Monoclonal antibodies in the treatment of chronic lymphocytic leukemia: if only it were simple

The necessary condition to cure any malignancy is to achieve a complete response (CR), which for years has been extremely rare in chronic lymphocytic leukemia (CLL). Fortunately, the days in which treatment of CLL revolved around the use of chlorambucil—an agent with which less than 10% CR was achieved—are over. Treatment of CLL has significantly improved over the last 2 decades. First, with the use of purine analogs, particularly fludarabine, the CR rate increased to 20% to 30%. Second, the combination of fludarabine with other cytotoxic agents and/or monoclonal antibodies has increased the CR rate up to 40% to 60%, with many of these responses being molecular (ie, without evidence of minimal residual disease as assessed by cytofluorometry or polymerase chain reaction [PCR]). Of note, there is already some indication that fludarabine-based regimens result not only in a higher CR but also longer response duration and, it is hoped, a prolonged survival.^1,2 

The 2 monoclonal antibodies most widely employed in CLL therapy are rituximab (an anti-CD20 monoclonal antibody that adds efficacy to chemotherapy) and alemtuzumab (an anti-CD52 agent that is particularly useful to improve responses obtained with chemotherapy). There are other monoclonal antibodies that offer promise in CLL treatment, including anti-CD22 (BL-22, epratuzumab), anti–HLA-DR (1D09C3), anti-CD23 (IDEC-152, lumiliximab), and anti-1D10 (Hu1D10, apolizumab).

The mechanism of action of monoclonal antibodies varies from one antibody to another and includes triggering of apoptosis by caspase-dependent or -independent pathways, antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and generation of reactive oxygen species (ROS).³  Things, however, are never simple. Mone and colleagues (page 1846) report in this issue a series of elegant studies showing that Hu1D10 has a paradoxical effect in CLL leukemic cells. Thus, Hu1D10 induces caspase-independent apoptosis and ROS generation (a desirable effect since it induces CLL leukemic cells' death), but it also activates the AKT survival pathway (an undesirable effect since this protects leukemic cells from death). In other words, the same agent leads to both death and survival signals in CLL leukemic cells. To overcome the negative effect of AKT activation, the authors combine Hu1D10 with the selective phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, leading to an enhanced activity of the antibody. This opens the door for clinical studies in which Hu1D10 will be combined with inhibitors of the AKT survival pathway such as UCN-01 (7-hydroxy-staurosporine).

Chemoimmunotherapy is gaining wide acceptance in the treatment of different oncohematologic disorders. What the Mone et al study illustrates is that mechanisms of action of monoclonal antibodies are complex and that when devising chemoimmunotherapy combinations, not only the different targets but also the mechanism of action of the agents, as well as the way to enhance their effects, should be considered. By pursuing this approach the CR rate in patients with CLL will continue to increase and, one hopes, this form of leukemia will eventually become curable.