There are clear dose-dependent toxic effects seen with fludarabine. Dose levels approximately 4 times greater (96 mg/m 2/day for 5 to 7 days) than that recommended for CLL (25 mg/m 2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received fludarabine at high doses (96 mg/m 2/day for 5 to 7 days) developed this severe neurotoxicity. This syndrome has been reported rarely in patients treated with doses in the range of the recommended CLL dose of 25 mg/m 2/day for 5 days every 28 days. The effect of chronic administration of fludarabine on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy. 

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine. In a Phase I study in solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy induced myelosuppression is often reversible, administration of fludarabine requires careful hematologic monitoring. 

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. 

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis. 

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with fludarabine. 

In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended. 

Of the 133 CLL adult patients in the two trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease.