Flavopiridol in the treatment of chronic lymphocytic leukemia

The synthetic flavone flavopiridol induces apoptosis of chronic lymphocytic leukemia cells in vitro; however, initial studies administering flavopiridol by a 24- to 72-h continuous intravenous infusion demonstrated no clinical activity. This review focuses on a novel dosing regimen that has achieved significant clinical activity in relapsed, poor-risk chronic lymphocytic leukemia.

Binding to human plasma proteins reduces free flavopiridol concentration and makes continuous intravenous infusion dosing ineffective. Pharmacokinetic modeling indicated that administering flavopiridol by a 30-min intravenous bolus followed by a 4-h continuous intravenous infusion would achieve serum concentrations necessary to induce in-vivo apoptosis. Our institution conducted a phase I study in relapsed chronic lymphocytic leukemia. Dose-limiting toxicity was acute tumor lysis syndrome resulting in fatal hyperkalemia. Careful monitoring and aggressive intervention for hyperkalemia, including hemodialysis if necessary, allowed flavopiridol to be given safely. Nineteen of 42 patients responded (45%), including five of 12 patients (42%) with del(17p13) and 13 of 18 patients (72%) with del(11q22).

Flavopiridol, when administered by a 30-min intravenous bolus followed by a 4-h continuous intravenous infusion, is active in high-risk, refractory chronic lymphocytic leukemia. Careful monitoring and aggressive intervention for tumor lysis syndrome and hyperkalemia is necessary for safe drug administration. Further studies to optimize the dose and schedule of administration, and to study this drug in other hematologic malignancies, are ongoing.