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.

中文翻译：

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接受维奈托克和阿扎胞苷治疗的初治 AML 患者的遗传风险分层和结局


欧洲白血病网 （ELN） 急性髓性白血病 （AML） 遗传风险分类系统基于对强化化疗的反应;它们区分接受维奈托克-阿扎胞苷治疗的老年患者结局的能力可能不是最佳的。这项对 3 期 VIALE-A 试验 （NCT02993523） 和 1b 期研究 （NCT02203773） 的汇总分析根据 2017 年和 2022 年 ELN 风险分类检查了预后分层，并得出了新的分子特征，根据总生存期 （OS） 区分维奈托克-阿扎胞苷治疗的患者。总体而言，分析了 279 例接受维奈托克-阿扎胞苷治疗的患者和 113 例接受安慰剂-阿扎胞苷治疗的患者。ELN 2017 或 2022 预后标准将大多数患者归类为不良风险 AML（维奈托克-阿扎胞苷分别为 60.2% 和 72.8%，安慰剂-阿扎胞苷分别为 65.5% 和 75.2%）。尽管与安慰剂-阿扎胞苷相比，维奈托克-阿扎胞苷在所有 ELN 风险组中的结果都有所改善，但 ELN 分类系统对维奈托克-阿扎胞苷结局的区分较差。通过应用生物信息学算法，得出了新的分子特征，以区分维奈托克-阿扎胞苷的 OS 结局。TP53、FLT3 内部串联重复 （FLT3-ITD）、NRAS 和 KRAS 的突变状态将患者分为高、中、低收益组（分别为 52%、25% 和 23% 的患者），每个组都与不同的中位 OS 相关 （分别为 26.5 个月 [95% 置信区间 （CI），20.2-32.7];12.1 个月 [95% CI，7.3-15.2];和 5.5 个月 [95% CI，2.8-7.6]）。ELN 预后分类器未提供维奈克拉-阿扎胞苷治疗患者 OS 结局的临床意义风险分层。 TP53、FLT3-ITD、NRAS 和 KRAS 突变状态允许将这些患者分为 3 个风险组，中位 OS 存在明显差异。这些试验在 www.clinicaltrials.gov 年注册为 #NCT02993523 和 #NCT02203773。