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Summary: Diffuse large B‐cell lymphoma (DLBCL) is a highly heterogenous malignancy, early identification of patients for relapse remains challenging. The potential to non‐invasively monitor tumour evolutionary dynamics of DLBCL needs to be further established. In the present study, 17 tumour biopsy and 38 plasma samples from 38 patients with high‐intermediate/high‐risk DLBCL were evaluated at baseline. Longitudinal blood samples were also collected during therapy. Circulating tumour DNA (ctDNA) was analysed using targeted sequencing based on a gene panel via a recently developed methodology, circulating single‐molecule amplification and re‐sequencing technology (cSMART). We found that the most frequently mutated genes were tumour protein p53 (TP53; 42·1%), histone‐lysine N‐methyltransferase 2D (KMT2D; 28·9%), caspase recruitment domain family member 11 (CARD11; 21·1%), cAMP response element‐binding protein binding protein (CREBBP; 15·8%), β2‐microglobulin (B2M; 15·8%), and tumour necrosis factor alpha‐induced protein 3 (TNFAIP3; 15·8%). The mutation profiles between ctDNA and matched tumour tissue showed good concordance; however, more mutation sites were detected in ctDNA samples. Either TP53 or B2M mutations before treatment predicted poor prognosis. Analysis of dynamic blood samples confirmed the utility of ctDNA for the real‐time assessment of treatment response and revealed that the increases in ctDNA levels and changes in KMT2D mutation status could be useful predictors of disease progression. Our present results suggest that ctDNA is a promising method for the detection of mutation spectrum and serves as a biomarker for disease monitoring and predicting clinical recurrence. [ABSTRACT FROM AUTHOR]