|
|
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.
 Previous Article | Table of Contents | Next Article 
PLENARY PAPER
Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia
John C. Byrd1,2,,
Thomas S. Lin1,
James T. Dalton1,3,
Di Wu3,
Mitch A. Phelps3,
Beth Fischer1,
Mollie Moran1,
Kristie A. Blum1,
Brad Rovin4,
Michelle Brooker-McEldowney1,
Sarah Broering1,
Larry J. Schaaf1,
Amy J. Johnson1,
David M. Lucas1,
Nyla A. Heerema5,
Gerard Lozanski5,
Donn C. Young6,
Jose-Ramon Suarez7,
A. Dimitrios Colevas8, and
Michael R. Grever1
1 Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus;
2 Department of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus;
3 Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus;
4 Division of Nephrology, Department of Medicine, The Ohio State University, Columbus;
5 Department of Pathology, The Ohio State University, Columbus;
6 Biostatistical Core, Comprehensive Cancer Center, The Ohio State University, Columbus;
7 Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ; and
8 Cancer Therapy and Evaluation Program, National Cancer Institute, Bethesda, MD
Despite promising preclinical 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. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute 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, 19 (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 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
L. Kujawski, P. Ouillette, H. Erba, C. Saddler, A. Jakubowiak, M. Kaminski, K. Shedden, and S. N. Malek
Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia
Blood,
September 1, 2008;
112(5):
1993 - 2003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. N. Fleming, M. Hogben, S. Frame, S. J. McClue, and S. R. Green
Synergistic Inhibition of ErbB Signaling by Combined Treatment with Seliciclib and ErbB-Targeting Agents
Clin. Cancer Res.,
July 1, 2008;
14(13):
4326 - 4335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Andritsos, A. J. Johnson, G. Lozanski, W. Blum, C. Kefauver, F. Awan, L. L. Smith, R. Lapalombella, S. E. May, C. A. Raymond, et al.
Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
May 20, 2008;
26(15):
2519 - 2525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ambrosini, S. L. Seelman, L.-X. Qin, and G. K. Schwartz
The Cyclin-Dependent Kinase Inhibitor Flavopiridol Potentiates the Effects of Topoisomerase I Poisons by Suppressing Rad51 Expression in a p53-Dependent Manner
Cancer Res.,
April 1, 2008;
68(7):
2312 - 2320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-R. A. Hussain, D. M. Lucas, A. J. Johnson, T. S. Lin, A. P. Bakaletz, V. X. Dang, S. Viatchenko-Karpinski, A. S. Ruppert, J. C. Byrd, P. Kuppusamy, et al.
Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium
Blood,
March 15, 2008;
111(6):
3190 - 3199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Sekine, T. Sugihara, S. Miyake, H. Hirai, M. Yoshida, N. Miyasaka, and H. Kohsaka
Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors
J. Immunol.,
February 1, 2008;
180(3):
1954 - 1961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Smith, V. Cimica, S. Chinni, K. Challagulla, S. Mani, and G. V. Kalpana
Rhabdoid Tumor Growth is Inhibited by Flavopiridol
Clin. Cancer Res.,
January 15, 2008;
14(2):
523 - 532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. W. Hauswirth and U. Jager
Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia
Haematologica,
January 1, 2008;
93(1):
14 - 19.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. G. Wierda
Treatments for Patients with Chronic Lymphocytic Leukemia
ASCO Educational Book,
January 1, 2008;
2008(1):
297 - 305.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Rixe and T. Fojo
Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient?
Clin. Cancer Res.,
December 15, 2007;
13(24):
7280 - 7287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. A. Blum, D. Young, S. Broering, M. S. Lucas, B. Fischer, T. S. Lin, M. R. Grever, and J. C. Byrd
Computed Tomography Scans Do Not Improve the Predictive Power of 1996 National Cancer Institute Sponsored Working Group Chronic Lymphocytic Leukemia Response Criteria
J. Clin. Oncol.,
December 10, 2007;
25(35):
5624 - 5629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Mitchell, M. A. Park, G. Zhang, A. Yacoub, D. T. Curiel, P. B. Fisher, J. D. Roberts, S. Grant, and P. Dent
Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells
Mol. Cancer Ther.,
December 1, 2007;
6(12):
3101 - 3112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Moutouh-de Parseval, L. Weiss, R. J. DeLap, R. D. Knight, and J. B. Zeldis
Tumor Lysis Syndrome/Tumor Flare Reaction in Lenalidomide-Treated Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
November 1, 2007;
25(31):
5047 - 5047.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. K. Manna, R. S. Aggarwal, G. Sethi, B. B. Aggarwal, and G. T. Ramesh
Morin (3,5,7,2',4'-Pentahydroxyflavone) Abolishes Nuclear Factor-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-{kappa}B-Regulated Gene Expression and Up-regulation of Apoptosis
Clin. Cancer Res.,
April 1, 2007;
13(7):
2290 - 2297.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Grever, D. M. Lucas, G. W. Dewald, D. S. Neuberg, J. C. Reed, S. Kitada, I. W. Flinn, M. S. Tallman, F. R. Appelbaum, R. A. Larson, et al.
Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997
J. Clin. Oncol.,
March 1, 2007;
25(7):
799 - 804.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
