Discordant cell-of-origin in refractory/relapsed LBCL at diagnosis and relapse.

Gene expression profiling (GEP)-based cell-of-origin (COO) classification is the gold standard for molecular subtyping of diffuse large B-cell lymphoma (DLBCL). However, the consistency of COO classification over time, particularly in relapsed or refractory (R/R) settings, remains insufficiently validated. In this longitudinal study, we assessed the stability and reproducibility of COO classification using the NanoString Lymph2Cx assay in paired primary and relapse samples from 84 patients with R/R LBCL. Of these, 90.2% were classified as either activated B-cell-like (ABC) or germinal center B-cell-like (GCB). COO inconsistencies were observed in 18 patients, with four patients showing a shift between ABC and GCB subtypes. While the Lymph2Cx assay demonstrates utility in COO determination, our findings raise important questions regarding the biological and clinical implications of COO shifts. Further investigation is needed to understand the mechanisms behind this instability and to refine the role of COO assessment in guiding therapeutic strategies for R/R LBCL.