Tumor Mutational Burden as a Prognostic Biomarker in Follicular Lymphoma

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Approximately 20% of patients experience early relapse within 24 months (POD24) of immunochemotherapy (ICT), a subgroup associated with poor prognosis and not well-identified by current prognostic indices. Given that tumor mutational burden (TMB) has been associated with outcome in various cancers, we investigated its potential as a prognostic biomarker in FL. Methods: TMB was estimated by next-generation sequencing using a 409-gene panel in a cohort of 119 patients diagnosed with FL grades 1–3A and treated with frontline immunotherapy or ICT. Results: Although TMB was not associated with clinical variables in non-transformed FL patients, higher TMB values were observed in patients harboring the t(14;18) translocation, mutations in BCL2, TNFRSF14, or genes involved in cellular migration (GNA13, GNAI2). Notably, patients with high TMB (>2.55 mutations per megabase) showed longer progression-free survival, lymphoma-specific survival, and overall survival, and had fewer mutations affecting the mTORC1 pathway. A higher proportion of POD24 patients was observed in the low TMB subgroup. In 25 paired diagnosis-relapse samples, TMB remained globally stable, although variations in the molecular landscape were observed. In addition, we analyzed TMB in a separate cohort of patients presenting transformed FL at diagnosis (n = 16). Higher TMB was also associated with the t(14;18) chromosomal translocation, but not with clinical features or survival. Conclusions: These findings support the potential of TMB as a prognostic biomarker in FL, providing molecular understanding beyond established clinical indices and aiding in the identification of patients at higher risk of early progression following ICT.