Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG)

Abstract

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with patient demographics and genetic features. Although the associations of acquired genetic alterations with patients’ sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling and outcome analyses in 1726 adults with AML (749 female and 977 male) and centrally reviewed cytogenetic data who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. We analyzed a validation cohort of 954 patients (465 female and 489 male) treated on frontline protocols of the German AML Cooperative Group. We found differences between women and men in frequencies of select gene mutations, co-occurring mutation patterns, cytogenetic characteristics and assignment to genetic-risk groups per the 2022 European LeukemiaNet classification, and in prognostic impact of some genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged < 60 years, WT1 mutations were female-specific and SF3B1 mutations male-specific adverse outcome prognosticators. We conclude that sex differences in the AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of considering patients’ sex in analyses of AML biology and prognostication.