TY - JOUR
T1 - A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes
T2 - a multicentre, observational cohort study
AU - GenoMed4All consortium
AU - Maggioni, Giulia
AU - Bersanelli, Matteo
AU - Travaglino, Erica
AU - Alfonso Piérola, Ana
AU - Kasprzak, Annika
AU - Sangerman Montserrat, Arnan
AU - Sauta, Elisabetta
AU - Sala, Claudia
AU - Matteuzzi, Tommaso
AU - Meggendorfer, Manja
AU - Gnocchi, Matteo
AU - Zhao, Lin-Pierre
AU - Tentori, Cristina Astrid
AU - Nachtkamp, Kathrin
AU - Dall'Olio, Daniele
AU - Mosca, Ettore
AU - Ubezio, Marta
AU - Campagna, Alessia
AU - Russo, Antonio
AU - Rivoli, Giulia
AU - Bernardi, Massimo
AU - Borin, Lorenza
AU - Voso, Maria Teresa
AU - Riva, Marta
AU - Oliva, Esther
AU - Zampini, Matteo
AU - Riva, Elena
AU - Saba, Elena
AU - D'Amico, Saverio
AU - Lanino, Luca
AU - Tinterri, Benedetta
AU - Re, Francesca
AU - Bicchieri, Marilena
AU - Giordano, Laura
AU - Angelotti, Giovanni
AU - Morandini, Pierandrea
AU - Kubasch, Anne Sophie
AU - Passamonti, Francesco
AU - Rambaldi, Alessandro
AU - Savevski, Victor
AU - Santoro, Armando
AU - van de Loosdrecht, Arjan A.
AU - Brogi, Alice
AU - Santini, Valeria
AU - Kordasti, Shahram
AU - Sanz, Guillermo
AU - Sole, Francesc
AU - Gattermann, Norbert
AU - Kern, Wolfgang
AU - Platzbecker, Uwe
N1 - Funding Information: GM and MBers had equal contribution as first authors. UG, MD-C, and MGDP had equal contribution as last senior authors. The study was done by the GenoMed4all consortium and supported by EuroBloodNET, the European Reference Network on rare haematological diseases. Funding for this study was provided by the EU Horizon 2020 programme (GenoMed4All project #101017549 to MGDP, GC, TH, UP, PF, and MD-C; Transcan_7_Horizon 2020 EuroMDS project #20180424 to MGDP, FS, UP, and PF; and HARMONY project #116026 to GC), 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). Funding Information: GM and MBers had equal contribution as first authors. UG, MD-C, and MGDP had equal contribution as last senior authors. The study was done by the GenoMed4all consortium and supported by EuroBloodNET , the European Reference Network on rare haematological diseases. Funding for this study was provided by the EU Horizon 2020 programme (GenoMed4All project #101017549 to MGDP, GC, TH, UP, PF, and MD-C; Transcan_7_Horizon 2020 EuroMDS project #20180424 to MGDP, FS, UP, and PF; and HARMONY project #116026 to GC), 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). Publisher Copyright: © 2023 Elsevier Ltd
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·0001 in EuroMDS vs p=0·011 in IWG-PM; TP53 p=0·030 vs p=0·037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0·0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0·046 in EuroMDS vs p<0·0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0·0073 in EuroMDS vs p<0·0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81·3 months, 95% CI 70·4–95·0 in men vs 123·5 months, 104·5–127·5 in women; hazard ratio [HR] 1·40, 95% CI 1·26–1·52; p<0·0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54·7 months, 95% CI 52·4–59·1 in men vs 74·4 months, 69·3–81·2 in women; HR 1·30, 95% CI 1·23–1·35; p<0·0001 in the GEMSD MDS registry; 40·0 months, 95% CI 33·4–43·7 in men vs 54·2 months, 38·6–63·8 in women; HR 1·23, 95% CI 1·08–1·36; p<0·0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information. A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43·0%) of 2025 patients from the EuroMDS cohort and 1003 (42·0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56·0%) patients from the EuroMDS cohort and 1265 (53·0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation: Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Funding: European Union (Horizon 2020 and Transcan programs), Italian Association for Cancer Research, Italian Ministry of Health, and Italian Ministry of University and Research.
AB - 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<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·0001 in EuroMDS vs p=0·011 in IWG-PM; TP53 p=0·030 vs p=0·037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0·0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0·046 in EuroMDS vs p<0·0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0·0073 in EuroMDS vs p<0·0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81·3 months, 95% CI 70·4–95·0 in men vs 123·5 months, 104·5–127·5 in women; hazard ratio [HR] 1·40, 95% CI 1·26–1·52; p<0·0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54·7 months, 95% CI 52·4–59·1 in men vs 74·4 months, 69·3–81·2 in women; HR 1·30, 95% CI 1·23–1·35; p<0·0001 in the GEMSD MDS registry; 40·0 months, 95% CI 33·4–43·7 in men vs 54·2 months, 38·6–63·8 in women; HR 1·23, 95% CI 1·08–1·36; p<0·0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information. A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43·0%) of 2025 patients from the EuroMDS cohort and 1003 (42·0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56·0%) patients from the EuroMDS cohort and 1265 (53·0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation: Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Funding: European Union (Horizon 2020 and Transcan programs), Italian Association for Cancer Research, Italian Ministry of Health, and Italian Ministry of University and Research.
UR - http://www.scopus.com/inward/record.url?scp=85147317999&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S2352-3026(22)00323-4
DO - https://doi.org/10.1016/S2352-3026(22)00323-4
M3 - Article
C2 - 36436542
SN - 2352-3026
VL - 10
SP - e117-e128
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 2
ER -