Circulating Tumor DNA and Immune Response Markers for Improved Treatment Outcome Prediction in Diffuse Large B‐Cell Lymphoma: A Scoping Review

ABSTRACT Early identification of refractory disease remains a significant unmet clinical need in patients with diffuse large B‐cell lymphoma (DLBCL). This scoping review was conducted to assess the current knowledge on the use of circulating tumor DNA (ctDNA), either alone or in combination with immune markers, as predictive tools for treatment outcome in previously untreated DLBCL patients. A systematic search of online databases PubMed, Embase, CINAHL, and Cochrane was performed from inception to May 2025. This focused on primary research studies investigating the use of ctDNA or immune markers to assess treatment response and predict outcomes in DLBCL. 61 publications were selected for inclusion. The key points of interest for this scoping review were: pre‐analytical sample handling, laboratory methodologies—including sequencing panels and platforms; and mutations or immune markers associated with prognosis or patient outcome. Strong evidence supports the utility of ctDNA analysis at key timepoints to evaluate treatment response: diagnosis, cycle 2 day 1, cycle 3 day 1, and end of treatment. ctDNA assays with adequate sensitivity can improve interpretation of FDG 18 ‐PET/CT scans, reducing unnecessary additional testing for patients. Molecular clustering on ctDNA also improves risk stratification. Elevated cytokines such as CXCL10 and IL‐10 and elevated numbers of myeloid derived suppressor cells in pre‐treatment samples are associated with inferior prognosis. ctDNA analysis shows promise in improving outcomes for patients with DLBCL. Assay standardization for ctDNA analysis is currently lacking. Further investigation into the additional value of immune marker analysis is required. This includes understanding the association between immune markers and molecular subgroups identified on ctDNA analysis.