PDF(Pubmed)
Abstract：
TP53 mutations have a prognostic significance in relapsed and refractory diffuse large B-cell lymphoma (rrDLBCL) patients, and their treatment still faces a great challenge. This study aimed to evaluate the prognosis of patients with TP53 mutations (TP53mut) in the context of CAR-T therapy (Chimeric antigen receptor T-cell therapy) as well as explore the heterogeneity in their cohort and identify the possible risk factors.
A retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients with TP53 mutations and their prognostic factors, receiving CAR-T therapy. And the expression level of TP53 and DDX3X, which was an important co-mutation of TP53 revealed in the cohort, were explored in public databases and cell lines.
The median overall survival time of 40 patients with TP53 mutations was 24.5 months, while their median progression-free survival time after CAR-T was 6.8 months. There were no significant differences in the ORR (objective remission rate, X2 = 3.0498, p > 0.05) and PFS (after CAR-T therapy) between the patients with wild-type and mutated TP53 genes after CAR-T therapy, while the OS of patients with TP53 mutations was significantly worse (p < 0.01). In patients with TP53 mutations, the performance status (ECOG score) was identified as the most important prognostic factor, while the efficacies of induction and salvage treatments were also correlated with the prognosis. Among molecular indicators, the co-mutations of Chr-17 and those located on the exon 5 of the TP53 gene showed a tendency for a worse prognosis. Moreover, the patients with TP53-DDX3X co-mutations were identified as a subgroup with an extremely bad prognosis. The expression levels of DDX3X and TP53 were explored in a public database and the cell lines with their co-mutations, which indicated that inhibiting the DDX3X gene could affect the proliferation of rrDLBCL cells and the expression of TP53.
This study indicated rrDLBCL patients with TP53 mutations was still the group of poor prognosis in the CAR-T therapy era. CAR-T therapy can benefit some TP53mut patients, and the performance status (ECOG) might help predict their prognosis. The study also revealed a subgroup of TP53-DDX3X co-mutations in rrDLBCL, which showed a strong clinical significance.
A retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients with TP53 mutations and their prognostic factors, receiving CAR-T therapy. And the expression level of TP53 and DDX3X, which was an important co-mutation of TP53 revealed in the cohort, were explored in public databases and cell lines.
The median overall survival time of 40 patients with TP53 mutations was 24.5 months, while their median progression-free survival time after CAR-T was 6.8 months. There were no significant differences in the ORR (objective remission rate, X2 = 3.0498, p > 0.05) and PFS (after CAR-T therapy) between the patients with wild-type and mutated TP53 genes after CAR-T therapy, while the OS of patients with TP53 mutations was significantly worse (p < 0.01). In patients with TP53 mutations, the performance status (ECOG score) was identified as the most important prognostic factor, while the efficacies of induction and salvage treatments were also correlated with the prognosis. Among molecular indicators, the co-mutations of Chr-17 and those located on the exon 5 of the TP53 gene showed a tendency for a worse prognosis. Moreover, the patients with TP53-DDX3X co-mutations were identified as a subgroup with an extremely bad prognosis. The expression levels of DDX3X and TP53 were explored in a public database and the cell lines with their co-mutations, which indicated that inhibiting the DDX3X gene could affect the proliferation of rrDLBCL cells and the expression of TP53.
This study indicated rrDLBCL patients with TP53 mutations was still the group of poor prognosis in the CAR-T therapy era. CAR-T therapy can benefit some TP53mut patients, and the performance status (ECOG) might help predict their prognosis. The study also revealed a subgroup of TP53-DDX3X co-mutations in rrDLBCL, which showed a strong clinical significance.
摘要：
背景：TP53突变在复发和难治性弥漫性大B细胞淋巴瘤（rrDLBCL）患者中具有预后意义，他们的治疗仍然面临着巨大的挑战。这项研究旨在评估在CAR-T疗法（嵌合抗原受体T细胞疗法）的背景下TP53突变（TP53mut）患者的预后，并探讨其队列中的异质性并确定可能的危险因素。
方法：回顾性研究TP53突变rrDLBCL患者的临床特征及其预后因素。接受CAR-T治疗。而TP53和DDX3X的表达水平，这是在队列中发现的TP53的重要共突变，在公共数据库和细胞系中进行了探索。
结果：40例TP53突变患者的中位总生存时间为24.5个月，而他们在CAR-T后的中位无进展生存期为6.8个月.ORR(客观缓解率，X2=3.0498，p>0.05）和CAR-T治疗后具有野生型和突变TP53基因的患者之间的PFS（CAR-T治疗后），而TP53突变患者的OS显著恶化(p<0.01)。在TP53突变的患者中，表现状态（ECOG评分）被确定为最重要的预后因素，而诱导和挽救治疗的疗效也与预后相关。在分子指标中，Chr-17和TP53基因外显子5上的共突变显示出预后较差的趋势。此外，TP53-DDX3X共突变患者被确定为预后极差的亚组.DDX3X和TP53的表达水平在公共数据库和具有它们的共突变的细胞系中进行了探索,表明抑制DDX3X基因可以影响rrDLBCL细胞的增殖和TP53的表达。
结论：这项研究表明，在CAR-T治疗时代，TP53突变的rrDLBCL患者仍然是不良预后组。CAR-T疗法可以使一些TP53mut患者受益，和表现状态（ECOG）可能有助于预测其预后。该研究还揭示了rrDLBCL中TP53-DDX3X共突变的一个亚组，显示出很强的临床意义。
方法：回顾性研究TP53突变rrDLBCL患者的临床特征及其预后因素。接受CAR-T治疗。而TP53和DDX3X的表达水平，这是在队列中发现的TP53的重要共突变，在公共数据库和细胞系中进行了探索。
结果：40例TP53突变患者的中位总生存时间为24.5个月，而他们在CAR-T后的中位无进展生存期为6.8个月.ORR(客观缓解率，X2=3.0498，p>0.05）和CAR-T治疗后具有野生型和突变TP53基因的患者之间的PFS（CAR-T治疗后），而TP53突变患者的OS显著恶化(p<0.01)。在TP53突变的患者中，表现状态（ECOG评分）被确定为最重要的预后因素，而诱导和挽救治疗的疗效也与预后相关。在分子指标中，Chr-17和TP53基因外显子5上的共突变显示出预后较差的趋势。此外，TP53-DDX3X共突变患者被确定为预后极差的亚组.DDX3X和TP53的表达水平在公共数据库和具有它们的共突变的细胞系中进行了探索,表明抑制DDX3X基因可以影响rrDLBCL细胞的增殖和TP53的表达。
结论：这项研究表明，在CAR-T治疗时代，TP53突变的rrDLBCL患者仍然是不良预后组。CAR-T疗法可以使一些TP53mut患者受益，和表现状态（ECOG）可能有助于预测其预后。该研究还揭示了rrDLBCL中TP53-DDX3X共突变的一个亚组，显示出很强的临床意义。
