Dr Sekeres on the Association Between Smoking and Disease Progression in MDS

“In this study, we looked at the relationship between smoking and these diseases, and what we found was absolutely fascinating. It turns out that people who smoke are at higher risk of developing higher-risk myelodysplastic syndromes.”

Mikkael A. Sekeres, MD, professor of medicine, chief,Division of Hematology, Leukemia Section, the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses findings from an analysis examining the association between smoking intensity, genetic mutations, and disease progression in patients with myelodysplastic syndromes (MDS) and clonal cytopenias of undetermined significance (CCUS).

This analysis included 1898 patients, in whom investigators assessed smoking history in relation to mutation burden, gene pathway alterations, and disease progression. Findings revealed that smokers and non-smokers had similar overall mutation rates at a mean of 2.0 (SD, 2.7); however, specific gene mutations were more prevalent among smokers, particularly in chromatin modification (P < .01) and RNA splicing pathways (P < .001). Mutations in ASXL1 (12% vs. 8%; P < .01), SF3B1 (9% vs. 6%; P < .05), U2AF1 (6% vs. 3%; P < .05), and ZRSR2 (2% vs. 1%; P < .05) were also more frequent among smokers.

Multivariable regression models, adjusted for sex, age, and disease group, demonstrated a significantly higher mutation burden in smokers compared with non-smokers (2.0 vs. 1.4; P = .04). Furthermore, a dose-response relationship was observed, with mutation frequency increasing in correlation with pack-years (PY) smoked (P = .006). At the 75th and 90th percentiles of PY, smokers had 1.8 and 3.5 times the number of mutations, respectively, compared with non-smokers.

Cumulative incidence of disease progression was significantly higher among long-term smokers compared with non-smokers or those with a shorter smoking history. The mean proportion of patients with disease progression was 27% (95% CI, 19%-36%) in those with at least 20 years of smoking vs 18% (95% CI, 13%-24%) in those with less than 20 years of smoking (P < .05). Additionally, smoking was associated with poorer overall survival in CCUS (HR, 1.91; 95% CI, 1.03-3.55; P = .04) but not in MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).

These findings indicate that smoking is linked to specific genetic alterations associated with MDS, some of which overlap with those implicated in smoking-related lung cancer. Sekeres emphasizes that smoking cessation should be strongly encouraged in patients with MDS, as reducing tobacco exposure may help mitigate disease progression and improve clinical outcomes.