ctDNA for MRD assessment is prognostic and predictive in newly diagnosed and relapsed/refractory lymphoma.

Circulating tumor DNA (ctDNA) is a novel biomarker to assess tumor burden, molecular residual disease (MRD), and treatment response in various cancers. To our knowledge, this study reports the largest real-world cohort to date evaluating ctDNA testing, ctDNA-MRD detection, and ctDNA clearance dynamics in newly diagnosed and relapsed/refractory lymphoma. We analyzed plasma from 144 patients with stage I to IV primary lymphoma (aggressive B-cell lymphoma, n = 110; aggressive T-cell lymphoma, n = 13; indolent B-cell lymphoma, n = 15; indolent T-cell lymphoma, n = 6; median, 7 samples per patient). ctDNA was evaluated using a personalized, tumor-informed, multiplex polymerase chain reaction assay (Signatera). Pretreatment ctDNA was detectable in 92% of the evaluable patients. End-of-treatment (EOT) ctDNA-MRD positivity was prognostic of inferior event-free survival (EFS; adjusted hazard ratio [HR], 22.43; 95% confidence interval [CI], 6.76-74.45; P < .0001). In multivariate analysis, EOT ctDNA-MRD positivity was the most powerful independent predictor of EFS (HR, 37.10; 95% CI, 6.20-221.8; P < .001), exceeding the prognostic value of EOT positron emission tomography (PET) positivity (HR, 5.88; 95% CI, 1.35-25.6). Early ctDNA clearance during first-line therapy was associated with significantly improved EFS (adjusted HR, 8.57; 95% CI, 2.55-28.81; P = .005). In the relapsed setting, following CART, ctDNA-MRD negativity predicted prolonged event-free intervals. ctDNA-MRD positivity during posttherapy surveillance was associated with significantly inferior EFS (adjusted HR, 33.74; 95% CI, 9.34-121.82; P < .0001). These data establish ctDNA as a robust biomarker for prognosis, treatment monitoring, and early relapse detection across B- and T-cell lymphoma subtypes, with superior prognostic value over conventional imaging, supporting its integration into response assessment.