Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II GEMIA protocol

Background and Objective. High-dose cytarabine (HDAra-C), mitoxantrone and etoposide are the mainstay of several active regimens against relapsed or r efractory acute myelogenous leukemia (AML). We designed a phase II study to assess the efficacy acid side effects of a time sequential application of mitoxantrone plus intermediate-dose Ara-C followed by HDAra-C plus etoposid e (GEMIA) in adult patients with refractory or relapsed AML. Design and Methods. Patients with refractory or relapsed AML were eligible for GEMIA salvage therapy, which comprised mitoxantrone 12 mg/m(2)/day on d ays 1-3, Ara-C 500 mg/m(2)/day as a 24-hour continuous infusion on days 1-3 , followed by HDAra-C 2 g/m(2)/12-hourly on days 6-8 and etoposide 100 mg/m (2)/12-hourly on days 6-8. Granulocyte colony-stimulating factor was starte d on day 14. In patients above the age of 55 the dose of Ara-C in the first sequence (days 1-3) was reduced to 250 mg/m(2). Results. Twenty patients were included, of whom 12 achieved complete remiss ion after GEMIA (60%, 95% CI 40-80%), one was refractory and five died earl y from infection. Two additional patients achieved partial remission after GEMIA and complete remission after consolidation chemotherapy, for a final CR rate of 70% (95% CI 48-88%). Neutrophils recovered at a median of 27 day s (range, 22-43) and platelets 46 days (range, 25-59) after the start of tr eatment. The median duration of remission was 133 days (range, 36-417+) whe reas overall survival time lasted for a median of 153 days (range, 13-554+) . Treatment-associated toxicity was comprised predominantly of infection, m ucositis and diarrhea that reached World Health Organization grades Ill-V i n 40%, 40% and 30% of patients, respectively. Despite the intention to rapi dly proceed to a hematopoietic stem cell transplant in patients in remissio n, only Rye patients reached the transplant. Interpretation and Conclusions. The GEMIA time sequential chemotherapy regi men appears effective in obtaining remissions in refractory and relapsed ad ult AML. The high toxicity seen, however, suggests that its design is amena ble to further improvements, especially in more elderly patients. Since rem issions are short-lived, more innovative post-remission strategies are need ed. (C) 1999, Ferrata Storti Foundation.