Novel Biomarkers in DLBCL

Abstract

Diffuse large B cell lymphoma (DLBCL) is the commonest aggressive lymphoma. Despite the advent of combined chemo-­‐immunotherapy, one third of patients still die from their disease. Prognostication of the disease still relies on a clinical scoring system known as the International Prognostic Index (IPI). This divides patients into risk categories. However marked heterogeneity within IPI sub-­‐categories persist. The IPI is a clinical score based predominantly on estimates of patient fitness and tumour burden, but does not utilize information regarding the biology of the tumour cell or the immune tumour microenvironment (TME), in which the malignant B cells reside. The latter is the focus of this thesis. The anti-­‐CD20 monoclonal antibody rituximab has improved the outcome for patients with DLBCL, however the impact of host genetics on its effectiveness is still unclear. The mechanisms of action for rituximab include antibody dependent cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC). Recent reports suggest genetic polymorphisms in the FCGR3A receptor (expressed on NK-­‐cells and monocytes which mediate ADCC) may be a predictor of event free and overall survival in B-­‐cell lymphoma. Data also implicates the same polymorphism in the susceptibility to rituximab induced late-­‐onset neutropenia (LON). There remains no data on the impact of genetic polymorphisms on either outcome or LON in genes involved in the CDC pathway such as C1qA. One hundred and fifteen DLBCL patients treated with ‘Ru CHOP’ (rituximab/cyclophosphamide/vincristine/doxorubicin/prednisolone) chemou immunotherapy were compared with 105 healthy Caucasian controls with regards to FCGR3Aq V158F and C1qAq A276G polymorphisms. Event free and overall survival (EFS and OS) and LON incidence were analysed for linkage to either polymorphism.