Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study.
Fludarabine phosphate (NSC 312878), an adenosine deaminase resistant analogue of 9-beta-D-arabinofuranosyladenine, has entered clinical trials. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform myelosuppression, as well as occasional nausea, vomiting, and hepatotoxicity. Three episodes of metabolic acidosis and lactic acidemia were noted. In addition, three patients suffered neurotoxicity. Two of these three patients had a severe neurotoxicity syndrome characterized by blindness, encephalopathy, and coma. Neither patient recovered neurological function. Neuropathological findings at autopsy were characterized by a diffuse, necrotizing leukoencephalopathy which was most severe in the occipital lobes. The medullary pyramids and posterior columns were also severely affected. This sporadic fatal neurotoxicity was observed only at doses greater than 40 mg/m2/day. The maximum tolerated dose for a 5-day infusion of fludarabine phosphate is thus 40 mg/m2/day.
D000138:Acidosis / Q000139:chemically induced; D000328:Adult; D001088:Arabinonucleotides / Q000009:adverse effects*; D001766:Blindness / Q000139:chemically induced; D001927:Brain Diseases / Q000139:chemically induced*; D003128:Coma / Q000139:chemically induced; D003711:Demyelinating Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008875:Middle Aged; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives
D001088:Arabinonucleotides; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate