Two Immunoglobul in G Fragment C Receptor Polymorphisms

Purpose: Although rituximab is now routinely used in the treatment of B-cell non-Hodgkin’s lymphoma, the mechanism of its antitumor effect is not clear. One potential mechanism of action involves antibody-dependent cellular cytotoxicity (ADCC). Two aspects of ADCC influence the effectiveness of this process: the susceptibility of tumor cells and the activation of effector cells via their immunoglobulin G fragment C receptors (Fc Rs). Several Fc R polymorphisms have been identified that may affect the killing function of natural killer cells and macrophages. Patients and Methods: The pretreatment tumor cells from 43 patients with follicular lymphoma were tested for their intrinsic susceptibility to rituximab-mediated ADCC. In addition, the Fc RIIIa (CD16) and Fc RIIa (CD32) polymorphisms were determined in an expanded group of 87 patients. The results were then correlated with clinical outcome of these patients. Results: No difference was found between the susceptibility of tumors from patients who clinically responded to rituximab versus those who did not respond. Conversely, both the Fc RIIIa 158 valine/valine and the Fc RIIa 131 histidine/histidine genotypes were found to be independently associated with the response rate and freedom from progression. Conclusion: These data support the hypothesis that ADCC plays an important role in the clinical effect of rituximab at the level of the effector cell. It will be important to include information on Fc receptor polymorphisms in future trials of rituximab therapy. J Clin Oncol 21:3940-3947. © 2003 by American Society of Clinical Oncology.