Fludarabine Phosphate

A fluorinated deamination-resistant nucleotide analog of the antiviral agent vidarabine (9-b-d-arabinofuranosyl-adenine), this compound is active in CLL and low-grade lymphomas. After rapid extracellular dephosphorylation to the nucleoside fludarabine, it is rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. This antimetabolite inhibits DNA poly-merase, DNA primase, DNA ligase, and ribonucleotide reductase, and is incorporated into DNA and

RNA. The triphosphate nucleotide is an effective chain terminator when incorporated into DNA, and the incorporation of fludarabine into RNA inhibits RNA function, RNA processing, and mRNA translation. A major effect of this drug may be its activation of apoptosis, which may explain its activity against indolent lymphoproliferative disease, where only a small fraction of cells are in S phase.

Fludarabine phosphate administered intravenously is rapidly converted to fludarabine in the plasma. The terminal t/2 of fludarabine is ~10 hours. The compound is primarily eliminated by renal excretion, and ~23% appears in the urine as fludarabine because of its relative resistance to deamination by adenosine deaminase (ADA).

Fludarabine phosphate (fludara) is available for intravenous use. The recommended dose of fludarabine phosphate is 20-30 mg/m2 daily for 5 days. The drug is administered intravenously by infusion during a period of 30 minutes to 2 hours. Dosage may need to be reduced in renal impairment. Treatment may be repeated every 4 weeks, and at these doses gradual improvement usually occurs during a period of 2-3 cycles.

Fludarabine phosphate is used primarily for the treatment of patients with CLL, although experience is accumulating that suggests effectiveness in B-cell lymphomas refractory to standard therapy. In CLL patients previously refractory to a regimen containing a standard alkylating agent, response rates of32-48% have been reported. Activity also has been seen with indolent non-Hodgkin's lymphoma, promyelocytic leukemia, cutaneous T-cell lymphoma, and Waldenstrom's macroglobulinemia. In patients with previously untreated low-grade lymphomas, fludarabine phosphate in combination with either cyclophosphamide or with dexamethasone and mitox-

antrone has resulted in a high rate of response.

Toxic manifestations include myelosuppression, nausea and vomiting, chills and fever, malaise, anorexia, and weakness. Lymphopenia and thrombocytopenia are dose limiting and possibly cumulative. CD4+ T cells are depleted with therapy. Opportunistic infections and tumor lysis syndrome have been reported. Peripheral neuropathy may occur at standard doses. Altered mental status, seizures, optic neuritis, and coma have been observed at higher doses and in older patients. Rarely, CLL patients may develop an acute hemolytic anemia or pure red cell aplasia during fludarabine treatment. Severe pneumonitis responsive to glucocorticoids has been encountered. Because a significant fraction of drug (~25%) is eliminated in the urine, patients with compromised renal function should be treated with caution, and initial doses should be reduced proportionate to serum creatinine levels.

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