Circulating Tumor DNA as a Biomarker of Treatment Response and Minimal Residual Disease in Diffuse Large B-Cell Lymphoma: A Literature Review

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and is characterized by pronounced molecular heterogeneity that is not always fully captured by standard histopathological assessment. Circulating tumor DNA (ctDNA) is increasingly regarded as a promising liquid-biopsy biomarker that enables non-invasive molecular tumor profiling, assessment of tumor burden, dynamic monitoring of treatment response, and detection of measurable/minimal residual disease (MRD). Modern analytical platforms, ranging from PCR-based assays to next-generation sequencing approaches, including CAPP-Seq and PhasED-Seq, have substantially expanded the possibilities of molecular monitoring in DLBCL. This review summarizes current data on the biological characteristics of ctDNA, contemporary methods for its analysis, concordance between ctDNA and tumor-tissue mutational profiles, and the clinical significance of baseline ctDNA levels, early molecular response, post-treatment MRD status, and molecular surveillance during remission. Special attention is given to ctDNA monitoring in patients receiving novel immunotherapies, including CAR-T cell therapy, bispecific antibodies, and antibody–drug conjugates. Emerging multi-omic approaches integrating genomic, epigenomic, and fragmentomic data are discussed as promising future directions. Key limitations of clinical implementation include insufficient standardization of preanalytical and analytical workflows, the confounding effect of clonal hematopoiesis of indeterminate potential, variability across technological platforms, and the lack of completed prospective randomized interventional studies demonstrating improved outcomes when therapy is modified according to ctDNA status. Overall, ctDNA is currently a highly informative prognostic biomarker in DLBCL; however, its full implementation as a predictive tool for treatment selection requires further harmonization, prospective validation, and confirmation in interventional clinical trials.