Ofatumumab: A Novel Anti-CD20 Monoclonal Antibody for the Treatment of Chronic Lymphocytic Leukemia

摘要

Abstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease arising from monoclonal proliferation of B lymphocytes. In the absence of poor risk features, CLL is characterized by an indolent clinical course but in 2012 it is still considered an incurable malignancy. Treatment of CLL is highly individualized and the majority of patients do not require treatment at the time of diagnosis. Therapy is, however, indicated for patients with advanced stage disease, high tumor burden, severe disease-related "B" symptoms, cytopenias, poor-risk cytogenetic features or repeated infections. Rituximab, a monoclonal antibody that targets the cell-surface molecule CD20 expressed on B-lymphocytes, is not widely used as a mono-therapy for CLL. Commonly employed first-line treatment regimens do include chlorambucil in conjunction with corticosteroids, fludarabine and cyclophosphamide or pentostatin and cyclophosphamide in conjunction with rituximab and, most recently, bendamustine and rituximab. While there have been substantial strides in finding aggressive combination chemo-immunotherapy regimens that have significant activity in the front-line setting, treatment options for patients with relapsed, poor risk, or refractory CLL are limited. Alemtuzumab, a monoclonal antibody targeting CD52 is increasingly becoming a part of the Oncologists' armamentarium to combat for poor-risk CLL associated with adverse cytogenetic aberrations or recurrent or progressive CLL, but its use has been limited due to concerns for infectious complications. Ofatumumab (Arzerra) is a novel, fully humanized anti-CD20 monoclonal antibody that binds to both small and large extracellular loops of CD20, has increased complement dependent cytotoxicity (CDC) and antibody dependent cytotoxicity (ADCC) compared to rituximab. Based on the results of a pivotal phase II study (Hx-CD20-406), which showed clinically meaningful and durable overall response rates, Ofatumumab was granted accelerated approval in October 2009 by U.S. Food and Drug administration for treatment of patients with fludarabine and alemtuzumab-refractory CLL. Several randomized trials are underway investigating its clinical benefit in CLL and other non-Hodgkin's lymphomas.