Francesco Albano, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Cosimo Cumbo, Francesco Tarantini, Giorgina Specchia

Abstract. Biological sex is increasingly recognized as a relevant dimension of heterogeneity in hematologic malignancies, extending beyond differences in incidence to clinical presentation, molecular architecture, immune regulation, prognosis, treatment-related toxicity, and potentially therapeutic response. However, the strength and consistency of these associations vary substantially across diseases, age groups, molecular subtypes, treatment settings, and clinical endpoints. Male predominance and sex-associated differences in mutational profiles and survival are supported by population-based and clinically annotated cohorts in selected malignancies, whereas evidence for sex-related differences in pharmacokinetics, treatment benefit, immunotherapy outcomes, and toxicity remains more limited and frequently hypothesis-generating. Observed disparities may also reflect differences in age, hormonal status, body composition, comorbidities, treatment exposure, healthcare access, and competing mortality. Most available studies are retrospective, rely on a binary administrative sex variable, and lack formal sex-by-treatment interaction testing or detailed information on menopausal and hormonal status. Biological plausibility should therefore not be interpreted as proof of causality or predictive value. Sex should be systematically reported and incorporated into appropriately adjusted analyses and prospective studies, but current evidence is insufficient to support sex-based treatment selection. A rigorously validated sex-informed framework may ultimately improve biological interpretation, prognostic modeling, and precision hematology.
Key words. Hematologic malignancies, prognosis, sex, treatment response, risk stratification.