Puzo Christian J, Hager Karl M, Rinder Henry M, Weinberg Olga K, Siddon Alexa J
Yale School of Medicine, New Haven, CT, USA.
Department of Laboratory Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
Ann Hematol. 2024 Dec;103(12):5359-5369. doi: 10.1007/s00277-024-06054-7. Epub 2024 Oct 24.
TP53 mutations in patients with AML and MDS frequently portend a poor prognosis, related to both p53 allele status and blast count. In 2022, the ICC and WHO released updated guidelines for classifying p53-mutated AML/MDS. The characteristics of p53 mutations, their associated co-mutations, and their effects on overall survival (OS) are not known in the context of these new guidelines. A retrospective chart review was undertaken for all patients with AML or MDS and at least one TP53 mutation detected on next generation sequencing (NGS) at Yale New Haven Hospital from 2015 to 2023. All patients (N = 210) met criteria for one of the 5 diagnostic classes based on WHO and ICC guidelines. Kaplan-Meier curves with associated log-rank testing and Cox proportional hazards model quantified the effects of clinical and molecular data on survival. Multi-hit pathogenic mutations were related to poorer OS in MDS but not AML using either the WHO (p = .02) or the ICC (p = .01) diagnostic criteria. The most significant predictors of OS in the sample overall were platelet count < 50 K (HR: 2.01, 95% CI [1.47, 2.75], p < .001) and TP53 VAF ≤ 40% (HR: 0.68, 95% CI[0.50, 0.91], p = .01). Blast count ranges, complex karyotype, and p53 mutation type or location, showed no association with OS. In our cohort defined by the 2022 ICC and WHO criteria, VAF and thrombocytopenia, rather than blast count or p53 mutation features, significantly predicted OS. These results speak to each criteria's ability to identify cases of similarly aggressive disease biology and prognosis.
急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者的TP53突变常常预示着预后不良，这与p53等位基因状态和原始细胞计数均有关。2022年，国际癌症研究机构（ICC）和世界卫生组织（WHO）发布了更新后的p53突变型AML/MDS分类指南。在这些新指南的背景下，p53突变的特征、其相关的共突变以及它们对总生存期（OS）的影响尚不清楚。对2015年至2023年在耶鲁纽黑文医院接受下一代测序（NGS）检测出至少一个TP53突变的所有AML或MDS患者进行了回顾性病历审查。所有患者（N = 210）均符合基于WHO和ICC指南的5种诊断类别之一的标准。采用相关对数秩检验的Kaplan-Meier曲线和Cox比例风险模型对临床和分子数据对生存的影响进行了量化。使用WHO（p = 0.02）或ICC（p = 0.01）诊断标准时，多重致病性突变与MDS患者较差的OS相关，但与AML患者无关。样本总体中OS的最显著预测因素是血小板计数<50K（HR：2.01，95%CI[1.47，2.75]，p < 0.001）和TP53变异等位基因频率（VAF）≤40%（HR：0.68，95%CI[0.50，0.91]，p = 0.01）。原始细胞计数范围、复杂核型以及p53突变类型或位置与OS均无关联。在我们根据2022年ICC和WHO标准定义的队列中，VAF和血小板减少症而非原始细胞计数或p53突变特征显著预测了OS。这些结果说明了每种标准识别具有相似侵袭性疾病生物学和预后病例的能力。
