Research paperReport of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML)
Introduction
The treatment of relapsed/refractory acute myeloid leukemia (AML) remains challenging and novel therapies are needed. AML blasts frequently overexpress the genes for the LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme reductase (HMG-CoAR) and therefore import and synthesize cholesterol at higher levels than normal myeloid progenitors [1]. Patients with AML and high white blood cell counts sometimes have marked hypocholesteremia at the time of diagnosis suggesting increased cholesterol metabolism and this typically resolves when patients achieve a complete remission (CR) [[1], [2]]. These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival [2]. In addition, inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy [2]. Thus, targeting the cholesterol pathway represents a potential therapeutic approach.
A previous Phase 1 trial demonstrated encouraging results with high dose pravastatin in combination with IA (idarubicin and intermediate dose cytarabine) [1]. This led to a Phase 2 trial of this combination in patients with relapsed AML [3]. The response rates in this trial were impressive: 75% CR/CR with incomplete count recovery (CRi). However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, this study was amended to treat patients with poor risk AML (CR/CRi <6 months following their last induction regimen or refractory disease). Here, we report the results in this poor risk group.
Section snippets
Methods
Patients were treated at SWOG institutions from April 2013 through November 2014. The protocol (registry: ClinicalTrials.gov Identifier: NCT00840177) was approved by each institution’s review board and signed informed consent was obtained from all registered patients. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Pravastatin
Results
Patient characteristics are listed in Table 1. Forty-six patients with a median age of 57 years (range 23–75) were enrolled. Twenty-four patients (52%) were male and the median white blood count (WBC) was 2600/uL (range 200–450,000). The median time from diagnosis to registration was 4.3 months (range 0.7–49.5). At the time of registration, 65% of patients were primary refractory and 35% had relapsed. The number of prior treatment regimens included: 1 (46% of patients), 2 (37% of patients), 3
Discussion
The CR/CRi rate in this poor risk relapsed/refractory population did not meet criteria for a positive study but is still encouraging given the poor risk population and suggests that targeting the cholesterol pathway may have therapeutic impact. In particular, a recent clinical trial of idarubicin/cytarabine (IA) in combination with either fludarabine (F) or clofarabine (C) in patients with relapsed/refractory AML, the CR/CR without platelet recovery rate was 38% for CIA and 30% for FIA [7]. Our
Funding
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers CA180888, CA180819, CA180816, CA180834, CA189808, CA189856, CA180855, CA189953, CA189854, CA11083, CA04919, CA73950, CA46113, CA76132, CA16385, and CA46282; and in part by Bristol-Myers Squibb Co. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or
Conflict of interest disclosure
A.S.A. has nothing to disclose; H.L. has nothing to disclose; L.C.M. is a member of advisory committees for Incyte, CTI Biopharma, and Wyeth; B.C.M. has nothing to disclose; M.L. has nothing to disclose. A.F.L. receives research funding and/or honoraria from Celgene; K.O. has nothing to disclose; M.O. has nothing to disclose; H.P.E. is a consultant for Novartis, Incyte, Celgene, Seattle Genetics, Pfizer, Daiichi Sankyo, Sunesis, Ariad, and Amgen, and receives research funding from Amgen,
Acknowledgements
We sincerely thank all of the patients, clinicians, nurses, and research coordinators who participated in this trial.
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