Kurtz DM, et al. - Given that outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure, researchers analyzed the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. In aggressive lymphomas, pretreatment ctDNA levels and molecular responses were independently prognostic of outcomes. The study findings suggested that these risk factors could potentially guide future personalized risk-directed approaches.

Methods

• Using a training and validation framework, the dynamics of ctDNA from 217 subjects treated at six centers were analyzed.
• Researchers densely portrayed early ctDNA dynamics during therapy utilizing cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set.
• These thresholds were evaluated in two independent validation sets.
• The prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans were assessed.

Results

• According to the findings obtained, ctDNA was detectable in 98% of patients before therapy.
• Findings revealed that pretreatment levels were prognostic in both front-line and salvage settings.
• ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes in the discovery set.
• Patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P=.0015; MMR: EFS, 82% v 46%; P < .001) in the first validation set.
• In the first validation set (EFS, 100% v 13%; P=.011), EMR also forecasted superior 24-month outcomes in patients receiving salvage therapy.
• In the second validation set, the prognostic value of EMR and MMR was further confirmed.
• In multivariable analyses involving International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival.