Fludarabine (DB01073): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Evolving Role in Oncology

Executive Summary

Fludarabine is a fluorinated purine nucleoside analog that has been a cornerstone of hematologic oncology for over three decades. Initially approved in 1991 for refractory B-cell chronic lymphocytic leukemia (CLL), its role has evolved significantly. This monograph provides a comprehensive analysis of Fludarabine, covering its chemical properties, molecular pharmacology, clinical applications, safety profile, and its shifting position in the therapeutic landscape.

Chemically, Fludarabine is a small molecule antimetabolite, administered as the prodrug fludarabine phosphate. Its key structural feature, a fluorine atom at the C2 position of the purine ring, confers resistance to deamination, enhancing its bioavailability and efficacy. Following administration, it is rapidly dephosphorylated to its main circulating metabolite, 2-fluoro-ara-A (F-ara-A), which is then phosphorylated intracellularly to the active cytotoxic triphosphate, F-ara-ATP.

The drug's mechanism of action is multifaceted. F-ara-ATP competitively inhibits key enzymes of DNA synthesis—including DNA polymerases, ribonucleotide reductase, and DNA primase—leading to DNA chain termination and apoptosis. This cytotoxic activity is effective against both dividing and quiescent cells, making it particularly useful in indolent malignancies like CLL. Concurrently, Fludarabine exerts profound immunosuppressive effects by inhibiting STAT1 activation, a pathway distinct from its direct DNA toxicity. This dual mechanism underpins its entire clinical profile: its efficacy as an antineoplastic agent in leukemias and lymphomas, and its indispensable role as a lymphodepleting agent in conditioning regimens for hematopoietic stem cell transplantation (HSCT) and CAR-T cell therapy.