title: 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.
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 x day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M2 x 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.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston 77030-4009, USA. skornbla@mdanderson.org
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Banker
authors.forename: Derek
authors.initials: D
authors.lastname: Stirewalt
authors.forename: Danny
authors.initials: D
authors.lastname: Shen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lemker
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Miloslav
authors.initials: M
authors.lastname: Beran
authors.forename: C Ellen
authors.initials: CE
authors.lastname: Jackson
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chen
authors.forename: Elihu
authors.initials: E
authors.lastname: Estey
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002784:Cholesterol / Q000097:blood*; D003561:Cytarabine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D015255:Idarubicin / Q000008:administration & dosage*; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D012449:Safety
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003561:Cytarabine; D002784:Cholesterol; D017035:Pravastatin; D015255:Idarubicin