The Bcl-2 family as a rational target for the treatment of B-cell chronic lymphocytic leukaemia

B-cell chronic lymphocytic leukaemia (B-CLL) is the most common lymphoid malignancy in the Western world, characterized by clonal growth and accumulation of monoclonal CD5+ B-cells in peripheral blood, bone marrow and peripheral lymphoid organs. Although the clinical course in B-CLL patients is highly variable, the most conserved feature is the prolonged survival of malignant B-cells, which has been associated to defects in the apoptotic machinery. The apoptosis defects are mainly determined by a defective balance among pro- and anti-apoptotic members of the Bcl-2 family, often related to resistance of CLL B-cells to chemotherapy. Purine nucleoside analogs or alkylating agents, alone or in combination, are the first-line treatment for B-CLL patients. Alternative, more specifically tailored therapeutics have been developed in recent years, including humanized monoclonal antibodies and kinase inhibitors. Here we shall review the drugs which are commonly used or are currently being assessed in clinical trials on B-CLL patients, their chemical structure, mechanisms of action, pharmacological properties, molecular targets, clinical efficacy and side effects, with a focus on drugs designed to promote apoptosis of malignant B-cells by targeting the Bcl-2 family.