Central nervous system toxicity of high-dose systemic cytosine arabinoside

Abstract

Forty-nine adult patients with acute leukemia in relapse, refractory to conventional therapy, were studied. Increasing quantities of i.v. bolus high-dose cytosine arabinoside (cytarabine) were administered using the following schedules: 3 g/m²every 12 hrs for 4-16 consecutive doses, or 4.5 g/m²every 12 hrs for 12 consecutive doses. Patients ages ranged 16-76 years (median: 38). Thirty-seven patients had previously received either induction or maintanance therapy with conventional doses of cytarabine. Cerebral or cerebellar dysfunction attributable to cytarabine was observed in eight patients and appeared 6-8 days (mean: 6.6) after the first dose and lasted 3-7 days (mean: 4.7). None of 12 patients receiving up to 24 g/m²total dose exhibited CNS toxicity; three of 19 receiving a total dose of 36 g/m²and one of 12 patients given a total dose of 48 g/m²developed reversible neurologic dysfunction. Four of six patients receiving 54 g/m²developed CNS toxicity (irreversible in two cases), a significantly greater incidence compared to toxicity in patients receiving ≤48 g/m²total dose (P< 0.01). CNS toxicity was dose-related since patients treated for 12 consecutive doses of 4.5 g/m²had significantly greater CNS toxicity than 12 consecutive doses at 3 g/m²(P< 0.04). Systemic cytarabine doses less than 54 g/m²can be administered with minimal CNS side-effects.