Abstract 4162: The importance of age-related cytokines in chronic lymphocytic leukemia

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is a disease of the elderly with the median age at diagnosis being 72 years. Prognosis is highly variable with the relative survival progressively worsening after age 65 years. In this study we have evaluated whether the age-related cytokines, IL-6, IL-8 and TNF-alpha, play a role in the poor survival of elderly patients with CLL. The plasma levels and biological effects of the age-related cytokines, IL-6, IL-8 and TNF-alpha, were evaluated in 193 CLL patients of varying ages. Patients were chosen randomly to reflect the age spectrum and sex distribution of the Manitoban CLL population. As predicted from population studies, the survival of patients progressively worsened with age, with the primary causes of death being CLL or one of its complications (infection or second tumors). Cytokine levels were increased in CLL compared to 37 age- and sex-matched controls. A third of patients aged </=65 years had increased IL-6, compared to 10% in patients < 65. A high correlation was found between the plasma levels of these three cytokines with age and Beta2-microglobulin (a measure of tumor burden). The plasma levels of the cytokines also correlated with each other, suggesting they increased in parallel. In contrast, the standard CLL prognostic markers IgVH mutational status, ZAP-70, CD38 and Rai stage did not correlate with cytokine levels or age. Patients with increased IL-6 or IL-8 had a poorer survival than those with normal levels. For IL-6, this difference was more marked for those </=65 years. Furthermore, focusing on older patients, multivariate analysis with backward selection of variables showed IL-6 and Beta2-microlgobulin to be significant predictors of survival, while the mutational status and Rai stage were not significant. The cause of death was due to CLL-related causes and not to frailty or cardiovascular disease. However, increased cytokine levels correlated with a higher lifetime incidence of cardiovascular disease. Thus, one source of cytokines may be cardiovascular disease, although CLL cells also secreted low amounts of IL-6 and IL-8. The two cytokines, in turn, significantly increased the adhesion of leukemic cells to stromal cells, suggesting that these cytokines may influence the microenvironment, which would contribute to poor survival. In summary, IL-6 and IL-8 are predictors of survival in CLL, where IL-6 is a stronger predictor of survival in older patients than mutational status or Rai stage. Importance of IL-6 and IL-8 may be associated with their role in facilitating the leukemic-stromal cell interaction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4162. doi:10.1158/1538-7445.AM2011-4162