Elevated markers of inflammation and endothelial activation and increased counts of intermediate monocytes in adult survivors of childhood acute lymphoblastic leukemia

Abstract

Background: Adult survivors of childhood malignancy are prone to accelerated atherogenesis and late cardiovascular complications. Plaque formation is initiated by recruitment of monocytes and T-cells into the intima, mediated by adhesion molecules and chemokines expressed by activated endothelial cells.

Aim: To assess markers of inflammatory activity, endothelial activation as well as monocyte heterogeneity in adult survivors of childhood acute lymphoblastic leukemia (ALL) who had been treated with chemotherapy without cranial irradiation.

Methods and results: We studied 27 (age: 18-28 years) healthy survivors of childhood ALL and 20 controls (age: 20-31 years). Flow cytometry was used to identify monocyte subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes which were further characterized by their expression of HLA-DR and β2-integrins CD11b/CD18 and CD11c/CD18. In ALL survivors we found increased levels of pentraxin-3 (median [interquartile range]: 0.63 [0.36-0.94] vs. 0.40 [0.32-0.57] ng/ml; p = 0.03), soluble vascular cell adhesion molecule-1 (687 [597-761] vs. 558 [534-702]ng/ml; p = 0.02), osteoprotegerin (mean ± SD: 5.24 ± 1.00 vs. 4.42 ± 1.34 pmol/l; p = 0.02) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (107.0 ± 23.6 vs. 89.5 ± 18.9 pg/ml; p = 0.01), whereas C-reactive protein, interleukin 6 and 18, TNF-α, monocyte chemotactic protein-1 and soluble intercellular adhesion molecule-1 were unchanged. Former ALL patients exhibited elevated counts of intermediate monocytes (6.3 ± 4.0 vs. 4.3 ± 1.5% of blood monocytes; p = 0.03). CD11b/CD18 and CD11c/CD18 expression on intermediate monocytes tended to be higher in ALL survivors (1917 ± 993 vs. 1396 ± 673 MFI [median fluorescence intensity]; p = 0.06 and 3883 ± 1445 vs. 3185 ± 645 MFI; p = 0.05, respectively).

Conclusion: Our findings suggest chronic inflammatory activation and immune dysregulation in adult survivors of childhood ALL, which can translate into late cardiovascular morbidity.