Matching treatments to the individual
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in the UK and is currently treated by chemotherapy together with an antibody (rituximab) to a lymphocyte associated protein (CD20), known as R-CHOP. However, a significant proportion of patients with DLBCL show no response (~10%), partial response (~15%) or relapse after initial response (20-30%). Importantly, DLBCL resistant to R-CHOP also respond poorly to any other currently available treatments. Thus, it is pivotal to identify cases not responding to R-CHOP, design and test new therapeutic strategies for this sub-group of DLBCL.
Among many prognostic markers investigated so far, sub-classification of DLBCL into various molecular phenotypes based on their gene expression has been consistently shown to be valuable in prognostic stratification, with the ABC (activated B-cell like) subtype being the poorest prognostic group. Biologically, the ABC-DLBCL is characterised by enhanced activation of a cellular pathway known as NF-kB and is sensitive to NF-kB inhibition. The applicants are conducting a phase-III clinical trial to evaluate whether addition of the NF-kB inhibitor bortezomib to R-CHOP improves the treatment outcome of DLBCL, particularly the ABC-subtype. The proposed investigations aim to identify and validate a series of potential markers for DLBCL prognosis and treatment stratification.