A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes : a multicentre, observational cohort study

Altres ajuts: the AIRC Foundation (Associazione Italiana per la Ricerca contro il Cancro; Milan, Italy; projects #22053 to MGDP, #26216 to GC, and #21267 to MTV), PRIN 2017 (Ministry of University and Research, Italy; project 2017WXR7ZT to MGDP), Ricerca Finalizzata 2016 and 2018 (Italian Ministry of Health, Italy; projects RF2016-02364918 to MGDP and NET-2018-12365935 to MGDP, FP, and MTV), the Cariplo Foundation (Milan, Italy; project #2016-0860 to MGDP), and the Beat Leukemia Foundation (Milan, Italy; to MGDP). Background: Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods: In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings: The study included 7792 (58·7%) men and 5492 (41·3%) women. 10 906 (82·1%) patients were White, and race was not reported for 2378 (17·9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p