The sex differences also translate in prognosis and survival rate differences between female and male AML patients [16, 17]. Although patient outcomes are also influenced by multiple factors such as age, genetic mutations, and comorbid conditions, sex is frequently identified as an independent risk factor. This raises the question of whether sex differences should be integrated into clinical decision-making for AML.

For MDS, the retrospective analysis of the GeoMed consortium including over 13,000 patients demonstrated that outcome prediction scores could be optimized by including sex, thereby resulting in an improved personalized sex-informed approach [18]. Although such a model does not yet exist for AML, it is conceivable that this may also apply. For other cancers, differences in chemotherapy responses and side effect profiles based on sex have been noted [19]. In addition to genomics, hormonal differences (especially during premenopausal phase) and sex-specific pharmacokinetics can contribute to these variations.

In MDS, sex-specific responses to hypomethylating agents might be attributed to underlying biological differences [20]. In AML, sex-stratified analyses from recent key clinical trials reveal diverse responses, as summarized in Table 1. The RATIFY study, a phase 3 trial of the FLT3 inhibitor midostaurin, demonstrated significantly prolonged survival in the cohort of midostaurin-treated patients compared to patients in the placebo arm [21]. However, an analysis stratified for sex (Supplementary Fig. S5A of the original publication) showed a difference in survival with mainly men benefiting from the addition of midostaurin (Hazard Ratio (HR) 0.43, 95% Confidence Interval (CI) 0.28–0.68; p < 0.01), while in women there was a trend for the placebo group to perform better (HR 1.42, 95% CI 0.91–2.21; p = 0.12). Similarly, the AGILE trial adding ivosidenib to azacitidine in IDH1-mutated AML patients found a survival benefit for men [22]. The same trend was found in the VIALE-A trial adding venetoclax to azacitidine, although differences were minor (females: HR 0.68, CI: 0.46–1.02 compared to males: HR 0.62, CI: 0.46–0.85) [23].

Conversely, there are also studies indicating a survival benefit for female AML patients compared to male patients. For example, the Quantum-First study (testing quizartinib plus chemotherapy for FLT3-ITD positive newly diagnosed AML patients) demonstrated benefits mainly in females but not in males [24]. In addition, the ADMIRAL trial adding a more FLT3-ITD specific inhibitor gilteritinib to chemotherapy for relapsed or refractory (R/R) FLT3-mutated AML showed an overall survival for females, but not for males [25].

The complexity of these findings underscores the necessity for larger studies in AML, based on which a sex-nuanced approach to treating AML can be invented. Personalized medicine, which tailors’ treatment based on individual patient characteristics, should then include not only genetic and molecular profiles, but should also consider sex as a vital factor. A respective precision oncology approach integrating sex-specific differences into therapeutic strategies has the potential to revolutionize AML treatment, thereby ensuring that both female and male patients receive the most effective and appropriate care.

Emerging technologies, such as single-cell sequencing and whole-genome sequencing, offer unprecedented opportunities to delve deeper into the molecular underpinnings of sex differences in AML in the future. By analyzing the tumor microenvironment and the immune landscape at a single-cell resolution, researchers will be able to better uncover sex-specific and potentially hormonally driven cellular interactions and signaling pathways that might drive disease progression and treatment resistance.

In an ideal scenario, future research should focus on designing clinical trials that specifically address sex differences in AML. These studies should not only stratify patients by sex but also be sufficiently powered to investigate the underlying mechanisms driving disparate outcomes, which can be achieved by increased sample sizes or larger collaborative efforts. Meanwhile, preclinical and animal models will be essential for advancing our understanding of how sex hormones and genetic factors influence AML biology and therapeutic responses.

In conclusion, disease biology and AML outcomes differ significantly between female and male patients. This highlights the importance of considering sex as a factor in AML management, especially with the recent increase in novel targeted strategies. Ultimately, prognostication and therapeutic strategies in AML could be improved by incorporating sex-specific considerations. Thus, we urge researchers to include sex-stratified analyses in their current studies to uncover the extent and relevance of differences, and to enable a more solid data basis.