Background: Fc gamma receptor (FCGR) polymorphisms have previously been linked to outcome in follicular lymphoma (FL) patients treated with the anti-CD20 monoclonal antibody (mAB), rituximab, as a monotherapy. This is thought to be due to differences in binding affinity of host effector cells for the therapeutic antibody between individuals with different genotypes. In particular, the R/R genotype of FCGR2A and the F/F genotype of FCGR3A have been correlated with a less favorable outcome compared to the higher affinity FCGR genotypes H/H and V/V, respectively. Previous studies have had relatively low statistical power and have used consecutive series of patients and the prognostic significance remains largely untested. Therefore, we questioned whether this association would hold up in the context of a chemotherapy regimen combined with a monoclonal antibody in a larger set of patients treated on Southwest Oncology Group (SWOG) clinical trials. Specifically, we wished to test whether the genotypes were predictive of survival following all treatment regimens, or just the regimens containing mAB.
Methods: Excess paraffin embedded tissue from 146 patients previously treated on SWOG clinical trials with chemotherapy alone (protocol S8809, N=70) or combined chemotherapy and mAB (anti-CD20 antibodies rituximab or I-131 tositumomab on protocols S9800 and S9911, N=33 and 43 respectively) were analyzed. DNA was extracted using the Qiagen RNA/DNA kit, then assayed for the R131H polymorphism (rs1801274) in FCGR2A and the V158F polymorphism (rs396991) for FCGR3A using a TaqMan SNP assay. Stratified Cox regression was used to assess marker associations with overall survival (OS).
Results: Patients in each clinical trial had similar IPI and FLIPI scores. Overall frequencies of the FCGR2A genotypes were 27% H/H, 54% R/H, 16% R/R. Frequencies of the FCGR3A genotypes were 36% FF, 41% VF, and 8% VV. There were no differences in genotype frequencies between trials and no associations between genotypes. Neither FCGR 2A nor 3A were associated with survival in S8809 (chemotherapy only). In S9800 and S9911 (chemotherapy + mAb), having at least 1 FCGR2A H allele was weakly associated with improved OS vs R/R (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.16–1.12, p=0.06), and having at least 1 FCGR3A V allele was more strongly associated with improved OS vs F/F (HR 0.28, 95% CI 0.10–0.80, p=0.02), with 5 year OS of 72% for F/F, 97% for V/F, and 100% for V/V. The interaction term between antibody usage and FCGR3A genotype was significant (p=.01), suggesting that the effect of this marker may be truly different in 9800/9911 than in 8809. All survival analyses held up after adjustment for IPI score.
Summary: Overall, we found an association of FCGR3A genotype with overall survival in patients treated with chemo + mAB (rituximab or I-131 tositumomab). An association with survival was not identified in patients treated with chemotherapy alone. Interestingly, in the analysis of the overall dataset we found significant evidence of an interaction between mAb therapy (S9800/S9911 vs. S8809) and FCGR3A. This study suggests that FCGR3A polymorphism status may be predictive of survival in FL patients given mAB-containing treatment as opposed to any treatment in general. Therefore, FCGR3A polymorphism status may be an important factor to consider in designing new FL trials with mAB-containing regimens.
Persky:Millennium, The Takeda Oncology Company: Consultancy, Research Funding. Dornan:Genentech, Inc.: Employment, Equity Ownership. Fisher:Genentech: Honoraria, Speakers Bureau. Maloney:Genentech, Biogen Idec, GSK: Membership on an entity's Board of Directors or advisory committees. Miller:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Research Funding; Milleneum: Consultancy. Rimsza:Genentech: Research Funding.
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