Dynamics of circulating tumour DNA in relapsed/refractory diffuse large B-cell lymphoma patients

The response to salvage chemotherapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor, and data on circulating tumour deoxyribonucleic acid (ctDNA) in this setting are limited. We evaluated ctDNA dynamics in 29 patients with relapsed or refractory DLBCL who received platinum-based salvage chemotherapy at the University Medical Center Groningen. In total, 124 plasma samples were analysed using low-coverage whole-genome sequencing to detect copy number alterations (CNAs) and targeted sequencing with a 115-gene panel for single- and multi-nucleotide variants (SNVs/MNVs). The complete response rate at the end of treatment was 55%, with a 1-year progression-free survival of 31%. At the R/R baseline, defined as the time after confirmation of relapse or refractory status and prior to initiation of salvage chemotherapy, CNAs were detected in 15 patients, SNVs in 27 and MNVs in 21. Patients with treatment failure had higher fraction of genome altered (FGA) and ctDNA levels at baseline. Low FGA combined with low metabolic tumour volume (MTV) at baseline was associated with favourable outcome. Clearance of all baseline SNVs at interim evaluation correlated with improved response, while persistence predicted failure (p < 0.05). Two of three patients with complete metabolic response at the end of treatment and detectable ctDNA relapsed, indicating ctDNA as a sensitive marker of minimal residual disease. These findings indicate the value of ctDNA profiling as a prognostic biomarker and as a tool for response-adapted treatment strategies in R/R DLBCL.