Minimal residual disease guided treatment approaches in non-Hodgkin lymphoma-Where we are and where we're headed.

Minimal residual disease (MRD) assessment, particularly through circulating tumor DNA (ctDNA), offers highly tumor-specific and quantitative measurement of treatment response across subtypes of B-cell non-Hodgkin lymphoma (NHL). Conventional imaging, including positron emission tomography (PET) scans, remains central to the NHL response criteria but lacks the analytical sensitivity to detect molecular disease. In contrast, ultrasensitive ctDNA can detect variants at frequencies as low as 1 part per million and allows more precise quantification of tumor burden throughout therapy. In large B-cell lymphoma, ctDNA kinetics predict clinical outcomes more accurately after frontline therapy than PET and retain prognostic value with targeted agents and chimeric antigen receptor T-cell therapy. In mantle cell lymphoma, undetectable MRD after induction identifies patients who can safely omit high-dose chemotherapy consolidation. Prospective clinical trials across NHL subtypes now routinely embed MRD assessment to test its utility in clinical decision-making, including timing and selection of therapy. Barriers to widespread adoption of MRD in NHL include a lack of standardized specimen collection and analysis, assay availability, and definitive evidence that treating molecular-only disease improves outcomes. Ongoing clinical trials are addressing this information gap and will guide how MRD can be integrated into routine clinical care.