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, Frederick R. Appelbaum

Research output: Contribution to journalArticle

Abstract

Following exposure to cytotoxic agents, acute myeloid leukemia (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 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/(M2· day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M 2·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 with 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 and 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.

Original languageEnglish (US)
Pages (from-to)2999-3006
Number of pages8
JournalBlood
Volume109
Issue number7
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

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Idarubicin
Pravastatin
Cytarabine
Acute Myeloid Leukemia
Cholesterol
Salvaging
Cytogenetics
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pharmacokinetics
Cytotoxins
Neutropenia
Serum
LDL Cholesterol
Toxicity
Triglycerides
Modulation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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

In: Blood, Vol. 109, No. 7, 01.04.2007, p. 2999-3006.

Research output: Contribution to journalArticle

Kornblau, SM, Banker, DE, Stirewalt, D, Shen, D, Lemker, E, Verstovsek, S, Estrov, Z, Faderl, S, Cortes, J, Beran, M, Jackson, CE, Chen, W, Estey, E & Appelbaum, FR 2007, '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', Blood, vol. 109, no. 7, pp. 2999-3006. https://doi.org/10.1182/blood-2006-08-044446
Kornblau, Steven M. ; Banker, Deborah E. ; Stirewalt, Derek ; Shen, Danny ; Lemker, Elizabeth ; Verstovsek, Srdan ; Estrov, Zeev ; Faderl, Stefan ; Cortes, Jorge ; Beran, Miloslav ; Jackson, C. Ellen ; Chen, Wenjing ; Estey, Elihu ; Appelbaum, Frederick R. / 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. In: Blood. 2007 ; Vol. 109, No. 7. pp. 2999-3006.
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AU - Kornblau, Steven M.

AU - Banker, Deborah E.

AU - Stirewalt, Derek

AU - Shen, Danny

AU - Lemker, Elizabeth

AU - Verstovsek, Srdan

AU - Estrov, Zeev

AU - Faderl, Stefan

AU - Cortes, Jorge

AU - Beran, Miloslav

AU - Jackson, C. Ellen

AU - Chen, Wenjing

AU - Estey, Elihu

AU - Appelbaum, Frederick R.

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AB - Following exposure to cytotoxic agents, acute myeloid leukemia (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 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/(M2· day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M 2·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 with 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 and 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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