Blood cancer discovery · 2025
Genetic and Phenotypic Correlates of Clinical Outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN Study.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Lachowiez Curtis A, Heiblig Mael, Aspas Requena Gaspar, Tavernier-Tardy Emmanuelle, Dai Fangyan, Ashango Amenech B, Peters Daniel T, Fang Jacob, Kaempf Andy, Long Nicola, Eide Christopher A, Kurtz Stephen E, Xie Wei, Agarwal Anupriya, Sahasrabudhe Aishwarya, McMahon Christine M, Amaya Maria L, Meyers Gabrielle, Gandhi Arpita, Leonard Jessica, Hayes-Lattin Brandon, Maziarz Richard T, Traer Elie, Cook Rachel J, Swords Ronan, Braun Theodore P, Saultz Jennifer N, Eckel Ashley M, Loken Michael R, Zeidner Joshua F, Tyner Jeffrey W, Pollyea Daniel A
Аннотация
UNLABELLED: Resistance to venetoclax (VEN)-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 VEN 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 patients with AML treated with hypomethylating agents combined with VEN. AML genetics and monocytic differentiation (HR = 1.89; 95% confidence interval, 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 antiapoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and antiapoptotic protein expression highlights the complementary role these factors impart following VEN-based therapy.
SIGNIFICANCE: AML with monocytic differentiation often occurs in the context of co-occurring mutations within signaling pathways. In certain AML subgroups (such as NPM1 wild-type and signaling pathway gene-mutated), a monocytic phenotype is associated with decreased overall survival following VEN-based therapy. See related commentary by Renders, p. 403.
SIGNIFICANCE: AML with monocytic differentiation often occurs in the context of co-occurring mutations within signaling pathways. In certain AML subgroups (such as NPM1 wild-type and signaling pathway gene-mutated), a monocytic phenotype is associated with decreased overall survival following VEN-based therapy. See related commentary by Renders, p. 403.