The clinical utility of plasma circulating tumor DNA in the diagnosis and disease surveillance in non-diffuse large B-cell non-Hodgkin lymphomas

<b>Aim:</b> Advances in circulating tumor DNA (ctDNA) analysis for diffuse large B-cell lymphoma (DLBCL) have prompted the evaluation of its utility in other non-Hodgkin lymphomas (NHLs), leading to significant insights into its potential applications.<b>Methods:</b> We retrospectively studied paired plasma and tissue/bone marrow biopsies of 203 non-DLBCL NHLs [87 follicular lymphomas (FL), 64 mantle cell lymphomas (MCL), 30 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL) and 22 marginal zone lymphomas (MZL)]. Genomic profiling was performed using a targeted next generation sequencing panel (Hemasalus^™). Longitudinal analyses were performed to explore plasma ctDNA utility in disease monitoring.<b>Results:</b> High plasma ctDNA detection rates were observed across NHL subtypes (FL: 88.5%, MCL: 90.6%, CLL/SLL: 100%, MZL: 68.2%), with high concordance of actionable mutations (FL: 87.4%, MCL: 93.8%, CLL/SLL: 93.3%, MZL: 81.8%) and multiple genetic aberrations exclusively identified in plasma. Particularly, <i>IGH-BCL2</i> and <i>IGH-CCND1</i> fusions were concordant between plasma and tumor biopsies in FLs (91.1%) and MCLs (91.3%), respectively. Longitudinal data demonstrated that ctDNA clearance correlated with complete response but ctDNA increases preceded radiological relapses.<b>Conclusion:</b> ctDNA exhibited high concordance with tumor biopsy in detecting genetic aberrations and demonstrated potential as a promising noninvasive approach to disease surveillance in non-DLBCL NHLs.