Influence of Statin Therapy On the Clinical Course of Chronic Lymphocytic Leukemia.
Authors: Friedman Daphne R , Harrison Jeremy D , Magura Lindsay A , Warren Holly A , Diehl Louis F , Weinberg J. Brice 
Published: October 2019

Abstract
Abstract 2344
Poster Board II-321

Background:
Chronic lymphocytic leukemia (CLL) is a common leukemia with variability in clinical outcomes. Treatment is required for symptomatic and/or progressive disease, but many patients are followed expectantly without therapy. Various prognostic markers, including elevated levels of lipoprotein lipase (LPL) mRNA or protein, can identify patients with high risk to require therapy or with reduced survival. We recently reported that within our cohort of CLL patients at Duke University and the Durham V.A. Medical Centers, women with an apolipoprotein E4 (APOE4) genotype have longer overall survival than do those with a non-APOE4 genotype. Given these findings, we hypothesized that statin treatment would alter the course of CLL. Here we report on the clinical outcome of CLL patients treated with statins at the time of diagnosis.

Methods:
335 patients with CLL were prospectively enrolled in an IRB-approved study at the Duke University and Durham V.A. Medical Centers from 1999 to the present. CLL diagnosis was confirmed by immunophenotyping for CD19+CD5+ clonal B-cells. Prognostic markers such as lymphocyte doubling time, IgVH mutation status, CD38 and ZAP70 expression, CLL cell LPL mRNA, and interphase cytogenetics were determined as previously described. We abstracted clinical data including treatment need, time to treatment, overall survival, and use of statins and serum lipid levels within a six-month interval of diagnosis and of first treatment.

Results:
At diagnosis, 189 patients were not taking a statin, 65 were, and 81 did not have these data available. Of the 254 patients in whom statin use at diagnosis was known, 181 (71%) were male and 73 (29%) were female. Therapy for CLL was not required in 132 (52%) patients, while 122 (48%) patients received at least one treatment. Initial treatments included single agent chlorambucil with or without prednisone (n = 59, 49%), purine analogue-based regimens (n = 45, 37%), and rituximab-containing regimens (n=47, 39%). Indications for therapy were recorded in 117 of the 122 patients (96%), and included increasing lymphocyte count (n = 49, 42%), anemia (n = 14, 12%), thrombocytopenia (n = 8, 7%), splenomegaly (n = 8, 7%), and lymphadenopathy (n = 49, 42%). The entire cohort has been followed for 0.05 to 25 years from diagnosis (median, 4.5 years), with a shorter follow up time in the patients who were on a statin at the time of diagnosis (2.4 vs. 5.6 years, p < 0.001). There was no statistically significant difference between patients taking statins or not taking statins at diagnosis in terms of sex, lymphocyte doubling time, IgVH mutation, CD38 or ZAP70 expression, or cytogenetic aberrations. However, patients receiving a statin at the time of diagnosis were less likely to require therapy (p = 0.044). This effect was seen primarily in women (p = 0.009) and in patients with CD38 negative CLL (p = 0.002). Notably, even though patients taking a statin at the time of diagnosis were less likely to ever require therapy, statin use was not associated with a significant improvement in overall or treatment-free survival. While elevated lipoprotein lipase (LPL) expression correlated with worse clinical outcomes, there was no significant correlation between statin use and CLL cell LPL mRNA levels. Likewise, there was no significant correlation between statin use and apolipoprotein E genotype. In addition, statin use at time of first treatment was not significantly associated with progression or time to progression. We did not find any significant correlation between total cholesterol, LDL, HDL, or triglyceride levels at diagnosis and treatment need. However this analysis was compromised by low numbers of patients with relevant clinical data (n = 26).

Conclusions:
Statin use at the time of diagnosis of CLL is associated with an improved clinical course, specifically a reduced likelihood of progressing to require therapy. This benefit is seen particularly in women and in those with low risk (CD38 negative) CLL. The mechanism of action of statins in altering the clinical course of CLL is unknown. Statins could be directly cytotoxic for CLL cells, could influence lipid-LPL-CLL biology, alter B-cell receptor signaling, or modify autocrine/paracrine survival signals. The benefit of statin use in women with CLL might reflect an interplay between estrogen, lipids, and CLL cells. Our findings have the potential to improve our understanding of CLL biology and possibly lead to novel CLL treatments.

Disclosures:
No relevant conflicts of interest to declare.