Obinutuzumab for relapsed or refractory indolent non-Hodgkin’s lymphomas

Abstract

The use of anti-CD20 monoclonal antibodies (mAbs), such as rituximab, in CD20-positive B-cell malignancies has dramatically improved the outcome of chronic lymphoid leukemia and non-Hodgkin’s lymphomas (NHL). However, the occurrence of relapse and development of rituximab-refractory disease highlight the need to develop novel anti-CD20 mAbs, with improved mechanisms of action. Obinutuzumab is the first humanized type II glycoengineered anti-CD20 mAb. In vitro and in vivo data suggested several differences compared with rituximab, including a low level of complement-dependent cytotoxicity and an increased direct nonapoptotic cell death. Moreover, the glycoengineered Fc-linked nonfucosylated oligosaccharide enhanced the Fc–Fcγ receptor (FcγR) IIIa interaction, resulting in improved antibody-dependent cellular cytotoxicity and phagocytosis. Preclinical models suggested that these differences translate into superior survival in murine lymphoma models. Phase I/II trials in monotherapy in relapsed or refractory B-cell NHL demonstrated that obinutuzumab has an acceptable safety profile, infusion-related reactions being the most common adverse event. In rituximab-refractory indolent NHL, the recent randomized phase III GADOLIN study demonstrated an improved median progression-free survival for patients treated with obinutuzumab plus bendamustine rather than bendamustine alone. Further trials are ongoing to determine the role of obinutuzumab as a first-line agent in the treatment of follicular lymphoma.