Understanding the Mechanisms of Resistance to Rituximab: Paving the Road for the Development of Therapeutic Strategies to Overcome Rituximab-Resistance

Abstract

Rituximab-resistance is an emerging challenge for both the scientific community and the practicing oncologist. Parallel to the improvement clinic outcomes, the incorporation of rituximab into the management of patients with B-cell lymphoma appears to be changing the biology of relapsed/refractory disease. At least in the patients with diffuse large B-cell lymphoma (DLBCL), previously established salvage rituximab-chemotherapy-based treatments [including high dose chemotherapy and autologous stem cell support (HDC-ASCS)] are less effective in patients failing rituximab immunochemotherapy induction. The estimated 3-year failure free survival in previously treated R-CHOP DLBCL following HDC-ASCT is only 33 %, stressing the need to: (1) understand the mechanisms responsible for rituximab-resistance, (2) identify cellular pathways playing a pivotal role in acquired resistance and (3) develop novel therapeutic strategies to overcome or circumvent rituximab-resistance in B-cell lymphoma. Pre-clinical models to study rituximab-resistance have been generated and characterized. Moreover, repeated exposure of lymphoma cells to rituximab, not only results in a decrease in rituximab anti-tumor activity, but also cross-resistance to multiple chemotherapy agents (suggesting shared pathways of resistance). Insightful information regarding the biological basis for rituximab-resistance is paving the next generation of clinical trials evaluating novel monoclonal antibodies, immunoconjugates, and/or targeted agents aimed at blocking key-regulatory proteins associated with acquired resistance. Here, we provide a general overview of the mechanisms associated with rituximab-resistance that have been identified so far and review some of the early therapeutic interventions being tested in pre-clinical models and in early clinical trials for patients with rituximab-resistant B-cell lymphoma.