Sex and Gender in Myeloid and Lymphoblastic Leukemias and Multiple Myeloma: From Molecular Mechanisms to Clinical Outcomes

Abstract

Biological sex and gender factors significantly influence the pathogenesis, progression, and treatment response in hematologic malignancies. This comprehensive review examines sex-specific differences in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma through systematic analysis of the peer-reviewed literature published between 2014-2024 and identified through structured searches of PubMed, Web of Science, and MEDLINE databases. Epidemiological data demonstrate higher disease incidence (57% male vs. 43% female in MM, 63% male vs. 37% female in AML hospitalizations for ages 18-39) and inferior outcomes in male patients across malignancy types (5-year relative survival rates of 48.8% vs. 60.4% in females with AML), while female patients exhibit superior survival despite experiencing greater treatment-related toxicities. Our analysis reveals consistent sex-specific patterns in molecular mechanisms, including distinct mutational profiles, differences in immune system function, and sex-based pharmacokinetic variations that collectively suggest the necessity for sex-differentiated treatment approaches. The review identifies reproducible patterns across diseases, particularly in cytogenetic and molecular characteristics, with females demonstrating favorable prognostic mutations in leukemias and higher rates of chromosomal abnormalities in multiple myeloma. Despite these identifiable patterns, significant knowledge gaps persist regarding the underlying mechanisms of sex-based outcome differences. Incorporating sex and gender considerations into precision medicine frameworks represents a critical advancement toward optimizing treatment strategies and improving clinical outcomes for patients with hematologic malignancies.

Keywords: gender disparities; hematologic malignancies; pharmacogenomics; sex differences; treatment outcomes.

Figure 1

Sex-specific patterns in AML reveal distinct genetic and clinical profiles. Female patients commonly exhibit FLT3-ITD, NPM1, DNMT3A, and WT1 mutations, associated with higher treatment toxicity but better survival (51% vs. 42% 5-year OS, p = 0.005) and faster response rates (MMR 80% vs. 45%, p = 0.018). Male patients who show higher incidence (977 vs. 749 in the cohort) typically present with U2AF1, RUNX1, SRSF2, and KIT mutations, correlating with poorer outcomes and slower treatment response [49].

Figure 2

Comparative analysis of sex-specific characteristics in multiple myeloma (MM) and acute myeloid leukemia (AML). The figure illustrates key differences between female (pink, left) and male (blue, right) patterns across four major categories: disease epidemiology, molecular features, clinical considerations, and treatment response.