Flavopiridol in the treatment of chronic lymphocytic leukemia.
OBJECTIVE
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.


RESULTS
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).


CONCLUSIONS
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.
Christian
Beth A
BA
Division of Hematology and Oncology, Ohio State University, Columbus, Ohio 43210, USA.
Grever
Michael R
MR
Byrd
John C
JC
Lin
Thomas S
TS
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D005419:Flavonoids / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D010880:Piperidines / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012008:Recurrence; D012306:Risk; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005419:Flavonoids; D010880:Piperidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C077990:alvocidib; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases