Fc_γ Receptor Polymorphisms Do Not Influence Progression Free Survival (PFS) of Follicular NHL Pateints Treated with Chop Followed by Rituximab (SWOG 9800).

INTRODUCTION: The expression of valine (V/V or V/F) at position 158 of the FC_γIIIA (CD16) in contrast to phenylalanine alone (F/F) has been associated with higher response rates and longer PFS to single agent Rituximab. A polymorphism in position 131 FC_γ RIIA (CD32) encodes histidine (H) or arginine (R) and has also been associated with improved outcome. These polymorphisms have been associated with higher affinity binding of human IgG1 and greater in vitro ADCC using effector cells and Rituximab, and suggest that the major mechanism of Rituximab is through the interaction with FC receptors on cells capable of mediating ADCC. There is no data on the effect of these polymorphisms on the outcome of Rituximab following or combined with chemotherapy.

METHODS: We evaluated these polymorhisms using DNA from blinded samples collected from patients on SWOG 9800, a phase II trial evaluating the sequential use of CHOP followed by single agent Rituximab (375 mg/m² x 4 weekly doses). We developed a SSCP method to rapidly determine these polymorphisms from DNA samples and confirmed this method through DNA sequencing. Briefly, DNA was amplified using specifically designed PCR primers that amplified the relevant portions of CD16 and CD32. PCR products were then run on SSCP gels under controlled conditions that allowed identification of the patterns associated with each of the polymorphisms. These results were then analyzed with respect to outcome based on the hypothesis that the presence of high affinity FC receptors would be associated with an improved outcome to CHOP followed by Rituximab in newly diagnosed patients with advanced stage follicular NHL.

RESULTS: DNA samples were successfully evaluated on 87/89 eligible patients (no DNA on 2 patients). The freqeuncy of CD16 V/V, V/F and F/F was 13%, 51%, and 37% and CD32 H/H, H/R and R/R was 36%, 44%, and 21% respectively. There was no significant association between any combination of phenotypes and the two year PFS following sequential treatment with CHOP followed by Rituximab. The two-year PFS for patients with V/V, V/F or F/F in CD16 was 55%, 80% and 75% and for patients with H/H, H/R and R/R was 71%, 76% and 78% respectively. For CD16 the presence of one V vs no V resulted in identical estimates of 2 year PFS of 75% (p=.56). Likewise the presence of one H vs no H in the CD32 polymorphism did not result in significantly different PFS (78% vs 74%. p=.88). We also determined the effect of the polymorphism’s on the clearance of PCR detectable disease by analysis for t(14:18). There was no impact on the clearance of molecular disease following CHOP alone. Twenty-two of 32 patients who were still PCR positive for t(14:18) after CHOP converted to PCR negative following Rituximab. There was a suggestion of a trend toward a higher rate of molecular remission following Rituximab for patients with CD16 with at least one V phenotype (V/V or V/F: 12/15 cleared vs 10/17 with F/F, p=.26). In conclusion, we found no evidence that the encouraging efficacy of CHOP followed by Rituximab antibody therapy for patients with advanced follicular NHL is dependent on the presence of high-affinity FC gamma receptor polymorphisms.