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

Abstract

PURPOSE:

Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (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 FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.

RESULTS:

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

CONCLUSION:

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

• Authors: Steven P Treon, Mark Hansen, Andrew R Branagan, Sigitas Verselis, Christos Emmanouilides, Eva Kimby, Stanley R Frankel, Nikolaos Touroutoglou, Barry Turnbull, Kenneth C Anderson, David G Maloney, Edward A Fox
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 3 Pg. 474-81 (Jan 20 2005) ISSN: 0732-183X [Print] United States
• PMID: 15659493 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD
• Antineoplastic Agents
• Codon
• FCGR3B protein, human
• GPI-Linked Proteins
• Receptors, IgG
• Rituximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD (genetics)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Codon
• Disease Progression
• Disease-Free Survival
• Female
• GPI-Linked Proteins
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Middle Aged
• Polymorphism, Genetic
• Receptors, IgG (genetics)
• Rituximab
• Treatment Outcome
• Waldenstrom Macroglobulinemia (drug therapy, genetics)