Study Identifies Sex-Related Differences in MDS Phenotypes, Genotypes, and Outcomes

Authors of the observational cohort study developed and validated novel sex-informed prognostic and genomic scoring systems for patients with myelodysplastic syndrome (MDS).

Findings from an observational cohort study suggest that incorporating sex information into clinical decision-making may help improve personalized treatment approaches for individuals with myelodysplastic syndrome (MDS). The study, published in The Lancet Haematology, found evidence that sex is a contributing factor to MDS phenotypes, genotypes, and clinical outcomes.

MDS encompasses a group of bone marrow disorders characterized by peripheral blood cytopenia and a risk of transformation into acute myeloid leukemia (AML). These conditions are very heterogenous, with risk assessment typically based on the percentage of bone marrow blasts, blood cytopenia, and cytogenetic abnormalities graded by the revised International Prognostic Scoring System (IPSS-R).

“Sex is a major source of diversity among patients in terms of pathophysiology, clinical presentation, prognosis, and treatment response,” the study authors wrote. “A new sex-informed approach to precision medicine could refine the decision-making process for various diseases.”

Even in the general population, life expectancy differs between men and women. And in MDS, there is already evidence of an association between sex and disease incidence, with more men than women affected by these conditions. MDS with deletion 5q, which has distinctive characteristics, has been seen more often in women. The effect of many risk factors for disease significantly differs with sex, and cardiovascular complications are the leading cause of mortality in low-risk MDS. Taken together, current data suggest that sex may have an impact on the natural history of MDS.

The retrospective, multicenter, observational cohort study analyzed a group of 13,284 patients—7792 men (58.7%) and 5492 women (41.3%)—aged 18 years or older who were definitively diagnosed with MDS between 1990 and 2016. The study included patient data from the EuroMDS network, International Working Group for Prognosis in MDS (IWG-PM), the Spanish Group of Myelodysplastic Syndromes registry (GESMD), and the Düsseldorf MDS registry. Patients with more than 20% bone marrow blasts, the threshold for AML, were excluded from the cohort.

The EuroMDS population was analyzed for correlations between sex and genomic features, with findings validated in the IWG-PM cohort. On the single-gene level, mutations within 7 genes were found to be more prominent in men: ASXL1, SRSF2ZRSR2, DDX41, IDH2, TET2, and U2AF1. Mutations in DNMT3A and TP53 were more common in women. There were a higher number of mutations in men overall, including point mutations and indels.

Mutations related to gene pathways, including splicing factor mutations and DNA methylation, were also more common in men. Conversely, mutations related to tumor suppression were more common in women.

The EuroMDS cohort was also analyzed for potential impacts of sex on clinical outcomes, with overall survival (OS) being the main end point. These findings were validated in the other 3 cohorts. Men showed worse median OS than women in the EuroMDS cohort (81.3 months versus 123.5 months), and this finding was confirmed with similar hazard ratios in the validation cohort.

The authors also built and validated new sex-informed prognostic models—a sex-informed prognostic scoring system and a sex-informed genomic scoring system—then compared them to the IPSS-R with a 5-to-5 mapping. The authors created a web portal that allows sex-informed outcome predictions.

The novel prognostic scoring categories led to the reclassification of 871 (43%) of 2025 patients in the EuroMDS cohort, 1003 (42%) of 2387 patients from the IWG-PM cohort. The new sex-informed genomic scoring system led to the reclassification of 1134 (56%) patients in the EuroMDS cohort and 1265 (53%) patients in the IWG-PM. In both models, sex demonstrated independent prognostic power.

Although the study was limited by its retrospective nature and relatively small selection of genes, the data came from a large population of including multiple cohorts and encompassed all of the genes most relevant to MDS.

Taken together, these data and prior research suggest that factoring sex into personalized decision-making for patients with MDS could help further individualize disease management. A sex-informed approach should also be considered in clinical trials, where these findings have the potential to improve participant selection for certain agents.


Maggioni G, Bersanelli M, Travaglino E, et al. A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study. Lancet Hematol. Published online November 24, 2022. doi:10.1016/S2352-3026(22)00323-4.

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