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 Blood, 1 April 2007, Vol. 109, No. 7, pp. 2999-3006.
Prepublished online as a Blood First Edition Paper on December 7, 2006; DOI 10.1182/blood-2006-08-044446.

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Submitted August 31, 2006
Accepted November 20, 2006

Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high dose Ara-C: A Phase 1 study

Steven M. Kornblau*, Deborah E. Banker, Derek Stirewalt, Danny Shen, Elizabeth Lemker, Srdan Verstovsek, Zeev Estrov, Stefan Faderl, Jorge Cortes, Miloslav Beran, C. Ellen Jackson, Wenjing Chen, Elihu Estey, and Frederick R Appelbaum

Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Seattle, WA
Fred Hutchinson Cancer Research Center, Seattle, WA
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Seattle, WA

* Corresponding author; email: skornblau{at}mdanderson.org.

Following exposure to cytotoxic agents, AML blasts elevate cellular cholesterol, in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase I study evaluated adding pravastatin (PV) (40-1680 mg/day days 1-8), to idarubicin (ida)(12 mg/M2/d, days 4-6) + high-dose cytarabine (HDAC) (1.5 g/M2/day by CI, days 4-7) in 15 newly diagnosed and 22 salvage patients with unfavorable (n=26) or intermediate (n=10) prognosis cytogenetics. Compared to historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride, total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV+Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML.


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