Flavopiridol in Chronic Lymphocytic Leukemia

Abstract

Whereas chronic lymphocytic leukemia (CLL) responds to therapy, patients invariably experience relapse, and many patients with advanced disease acquire mutation or deletion of the p53 gene, resulting in resistance to most standard therapies. Alemtuzumab is active against p53-deficient CLL but is ineffective against bulky nodal disease and causes significant immunosuppression. Therefore, new therapies for patients with high-risk, relapsed CLL are needed. The synthetic flavone flavopiridol induces apoptosis of CLL cells in vitro, but clinical trials administering flavopiridol by 24–72–hour continuous intravenous (I.V.) infusion observed no clinical activity. Binding to human plasma proteins resulted in inadequate free flavopiridol concentrations with continuous I.V. infusion dosing schedules. Pharmacokinetic modeling indicated that administering flavopiridol by 30-minute I.V. bolus followed by 4-hour continuous I.V. infusion would achieve serum concentrations necessary to induce in vitro apoptosis. A phase I study demonstrated the clinical activity of this novel dosing regimen of flavopiridol in patients with relapsed, genetically high-risk CLL. The dose-limiting toxicity was acute tumor lysis syndrome, which resulted in fatal hyperkalemia in 1 patient. However, flavopiridol can be given safely with close monitoring and aggressive intervention for hyperkalemia, including hemodialysis if necessary. Nineteen of the first 42 patients in the phase I study had a partial response (45%), including 5 of 12 patients (42%) with del(17p13) and 13 of 18 patients (72%) with del(11q22). Ongoing phase II studies are studying modifications to optimize the dose and schedule of administration and to minimize treatment-related toxicities such as transient neutropenia and cytokine release syndrome. Flavopiridol is also being studied in acute leukemias, lymphomas, and solid malignancies.