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Blood, 15 January 2007, Vol. 109, No. 2, pp. 399-404.
Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-05-020735.


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Submitted May 1, 2006
Accepted August 22, 2006

Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia

John C. Byrd*, Thomas S Lin, James T Dalton, Di Wu, Mitch A Phelps, Beth Fischer, Mollie Moran, Kristie A Blum, Brad Rovin, Michelle Brooker-McEldowney, Sarah Broering, Larry J Schaaf, Amy J Johnson, David M Lucas, Nyla A Heerema, Gerard Lozanski, Donn C Young, Jose-Ramon Suerez, A. Dimitrios Colevas, and Michael R Grever

Division of Hematology-Oncology, Dept. of Internal Medicine, Ohio State University, Columbus, OH
Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH
Division of Nephrology, Dept. of Medicine, Ohio State University, Columbus, OH
Dept. of Pathology, Ohio State University, Columbus, OH
Biostatistical Core, Comprehensive Cancer Center, Ohio State University, Columbus, OH
Sanofi Aventis Pharmaceuticals, Bridgewater, NJ
Cancer Therapy & Evaluation Program, National Cancer Institute, Bethesda, MD

* Corresponding author; email: john.byrd{at}osumc.edu.

Despite promising pre-clinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic derived schedule of administration of this agent. Based upon pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase I study utilizing a 30 minute loading dose followed by four hour infusion administered weekly for four of six weeks in patients with refractory CLL. Forty-two patients were enrolled on three cohorts (cohort 1: 30 mg/m2 loading dose followed by 30 mg/m2 four-hour infusion; cohort 2: 40 mg/m2 loading dose followed by 40 mg/m2 four-hour infusion; and cohort 3: level 1 dose for treatments 1-4, then a 30 mg/m2 loading dose followed by 50 mg/m2 four-hour infusion). The dose limiting toxicity using this novel schedule was hyper-acute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200 x 109/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, nineteen (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high risk disease, including 5 of 12 (42%) with del(17p13.1) and 13 of 18 (72%) with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high risk genetic features have achieved durable responses thereby justifying further study of flavopiridol in CLL and other diseases.


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