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Sex influences the regulatory mechanisms of the hematopoietic system [1] as well as both innate and adaptive immune responses. Age- and sex-specific discrepancies in autoimmune conditions and cancers, including hematologic malignancies, suggest that genetic and endocrine sex-related variability contributes to disease development and progression through epigenetic mechanisms such as imprinting, X-chromosome inactivation, escape genes, sex-hormone regulation, and behavioral factors [2]. Sex differences are increasingly recognized in hematologic diseases. Myeloid malignancies, including acute myeloid leukemia (AML), exhibit a male predominance [3-5]. Data from previous clinical cohorts demonstrated different molecular characteristics of myeloid malignancies according to sex. In both AML and MDS, large-scale genomic studies have revealed profound sex-associated differences with a female predominance of mutations such as NPM1, DNMT3A, and FLT3-ITD and a male predominance of spliceosome complex and myelodysplasia-related genes (many on the X chromosome: BCOR, BCORL1, SMC1A, STAG2, ZRSR2). Moreover, sex-related differences have been reported in pharmacological efficacy and toxicity. Numerous studies suggest that sex differences influence outcomes in AML patients [6-10]. Male patients with myeloid malignancies generally exhibit inferior survival compared with female ones [7-11]. However, sex is usually considered a confounding factor and is not incorporated into prognostic scoring systems currently used for AML. Recently, Tettero et al. [12] reported sex-based differences in outcomes from randomized phase III AML trials. Some studies have shown a survival advantage for male AML patients compared to females: the RATIFY trial of the FLT3 inhibitor midostaurin [13] demonstrated improved overall survival (OS) primarily in men (HR 0.43, 95% CI 0.28–0.68; p < 0.01). Similarly, the AGILE trial adding ivosidenib to azacitidine in IDH1-mutated AML found a survival benefit in males [14]. A similar but less pronounced trend was observed in the VIALE-A trial [15]. Conversely, the QUANTUM-First and ADMIRAL studies showed overall survival advantages for females [16, 17]. In this context, we performed a sex-stratified analysis of patients enrolled in the AML1310 GIMEMA trial for adults with newly diagnosed AML to investigate the impact of sex differences on disease features and outcomes. The trial integrated pretreatment cytogenetic and mutational profiles with post-consolidation measurable residual disease (MRD) as measured by multiparametric flow cytometry (MFC) to guide treatment decisions [18, 19]. A recent 6-year update [20] confirmed the long-term benefit of a risk-adapted MRD-driven strategy to determine post-remission therapeutic decisions. Mutational profiling, cytogenetic, and outcome analyses were performed by sex in 500 adults with de novo AML (male 52%, female 48%) treated in the AML1310 trial between 2012 and 2015. Patients received post-consolidation autologous (AuSCT) or allogeneic stem cell transplantation (AlloSCT) according to their risk profile. Four categories were identified by integrating NCCN 2009 disease risk and post-consolidation MRD status: favorable or poor-risk (eligible to AuSCT or AlloSCT, respectively); intermediate-risk (IR) MRD-negative or MRD-positive (treated with AuSCT or AlloSCT, respectively). A fifth subgroup of IR patients with no leukemia-associated immunophenotype (LAIP) received AuSCT. Among the 500 patients analyzed, 260 (52%) were male and 240 (48%) female, with a median age of 49 years (range, 18–61). Baseline demographic and clinical characteristics were well balanced between sexes. No significant differences were observed in age, WHO performance status, white blood cell count, or platelet count, although females presented slightly lower median hemoglobin values (8.7 g/dL vs. 9.1 g/dL, p = 0.023). The distribution of NCCN risk and ELN2017 reclassification [21] were similar in males and females as was the frequency of recurrent genetic lesions, including FLT3-ITD, NPM1, CBFβ/MYH11, and RUNX1T1 mutations, and their co-occurrence patterns (Table 1). Following induction therapy, complete remission (CR) was achieved in 73% of patients, with no difference between males and females. In the intermediate-risk group, MRD negativity (< 3.5 × 10−4 residual leukemic cells) was observed in 46% of evaluable cases (54% of males and 36% of females; p = 0.16). Overall, the rate of MRD negativity remained comparable between sexes (52% vs. 51%). After a median follow-up of 6.4 years, the estimated 6-year overall survival (OS) for the entire cohort was 42.7% (95% CI, 38.3–47.6). OS did not differ significantly between sexes (39.4% vs. 46% for males vs. females, respectively, p = 0.218), and disease-free survival (DFS) was also similar (40.2% vs. 43.6% for males vs. females, respectively, p = 0.231). Sex-stratified analysis of the 6-year update of the GIMEMA AML1310 trial revealed a significant interaction between sex and NPM1 mutation status. Compared with men, women with NPM1 mutations showed superior 6-year OS (52.4% vs. 33.8% and median not reached vs. 1.87 years for female vs. males, respectively; p = 0.032) (Figure 1a) and better survival among MRD-positive patients after consolidation (66.5% vs. 45% and median not reached vs. 4.22 years for post-consolidation MRD-positive females vs. males, respectively; p = 0.015) (Figure 1b). Female NPM1-mutated patients also demonstrated improved 6-year DFS as compared to their male counterpart (47% vs. 35%; median 3.05 years vs. 1.26 years; p = 0.085) (Figure 1c). The overall 6-year cumulative incidence of relapse (CIR) was 42% overall, with a higher CIR in males than females (45% vs. 39%; p = 0.0933) and in MRD-positive males compared to females (54% vs. 35%; p = 0.028). Overall survival at 6 years also differed according to post-consolidation therapy: 50.6% after allogeneic transplantation (AlloSCT) and 67.4% after autologous transplantation (AuSCT; p = 0.007), with females deriving the greatest benefit from AuSCT (76% vs. 60%; median not reached; p = 0.032) (Figure 1d). No significant sex-related differences in OS or DFS were observed following AlloSCT. In conclusion, our results indicate that sex differences translate into prognostic and survival differences among AML patients enrolled in the GIMEMA AML1310 trial. A favorable impact of NPM1 mutation was observed in females. Whether these differences arise from hormonal, genetic, or pharmacokinetic factors—beyond age and comorbidities—remains unclear. Strengths of this investigation include the 6-year follow up of adult cohort AML 1310 trial, the resort to a homogeneous treatment approach, centralized MFC MRD assessment and subsequent MRD-driven consolidation, the relative homogeneity of the Italian population diagnosed in a recent time period (2012–2015). Limitations of our data include the use of 2009 NCCN risk categorization and the absence of data on additional prognostic molecular markers. However, a post hoc analysis confirmed the predictive value of the ELN 2017 risk stratification when applied to AML1310 data [21]. These results underscore, in our opinion, the importance of incorporating sex-stratified analyses into current and future AML trials. As recently demonstrated by the GenoMed consortium for MDS [22], a more personalized approach that integrates sex as a biological variable could meaningfully enhance clinical decision-making and outcome prediction in AML. All participants gave their informed consent, and the study was conducted in accordance with the Declaration of Helsinki after approval by the ethics committees of the participating hospitals/academic institutions. Roberto Cairoli conflicts of interest with honoraria: Abbvie Gilead, Pierre Fabre, Gentili Pharma, Celgene, Menarini Stemline, Astellas, Beigene, Servier, Daichi Sankyo, Otsuka. Mario Luppi conflicts of interests unrelated Advisory Board and meeting with honoraria: Abbvie, Jazz Pharma, Novartis, Grifols, Sanofi, Incyte, Istituto Gentili, Roche, Astrazeneca, Otsuka. The other authors declare no conflicts of interest. The authors have nothing to report.