Diffuse large B-cell lymphoma—treatment approaches in the molecular era

Abstract

Molecular analyses have led to the definition of diffuse large B-cell lymphoma (DLBCL) subtypes, with differential therapeutic responses, and identification of driver mutations that represent the 'Achilles Heel' of these tumours DLBCL can be classified into three different molecular cell-of-origin subtypes: germinal centre B-cell (GCB), activated B-cell (ABC) and primary mediastinal B-cell lymphoma (PMBL) Patients with DLBCL at the highest risk for disease relapse after standard immunochemotherapy are patients with ABC DLBCL and those whose tumours harbour MYC translocations Constitutive activation of the NF-κB pathway is the hallmark of ABC DLBCL; sensitivity to upstream versus downstream inhibition of NF-κB is likely determined by specific mutations found in ABC DLBCL Downstream NF-κB pathway inhibitors include those targeting the ubiquitin-proteasome complex; upstream inhibitors include inhibitors of B-cell receptor signalling and inhibitors targeting other aberrant signalling pathways in ABC DLBCL Overcoming drug resistance in DLBCL will ultimately require identification of cooperating mutations and rational combination therapies targeting the signalling pathways implicated in the pathogenesis of this disease