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 I Study.

In vitro data demonstrate that AML blasts commonly increase intracellular cholesterol (chol), via increased uptake or synthesis, and that this defensive adaptation increases chemoresistance. Blockade of HMG-CoA reductase with statin class agents restores chemosensitivity in AMLs in vitro. To test the clinical significance of these findings, the safety and apparent efficacy of adding pravastatin (PV) (at doses of 40, 80, 160, 320, 480, 680, 880, 1080 or 1280mg/d days 1–8) to a standard induction regimen of Idarubicin (IDA) (12 mg/M²/d days 4–6) + high Dose ara-C (HDAC) (1.5 g/M²/d by CI on days 4–7) was tested in a phase 1 study. Thirty adult pts (median age 55 yr), including 13 newly diagnosed (New), 4 primary refractory (PR), 9 in first relapse (R1) and 4 in second relapse(R2), with unfavorable (N=21) or predominantly intermediate (n=8) prognosis cytogenetics were treated. The toxicity profile was typical of Ida-HDAC alone, with no excess in hepatic toxicity, infections or CPK elevations. The mean duration of neutropenia <1000/mm³ was increased by the addition of PV, from 29 to 32 days with 40–320mg/day, and to 42 days for doses >320mg, but the duration of thrombocytopenia was unaffected. Among pts with a starting WBC ≥10K or absolute blast count (ABC) ≥5K treatment with PV alone produced a ≥25% decrease in WBC or ABC in 5/9 and 4/7, compared to 3/13 and 1/8 among historical Ida-HDAC controls (p=0.07 and 0.10 respectively). The frequency of a >25% increases in WBC or ABC did not differ from historical Ida-HDAC treated controls. This suggests that “loading” for 3 days before the initiation of chemotherapy was not detrimental. Triglyceride levels decreased in all pts at all dose levels progressively from D0 to 4 to 8 and generally did not rebound by D14. Total serum cholesterol and LDL levels decreased by D4 without relationship to dose in 29/30 and 24/30 cases respectively, with partial rebound by D8 commonly observed at doses of PV <1080mg/day. Serum HDL levels were unaffected. Intracellular (IC) chol increased by D4 in 14/23 and 10 of these 14 had increased IC-LDL, however most of these returned toward the D0 levels by D8. Additional lab correlate and PK studies are pending. There was an inverse correlation between serum and IC chol levels at D0, D4 and D8. Among 28 evaluable pts, CR/CRp was obtained in 16 (9 New, 1PR, 5 R1 and 1 R2). The change in total serum chol level at D4 did not differ between those achieving CR vs. non-responders, but at D8 (P=0.08) and D14 (P=0.04) non responders had significantly higher total serum chol levels. Notably, 6 of 9 newly diagnosed pts with unfavorable cytogenetics achieved CR. The MTD for PV+Ida-HDAC has not been reached. The highly encouraging response rates of 70% in this predominantly poor prognosis population of newly diagnosed patients and 47% among salvage pts, as compared to expected CR rates of 47% and 25%, suggest that a phase II study should be performed to further evaluate the effect of chol modulation on response in AML.