TY - JOUR
T1 - Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C
T2 - A phase 1 study
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.
PY - 2007/4/1
Y1 - 2007/4/1
N2 - 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.
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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U2 - 10.1182/blood-2006-08-044446
DO - 10.1182/blood-2006-08-044446
M3 - Article
C2 - 17158228
AN - SCOPUS:33947594969
SN - 0006-4971
VL - 109
SP - 2999
EP - 3006
JO - Blood
JF - Blood
IS - 7
ER -