Statin use and need for therapy in chronic lymphocytic leukemia

The in vitro observation that statins reduce CD20 surface expression on B lymphocytes, induce conformational changes in CD20, and decrease the ability of rituximab to bind to B-cell lymphoma cells raised the question of whether concomitant use of these agents with rituximab-containing chemotherapy regimens might reduce these regimens’ effectiveness [1]. A retrospective analysis of patients with follicular and diffuse large B-cell lymphomas treated with rituximab-containing regimens did not demonstrate decreased response to these regimens among patients who received statin drugs at the time of therapy. However, patients with follicular lymphoma who took statin drugs at the time of diagnosis or therapy had an improved event-free survival [2]. Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy that is similar to follicular lymphoma in several ways: both are indolent B-cell malignancies, often with long latencies, in which therapy is almost never curative. Because of the findings in follicular lymphoma, we considered whether statins might have an effect in CLL. At a pre-clinical level, there is already in vitro evidence that statins have anti-CLL activity, inducing CLL cytotoxicity and apoptosis [3,4]. Statins inhibit 3hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, reducing circulating total cholesterol and low-density lipoprotein levels [5]. Lipoproteins and associated enzymes have prognostic significance in CLL. For example, elevated CLL cell lipoprotein lipase (LPL) is associated with poor prognosis [6,7]. Apolipoprotein E (APOE) genotype has prognostic significance in American, British, and Italian patients with CLL [6,8,9]. Recently, using a metabolomic approach, significantly higher serum cholesterol and fatty-acid side chains from very-low-density lipoproteins and low-density lipoproteins were found in high-risk patients with CLL [10]. Despite these findings, one retrospective study of patients with earlystage CLL who took statins at the time of diagnosis found no impact on clinical outcomes [11]. Because of the data regarding statin use in follicular lymphoma as well as the correlation between lipoprotein pathways and prognosis in CLL, we hypothesized that statin use in our cohort of patients with CLL might affect the need for treatment and the time to first treatment. Patients with CLL were enrolled in an Institutional Review Board-approved study at the Duke University and Durham VA Medical Centers. Clinical data were collected from chart review according to the National Cancer Institute (NCI) Working Group criteria [12]. Follow-up time was calculated from the time of diagnosis to the last documented evaluation at our Centers. Statin use at diagnosis and at treatment was determined from chart review, within 3 months before to 3 months after each time point. Data regarding statin use, including dose and type, as well as total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, were collected. Prognostic markers, including IgVH (immunoglobulin heavy chain variable) mutational status, CD38, ZAP-70, and LPL expression,