TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy. Twenty-nine patients (15%) developed a newly detectable TP53 mutation in the context of relapsed/refractory disease. The median variant allelic frequency (VAF) was 15% (range, 1.1%–95.6%). TP53 mutations were more common after intensive therapy versus lower-intensity therapy (23% vs. 10%, respectively; p = 0.02) and in patients who had undergone hematopoietic stem cell transplant versus those who had not (36% vs. 12%, respectively; p = 0.005). Lower TP53 VAF was associated with an increased likelihood of complete remission (CR) or CR with incomplete hematologic recovery (CRi) compared to higher TP53 VAF (CR/CRi rate of 41% for VAF < 20% vs. 13% for VAF ≥ 20%, respectively). The median overall survival (OS) after acquisition of TP53 mutation was 4.6 months, with a 1-year OS rate of 19%. TP53 VAF at relapse was significantly associated with OS; the median OS of patients with TP53 VAF ≥ 20% was 3.5 months versus 6.1 months for those with TP53 VAF < 20% (p < 0.05). In summary, new TP53 mutations may be acquired throughout the course of AML therapy. Sequential monitoring for TP53 mutations is likely to be increasingly relevant in the era of emerging TP53-targeting therapies for AML.

中文翻译：

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急性髓系白血病治疗过程中 TP53 突变的发展

急性髓系白血病 (AML) 中的TP53突变与标准治疗耐药和不良结局相关。在 AML 治疗过程中新检测到的TP53突变的发生率和预后影响尚未得到很好的描述。我们回顾性分析了 200 名新诊断的TP53野生型 AML 患者，这些患者在一线治疗后复发或难治。29 名患者 (15%)在复发/难治性疾病中出现了新可检测的TP53突变。中位变异等位基因频率 (VAF) 为 15%（范围为 1.1%–95.6%）。与低强度治疗相比，强化治疗后TP53突变更为常见（分别为 23% 与 10%； p  = 0.02），并且在接受造血干细胞移植的患者与未接受造血干细胞移植的患者中（分别为 36% 与 12%，分别；p  = 0.005）。与较高的TP53 VAF 相比，较低的TP53 VAF 与完全缓解 (CR) 或 CR 伴不完全血液学恢复 (CRi) 的可能性增加相关（ VAF < 20% 时 CR/CRi 率为 41%，VAF ≥ 20 时 CR/CRi 率为 13%） ％， 分别）。获得TP53突变后的中位总生存期 (OS) 为 4.6 个月，1 年 OS 率为 19%。复发时TP53 VAF 与 OS 显着相关；TP53 VAF ≥ 20%的患者的中位 OS为 3.5 个月，而TP5 3 VAF < 20%的患者的中位 OS 为 6.1 个月( p  < 0.05)。总之，在整个 AML 治疗过程中可能会获得新的TP53突变。在新兴的TP53靶向治疗 AML时代，对TP53突变的连续监测可能越来越重要。