Fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine), a novel
purine nucleoside, has demonstrated excellent preclinical antitumor activity and little toxicity in phase I clinical trials. We evaluated the clinical use of
fludarabine given as a continuous intravenous (IV) infusion for
remission induction in patients with relapsed or refractory
leukemia. Thirty infusions were administered to 25 patients. At doses less than or equal to 125 mg/m2/d for five days, only three of 17 patients cleared their bone marrow of leukemic cells, and none achieved complete remission (CR). Nine patients received doses of 150 mg/m2/d for five days or 125 mg/m2/d for seven days. Four of these patients achieved CR (three patients with
acute nonlymphoblastic leukemia (
ANLL), one patient with
acute lymphoblastic leukemia (ALL]. However, severe CNS toxicity was encountered in five patients at the two highest dose levels. Initial symptoms of neurotoxicity were delayed from 21 to 43 days after starting treatment and consisted of
optic neuritis,
cortical blindness, altered mental status, and
generalized seizure. Only one patient regained visual and neurologic function; four other patients experienced progressive neurologic deterioration and died. Clinicopathologic evaluation suggested widespread, severe
demyelination as the etiology of these reactions. We conclude that
fludarabine is an effective
drug for
remission induction in acute
leukemia. However, doses required to achieve CR are associated with unacceptable CNS toxicity. In view of its potent antileukemic activity, further evaluation of
fludarabine at lower doses (less than or equal to 75 mg/m2/d for five days) may be warranted in combination with other chemotherapeutic agents for the treatment of patients with acute
leukemia.