Circulating Angiogenic Cytokines in Chronic Lymphocytic Leukemia: Relationship to Modern Prognostic Factors and Effect of Fludarabine-Based Treatment

Angiogenesis has been studied in chronic lymphocytic leukemia (CLL) since mid 1990s. Given the extraordinary heterogeneity of clinical course of CLL patients, angiogenesis assessment may potentially improve prognostic stratification. There are numerous reports on increased markers of angiogenesis in CLL; however, data on possible association of angiogenic markers with modern prognostic factors are very scarce. Therefore, we evaluated prognostic significance of angiogenic cytokines, namely basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), endostatin, and angiopoietin-2 (Ang-2) in patients with untreated CLL. Plasma levels of angiogenic factors were quantified using enzyme-linked immunosorbent assay (bFGF, VEGF, n=106; endostatin, n=83, Ang-2, n=55). Eighty healthy donors served as control group. Relationship of angiogenic markers to modern prognostic factors (IgVH mutation status, cytogenetic aberrations detected by fluorescent in situ hybridization [FISH]) was also analyzed. Results: bFGF, VEGF, and endostatin were significantly elevated in CLL patients when compared to controls (bFGF, VEGF: p<0.0001, endostatin: p=0.039); Ang-2 levels were not different from the control (p=0.192). There were no differences in angiogenic factors with regard to gender, clinical course or modified Rai stage. Similarly, no association of angiogenic factors with IgVH or FISH was identified. Interestingly, in a pilot subgroup of 16 patients with serial measurements before and after successful fludarabine-based combination treatment, levels of bFGF as well as VEGF decreased significantly (p<0.0001 and p=0.0027, respectively). In conclusion, our study confirms that angiogenic signaling is intensive in CLL. Fludarabine-based treatment may have intrinsic antiangiogenic properties. Further research is needed for better understanding of angiogenic processes, especially with respect to possible refinement of individual patient’s prognosis in this disease.