New horizons in the treatment of chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, accounting for approximately 30% of all leukemias in Europe and North America. Recently, significant progress in the characterization and understanding of the biology and prognosis of CLL has provided new opportunities for the development of innovative, more effective therapies. Several new anti-CD20 monoclonal antibodies directed against lymphoid cells have been developed and are under investigation in preclinical studies and clinical trials. Currently, the most promising is obinutuzumab, a novel third generation anti-CD20 monoclonal antibody that exhibits superior caspase-independent apoptosis and antibody-dependent cellular cytotoxicity than rituximab. The antibody has shown a safety profile similar to that of rituximab and promising efficacy in patients with CLL. The CD37 antigen may be advantageous over CD20 in diseases in which the level of CD37 expression is higher than that of CD20. The results of recent preclinical and early clinical studies suggest that anti-CD37 antibodies and related agents can be useful in the treatment of CLL, and many small molecule inhibitors targeting B-cell antigen receptor (BCR) signaling pathways have recently been under investigation in patients. Promising clinical results have been observed with a Btk inhibitor, ibrutinib, and a selective inhibitor of PI3Kδ, idelalisib. Several other agents including immunomodulating agents and those targeting the antiapoptotic bcl-2 family of proteins also show promise in treating CLL. Moreover, immune-based treatment strategies intended to augment the cytotoxic potential of T cells offer exciting new treatment options for patients with CLL.