Molecular Surveillance of Aggressive Large B-cell Lymphoma using Circulating Tumor DNA Duplexes

Treatment failure affects one-third of patients with aggressive large B-cell lymphoma (LBCL), and current tools are inadequate in determining remission. We investigated the added value of longitudinal ctDNA monitoring in plasma by duplex sequencing. Clearance of ctDNA after 2 or 4 cycles of immunochemotherapy identified patients with excellent survival, whereas elevated interim ctDNA levels among those with measurable residual disease (MRD) predicted refractory disease. Two-year progression-free survival rates based on end-of-therapy MRD varied greatly (94.3% vs 18.2%, negative and positive, respectively), and ctDNA analysis resolved most false radiological response assessments and revealed poor targeting of post-treatment interventions to MRD-positive cases. In surveillance, ctDNA was detectable at least 3 months before clinical relapse, while patients with isolated central nervous system relapses had the shortest plasma ctDNA lead times. Overall, ctDNA monitoring with ultra-sensitive duplex sequencing offers a dynamic molecular tool that can guide clinical decision-making in LBCL.