Inflammatory Cytokine Profiles Are Similar in MDS and Unexplained Cytopenias, Study Suggests

Unexplained cytopenias often occur prior to myelodysplastic syndromes (MDS), but there is currently a lack of research on cytokine profiles in patients with clonal cytopenias of undetermined significance (CCUS) and idiopathic cytopenias of undetermined significance (ICUS). A study published in HemaSphere compared the cytokine profiles of patients with ICUS, CCUS, lower-risk MDS (LR-MDS), higher-risk MDS (HR-MDS), and healthy controls to better understand these profiles and their potential prognostic impacts.

In recent years, next-generation sequencing (NGS) panels have allowed more accurate diagnosis of MDS and the identification of patients with CCUS or ICUS. While CCUS is associated with MDS development within 10 years, ICUS without any known genetic aberrations rarely leads to myeloid malignancies. The current study aimed to identify associations between cytokine levels and mutation status, clinical presentation, and outcomes in high- and low-risk MDS, ICUS, and CCUS.

The study included 111 patients: 41 with ICUS, 30 with CCUS, 22 with LR-MDS, 18 with HR-MDS, and 21 elderly controls. Luminex assays and enzyme-linked immunosorbent assays were used to examine 20 cytokines in blood plasma samples at the time of diagnosis.

Compared with controls, all patient groups had higher levels of proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-10, and C-X-C motif chemokine 10 (CXCL10). The patient groups also had lower levels of active transforming growth factor beta 1 (TGF-β1), CCL5/regulated on activation normal T-cell expressed and secreted (RANTES), and the calcium-binding protein S100A4 compared with the control group. Patient cytokine profiles differed, and there were no cytokine clusters related to specific diseases or age groups.

Across patient groups, there were direct correlations between cytokine levels. Higher levels of IL-6, TNF-α, IL-10, and CXCL10 directly correlated with lower levels of TGF-β1, RANTES, and S100A4 in all patient cohorts. In general, the cytokine levels seen in patients with ICUS and CCUS were similar to those seen in patients with LR-MDS, while HR-MDS patients showed higher IL-10 and IL-8 levels compared with the other cohorts.

Elevated IL-10, TNF-α, and IL-6 levels were also associated with anemia, although only IL-10 had a significant association after Bonferroni correction. Anemia was not associated with any of the 7 cytokines found significant in the study in a multivariate analysis. Patients with thrombocytopenia had low levels of TGF-β1, RANTES, and S100A4 and high levels of CXCl10 compared with patients who did not have thrombocytopenia. After multivariate analysis and Bonferroni correction, the association remained significant.

A higher systemic inflammatory cytokine load was predictive of shorter overall survival (OS) in this study population. These patients were identified by high levels of cytokines—including IL-6, TNF-α, IL-10, and CXCL10—and were found to have more inflammatory comorbidities such as diabetes, ischemic heart disease, and autoinflammatory diseases compared with controls.

A total of 23 patients with CCUS and MDS were considered to have high inflammatory loads, 21 of whom died during follow-up. In a multivariate analysis, the hazard ratio for shorter OS in patients with a high inflammatory load was 2.5 (95% CI, 1.4-5.0; P = .004). Median OS was 21 months in those with high inflammatory loads versus 64 months in patients who did not. Survival was also aligned with diagnosis, with ICUS patients surviving the longest and HR-MDS patients facing the shortest survival.

“In summary, our data reveal that the inflammatory cytokine signatures of patients with ICUS and CCUS are similar to formerly described signatures of patients with LR-MDS and, in part, HR-MDS,” the authors wrote. “These findings suggest that inflammatory cytokines might be involved in the early pathogenesis of unexplained cytopenias, irrespective of the presence of myeloid clones.”

Pending further research, the data support the notion that inflammatory cytokines might be helpful for risk assessment and could potentially serve as therapeutic targets in patients with early myeloid diseases.

Reference

Nielsen AB, Hansen JW, Orskov AD, et al. Inflammatory cytokine profiles do not differ between patients with idiopathic cytopenias of undetermined significance and myelodysplastic syndromes. Hemasphere. 2022;6(5):e0713. Published online April 22, 2022. doi:10.1097/HS9.0000000000000713