Genetic and Phenotypic correlates of clinical outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN study

Abstract Resistance to venetoclax-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical venetoclax resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis inclusive of 678 patients comprehensively characterized the prognostic role of monocytic differentiation in AML patients treated with hypomethylating agents combined with venetoclax. AML genetics and monocytic differentiation (HR: 1.89, 95% CI: 1.35-2.66, p < 0.001) in NPM1 wild-type cases correlated with an increased risk of death. Clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and anti-apoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and anti-apoptotic protein expression highlights the complementary role these factors impart following venetoclax-based therapy.