Are We Ready To Stratify Treatment for Diffuse Large B-Cell Lymphoma Using Molecular Hallmarks?

Abstract

abstract Learning Objectives: After completing this course, the reader will be able to: Describe the oncogenic drivers in DLBCL, especially those that have recently been identified, and how they relate to the oncogenic DLBCL subtypes.Describe the prognostic and potentially predictive implications of DLBCL COO subtype for chemotherapy and rituximab.Outline the evidence for novel targeted therapies and therapeutic strategies in DLBCL, how they may be stratified by DLBCL subtype or to specific tumor molecular features, and how these strategies can be incorporated into current treatment paradigms and prospective clinical trial design. CME This article is available for continuing medical education credit at CME.TheOncologist.com The division of the heterogeneous entity of diffuse large B-cell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-κB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as next-generation sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence.