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 patients with cancer, including hematologic malignancies. 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-IV primary lymphoma (aggressive B-cell, n=110; aggressive T-cell, n=13; indolent B-cell, n=15; indolent T-cell, n=6; median of seven samples per patient). ctDNA was evaluated using a personalized, tumor-informed, multiplex PCR assay (Signatera TM ). Pretreatment ctDNA was detectable in 94.3% of evaluable patients. End-of-treatment (EOT) ctDNA-MRD positivity was prognostic of inferior event-free survival (EFS) (adjusted HR, 22.43; 95% CI, 6.76–74.45; p<0.0001). 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<0.001), exceeding the prognostic value of EOT PET/CT 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=0.005). In the relapsed setting following CAR-T therapy, ctDNA-MRD negativity predicted prolonged event-free intervals. ctDNA-MRD positivity during post-therapy surveillance was associated with significantly inferior EFS (adjusted HR: 33.74, 95%CI: 9.34-121.82, p<0.0001). 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.