Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia

Ten pediatric patients with refractory leukemia received continuous infusion high-dose cytosine arabinoside (ara-C) according to one of two escalating dosage schedules: (1) a 500-mg/m² rapid infusion loading dose followed by 3.5 g/m² per day continuous infusion daily for four days, or (2) a 600-mg/m² rapid infusion loading dose followed by 5.0 g/m² per day continuous infusion daily for four consecutive days. Major toxicity at the lower dosage level was grade IV hematopoietic aplasia of three weeks' duration. At the higher dosage level, there was a prohibitive toxicity in multiple organ systems including transient noncardiogenic pulmonary edema, fungal infections, peritonitis, severe diarrhea, transaminase elevations, and one treatment-related death due to acute renal failure. In contrast to other methods of administration of high-dose ara-C, no CNS toxicity occurred. Oncolytic responses were seen in all patients and two achieved brief, partial remissions. Steady-state plasma ara-C concentrations were 13 to 40 μmol/L at the 3.5-g/m² dosage level and 10 to 225 μmol/L at the 5-g/m² dosage level; CSF concentrations at both dosages ranged from 2 to 5 μmol/L. Intracellular levels and ratios of 1-β-D-arabinofuranosylcytidine-5'triphosphate and endogenous deoxycytidine 5'-triphosphate in marrow blasts varied widely at steady state infusion. No positive correlation existed between steady-state plasma ara-C levels, toxicity, oncolytic effect, or intracellular nucleotide concentration.