Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia

Neurological toxicity occurred in 8/219 patients treated with fludarabine (FAMP), 30 mg/m² per day and cytosine arabinoside (Ara-C), 0.5 g/m² per hour for 2-6 hours for 5 days, for new or relapsed acute leukemia or myelodysplasia. Two patients developed severe, progressive cerebral dysfunction that was ultimately fatal. This toxicity was similar to that seen with high-dose fludarabine therapy and was limited to patients with serum creatine ≥2.0 mg/dl and age over 60 years, occurring in 2/9 such patients compared to 0/210 among the other patients (p< 0.005). Since FAMP is partially excreted by the kidney, toxicity in these two patients was likely due to receiving an effectively high dose of FAMP. Five patients developed peripheral neuropathy but there was no association with age, creatinine, dose of Ara-C, or number of courses. A patient, who also received intrathecal Ara-C, developed myelopathy. At this dose rate and duration of Ara-C peripheral neuropathy rarely arises, and cerebral toxicity is not seen. Neither toxicity was observed in 481 chronic lymphocytic leukemia patients treated with FAMP alone, by the same dose and schedule, suggesting that combination with Ara-C is important for the development of at least the peripheral neuropathy. The incidence of neurotoxicity with FAMP/Ara-C is low especially in comparison with high-dose Ara-C therapy (3 g/m² over 2 hours). Cerebral toxicity can likely be decreased by dose reduction of FAMP in patients with increased creatinine and peripheral neuropathy decreased by detailed neurological examination before courses of FAMP/Ara-C.