Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia

This study was performed to examine the feasibility and toxicity of the combination of mitoxantrone, fludarabine, cytarabine as bolus (B) or continuous infusion (CI) and granulocyte- colony stimulating factor (G-CSF) in patients with recurrent and refractory acute myeloid leukemia (AML).

29 patients with relapsed (n =17) or refractory (n =12) AML were treated with the Mito-FLAG protocol consisting of mitoxantrone (7 mg/m(2), days 1/3/5), fludarabine (15mg/m(2), every 12 h, days 1-5), cytarabine (Ara-C) as bolus infusion (1000 mg/m(2) over 1 h, every 12 h, days 1-5) (n =15) or as continuous infusion (100-150 mg/m(2) over 24 h, days 1-5) (n =14), and G-CSF (5 mgr;g/ kg/day, day 0 until a neutrophile count of 0.5 x10(9)/l).

17 patients (59%) and 1 patient (3%) achieved complete remission (CR) and partial remission (PR), respectively; thus the overall response rate was 62%. Following Mito-FLAG, 5 patients with CR underwent high-dose therapy (HDT) with allogeneic (n = 2) or autologous (n = 3) stem cell transplantation (SCT). With a median follow-up of 28 (range 6-54) months, 4 transplanted patients are alive in CR (n = 2) or in relapse (n = 2). The median duration of event-free survival (EFS) and overall survival (OS) was 3.2 and 6.8 months, and probabilities of EFS and OS after 1 year were 14 and 34%, respectively. The 1-year rates for EFS and OS in this group were 18 and 53%, respectively. Median duration of WHO grade 4 granulocytopenia and thrombocytopenia was 20 and 23 days, respectively. Nonhematological side effects were moderate, predominantly reaching WHO grades 1-2. Neutropenic fever was seen in 85% of courses, with a median duration of 4 (1-38) days. Four patients (14%) suffered an early death because of aplasia (n = 2), pneumonia (n =1) or progressive AML (1 nonresponding patient).

Our data suggest that the Mito-FLAG protocol is feasible and can be safely performed with both schedules of Ara-C. In this study the regimens have shown high efficacy and acceptable toxicity in patients with relapsed or refractory AML. We currently examine the importance of bolus versus continuous infusion of Ara-C as part of the Mito-FLAG regimen in a prospective randomized multicenter trial.