Standard-of-care first-line immunochemotherapy containing an anti-CD20 monoclonal antibody and an anthracycline, such as R-CHOP, Pola-R-CHP, or DA-EPOCH-R.

Diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) are aggressive lymphomas commonly treated with first-line immunochemotherapy. Some patients experience disease progression or relapse despite treatment. PET/CT is used to assess treatment response, but it may not identify small amounts of residual lymphoma. Circulating tumor DNA (ctDNA) consists of tumor-derived DNA fragments detectable in blood. This prospective observational study will use PhasED-seq to assess plasma ctDNA before, during, and after first-line therapy in approximately 100 patients with newly diagnosed DLBCL or HGBL. The primary objective is to evaluate the association between ctDNA status approximately 8 weeks after completion of first-line therapy and subsequent progression-free survival. Additional analyses will examine overall survival, earlier ctDNA findings, and baseline tumor molecular subtypes. PET/CT findings will provide complementary information for exploratory analyses. The findings may inform future studies of response-adapted treatment.