Low dose clofarabine in combination with a standard remission induction in patients 18-60 years with previously untreated intermediate and bad risk AML or high risk MDS:combined Phase I/II results of the EORTC/GIMEMA AML-14A Trial

Background: Clofarabine, a second-generation purine analog, is highly active as a single agent in AML and has synergistic activities with cytosine arabinoside (Ara-C). We herein report the results of the combined phase I and II parts of the EORTC/GIMEMA AML-14A study. Methods: Patients aged 18-60 years with previously untreated intermediate/high-risk AML or high-risk MDS were randomized for remission induction chemotherapy (1 or 2 cycles) between 1-hr infusion (Arm A) or push injection (Arm B) of clofarabine administered at 10 mg/m2 on days 2, 4, 6, 8 and 10 in combination with Ara-C (100 mg/m2/day on days 1-10) and idarubicin (10 mg/m2/day, on days 1, 3, and 5). One cycle of consolidation including Ara-C and idarubicin was administered in patients who achieved a CR/CRi. Primary endpoint was the CR/CRi rate after 1 or 2 cycles. Results: Among the 62 eligible patients (31 in each randomized arm), 5 had high-risk MDS. Median age was 50 years (range 20-60). The CR/CRi rate after induction was 84% (26 of 31 patients) in each arm (95% CI: 66-95%). During the induction/consolidation phase, 4 toxic deaths occurred in Arm A and one in Arm B. However, documented fungal infections during the induction phase were more frequent in Arm B (29%) than in Arm A (13%). Conclusions: Both low dose clofarabine containing regimens yielded an impressive CR/CRi rate (84%) with acceptable toxicity among patients with intermediate/high-risk AML or high-risk MDS.