FCGR3A-158V/F Polymorphism May Correlate with the Levels of Immunoglobulin in Patients with Non-Hodgkin’s Lymphoma after Rituximab Treatment as An Adjuvant to Autologous Stem Cell Transplantation.

Recent studies have indicated that patients who receive stem cell transplantation (SCT) and an adjuvant rituximab demonstrate an increased risk of developing hypogammaglobulinemia. We have found that such hypogammaglobulinemia were due to the delayed recovery of memory B cells with an abnormal cell marker expression and impaired immunoglobulin production in vitro. (Nishio et al. Eur J Haemtol, 2006, Nishio et al. Br J Haematol, 2007) However, no speculation has been made regarding what factor(s) determined the risk of developing hypogammaglobulinemia after autologous SCT with the identical conditioning regimen and rituximab. Accumulated evidences have shown that FCGR3A of valine (V) allele has a higher affinity to human IgG than the phenylalanine (F) allele, and that cells bearing the FCGR3A V allele mediate antibody dependent cellular cytotoxicity more effectively. Compatibly, previous clinical studies that have examined single nucleotide polymorphisms (SNPs) of Fc receptor genes demonstrated that FCGR3A gene SNPs are associated with the response to rituximab, as a single agent, in patients with follicular lymphoma or Waldenstrom’s macroglobulinemia. These findings suggest that FCGR3A SNPs may be related to the levels of immunoglobulin after SCT and an adjuvant rituximab. To clarify this hypothesis, the FCGR3A-158V/F genotype and the levels of serum immunoglobulin six months after SCT were tested in twenty non- Hodgkin’s lymphoma (NHL) patients having received autlogous peripheral blood stem cell transplantation (APBSCT) with an adjuvant rituximab. We also compared the levels of immunoglobulin in ten NHL patients who received an identical conditioning regimen and APBSCT, but no rituximab (control group). Of the twenty patients tested for the FCGR3A-158V/F polymorphism, seven patients (35%) had homozygous F/F (158 F/F), 12 (60%) had heterozygous V/F (158 V/F), and one (5%) had homozygous V/V (158 V/V). Since only one patient was found to have 158 V/V polymorphism in this study, we defined those patients who had 158 F/F as the low affinity group, while those who had at least one 158 V allele were defined as the high affinity group following the previous definition by Anolik et al (Arthritis Rheum 2003). The three groups were not different in terms of gender, age, the disease stage, bone marrow involvement or number of extranodal sites involved at diagnosis. Before starting induction therapy, there was no significant difference in the levels of immunoglobulin among three groups. However, after APBSCT, the levels of IgG were significantly lower in the low affinity group (6.87 ± 2.38 g/l) than those in the high affinity group (10.20 ± 2.43 g/l) and control group (10.64 ± 3.04 g/l; both P<0.05). In addition, a significant difference was seen in the levels of IgA between the low affinity group (0.95 ± 0.64 g/l) and control group (1.63 ± 0.51 g/l) (P<0.05). The levels of IgA in the high affinity group (1.19 ± 0.55 g/l) were not significantly different from either those of control group or the low affinity group. In contrast to the levels of IgG or IgA, no significant differences were observed in the levels of IgM among three groups. These data suggest that the FCGR3A genotype may influence not only the outcome of rituximab therapy, but also the levels of IgG and IgA after APBSCT and rituximab.