Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), −17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS (‘EPI6’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

目前针对高级别TP53突变骨髓肿瘤（≥10% 原始细胞）的治疗除了少数对一线治疗 (CR1) 完全缓解的同种异体干细胞移植外，无法提供有意义的生存获益。为了确定对一线治疗 (CR1) 完全缓解和结果的可靠的治疗前预测因素，我们收集了 242 名患有TP53突变骨髓肿瘤且原始细胞≥10% 的个体的队列，并具有详细注释的临床、分子和病理学数据。检查的主要结果是 CR1 和 24 个月生存率 (OS24)。在这个老年队列（中位年龄 68.2 岁）中，74.0% 的人接受一线非强化治疗（低甲基化药物 +/- Venetoclax），总体队列 CR1 率为 25.6% (50/195)。我们还确定了几个预测 CR1 较差的治疗前因素，包括男性 ( P = 0.026)、≥2 常染色体单体 ( P < 0.001)、−17/17p ( P = 0.011)、多重命中TP53等位基因状态 ( P < 0.001）和CUX1共同改变（ P = 0.010）。在整个队列的单变量分析中，较差的 OS24 由 ≥2 个单体 ( P = 0.004)、 TP53 VAF > 25% ( P = 0.002)、 TP53剪接点突变 ( P = 0.007) 和既往治疗过的骨髓肿瘤 ( P = 0.001）。此外， CUX1 、 U2AF1 、 EZH2 、 TET2 、 CBL或KRAS （“ EPI6 ”签名）中的突变/缺失预测 OS24 较差（HR = 2.0 [1.5–2.8]； P < 0.0001）。 在 HMA +/-Ven 治疗个体 ( N = 144) 的亚组分析中， TP53 VAF 和单体不影响 OS24。 HMA +/-Ven 治疗个体的风险评分结合了三种治疗前预测因素，包括TP53剪接点突变、 EPI6和既往治疗的骨髓肿瘤，分为 3 个不同预后组：中等、中等较差和中位数显着不同的较差（12.8， 6.0、4.3 个月）和 24 个月（20.9%、5.7%、0.5%）生存率（ P < 0.0001）。我们的数据首次在看似单一的高风险队列中确定了几个预测反应和 24 个月生存率的基线因素。