Prognosis and Efficacy Analysis of Diffuse Large B-Cell Lymphoma with TP53 Mutations: A Single-Center Study
Authors: Zhang Haiyan , Zhang Xiang , Wang Jinghan , Zhang Xuewu , Lv Yunfei , Zhu Yanan , Wei Juying , Yang Min , Xu Gaixiang , Ye Xingnong , Lou Yinjun , Yang Chunmei , Meng Haitao , Xie Wanzhuo , Tong Hongyan , Yu Wenjuan 
Published: December 2024

Background:
TP53 is frequently mutated in most cancer types and closely associated with tumor initiation and progression. TP53 mutations are often closely associated with poor prognosis and low treatment response. It has also been confirmed that patients with TP53 mutations were correlated with low response rate to immunochemotherapy and TP53 mutations had been identified as an independent biomarker of poor prognosis in patients with certain indolent lymphoma, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma(MCL). However, there are few studies about the relationship between TP53 mutations and the survival or therapeutic efficacy of Diffuse Large B-Cell Lymphoma (DLBCL) yet.
Objective:
Our study aims to explore the prognostic value of TP53 mutations in DLBCL and find clues about the potential benefits of different treatments.
Methods:
We retrospectively analyzed the data and survival of 436 patients with DLBCL who were newly diagnosed in the hematological department of the First Affiliated Hospital of Zhejiang University from January 2018 to August 2023. TP53 mutations were detected by next-generation sequencing. We excluded patients with malignancy, HIV infection, and pregnancy.
Results:
TP53 mutations were detected in 106 patients, with a mutation rate of 24.31%. The main type of TP53 mutations was missense mutation and the mutation sites were concentrated in exons 5-8. Multivariate analysis showed that TP53 mutations were independent factors of poor prognosis in patients with DLBCL(P&lt;0.001; P&lt;0.001). In subgroup analysis, TP53 mutations had poor prognostic effect in GCB subtypes (P&lt;0.001; P&lt;0.001) but not in non-GCB subtypes(P=0.258; P=0.277). TP53 mutations also had poor survival in double-expressor lymphomas(P=0.003; P&lt;0.001). The optimal cut-off value of VAF calculated by X-tile software was 60%. Patients with VAF≥60% had worse OS and PFS than those with VAF&lt;60%(P=0.020; P&lt;0.005). Those cases with TP53 mutations occurred in the DNA-binding domains (DBD) region had a inferior survival(P&lt;0.001; P&lt;0.001). But the survival of the cases with TP53 mutations occurred in the non-DBD region did not differ from those with TP53 wild type(P=0.115; P=0.084). There was no statistically significant difference in survival between patients with a single TP53 mutation and multiple TP53 mutations(P=0.543; P=0.835). Those with TP53 gain-of-function (GOF) and loss-of-function (LOF) class mutations were associated with worse OS and PFS compared with TP53 wild type. However, the survival is comparable in patients with TP53 GOF and LOF class mutations(P=0.861; P=0.484). Patients with TP53 mutations had a poor response to R-CHOP. Intensive treatments such as R-Hyper CVAD or R-DA-EPOCH could not benefit patients, and also with R-CHOP combined with BTK inhibitors. Encouragingly, the demethylating drug azacitidine with R-CHOP displayed therapeutic efficacy improvement. After 3-4 cycles of treatment with azacitidine combined with R-CHOP, 9 (75%) patients achieved complete remission and 3 (25%) patients reached partial remission. The complete response rate and overall response rate of azacitidine with R-CHOP were significantly higher than those in the R-CHOP group (P=0.017; P=0.031). As of the end of follow-up, none of the 12 patients had disease progression, and the median follow-up time was 13.07(IQR, 10.23-19.77; range, 7.53-26.87) months.
Conclusion:
TP53 mutations have very important prognostic significance in DLBCL. Azacitidine with R-CHOP may be beneficial in DLBCL patients with TP53 mutations.