Baseline Plasma Cell-Free and Circulating Tumor DNA Across Lymphoma Subtypes and its Prognostic Impact in Diffuse Large B-Cell Lymphoma

Background: Circulating tumor DNA (ctDNA) analysis enables real‑time assessment of the tumor burden and genomic complexity in lymphomas. However, real‑world evidence across lymphoma subtypes is limited. Methods: We analyzed cell‑free DNA (cfDNA) and ctDNA data from 336 consecutive patients with newly diagnosed Hodgkin or non-Hodgkin lymphoma in 2022 and evaluated their prognostic impact in diffuse large B‑cell lymphoma (DLBCL). Results: , constituted the dominant class of genes with recurrent alterations. Plasma variant profiles closely mirrored publicly available, tissue‑based next-generation sequencing datasets. The baseline ctDNA burden correlated with adverse clinical features, and ctDNA positivity was associated with failure to achieve complete remission. In DLBCL, elevated cfDNA (top quartile) and a high International Prognostic Index (IPI) were independently associated with shorter overall and progression‑free survival. However, the total variant count per patient was not significantly associated with survival after adjustment. Conclusions: Baseline plasma cfDNA and ctDNA assessments are feasible in routine practice and recapitulate tissue-variant landscapes. Elevated cfDNA concentrations-but not the total variant count-were independently associated with survival in DLBCL, providing prognostic information beyond the IPI and supporting integration of plasma-based biomarkers into multiparameter risk models. Gene‑level ctDNA associations should be regarded as exploratory and hypothesis‑generating.