Rituximab (Rituxan) is a chimeric IgG1 anti-CD20 monoclonal antibody increasingly used in the treatment of non-Hodgkin’s lymphoma (NHL). Previous in vitro studies have suggested the role of antibody-dependent cellular cytotoxicity (ADCC) and FcgR-positive effector cells (natural killer and macrophage) in the antitumor effects of anti-CD20 antibodies, but the actual mechanism of rituximab action in vivo remains largely unknown. The FCGR3A gene coding for the FcgRIIIa receptor displays a functional dimorphism with either a phenylalanine (FCGR3A-158F) or a valine (FCGR3A-158V) at amino acid 158, with a higher affinity of human IgG1 and increased ADCC for the latter. The aim of this study was thus to determine the influence of this FCGR3A polymorphism on clinical and molecular responses to rituximab.
The FCGR3A genotype was determined by a nested polymerase chain reaction followed by allele-specific restriction enzyme digestion (PCR-ASRED) in a population of 49 patients who had received rituximab (375 mg/m² × 4) for untreated follicular non-Hodgkin’s lymphoma. The FCGR2A-131H/R genotype was also determined by PCR-ASRED as a control, because this gene colocalizes with the FCGR3A gene. Clinical and molecular responses were evaluated at 2 months (M2) and at 1 year (M12). Molecular analysis of the BCL2-JH gene rearrangement was performed by PCR at M2 and M12; molecular response was defined as a disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow. The entire clinical results of this cohort have been published (Blood 97:101, 2001).
FCGR3A-158V homozygous patients represented 20% of the population, whereas FCGR3A-158F homozygous and heterozygous patients (FCGR3A-158F carriers) were 35% and 45%, respectively. The objective response rates at M2 and M12 were 100% and 90% (complete remission [CR] + unconfirmed CR [CRu] = 40% and 70%) in FCGR3A-158V homozygous patients compared to 67% (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.2-1.9; P = .03) and 51% (RR = 1.7, 95% CI = 1.2-2.5; P = .03) in FCGR3A-158F carriers (CR + CRu = 23% and 33%).
A molecular response was observed at M12 in 5 of 6 of homozygous FCGR3A-158V patients compared to 5 of 16 FCGR3A-158F carriers (RR = 2.8, 95% CI = 1.2-6.4; P = .04). In multivariate analysis, the homozygous FCGR3A-158V genotype was associated with a greater chance to have a clinical response at M2 (P = .02) and at M12 (P = .01), as well as molecular response at M12 (P = .04). On the contrary, FCGR2A-131H/R polymorphism influenced neither clinical nor molecular responses.
CONCLUSION: We have reported here for the first time an easily assessable predictive factor for both clinical and molecular responses to rituximab. This will certainly introduce new pharmacogenetic approaches in the management of NHL patients in order to tailor rituximab treatment to FCGR3A genotype.