Levels of Circulating Endothelial Cells and Endothelial Progenitors Correlate with Disease Status and Treatment Response in Human Lymphoma Subtypes of CLL and MCL.

Increases in the number of circulating endothelial cells (CECs) and endothelial progenitors (EPCs) have been reported in various pathological conditions including cancer. Both preclinical and clinical studies in a number of human malignancies have shown that the kinetics of CECs and EPCs correlate with clinical outcomes in patients who undergo anti-angiogenic treatment. Angiogenesis biomarkers in lymphoproliferative diseases have been undefined to date. We investigated the dynamics of circulating peripheral blood levels of endothelial cells and progenitors in lymphoma patients as potential biomarkers of disease status and treatment response.

Circulating CD45^-CD146⁺CD34⁺CD31⁺ mature endothelial cells (CECs) and CD45^-/dimCD133⁺VEGFR2⁺ endothelial progenitors (EPCs) were measured by 4-color flow cytometry in 79 lymphoma patients with chronic lymphocytic lymphoma/leukemia (CLL, n=38) and mantle cell lymphoma (MCL, n=41). Normal volunteers served as controls (n=5). Non-parametric Kruskal-Wallis tests were performed to compare the difference in median marker values of different groups. Mann-Whitney tests were then used to compare marker values in pair-wise fashion between clinical groups. P-values were adjusted for multiple comparisons using the Bonferroni method.

In CLL, the CECs were 525 ± 656/mL in previously untreated patients (n=27), and 50 ± 49/mL in patients with remission following fludarabine-based therapy (n=11), compared to 81 ± 51/mL in normal controls (n=5). Significant differences in CECs were observed in patients with untreated disease compared to patients in remission (p=0.0006) and normal controls (p=0.01). EPCs trended down during remission following treatment from 350 ± 932/mL to 45 ± 84/mL (p=0.052). In MCL, CECs were 397 ± 433/mL in previously untreated patients (n=11), 73 ± 85/mL in patients with remission following R-CHOP-based therapy (n=9), and 110 ± 215/mL in patients with relapse (n=21). A significant decline of CECs was detected in remission compared to pretreatment values (p=0.03). In addition, a significant difference in EPCs was noted comparing pre-therapy baseline values (383 ± 445) to normal controls (86 ± 53/mL) (p=0.03). EPCs trended down in remission from 383 ± 445/mL to 103 ± 138/mL (p=0.052). No significant differences were observed for baseline pretreatment CEC and EPC values between CLL and MCL.

Dynamic levels of circulating endothelial cells and endothelial progenitors appear to correlate with disease status and treatment response in CLL and MCL. Large-scale studies are warranted to further evaluate the prognostic significance of these results, and to investigate whether circulating pro-angiogenic cell populations in selected lymphoma subtypes may be useful as biomarkers to select patients for and monitor response to anti-angiogenic therapy.

No relevant conflicts of interest to declare.