Abstract
Introduction
Although chronic lymphocytic leukemia (CLL) is a generally indolent malignancy, there is a spectrum of disease aggressiveness. Clinical and molecular prognostic markers are helpful for the clinician and for the patient, in terms of disease management and life planning. Additional prognostic markers can help with further risk stratification, especially for CLL patients with “low-risk” disease. The prognostic value of absolute monocyte count (AMC) has been evaluated in various malignancies, including CLL where elevated AMC at diagnosis was shown to be associated with rapid time to first therapy (TTT), and in one series, inferior overall survival (OS). The mechanism by which elevated AMC is associated with worse treatment free survival is not known. However, CD14, which is secreted by monocytes, improves in vitro CLL cell survival, and is found at high levels in the serum of CLL patients. We hypothesized that elevated AMC at the time of CLL diagnosis is associated with inferior survival and that elevated serum CD14 is associated with high AMC and worse survival.
Methods
CLL patients followed at the Duke University and Durham VA Medical Centers and enrolled in an IRB approved protocol to collect clinical data and blood samples were evaluated. We selected patients for whom AMC was measured between three months prior to diagnosis to three months after diagnosis. We evaluated the correlation between AMC and TTT and OS, with AMC as a continuous and as a dichotomized variable. We also assessed the prognostic capability of AMC in relation to other clinical and molecular prognostic markers, such as Rai stage, race, interphase cytogenetics by FISH, CD38 and ZAP70 expression, and IGHV mutation status. We measured serum CD14 levels using an ELISA assay, and evaluated the correlation between CD14 levels and clinical outcomes or AMC. Cox proportional hazard models were used to evaluate time to event outcomes, Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare AMC to other prognostic markers, and Pearson’s correlation test was used to compare continuous variables.
Results
From a cohort of over 600 CLL patients, we selected 222 patients with AMC measured ± three months from the date of diagnosis. AMC ranged from 0 to 7.63 cells/mL. With a median follow up of 5.2 years (range 0.1 – 18.2), 102 patients (46%) had been treated, and 59 patients (27%) died. This was not significantly different from the entire cohort. Higher AMC was significantly correlated with shorter TTT (p = 0.002, hazard ratio 1.37, 95% CI 1.12 – 1.68) and inferior OS (p = 0.017, hazard ratio 1.39, 95% CI 1.06 – 1.83). There was no significant difference in AMC in patients stratified by Rai stage, race, interphase cytogenetics, CD38 or ZAP70 expression, or IGHV mutation status. When combined with molecular prognostic markers (IGHV mutation status, CD38 and ZAP70 expression, and interphase cytogenetics) in multivariate models, AMC retained significant prognostic power for TTT and OS. The serum soluble CD14 levels were measured in CLL patients from this cohort, with a mean CD14 level of 2.3 ug/mL. The prognostic significance of serum CD14 and correlation with AMC will be presented.
Conclusions
Absolute monocyte count at the time of CLL diagnosis is associated with inferior clinical outcomes – both TTT and OS. These results confirm and extend other reports evaluating the prognostic significance of circulating monocytes in CLL. Our evaluation of serum CD14, a monocyte-derived secreted protein that promotes CLL cell viability, in concert with AMC may provide a possible explanation for the associations identified in this cohort of patients. As an easily measured clinical marker, AMC can be readily used and/or combined with other prognostic markers to improve risk stratification and patient counseling at the time of diagnosis.
Disclosures:
No relevant conflicts of interest to declare.
Prognostic Significance of the IgVH Mutation Status and Immunohistochemical Analysis of ZAP70 and CD38 in Bone Marrow Biopsies in Chronic Lymphocytic Leukemia