为了表征年长、新诊断无强化治疗的AML患者的基因组景观和白血病致病途径，并研究其临床意义，在一项前瞻性III期临床试验中，进行了全面的遗传学分析，包括在604例患者中对263个基因进行有针对性的DNA测序。通过肿瘤遗传树模型和层次聚类分析描绘了白血病发展轨迹，采用多变量Cox回归模型获得了预后分组。克隆造血相关基因（ASXL1、TET2、SRSF2、DNMT3A）的突变频率最高。肿瘤遗传模型算法生成了一个由根节点发出的有五个分支的树，分别与ASXL1、DDX41、DNMT3A、TET2和TP53相关，暗示了白血病起始事件，形成了进一步的亚分支。无监督聚类结果与树模型识别的基因组分组一致。多变量分析发现FLT3内部串联重复（ITD）、SRSF2和TP53突变是不良预后因素，而DDX41突变则具有显著有利的效果。基于阿凯克信息准则的后向逐步消除得出了三个遗传风险组：DDX41突变（有利风险）、DDX41野生型/FLT3-ITD阴性/TP53野生型（中度风险）和FLT3-ITD或TP53突变（高风险）。我们的数据揭示了年长AML患者白血病发展的不同轨迹，并为接受较低强度治疗的患者提供了临床有意义的基因结果分层的基础。© 2023. 作者。

To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41wildtype/FLT3-ITDneg/TP53wildtype (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.© 2023. The Author(s).