Single Nucleotide Polymorphisms (SNPs) of FCγRIIA and FCγRIIIA in Patients with Diffuse Large B-Cell Lymphoma Have No Impact On Treatment Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with CHOP with and without Rituximab: Results From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymhoma Study Group (DSHNHL).

During the last decade the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has significantly improved by the addition of rituximab (R) to the standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Despite this improvement in response rates, event- progression and overall survival, about one third of the patients with DLBCL will eventually fail. The main therapeutic efficacy of rituximab is not fully elucidated. One major effector mechanism is by antibody dependent cellular cytotoxicity (ADCC) mediated by cell-bound rituximab via its FCg part that activates effector cells by binding to their Fcg receptor (FCγR). Three classes and eight subclasses of FCγR have been described. SNPs have been detected for FcgRIIA at amino acid position (AA) 131 where histidin is substituted by arginin (131 R/H) and for FCγRIIIA at position 158, where phenylalanine is substituted by valine (158 V/F). These SNPs have an increased affinity to Fcg and induce a stronger ADCC which explains better responses to rituximab treatment in follicular lymphoma. The aim of this study was to determine the impact of FCγRIIA and FCγRIIIA SNPs on the outcome R-CHOP chemotherapy in elderly patients with newly diagnosed DLBCL.

In the RICOVER-60 therapy study 1222 elderly patients (aged 61-80 years) were randomly assigned to 6 or 8 cycles of CHOP, both with or without rituximab (Pfreundschuh et al., Lancet Oncology 2008). The control group (n=100) consisted of anonymous healthy blood donors of Saarland University Institute of Transfusion Medicine. Available for this study were peripheral blood samples from 570 patients who were representative for the entire RICOVER-60 population. The 2 FCgR SNPs FCγ-RIIa AA 131 R/H and FCγ-RIIIa 158 V/F were determined and univariate and multivariate analyses adjusting for the IPI-relevant risk factors (LDH, ECOG performance status, advanced stage and >1 extranodal involvement) were performed for the entire study population and separately for patients receiving or not receiving rituximab.

Frequencies of FCγ-RIIa and FCγ-RIIIa polymorphisms were not different in healthy controls compared to DLBCL patients. In our statistical analyses finaly 512 patients were included. The characteristic for the groups were for group 1 (6x CHOP-14) 127 patients (24.8%), for group 2 (8x CHOP-14) 122 patients (23.83%), for group 3 (6x CHOP-14+8x rituximab) 124 patients (24.22%) and for group 4 (8x CHOP-14 + 8x rituximab) 139 patients (27.15%) [fisher test (included vs excluded): p=0.4691]. The median age at admission was the same for included and excluded patients. The gender characteristics for the included patients were well balanced [fisher test (included vs excluded): p=1.0000]. The median observation time for the included vs. excluded patients was 40.25 months vs. 34.50 months. This verification shows that the collective of included patients represents the whole RICOVER-60 population. Statistical analyses of overall survival, 3 year event-free survival and 3 year overall-survival were done for the complete RICOVER-60 population. 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In summary, event-free, progression free, overall survival and complete remission rates were not different among patients with FCγ-RIIa (AA 131R/H) and FCγ-RIIIa (AA 158 V/F) SNPs, irrespective of whether the entire RICOVER-60 population was analysed or when patients treated with and without rituximab were analysed separately.

FCγ-RIIa and FCγ-RIIIa SNPs have no influence on the outcome of patients treated with CHOP-14 with or without rituximab. Therefore, modifications of schedule and dose of rituximab according to the underlying FCγ-R SNPs are not justified.

Supported by a HOMFOR grant of Saarland University Medical School, Homburg, Germany

Pfreundschuh:Roche MabThera Advisory Board: Consultancy, Honoraria.