Background: AML patients who achieve a “good CR” meaning CR with count recovery (ANC > 1000/ μL, platelets > 100,000/ μL) by day 35 of induction therapy without evidence of minimal residual disease (MRD) on flow cytometry or cytogenetics are less likely to relapse than patients who enter CR with MRD or have slower count recovery. At our institution approximately 75% of CRs are “good CRs” and the good CR rate has been 50%. To improve the latter we combined idarubicin + Cytarabine with the HMG-CoA reductase inhibitor pravastatin (IAP) in newly-diagnosed AML because (a) high intracellular cholesterol levels in AML cells may be an adaptive mechanism of chemoresistance and (b) IAP resulted in higher than expected CR rates in relapsed/refractory AML (Advani et al, ASCO, 2013).
Methods: Patients age 18 to 74 with untreated AML (except APL) or MDS/MPN with ≥10% blasts and an anticipated <10% treatment-related mortality rate (Walter et al. 2001) were eligible. Patients received pravastatin (1,280 mg po daily days 1-8), cytarabine (1.5 g/m(2) IV daily, days 4-7) and idarubicin (12 mg/m(2) IV daily, days 4-6). Patients were taken off study if the bone marrow examination between days 17-20 revealed more than 60% myeloid blasts, or if MRD were present between days 31-38. Up to 3 cycles of consolidation with a shortened course of the same regimen was permitted (2 days of IA). Maximum sample size was 50 pts. The study was to stop early if after evaluation of each cohort of 5 patients either (a) the Bayesian posterior probability was < 5% that the true good CR rate was ≥ 70% or (b) the posterior probability was >25% that the TRM rate by day 28 was≥ the historical 5%. Thus parameterized the probability that early stopping would occur if the true good CR rate was 70% and the true TRM rate 5% was 17% after entry of 25 patients, 23% after entry of 30 patients, and 30% after entry of 40 patients.
Results: Between May 2013 and April 2014, 24 patients [AML=21 (87%), MDS=2 (9%), CMML=1 (4%)] were treated per protocol. Median age was 57 (range, 35-72) and per ELN classification, 4 (19%), 4 (19%), 6 (29%) and 7 (33%) AML patients had favorable, intermediate-1, intermediate-2 and adverse risk cytogenetics, respectively. Twenty-three (96%) patients completed induction and 9 (37.5%) received consolidation per protocol. Conventional CR was achieved in 17 (71%) patients but only 12 (50%) achieved “good CR”. Two (8.3%) patients died within 28 days after induction (from typhlitis and septic shock (day and five (21%) patients had persistent disease. Given the above noted stopping rules accrual ceased after entry of these 24 patients. 6 patients relapsed after initial CR (3 before HCT and 3 after HCT). Median time to relapse was 112 days (range, 49-164). and 3 patients died between days 175 and 285 after induction therapy from multi-organ system failure and sepsis. The most common grade 3-4 adverse effects were infections (including febrile episodes), gastrointestinal and dermatologic and were observed in 100%, 80% and 50% of patients, respectively. Nineteen (79%) patients were alive after median follow-up of 7.2 months (range, 0.4-11.9).
Conclusion: IAP did not meet the pre-defined criteria for success: good CR rate ≥ 70%, TRM rate < 5% leading to early stopping with only a 17% chance that such stopping would have occurred if these were the true rates with this therapy. While it remains possible that our 24 patients were “more unfavorable” than the historical population, stressing the need for development of observed/expected ratios applicable to individual patients in a trial, the demographics of the IAP population suggest this was not the case.
Off Label Use: Pravastatin is not FDA approved for treatment of AML.
Asterisk with author names denotes non-ASH members.