Polymorphisms in FcγRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström's macroglobulinemia

Abstract

Purpose: Rituximab is an important therapeutic for Waldenström's macroglobulinemia (WM). Polymorphisms in FcγRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. Patients and Methods: Sequence analysis of the entire coding region of FcγRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. Results: Variations in five codons of FcγRIIIA were identified. Two were commonly observed (FcγRIIIA-48 and FcγRIIIA-158) and predicted for amino acid polymorphisms at FcγRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcγRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcγRIIIA-158F/F were always FcγRIIIA-48L/L, and patients with either FcγRIIIA-L/R or -L/H always expressed at least one valine at FcγRIIIA-ISS (P ≤ .001). The response trend was higher for patients with FcγRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcγRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcγRIIIA-48L/L were higher when at least one valine was present at FcγRIIIA-158 (P = .057), thereby supporting a primary role for FcγRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcγRIIIA-48 and -158 polymorphisms. Conclusion: The results of these studies therefore support a predictive role for FcγRIIIA-158 polymorphisms and responses to rituximab in WM. © 2005 by American Society of Clinical Oncology.