Chronic lymphocytic leukaemia (CLL) is one of the most common types of adult leukaemia. The majority of CLL patients are not symptomatic at diagnosis, but the majority will develop symptoms from the disease at some time point. Therapy for CLL has evolved significantly. Alkylator therapy has been shown to be inferior to fludarabine in randomised phase III studies [1–3]. Following this, promising phase II data [4, 5] with fludarabine and cyclophosphamide led to initiation and recently reported complete phase III studies demonstrating that this combination is superior to fludarabine monotherapy with respect to response rate, complete response rate (CR) and progression-free survival (PFS) [6, 7]. Thus, phase III studies have taken the field of CLL forward, but it is uncertain that further addition of chemotherapy to these regimens will either be possible relative to toxicity or beneficial with respect to improvement in response duration and overall survival (OS). Indeed, if progress is to be appreciated we will likely need to utilise therapeutic agents that work differently in CLL.
Monoclonal antibodies represent such a therapy. Like most effective anti-cancer therapies, monoclonal antibodies have the potential to recruit several different cytotoxic pathways through antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC) and direct induction of apoptosis through initiation or disruption of signal transduction. This review will focus both on monoclonal antibodies that have already demonstrated benefit in CLL and those for whom significant promise exists in preclinical or early phase I testing.
Rituximab is a chimeric monoclonal antibody that targets an external epitope of the CD20 antigen. CD20 is broadly and selectively expressed on B cells, not modulated, and therefore represents a good therapeutic target for a therapeutic monoclonal antibody. The function of CD20 is uncertain, but it appears to act as a calcium channel that interacts with the B-cell immunoglobulin receptor complex [8, 9]. Data on the shedding of CD20 in CLL and related non-Hodgkin’s lymphoma (NHL) is controversial, with one group having noted significant levels of soluble CD20 in the sera of patients with both of these diseases. In each case, increased levels of soluble CD20 correlated with poorer survival [10–12]. Utilising an alternative, more direct anti-CD20 assay, another group failed to confirm the presence of significant soluble CD20 in CLL or related B-cell malignancies . Therefore, both the presence and clinical impact of soluble CD20 must be further explored to resolve these conflicting results.
Understanding how rituximab mediates cell death in CLL will improve our ability to develop it. Like most other therapeutic antibodies, rituximab has been proposed to utilise several mechanisms including ADCC, CDC, and a direct pro-apoptotic effect. In lymphoma, where the CD20 target is generally expressed at a more abundant copy number, both in vitro and in vivo experiments support the importance of ADCC as a major mechanism of action ...