Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups. Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147.

中文翻译：

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使用高维混合治愈模型在细胞遗传学正常的急性髓系白血病患者中识别长期幸存者以及复发风险较高或较低的患者

细胞遗传学正常的急性髓系白血病 (CN-AML) 患者可能携带与预后相关的基因突变，因此被归类为 2022 年欧洲白血病网 (ELN) 三个遗传风险组之一。然而，这些遗传风险人群的无复发生存率 (RFS) 仍然存在异质性。我们的训练集包括 306 名参加肿瘤学临床试验联盟的成人，年龄 < 60 岁，患有新发 CN-AML，他们实现了完全缓解，并且可以从诊断样本中获得集中审查的细胞遗传学、RNA 测序和基因突变数据（联盟试验A152010）。为了克服存在长期幸存者时 Cox 比例风险模型的缺陷，我们开发了一种惩罚半参数混合治愈模型 (MCM) 来预测 RFS，其中 RNA 测序数据构成预测空间。为了验证模型性能，我们采用了来自德国急性髓性白血病合作组 (AMLCG) 的独立测试集，该测试集由 40 名年龄 < 60 岁的新发 CN-AML 患者组成，这些患者实现了完全缓解，并对治疗前进行了 RNA 测序样本。对于训练集，有显着的非零治愈率 (p = 0.019)，估计有 28.5% 的患者已治愈。我们的 MCM 包括 112 个与治愈或长期 RFS 相关的基因，以及 87 个与潜伏期或短期复发时间相关的基因。训练集的曲线下面积和 C 统计量分别为 0.947 和 0.783，测试集的曲线下面积和 C 统计量分别为 0.837 和 0.718。我们在 CN-AML 中发现了一种新颖的、与预后相关的分子特征，它可以识别独立于 2022 年 ELN 遗传风险组的患者亚组。试验注册 伴随研究 CALGB 8461、9665 和 20202（在 www.clinicaltrials.gov 注册的试验分别为 NCT00048958、NCT00899223 和 NCT00900224）的数据来自肿瘤临床试验联盟数据共享研究 A152010。 AMLCG 2008 试验的数据在 www.clinicaltrials.gov 上注册为 NCT01382147。