Despite general improvements in the outcomes of patients with diffuse large B cell lymphoma (DLBCL), a subset of patients have high-risk disease and require more intensive therapy. Now, an analysis of circulating tumour DNA (ctDNA) demonstrates the potential of ctDNA levels as predictors of outcome and of high-risk disease requiring more aggressive treatment.

Samples from 217 patients diagnosed with DLBCL or primary mediastinal large B cell lymphoma at six treatment centres were obtained, and 98% were found to have detectable ctDNA before treatment. Patients were then assigned to either the discovery (n = 130) or validation (n = 73) sets for ctDNA monitoring during treatment, with changes in somatic alterations being used to quantify changes in ctDNA.

Initial investigations indicated that ctDNA levels were dramatically reduced in responders within 1 week of commencing treatment, such that responders and nonresponders could be perfectly discriminated by the end of the first treatment cycle. These promising findings were then confirmed in the discovery cohort, in which patients with an early molecular response (EMR; defined as >100-fold (2-log) decrease in ctDNA levels after one cycle of treatment) and those with a major molecular response (MMR; defined as a >2.5-log decrease after two cycles) had significantly improved 24-month event-free survival (EFS) of 83% versus 50% (P = 0.0015) and 82% versus 46% (P < 0.001), respectively. Patients with an EMR who ultimately required salvage therapy also had superior 24-month EFS of 100% versus 13% (P = 0.011). Both EMR and MMR were predictive of outcomes independent of the findings of PET–CT imaging.

These data provide evidence that dynamic alterations in ctDNA levels can provide early indications of clinical outcome. Such measures could be incorporated into novel trial designs and enable improved patient stratification in this setting.