Unexpected acute neurologic toxicity in the treatment of children with acute lymphoblastic leukemia

Background: Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolida-tion and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL. Purpose: This report describes these toxic effects and outlines our suc-cessful approach to the problem. Methods: The standard four-drug in-duction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/ m² every 6 hours four times daily in four weekly courses concomitant with week-ly triple intrathecal therapy-MTX, ARA-C, and hydrocortisone-plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercapto-purine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy. Results: Twenty-five of the 138 patients evalu-ated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite dis-continuation of intrathecal ARA-C, which eliminated simultaneous in-travenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amend-ment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study. Conclusion: These findings sug-gest that folate replacement due to ad-ministration of leucovorin modulated MTX toxicity and/or modified an inter-action among VP-16, ARA-C, intrathe-cal therapy, and the central nervous system. [J Natl Cancer Inst 84:252-256, 1992]