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

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 Dusseldorf 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 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0middot0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0middot0062 in the IWG-PM cohort; IDH2 p<0middot0001 in EuroMDS vs p=0middot042 in IWG-PM; TET2 p=0middot031 vs p=0middot035; U2AF1 p=0middot033 vs p<0middot0001) and mutations in two genes were enriched in women (DNMT3A p<0middot0001 in EuroMDS vs p=0middot011 in IWG-PM; TP53 p=0middot030 vs p=0middot037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0middot0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0middot046 in EuroMDS vs p<0middot0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0middot0073 in EuroMDS vs p<0middot0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81middot3 months, 95% CI 70middot4-95middot0 in men vs 123middot5 months, 104middot5-127middot5 in women; hazard ratio [HR] 1middot40, 95% CI 1middot26-1middot52; p<0middot0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54middot7 months, 95% CI 52middot4-59middot1 in men vs 74middot4 months, 69middot3-81middot2 in women; HR 1middot30, 95% CI 1middot23-1middot35; p<0middot0001 in the GEMSD MDS registry; 40middot0 months, 95% CI 33middot4-43middot7 in men vs 54middot2 months, 38middot6-63middot8 in women; HR 1middot23, 95% CI 1middot08-1middot36; p<0middot0001 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 (43middot0%) of 2025 patients from the EuroMDS cohort and 1003 (42middot0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56middot0%) patients from the EuroMDS cohort and 1265 (53middot0%) 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. Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved

The EU Center of Excellence for Exascale in Solid Earth (ChEESE): Implementation, results, and roadmap for the second phase

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Mechanisms of resistance to the hypomethylating agent azacitidine in Myelodysplastic Syndromes

MECHANISMS OF RESISTANCE TO THE HYPOMETHYLATING AGENT AZACITIDINE IN MYELODYSPLASTIC SYNDROMES. GenOMeC_XXXII cycle. PhD Candidate: ALICE BROGI Tutor: PROF. VALERIA SANTINI Myelodysplastic syndromes (MDS) are a clinically heterogeneous group of clonal disorders, characterized by ineffective erythropoiesis, dysplastic changes of hematopoietic marrow precursors, genetic and epigenetic abnormalities, which share a high frequency of progression to acute myeloid leukemia. Hypomethylating agents (HMA) are standard of care for MDS and may improve survival of high risk MDS, but predictive factors for clinical response and optimal therapeutic duration remain to be defined. The great majority of MDS patients present with profound epigenetic abnormalities and it is believed that the clinical activity of HMAs is due to reversal of aberrant DNA methylation. However, still only ~50% of patients with MDS have a clinical response to HMAs and all of them will invariably lose response after variable length of time. Despite extensive studies of promoter DNA methylation over the last decade, the identification of specific epigenetic markers that may identify at diagnosis those patients who will benefit from HMA therapy remains elusive. For this reason, in this thesis 22 patients affected by high-risk MDS, treated with the hypomethylating agent azacitidine (75 mg/m2/d for 7 days every 28 days) were included. Bone marrow aspirate were collected before and after treatment with the drug. For some of those patients who responded to the treatment, we had specimens during remission and at relapse, when they lost response. All samples were screened for methylation, expression and somatic mutational profile. Methylation profile analysis demonstrated that methylation could be an indicator of response and loss of response. After treatment with azacitidine, the global genome methylation decreased while at relapse increased in specific genomic regions. The analysis of differentially methylated regions (DMRs) in samples at relapse showed an enrichment in biological processes related to neutrophil and granulocyte pathways correlated with a block of maturation of these cells. At baseline, methylation pattern was different between responder and non-responder patients. Moreover, the comparison between primary resistant and secondary resistant cases identified 7 different methylated clusters. Further analysis of these regions could help to understand why some patients did not respond to the therapy while others initially responded and developed the resistance later. Then, RNA-Seq was performed and expression and methylation results were combined. Since mechanisms of resistance to HMA in MDS cannot be correlated with a unique factor given the complexity of this disease, topologically associated domains (TADs) were studied in our primary and secondary resistant cases. TADs analysis allowed to understand the correlation and the spatial organization of differentially expressed genes associated with differentially methylated regions. In our cohort, 75 TADs were found and this result reflected the complexity of 3D-genome organization. By using Phenolyzer, several genes more associated with leukemia and myeloid disorders were identified. However, by using this bioinformatic tool, we discovered an important role of MAP2K1 as a seed gene. MAP2K1 was linked with many of other genes in the 75 TADs and it is strongly considered a key gene in the development of leukemia’s disease. These studies would improve our understanding of the mechanisms behind HMA response, ultimately allowing us to better select patients who will benefit from this kind of therapy and avoid exposure to anyhow toxic drugs like HMA that require long treatment (at least 6 cycles) before their activity is evident

La culture des plantes au Moyen Âge. Hildegarde de Bingen, une femme au savoir précurseur

National audienc

"La culture des plantes au Moyen Âge. Hildegarde de Bingen, une femme au savoir précurseur"

National audienc

Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy

The safety profile of fingolimod is well established in clinical trials and post-marketing studies. This study aimed to evaluate the safety and tolerability of fingolimod in a cohort of Italian patients with relapsing-remitting multiple sclerosis (RRMS). This is a non-comparative, open-label, multicentre, interventional study conducted in patients with RRMS with no suitable alternative treatment option. Safety and tolerability of fingolimod 0.5&nbsp;mg were assessed by recording adverse events (AEs) and serious AEs (SAEs). Of the 906 patients enrolled in the study, 91&nbsp;% of the patients completed the study. AEs and SAEs were reported in 35.4 and 2.9&nbsp;% of the patients, respectively. Most common AEs reported were headache (4.1&nbsp;%), influenza (2.1&nbsp;%), lymphopenia (1.8&nbsp;%), asthenia (1.8&nbsp;%) and pyrexia (1.8&nbsp;%). Increased alanine aminotransferase levels and hypertension were reported as AE in 1.0 and 1.4&nbsp;% of the patients, respectively. Macular oedema was reported in three patients. These results emphasize the safety of fingolimod in patients representing the real-world clinical practice in the Italian population. Fingolimod was safe and well tolerated in this population, which, compared to those enrolled in pivotal trials in terms of concomitant diseases and used medications, is broader. Trial registration: EudraCT 2011-000770-60