TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy.

Liting Chen,Jianfeng Zhou,Xiaolu Long,Liang Huang,Min Xiao,Jia Gu,Chunrui Li,Miao Zheng,Yi Xiao,Wei Mu

doi:10.3390/diagnostics11050844

Liting Chen, Jianfeng Zhou + Show 8 more

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https://doi.org/10.3390/diagnostics11050844

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Abstract

Chimeric antigen receptor T (CAR T) cell immunotherapy has shown remarkable efficacy in non-Hodgkin’s lymphoma (NHL) patients. Minimal residual disease (MRD) monitoring in NHL is essential after CAR T cell therapy, which can be achieved by monitoring circulating tumor DNA (ctDNA). The mutation of TP53 in NHL has been suggested to be associated with a poor prognosis. However, whether TP53-mutated ctDNA can be used as a biomarker remains undetermined. In this study, a total of 40 patients with mutated TP53 who received CAR T cell treatment were analyzed, and specific probes targeting 29 different TP53 mutation sites in the 40 patients were designed and verified. Then, the presence of TP53-mutated ctDNA in longitudinal plasma samples was tracked by droplet digital PCR. Patients were stratified into two groups, favorable or unfavorable, based on their highest ctDNA level using a MAF cutoff of 3.15% according to the ROC curve. The unfavorable group had significantly worse PFS than the favorable group (p < 0.001). Our results suggest that patients with mutated TP53 with a favorable ctDNA profile in the first trimester have better prognostic outcomes than patients with an unfavorable profile, and ctDNA can be a reliable predictor of the subsequent clinical outcome.

Highlights

Non-Hodgkin’s lymphoma (NHL) accounts for approximately 90% of all lymphomas and has a wide range of histological appearances and clinical features at presentation, making its diagnosis and treatment difficult [1]
non-Hodgkin’s lymphoma (NHL) patients with established TP53 mutations who were treated with chimeric antigen receptor T (CAR T) cell therapy and had circulating tumor DNA (ctDNA) tracked at Tongji Hospital between July 2018 and December 2020 were included in this study (Figure 1)
TP53 mutations were detected in 21% (78/370) of patients, consistent with previous studies [13]

Summary

Introduction

Non-Hodgkin’s lymphoma (NHL) accounts for approximately 90% of all lymphomas and has a wide range of histological appearances and clinical features at presentation, making its diagnosis and treatment difficult [1]. Circulating tumor DNA (ctDNA) detection has emerged as a promising minimally invasive technique to determine MRD and further assess the treatment response. Droplet digital PCR (ddPCR) is a highly sensitive form of PCR based on water–oil emulsion droplet technology [5]. This technology can provide high precision and absolute quantification of nucleic acid target sequences and can be used for ctDNA monitoring [6]. This method has been successfully utilized to validate mutations identified in ctDNA

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