Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia

Abstract

Purpose: Pharmacokinetics, toxicity, and therapeutic efficacy of two different methotrexate (MTX) infusions for remission induction of relapsed childhood acute lymphoblastic leukemia (ALL) were investigated in a randomized multicenter trial.

Patients and methods: Sixty patients with early bone marrow relapse received a polychemotherapy induction protocol starting with either 12 g/m2 MTX as a 4-hour infusion (high-dose [HDM]) or 1 g/m2 as a 36-hour infusion (intermediate-dose [IDM]). In HDM, leucovorin (LCV) was administered orally (12 times, 15 mg/m2 every 6 hours), beginning at hour 24. In IDM, only two doses were administered at hours 48 and 54.

Results: Median serum MTX concentrations during infusion were 716 mumol/L in HDM and 7.2 mumol/L in IDM. In HDM, MTX serum levels at hour 24 (median, 2.8 mumol/L) were significantly less than steady-state levels of IDM. Concentrations greater than 1 mumol/L were maintained for 36 hours with HDM and 45 hours with IDM. General tolerance to treatment was better in the HDM group. Mucosal lesions occurred significantly more often and were more severe after IDM treatment. A median treatment delay of 3 days was required in the IDM group but not in the HDM group. At day 15, complete remission (CR) was documented in 45% of IDM- and 48% of HDM-treated patients. Persistent blasts (> 5%) appeared more frequently in HDM than in IDM (35% v 19% of patients; P = NS). After completion of induction therapy, 28 of 30 patients in each group achieved CR.

Conclusion: Both regimens produced the same remission rates. The tendency to better antileukemic activity of IDM was accompanied by more severe side effects as a consequence of long-lasting cytotoxic MTX levels. Hence, long-term infusion of IDM followed by low-dose LCV is an effective treatment for recurrent ALL.