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Multicenter Study
. 2025 Sep 3;6(5):437-449.
doi: 10.1158/2643-3230.BCD-24-0256.

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

Curtis A Lachowiez #  1 , Mael Heiblig #  2 , Gaspar Aspas Requena  3 , Emmanuelle Tavernier-Tardy  4 , Fangyan Dai  5 , Amenech B Ashango  5 , Daniel T Peters  6 , Jacob Fang  7 , Andy Kaempf  1 , Nicola Long  1 , Christopher A Eide  1 , Stephen E Kurtz  1 , Wei Xie  8 , Anupriya Agarwal  1 , Aishwarya Sahasrabudhe  1 , Christine M McMahon  7 , Maria L Amaya  7 , Gabrielle Meyers  1 , Arpita Gandhi  1 , Jessica Leonard  1 , Brandon Hayes-Lattin  1 , Richard T Maziarz  1 , Elie Traer  1 , Rachel J Cook  1 , Ronan Swords  1 , Theodore P Braun  1 , Jennifer N Saultz  1 , Ashley M Eckel  5 , Michael R Loken  5 , Joshua F Zeidner #  6 , Jeffrey W Tyner #  1 , Daniel A Pollyea #  7
Affiliations
Multicenter Study

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

Curtis A Lachowiez et al. Blood Cancer Discov. .

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.

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.

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Conflict of interest statement

C.A. Lachowiez reports grants from OCTRI KL2 (KL2TR002370) during the conduct of the study as well as personal fees from AbbVie, Servier, Rigel, Syndax, BMS, and COTA Healthcare outside the submitted work. E. Tavernier-Tardy reports personal fees from AbbVie, Bristol Myers Squibb, and Celgene and grants from Pfizer and Servier outside the submitted work. C.M. McMahon reports other support from Kura and Syndax outside the submitted work. A. Gandhi reports other support from CareDx, OncLive, MJH Life Science, and Orca Bio outside the submitted work. J. Leonard reports other support from Autolus, KiTE, Amgen, Adaptive, Pfizer, and AbbVie outside the submitted work. E. Traer reports other support from AbbVie, Servier, Astellas, Daiichi Sankyo, and Syndax; grants from Prelude, Schrödinger, and AstraZeneca; and grants and other support from Rigel and Incyte outside the submitted work. T.P. Braun reports personal fees from Novartis and Blueprint Medicines and grants from Blueprint Medicines and AstraZeneca outside the submitted work. J.N. Saultz reports other support from Rigel and grants from the American Society of Hematology outside the submitted work. A.M. Eckel reports other support from Hematologics, Inc. outside the submitted work. M.R. Loken reports other support from Hematologics, Inc. during the conduct of the study. J.F. Zeidner reports grants and personal fees from AbbVie, AstraZeneca, Novartis, Shattuck Labs, Sumitomo Pharma, Gilead, and Sellas; grants from Arog, Astex, Faron, Jazz, Loxo, Merck, Newave, Stemline, Zentalis, and Akesobio; and personal fees from Daiichi Sankyo, Foghorn, Genmab, Ipsen, Servier, Syndax, and Neogenomics outside the submitted work. J.W. Tyner reports grants from Aptose, AstraZeneca, Constellation, Genentech, Incyte, Acerta, and Meryx and other support from Recludix outside the submitted work. D.A. Pollyea reports personal fees from Kura, Novartis, Syros, Ryvu, Qihan, Zentalis, LINK, Daiichi Sankyo, Aptevo, Rigel, Sumitomo, Adicet, Gilead, Oncoverity, Boehringer Ingelheim, Sanofi, MEI, Syndax, Beigene, Servier, and Astellas; grants and personal fees from Bristol Myers Squibb, AbbVie, and Karyopharm; and grants from Teva outside the submitted work. No disclosures were reported by the other authors.

References

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