Sex disparity in acute myeloid leukemia – evidence from a study of FLT3-ITD mutated patients

Little attention has been directed at untangling sex-related molecular and phenotypic differences in AML. While increased incidence and poor risk is generally associated with a male phenotype, FLT3 -ITD, NPM1 and DNMT3A mutations are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3 -ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity responses in four cohorts: the Beat AML cohort, the LAML-TCGA cohort and two independent HOVON/SAKK clinical trial-associated cohorts, comprising a total of 1755 AML patients. We found that sex-associated molecular differences were prevalent in FLT3 -ITD mutated AML. Co-occurrence of FLT3 -ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3 -ITDs were characterised by additional mutations in genes involved in RNA splicing and epigenetic modification. Female and male FLT3 -ITD mutated AML had diverging expression of multiple leukemia-associated genes, as well as discrepant ex vivo drug-responses, suggestive of discrete functional properties. Surprisingly, we found significant prognostication of FLT3 -ITD only in female patients. Thus, we suggest optimisation of FLT3- ITD mutation status as a clinical tool in a sex-adjusted manner. We further hypothesize that prognostication, prediction and development of therapeutic strategies in AML can be improved by including sex-specific considerations.