Fludarabine phosphate toxicity

Fludarabine phosphate (2-fluoro-arabinofuranosyladenine monophosphate) is rapidly dephosphorylated to 2-fluoro-arabinofuranosyladenine and then phosphorylated intracellularly by deoxycytidine kinase to the triphosphate. This metabolite interferes with DNA synthesis through inhibition of DNA polymerase- and ribonucleotide reductase, and it also induces apoptosis. Fludarabine phosphate is used chiefly in the treatment of low-grade non-Hodgkin s lymphoma and chronic lymphocytic leukemia (CLL). Fludarabine phosphate is given parentally and is excreted primarily in the urine its dose-limiting toxicity is myelosuppression. 

Chun HG, Leyland-Jones BR, Caryk SM, Hoth DF. Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep 1986 70(10) 1225-8. 

Toxic manifestations include myelosuppression, GI symptoms, rashes, and abnormal liver function studies at standard (4 mg/rri ) doses. Depletion of normal T cells occurs at these doses, and neutropenic fever and opportunistic infections can occur. Immunosuppression may persist for several years after discontinuation of pentostatin therapy. At higher doses (10 mg/m ), major renal and neurological complications are encountered. The use of pentostatin in combination with fludarabine phosphate may result in severe or even fatal pulmonary toxicity. 

Cladribine is indicated in the treatment of hairy cell leukemia, whereas fludarabine phosphate is utilized in chronic lymphocytic leukemia. In addition to myelosuppression, fludarabine phosphate can induce hemolytic anemia, and severe CNS toxicity has been noted with high doses. 

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