Molecular subtypes of DLBCL: are we ready to translate our knowledge into the change of treatment paradigms?

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with disparate outcomes. While about two-thirds of patients have historically been cured with standard frontline chemoimmunotherapy, those who relapse or are refractory have typically had poor outcomes. Early efforts to tailor treatment based on molecular subtypes categorized by gene expression profiling (germinal center–like and activated B-cell–like) or approximation by immunochemistry algorithms did not substantially impact therapy in DLBCL. Genomic profiling led to the discovery of up to 7 subtypes with shared genetic alterations. The LymphGen and DLBclass are classifiers that assign patients to these subtypes. A clinical trial is under design to specifically treat subtypes of DLBCL in the frontline setting with targeted therapies in combination with standard treatment. Importantly, some of the most efficacious therapeutic approaches in relapsed/refractory DLBCL (chimeric antigen-receptor T cells and bispecific antibodies) appear to work independently of molecular subtype, although these agents' effectiveness may be impacted by the tumor microenvironment. Bispecific antibodies are being studied in newly diagnosed patients in combination with standard chemoimmunotherapy regimens. While future treatment may incorporate drugs with novel mechanisms and/or immunotherapies in the frontline setting, targeting by molecular subtype continues to hold promise as our treatment regimens evolve. Potential strategies could include escalation with specific therapies when response is inadequate, de-escalation of chemotherapy with continuation or addition of targeted agents in those with early complete responses, and refined algorithms to select appropriate treatment in high-risk or relapsed/refractory disease.