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Blood, 19 March 2009, Vol. 113, No. 12, pp. 2637-2645. Prepublished online as a Blood First Edition Paper on November 3, 2008; DOI 10.1182/blood-2008-07-168583. This Article Full Text (PDF) All Versions of this Article: blood-2008-07-168583v1 113/12/2637    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Phelps, M. A. Articles by Dalton, J. T. Search for Related Content PubMed PubMed Citation Articles by Phelps, M. A. Articles by Dalton, J. T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 16, 2008 Accepted October 17, 2008 Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia Mitch A. Phelps, Thomas S. Lin, Amy J. Johnson, Eunju Hurh, Darlene M. Rozewski, Katherine L. Farley, Di Wu, Kristie A. Blum, Beth Fischer, Sarah M. Mitchell, Mollie E. Moran, Michelle Booker-McEldowney, Nyla A. Heerema, David Jarjoura, Larry J. Schaaf, John C. Byrd, Michael R. Grever*, and James T. Dalton Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, United States Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, United States Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, United States Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, United States * Corresponding author; email: michael.grever{at}osumc.edu. We previously reported interim results of a phase I trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one of 52 patients (40%) with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17/43 fludarabine refractory patients (40%), 7/18 patients (39%) with del(17p13) and 14/19 patients (74%) with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Non-compartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically-derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK appears to describe some, but not all, variability in response and toxicity. This study is registered at http://www.clinicaltrials.gov as study ID NCI-5746. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Delgado, D. W. Milligan, and P. Dreger Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood, September 24, 2009; 114(13): 2581 - 2588. [Abstract] [Full Text] [PDF]

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