Blood, 1 March 2004, Vol. 103, No. 5, pp. 1567-1568.
Emili Montserrat University of Barcelona
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, antibodydependent 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.
References
1. Eichorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide (FC)
induces higher remission rates and longer progression free survival than fludarabine (F)
alone in first line therapy of advanced chronic lymphocytic leukemia (CLL): results of a
phase III study (CLL4 protocol) of the German Study Group (GCLLSG) [abstract].
Blood. 2003;102: 72a. Abstract 243.
2. Byrd JC, Rai KR, Peterson BL, et al. The addition of rituximab to fludarabine
significantly improves progression-free and overall survival in previously untreated
patients with chronic lymphocytic leukemia (CLL) patients. Blood. 2003;102: 73a.
Abstract 245.
3. Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to
monoclonal antibody therapy. Semin Oncol. 2003;4: 424-433.