Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine

Dohner, H; Pratz, KW; Pullarkat, VA; DiNardo, CD; Recher, C; Wei, AH; LIU, Z; Jonas, BA; Thirman, MJ; Schuh, AC; Babu, S; Li, X; Ku, G; Sun, Y; Potluri, J; Dail, M; Chyla, B; Pollyea, DA

Author(s): Dohner, H; Pratz, KW; Pullarkat, VA; DiNardo, CD; Recher, C; Wei, AH; LIU, Z; Jonas, BA; Thirman, MJ; Schuh, AC; Babu, S; Li, X; Ku, G; Sun, Y; Potluri, J; Dail, M; Chyla, B; Pollyea, DA;
Details: Publication Year 2024-11-21,Volume 144,Issue #21,Page 2211-2222
Journal Title: Blood
Abstract: The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.
Publisher: ASH
Keywords: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use; *Azacitidine/therapeutic use/administration & dosage; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration & dosage; *Leukemia, Myeloid, Acute/drug therapy/genetics/mortality; Mutation; Prognosis; Risk Assessment; *Sulfonamides/therapeutic use/administration & dosage; Treatment Outcome; Clinical Trials, Phase III as Topic; Clinical Trials, Phase I as Topic; Randomized Controlled Trials as Topic
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 39133921
Publisher's Version: https://doi.org/10.1182/blood.2024024944
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-14 09:49:33

Last Modified: 2024-12-05 10:33:37