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Polymorphisms in FcRIIIA (CD16) Receptor Expression Are Associated With Clinical Response to Rituximab in Waldenström’s Macroglobulinemia

From the Bing Program for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston; CareStat, Newton, MA; UCLA Medical Center, Los Angeles, CA; Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Nevada Cancer Center, Las Vegas, NV; Fred Hutchinson Cancer Research Center, Seattle WA; and Karolinska University Hospital, Stockholm, Sweden

Address reprint requests to Steven P. Treon, MD, MA, PhD, Bing Program for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, LG102, 44 Binney St, Boston, MA 02115; e-mail: steven_treon{at}dfci.harvard.edu

PURPOSE: Rituximab is an important therapeutic for Waldenström’s macroglobulinemia (WM). Polymorphisms in FcRIIIA (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 FcRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.

RESULTS: Variations in five codons of FcRIIIA were identified. Two were commonly observed (FcRIIIA-48 and FcRIIIA-158) and predicted for amino acid polymorphisms at FcRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcRIIIA-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 FcRIIIA-158F/F were always FcRIIIA-48L/L, and patients with either FcRIIIA-L/R or -L/H always expressed at least one valine at FcRIIIA-158 (P .001). The response trend was higher for patients with FcRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcRIIIA-48L/L were higher when at least one valine was present at FcRIIIA-158 (P = .057), thereby supporting a primary role for FcRIIIA-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 FcRIIIA-48 and -158 polymorphisms.

CONCLUSION: The results of these studies therefore support a predictive role for FcRIIIA-158 polymorphisms and responses to rituximab in WM.

Supported by the Bing Program for Waldenström’s Macroglobulinemia and the Research Fund for Waldenström’s at the Dana-Farber Cancer Institute, the International Waldenström’s Macroglobulinemia Foundation, and a National Institutes of Health Career Development Award (K23CA087977-03) to S.P.T.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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