Clofarabine: Structure, mechanism of action, and clinical pharmacology

Similar to fludarabine and cladribine, clofarabine (2-chloro-2'-fluoro-2'- deoxyarabinosyladenine) is resistant to deamination by adenosine deaminase due to the presence of a halogen group at the two position of the base. However, unlike other 2'-deoxyadenosine analogs, clofarabine also has a halogen in the sugar that prevents cleavage of the glycosidic bond by purine nucleoside phos- phorylase. The cytotoxic activity of clofarabine is due to both its inhibition of ribonucleotide reductase and its efficient incorporation in DNA, where it inhibits DNA synthesis. While some activity has been observed in lymphoid malignancies, clinical efficacy has primarily been observed in acute leukemias. The recommended dose of clofarabine for adult acute leukemia (40 mg/m²/day x 5 days) results in plasma levels of around 1 μM. The accumulation of clofarabine triphosphate in circulating leukemia cells is dose dependent, with a long half-life. This is particularly the case in responders, resulting in incremental increases in clofarabine triphosphate with every daily infusion of the drug. The actions of clofarabine triphosphate on ribonucleotide reductase and incorporation in the DNA repair patch suggest that a mechanism-based combination with arabinosyl- cytosine and DNA-damaging agents would be effective. Combination clinical trials have been conducted, while new trials are underway.