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.
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.
Kornblau
Steven M
SM
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
Banker
Deborah E
DE
Stirewalt
Derek
D
Shen
Danny
D
Lemker
Elizabeth
E
Verstovsek
Srdan
S
Estrov
Zeev
Z
Faderl
Stefan
S
Cortes
Jorge
J
Beran
Miloslav
M
Jackson
C Ellen
CE
Chen
Wenjing
W
Estey
Elihu
E
Appelbaum
Frederick R
FR
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003561:Cytarabine; D002784:Cholesterol; D017035:Pravastatin; D015255:Idarubicin