The DIRECT study: A roadmap for ctDNA-based risk prediction, molecular profiling and MRD detection in Diffuse Large B Cell Lymphoma

DIRECT was a prospective, multisite study assessing the feasibility and utility of circulating tumor DNA (ctDNA) in 188 patients with aggressive B-cell non-Hodgkin lymphoma using a lymphoma-customized assay and open-source pipeline. CtDNA fraction assessed by copy number alterations in pre-treatment plasma identified high-risk patients more effectively than existing clinical risk scores. In 74.5% of cases ctDNA was equivalent or superior to biopsy for genetic profiling. Patients not suitable for ctDNA genotyping had low tumor volumes and could be predicted from simple clinical factors. Finally, a phased variant-supported minimal residual disease (MRD) assay was predictive of outcomes in all groups analyzed. Patients achieving ctDNA clearance at end of treatment had an extremely low 2-year progression rate (<5%). However, false positive MRD results were common in patients with transformed indolent lymphoma. This study highlights the considerable potential, but also the caveats and limitations, of ctDNA technology when applied to aggressive B-cell lymphoma.