Upfront therapy for diffuse large B-cell lymphoma: looking beyond R-CHOP

Introduction: Diffuse large B-cell lymphoma (DLBCL) is not a single entity but instead represents a collection of interrelated malignancies having distinct molecular features. Recent multiomics studies have independently identified the presence of at least five different subsets of DLBCL, further subcategorizing previously recognized subtypes of this disease. Clinical trials attempting to improve outcomes with the addition of novel therapeutic agents have approached advanced-stage DLBCL as either a single entity or as an overly broad subtype, and have been largely unsuccessful. Areas covered: We review, here, in detail the similarities between the novel advanced molecular classification systems. We also review several large phase-3 clinical trials in DLBCL, including those that failed to demonstrate an improvement in outcomes. We explore details of the POLARIX trial data supporting the use of the anti-CD79B antibody drug conjugate (ADC) polatuzumab vedotin. Expert opinion: Future efforts to improve the outcomes of frontline treatment of DLBCL patients will require a precision medicine approach in which individual-targeted agents are used to treat patients with specific subgroups of DLBCL, based on molecular features. This will require a validated molecular assay with results available in real-time and coordinated effort by academic clinical investigators and industry partners.