Supplemental FIgure 5 from Genetic and Phenotypic Correlates of Clinical Outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN Study

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.

doi:10.1158/2643-3230.30296481

Supplemental FIgure 5 from Genetic and Phenotypic Correlates of Clinical Outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN Study

https://doi.org/10.1158/2643-3230.30296481

journal contribution

posted on 2025-10-07, 14:40 authored by Curtis A. Lachowiez, Mael Heiblig, Gaspar Aspas Requena, Emmanuelle Tavernier-Tardy, Fangyan Dai, Amenech B. Ashango, Daniel T. Peters, Jacob Fang, Andy Kaempf, Nicola Long, Christopher A. Eide, Stephen E. Kurtz, Wei Xie, Anupriya Agarwal, Aishwarya Sahasrabudhe, Christine M. McMahon, Maria L. Amaya, Gabrielle Meyers, Arpita Gandhi, Jessica Leonard, Brandon Hayes-Lattin, Richard T. Maziarz, Elie Traer, Rachel J. Cook, Ronan Swords, Theodore P. Braun, Jennifer N. Saultz, Ashley M. Eckel, Michael R. Loken, Joshua F. Zeidner, Jeffrey W. Tyner, Daniel A. Pollyea

<p>Overall survival within the US cohort (n = 279) based on the presence of signaling pathway mutations including (A) NRAS, (B) KRAS, (C) PTPN11, (D) BRAF, (E) NF1, and (F) WT1. Reported p-values utilized the cox model Wald test.</p>

Funding

National Center for Advancing Translational Sciences (NCATS)

United States Department of Health and Human Services

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Leukemia and Lymphoma Society (LLS)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

History

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1.
DOI - Is supplement to Genetic and Phenotypic Correlates of Clinical Outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN Study

ARTICLE ABSTRACT

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. 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