Summary Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next‐generation sequencing (NGS) approach (EuroClonality‐NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R‐CHOP‐treated diffuse large B‐cell lymphoma (DLBCL) patients at baseline ( n = 68) and after two cycles ( n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high‐risk International Prognostic Index and a trend to shorter 2‐year progression‐free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5‐log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2‐year PFS of 76% vs. 0%, p &lt; 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2‐year PFS of 83% vs. 38%; p &lt; 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2‐year PFS of 84% vs. 17% vs. 0%, p &lt; 0.001). EuroClonality‐NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Liquid biopsy for molecular characterization of diffuse large B‐cell lymphoma and early assessment of minimal residual disease