Fludarabine

Fludarabine is a purine analogue antimetabolite used as chemotherapy for hematologic malignancies. It is marketed as fludarabine phosphate and is used to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, as well as various non-Hodgkin lymphomas, either as monotherapy or in combination regimens such as fludarabine-cyclophosphamide-rituximab (FCR). It is typically given by intravenous infusion.

Mechanism of action: Fludarabine is taken up by cells and converted intracellularly to its active triphosphate form (F-ara-ATP). This metabolite inhibits DNA synthesis by incorporating into DNA and by inhibiting DNA polymerases and ribonucleotide reductase, leading to DNA strand breaks and cell death. Lymphocytes are particularly sensitive to its effects, contributing to both therapeutic activity and immunosuppression.

Administration and dosing: Fludarabine is administered as an IV infusion, often as fludarabine phosphate. Dosing commonly involves daily administration for several days per cycle, with cycles repeated at intervals (frequently every 28 days). In combination regimens, fludarabine is used with agents such as cyclophosphamide and rituximab. Dosing is adjusted for age, performance status, and renal function.

Pharmacokinetics and metabolism: The drug is activated intracellularly to F-ara-ATP and is eliminated predominantly by the kidneys. Renal impairment necessitates dose adjustments to reduce toxicity.

Adverse effects and cautions: The most common and dose-limiting toxicity is myelosuppression, leading to neutropenia and thrombocytopenia, with an increased risk of infections. Other adverse effects include fatigue, nausea, mucositis, hepatic enzyme elevations, and, less commonly, renal dysfunction or neurotoxicity. Live vaccines should be avoided during treatment, and caution is advised with nephrotoxic drugs and other immunosuppressive therapies.

History and approval: Fludarabine was developed in the late 20th century and has since become a standard option in the management of CLL and certain lymphomas, often as part of combination regimens.