Beyond XX and XY, Understanding Sex Differences in Leukemia

Sex-based variations are significant among the major subtypes of leukemia. This review briefly discusses the current understanding and knowledge gaps related to sex differences in epidemiology; mortality and survival rates; risk factors, and epigenetic, metabolomic, and sex-specific patterns. Males have higher incidence rates and mortality rates of leuke-mia than females do, highlighting the significance of biological and epidemiologic factors. Sex-based differences were reported in only 0.5% of the clinical trials, an underreporting may be resulting from a persistent lack of awareness or prioritization of integrating sex as a significant variable in research findings. Interesting sex-based patterns arise that sub-stantially impact disease epidemiology. An intriguing medical enigma in leukemia is treatment response, where women have higher overall survival rates but more severe treatment-related toxicity. However, ALL in pediatric patients contradicts this enigma, suggesting that gender differences may be less pronounced during childhood when hor-monal levels are low. Sex-based risk factors are discussed at both the environmental and genetic levels where epigenetic variations, such as DNA methylation, affect gene expres-sion differently in males versus females. Hematological and biochemical patterns are shown from a sex-based perspective in this review. Furthermore, there are clear signs of sex-based differences in the recognition of various metabolites in males and females, which could support the foundation for future research. We encourage researchers not only to perform sex-stratified analyses in their ongoing studies but also to design sex-based clinical trials.