Abstract
Fludarabine phosphate (NSC 312878), an adenosine deaminase resistant analogue of 9-β-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.
Footnotes
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↵1 This investigation was supported by Grant CH-199 awarded by the American Cancer Society.
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↵2 Supported by USPHS Grant 1K08 CA00994-01 awarded by the National Cancer Institute, Department of Health and Human Services.
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↵3 Supported by an American Cancer Society Faculty Research Award. To whom requests for reprints should be addressed, at the Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
- Received March 7, 1986.
- Revision received June 24, 1986.
- Accepted July 31, 1986.
- ©1986 American Association for Cancer Research.
Volume 46, Issue 11
