with previously untreated intermediate and bad-risk acute myeloid leukemia or high-risk myelodysplastic syndrome: Combined phase I/II results of the EORTC/GIMEMA AML-14A trial

The prognosis of younger patients with intermediate/high risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndromes (MDS) remains unsatisfactory.1–4 Clofarabine is a purine nucleoside analog that is highly active as a single agent in AML.5 Furthermore, synergy between clofarabine and Ara-C has been demonstrated in vitro6 and in AML patients.6–8 We have recently reported the results of the randomized phase I part of the EORTC/GIMEMA-AML-14A trial and identified clofarabine at 10 mg/m2/day on days 2, 4, 6, 8 and 10 as the maximum tolerated dose (given either in a 1-hour infusion or as push injection) in combination with Ara-C and idarubicin.9 We decided to administer clofarabine on these five days because we hypothesized that the synergy between clofarabine and Ara-C would be more effective when clofarabine was present in the leukemic cells during the entire period of Ara-C administration. Furthermore, we hypothesized that push injections of clofarabine might result in higher clofarabine peak levels than a 1-hour infusion schedule, leading to a better interaction with Ara-C and more pronounced anti-leukemic effects. We report the final results of the combined phase I and II parts of the trial.