Risk Stratification in Diffuse Large B Cell Lymphoma: A Review of Novel FDG PET/CT Imaging and Liquid Biopsy Biomarkers and Suggestions for Future Directions to Improve Prognostic Accuracy

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2026 Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoid cancer, accounting for up to 25-30% of non-Hodgkin lymphoma. Current first-line treatment regimens, which include rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are effective in 60-70% of patients, however, the remaining 30-40% of patients have a poor prognosis with limited response to salvage therapy. Many attempts to accurately risk stratify patients prior to and throughout treatment have been developed, including baseline clinical factors such as the International Prognostic Index (IPI) and treatment response by interim18F-FDG PET/CT using Lugano Classificaiton and Response Evaluation Criteria in Lymphoma (RECIL). However, these have been ineffective in improving clinical prognosis in these patients. There is need for better risk stratification with identification of the patients at highest risk of treatment failure. New quantitative PET parameters, such as Metabolic Tumor Volume (MTV) and dissemination features (Dmax) have recently been shown to be robust predictors of prognosis in DLBCL. Emerging biomarkers and liquid biopsy are also being evaluated in this setting, including circulating tumor DNA (ctDNA), and have been shown to be independently prognostic of patient outcomes. When molecular response, measured by ctDNA levels, is combined with interim PET/CT, it is possible to identify a subset of patients with extremely high risk of treatment failure, which may allow for earlier intervention or alternative therapies, for example, autologous bone marrow transplantation or chimeric antigen receptor T cells (CAR-T). Current and emerging PET/CT parameters will likely need to be factored into an algorithm with clinical factors and molecular markers, both at baseline and throughout treatment as dynamic response markers. In this educational exhibit we review potential approaches for integrating novel ctDNA biomarkers from liquid biopsy with PET/CT for evaluation of therapy response and recurrence in DLBCL as well as future directions for research.

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