Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Abstract

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue.

Funding: F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Keywords: B-cell lymphoma; CD20; Chronic lymphocytic leukemia; Diffuse large B-cell lymphoma; Follicular lymphoma; Monoclonal antibody; Non-Hodgkin lymphoma; Rituximab; Safety; Treatment outcome.

Fig. 1

Mechanisms of rituximab-mediated cell death. Rituximab-coated B cells are killed by at least four different mechanisms: (1) binding of rituximab to CD20 on the B-cell surface causes activation of the complement cascade, which generates the membrane attack complex (MAC), which can directly induce B-cell lysis by complement-dependent cytotoxicity (CDC). (2) Binding of rituximab allows interaction with natural killer (NK) cells via Fc receptors (FcRs) III, which leads to antibody-dependent cellular cytotoxicity (ADCC). (3) The Fc portion of rituximab and the deposited complement fragments allow recognition by both FcRs and complement receptors on macrophages, which leads to phagocytosis and ADCC. (4) The crosslinking of several molecules of rituximab and CD20 in the lipid raft determines the interaction of these complexes with elements of a signaling pathway involving Src kinases that mediate direct apoptosis. FCR Fc receptor, FCγR Fcγ receptor. (Republished with permission of the American Society of Hematology from Jaglowski et al. [166]; permission conveyed through the Copyright Clearance Center)