Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma

Abstract

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.

Graphical abstract

Figure 1.

CONSORT diagrams. (A) Patients with FL in the GALLIUM trial and (B) patients with DLBCL in the GOYA trial. Q2S, Q2Solutions.

Figure 2.

PFS. Data show PFS in patients with the FCGR2A 131 (A), FCGR2B 232 (B), or FCGR3A 158 (C) SNP genotype with FL treated with rituximab (R) or obinutuzumab (G) plus chemotherapy in the GALLIUM trial.

Figure 3.

Forest plot representing survival analysis and the impact of the Fcγ receptor genotypes on PFS per treatment arm. (A) Patients with FL in the GALLIUM trial; (B) patients with DLBCL in the GOYA trial. Time to event was defined by PFS (in days). All analyses were unadjusted and unstratified. Variables for the univariate analysis included biomarker and treatment arm. P-value (for hypothesis testing of whether the biomarker effect was equal to 0) was calculated with the Wald test. Adjusted P-values were corrected for multiple comparisons by the Benjamini and Hochberg method. Adj, adjusted; G, obinutuzumab; R, rituximab.

Figure 4.

PFS. Data show PFS according to FCGR2A 131 (A), FCGR2B 232 (B), and FCGR3A 158 (C) SNP genotype for patients with DLBCL treated with rituximab (R) or obinutuzumab (G) plus chemotherapy in the GOYA trial.