Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma: from Bench to Bedside?

Diffuse large B-cell lymphoma (DLBCL) is a curable disease with variable outcomes due to underlying heterogeneous clinical and molecular features-features that are insufficiently characterized with our current tools. Due to these limitations, treatment largely remains a "one-size-fits-all" approach. Circulating tumor DNA (ctDNA) is a novel biomarker in cancers that is increasingly utilized for risk stratification and response assessment. ctDNA is readily detectable from the plasma of patients with DLBCL but has not yet been incorporated into clinical care to guide treatment. Here, we describe how ctDNA sequencing represents a promising technology in development to personalize the care of patients with DLBCL. We will review the different types of ctDNA assays being studied and the rapidly growing body of evidence supporting the utility of ctDNA in different treatment settings in DLBCL. Risk stratification by estimation of tumor burden and liquid genotyping, molecular response assessment during treatment, and monitoring for measurable residual disease (MRD) to identify therapy resistance and predict clinical relapse are all potential applications of ctDNA. It is time for clinical trials in DLBCL to utilize ctDNA as an integral biomarker for patient selection, response-adapted designs, and surrogate endpoints. As more ctDNA assays become commercially available for routine use, clinicians should consider liquid biopsy when treatment response is equivocal on imaging. Incorporating MRD may also guide decision-making if patients experience severe treatment toxicities. Though important barriers remain, we believe that ctDNA will soon be ready to transition from bench to bedside to individualize treatment for our patients with DLBCL.