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突变髓系肿瘤（原始细胞≥10%）的治疗，除少数对一线治疗达到完全缓解（CR1）的患者接受异基因干细胞移植外，其他方案均无法提供有意义的生存获益。为识别能够可靠预测一线治疗完全缓解（CR1）及预后的治疗前因素，我们收集了242例TP53突变且原始细胞≥10%的髓系肿瘤患者数据，这些数据包含详细标注的临床、分子及病理学信息。研究的核心结局指标为CR1率和24个月总生存率（OS24）。在这个老年患者队列（中位年龄68.2岁）中，74.0%的患者接受一线非强化方案（低甲基化药物联合或不联合维奈托克）治疗，整体CR1率为25.6%（50/195）。我们进一步发现多个与较低CR1率相关的治疗前预测因素，包括男性（P=0.026）、≥2条常染色体单体（P<0.001）、-17/17p缺失（P=0.011）、TP53多等位基因突变状态（P<0.001）以及CUX1共突变（P=0.010）。在全队列的单变量分析中，较差的OS24与以下因素相关：≥2条单体（P=0.004）、TP53 VAF>25%（P=0.002）、TP53剪接区突变（P=0.007）以及既往接受过治疗的髓系肿瘤史（P=0.001）。此外，CUX1、U2AF1、EZH2、TET2、CBL或KRAS的突变/缺失（即“EPI6”特征）也预示着较差的OS24（HR=2.0 [1.5–2.8]；P<0.0001）。在接受HMA联合或不联合维奈托克治疗的亚组分析（N=144）中，TP53 VAF和单体数量对OS24无显著影响。基于该亚组患者的三项治疗前预测因素——TP53剪接区突变、EPI6特征及既往治疗史——构建的风险评分系统，可将患者分为三个预后不同的层级：中危、中高危和高危组，其三组中位生存期（12.8、6.0、4.3个月）和24个月生存率（20.9%、5.7%、0.5%）均存在显著差异（P<0.0001）。本研究首次在这个看似同质的高危患者队列中，明确了多项能够预测治疗反应和24个月生存率的基线因素。
Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms
肿瘤(癌症)患者之家