Beyond XX and XY, Understanding Sex Differences in Leukemia

The major subtypes of leukemia show sex differences. This review summarizes current knowledge and identifies gaps regarding sex differences across acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoblastic leukemia in epidemiology, mortality and survival rates, risk factors, and epigenetic, metabolomic, and sex-specific patterns. Males have higher incidence and mortality rates of leukemia compared to females, emphasizing the importance of biological sex. Underreporting of sex differences in leukemia is highlighted, suggesting that sex is often overlooked as a research variable. A significant clinical observation is that women demonstrate higher overall survival rates but experience more severe treatment-related toxicity. Clinically, women tend to survive longer but experience more severe side effects. In contrast, a significant clinical observation in pediatric leukemia contradicts this enigma, suggesting that sex differences may be less pronounced during childhood. These differences play a significant role in how the disease develops. This review presents a sex-based perspective for hematological and biochemical patterns, genetic risk factors, environmental, lifestyle, and parental risk factors, epigenetics and metabolites. Furthermore, males and females might have different responses to the same toxic, environmental, and hormonal exposures. Trying to understand these disparities better based on molecular mechanisms is considered an approach for precision medicine.