Alvocidib (flavopiridol) for the treatment of chronic lymphocytic leukemia

Alvocidib, which has orphan drug designation in chronic lymphocytic leukemia (CLL) from the FDA and the EMA, is a plant-derived semisynthetic flavone that acts as a cyclin-dependent kinase inhibitor. It induces apoptosis in CLL cells in vitro and was introduced into clinical trials in CLL as an intravenous infusion in 1997, which proved disappointing. Since the drug avidly binds to plasma proteins, higher serum concentrations were required for clinical antileukemia activity than those suggested by in vitro studies. Subsequent studies utilizing bolus plus infusional doses revealed significant activity against CLL, even in patients with unfavorable characteristics. However, significant toxicity including high rates of major tumor lysis syndrome, cytokine release syndrome and secretory diarrhea were also observed.

The chemistry, pharmacodynamics, pharmacokinetics and metabolism of alvocidib are briefly discussed and phase I-II studies in CLL are discussed in detail. To date, no phase III studies in CLL have been reported.

A number of much less toxic drugs with similar efficacy against CLL both with and without unfavorable cytogenetics have come to market. Furthermore, enthusiasm for the development of alvocidib as a single agent for the treatment of CLL has waned, primarily due to its toxicity.