TP53-mutant acute lymphoblastic leukemia (ALL) in adults is a high-risk subtype with poor outcomes, yet its molecular landscape and clinical implications remain incompletely defined. In this multi-institutional study of 830 adult ALL patients treated at eight academic centers between 2010 and 2024, we demonstrated that TP53 mutations are independent predictors of inferior overall survival in both B-ALL (median, 1.9 vs 5 years) and T-ALL (1.6 vs 9.5 years), irrespective of age, biologic disease subtype, or therapy. Genomic profiling revealed that >90% of TP53 mutations were DNA-binding domain missense variants, frequently co-occurring with hypodiploidy in B-ALL and NOTCH1/FBXW7 mutations in T-ALL. Unlike myeloid malignancies, biallelic TP53 mutations did not worsen outcomes, and variant type (missense vs truncating) did not influence survival. TP53-mutant B-ALL exhibited higher CD20 positivity than TP53-wild type B-ALL (65% vs 31%) but had inferior responses to conventional chemotherapy. Novel immunotherapies (e.g., inotuzumab/blinatumomab) or venetoclax-containing combination regimens improved remission rates, yet relapses were common, often with CD19/CD20/CD22 loss (triple-negative) or acquisition of new mutations. Allogeneic transplantation in first remission trended toward survival benefit (median, 3.3 vs 2.2 years). These findings underscore TP53-mutant ALL as a distinct, chemo-resistant entity necessitating tailored approaches, with antigen escape highlighting challenges of immunotherapy durability.
TP53突变型成人急性淋巴细胞白血病（ALL）是一种预后不良的高危亚型，但其分子图谱和临床意义尚未完全明确。这项多中心研究纳入2010年至2024年间在八家学术中心接受治疗的830例成人ALL患者，结果显示：无论年龄、疾病生物学亚型或治疗方案如何，TP53突变均为B-ALL（中位生存期1.9年vs 5年）和T-ALL（1.6年vs 9.5年）总体生存率下降的独立预测因子。基因组分析显示>90%的TP53突变发生在DNA结合域错义变异位点，在B-ALL中常与低二倍体共存，在T-ALL中常伴NOTCH1/FBXW7突变。与髓系恶性肿瘤不同，双等位基因TP53突变并未加剧预后恶化，且变异类型（错义与截短变异）不影响生存率。TP53突变型B-ALL较野生型表现出更高的CD20阳性率（65% vs 31%），但对传统化疗反应较差。新型免疫疗法（如奥加伊妥珠单抗/贝林妥欧单抗）或含维奈克拉联合方案虽能提高缓解率，但复发常见，常伴随CD19/CD20/CD22丢失（三重阴性）或新突变出现。首次缓解期进行异基因造血干细胞移植显示出生存获益趋势（中位生存期3.3年vs 2.2年）。这些发现证实TP53突变型ALL是一种独特的化疗耐药亚型，需制定个体化治疗方案，而抗原逃逸现象凸显了免疫疗法持久性面临的挑战。
Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults
肿瘤(癌症)患者之家