Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia

Purpose: To determine the remission rate and toxicity of mitoxantrone, etop oside, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/o r refractory acute myeloid leukemia. Patients and Methods: MEC therapy consisted of mitoxantrone 6 mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2 hours fo llowed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of phar macokinetic interactions, drug doses were decreased to 60% of those found t o be effective without coadministration of CSA, MDR expression was evaluate d by reverse transcriptase polymerase chain reaction, flow cytometry, and t he ability of CSA at 2.5 mu mol/L to increase intracellular accumulation of H-3-daunomycin in blasts from bone marrow specimens. Results: The remission rate was 35% (n = 23 of 66), Overall, 35% of patient s (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achiev ed partial remission, and 9% of patients (0 = 6) died of infection. Exposur e to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59), toxicities included infection, cardiotoxicity, myelosuppre ssion, stomatitis, and reversible increases in serum creatinine and bilirub in, In most who had relapsed while receiving therapy or whose induction the rapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients. Conclusion: Serum levels of CSA capable of reversing multidrug resistance a re achievable in children with acceptable toxicity, The CR rate of 35% achi eved in this study is comparable to previously reported results using stand ard doses of mitoxantrone and etoposide, The use of CSA may have improved t he response rate for the MDR1-positive patients so that it was not differen t from that for the MDR1-negative patients. (C) 2000 by American Society of Clinical Oncology.