Personalized Frontline Therapy in Diffuse Large B-Cell Lymphoma: Integrating Circulating Tumor DNA for Real-Time Adaptive Treatment Stratification

This review analyzed approximately 115 peer-reviewed studies published between 2010 and 2025, focusing on molecular subtyping and circulating tumor DNA (ctDNA)-guided approaches in Diffuse Large B-Cell Lymphoma (DLBCL). Evidence was synthesized from retrospective cohorts, prospective clinical trials, and translational studies, highlighting how molecular heterogeneity, clonal evolution, and the tumor microenvironment complicate classification and treatment. While molecular subtypes such as MCD, BN2, EZB, A53, and ST2 have improved prognostication, their routine use in clinical practice remains limited due to cost, complexity, and restricted access to sequencing platforms. Tumor-informed ctDNA assays show promise for minimal residual disease (MRD) monitoring and adaptive therapy, yet their predictive power for CAR-T therapy, bispecific antibodies, and checkpoint inhibitors is still incompletely understood. Overall, the literature converges on the need for integrated strategies combining ctDNA, molecular subtyping, and immune microenvironment analysis to personalize frontline therapy.