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). However, currently available clinical tools are inadequate for determining remission and fail to detect recurrence early. We investigated the added value of longitudinal monitoring of circulating tumor DNA (ctDNA) in plasma by targeted duplex sequencing during therapy and follow-up in high-risk LBCL patients treated in a Nordic phase II trial. Early clearance of ctDNA after the first two immunochemotherapy cycles provided a rapid pharmacodynamic measure of treatment efficacy with excellent negative predictive value (NPV, 91%) for progression. Later clearance after four cycles improved prognostication, and elevated interim ctDNA levels among those with a measurable residual disease (MRD) predicted refractory disease. At the end of therapy, MRD was a strong independent predictor of outcome, with two-year progression-free survival rates varying greatly (Hazard ratio = 18.7; 94.3% vs 18.2%, MRD negative and positive, respectively). Moreover, end-of-therapy ctDNA analysis resolved most false radiological response assessments and revealed poor targeting of post-therapy interventions to MRDpositive cases. On surveillance, ctDNA was detectable at least 3 months before systemic clinical relapse (median 6 months), while the patients with isolated central nervous system relapses had the shortest plasma ctDNA lead times. Overall, we demonstrate that ctDNA monitoring using an ultrasensitive technique provides a dynamic molecular tool to guide clinical decision-making during therapy and follow-up in patients with LBCL.