Fludarabine

Dose-dependent toxic effects were seen with fludarabine.  Dose levels ~4 times greater than that recommended for CLL were associated with a syndrome characterized by delayed blindness, coma and death. Thirteen of 36 patients (36%) who received fludarabine at high doses (96 mg/m²/day for 5 to 7 days) developed this severe neurotoxicity. 

Severe bone marrow suppression (eg, anemia, thrombocytopenia, and neutropenia), has been reported in patients treated with fludarabine.  While chemotherapy induced myelosuppression is reversible, administration of  fludarabine requires careful hematologic monitoring.

Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. Clinically significant cytopenia in the reported cases has ranged from ~2 months to ~1 year; these episodes have occurred both in previously treated or untreated patients.

Cases 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.  Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis.

Transfusion-associated graft-versus-host disease has been seen rarely after transfusion of non-irradiated blood in fludarabine-treated patients.  Should give consideration to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with fludarabine. 

Patients undergoing therapy should be closely monitored for signs of hematologic and nonhematologic toxicity.  Periodic assessment of peripheral blood counts is recommended to detect the development of anemia, neutropenia and thrombocytopenia.

Tumor lysis syndrome associated with fludarabine treatment has been reported in CLL patients with large tumor burdens.  Since fludarabine can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

There is inadequate data on dosing of patients with renal insufficiency. In patients with renal insufficiency, use caution with fludarabine administration.  Patients with moderate impairment of renal function (CrCl 30-70 mL/min/1.73m²) should have their fludarabine dose reduced by 20% and monitored closely.  Fludarabine is not recommended for those with severely impaired renal function (CrCl <30 mL/min/1.73m²).