IMPACT OF FCGR3A V158F POLYMORPHISM ON RITUXIMAB EFFICACY: A TARGETED LITERATURE REVIEW
Author(s)
Saif Huda, MD1, Jamie Sebaaly, PharmD2, Dustin Cavida, PharmD2, Therese Aubry de Maraumont, PharmD, MSc2, Sarah Hodgkinson, PhD3, Martin Dalziel, PhD3, Moushmi Singh, MSc4, ISTVAN M. MAJER, PhD5, Ho Jin Kim, MD6;
1Walton Centre NHS Foundation Trust, and University of Liverpool, Liverpool, United Kingdom, 2Amgen Inc., Thousand Oaks, CA, USA, 3Oxford PharmaGenesis, Oxford, United Kingdom, 4Amgen, Uxbridge, United Kingdom, 5Amgen Europe GmbH, Global HEOR, Rotkreuz, Switzerland, 6Research Institute and Hospital of National Cancer Center, Goyang, Korea, Republic of
1Walton Centre NHS Foundation Trust, and University of Liverpool, Liverpool, United Kingdom, 2Amgen Inc., Thousand Oaks, CA, USA, 3Oxford PharmaGenesis, Oxford, United Kingdom, 4Amgen, Uxbridge, United Kingdom, 5Amgen Europe GmbH, Global HEOR, Rotkreuz, Switzerland, 6Research Institute and Hospital of National Cancer Center, Goyang, Korea, Republic of
OBJECTIVES: Rituximab is widely used in B-cell-mediated autoimmune diseases and lymphomas to deplete B-cells through antibody-dependent cellular cytotoxicity (ADCC). ADCC relies on interactions between monoclonal antibodies and Fc gamma receptors on effector cells. A genetic polymorphism in FCGR3A V158F alters receptor affinity for antibodies like rituximab, and the F allele has been associated with reduced ADCC and weaker B-cell depletion. This targeted literature review assessed the epidemiology of the FCGR3A V158F polymorphism and its relationship to rituximab effectiveness.
METHODS: A literature review was conducted through August 2025, supplemented by structured large-language-model searching, hand searches of clinical trials registries, clinical guidelines, and health technology assessment submissions. Evidence across populations, diseases, and study designs was included to characterize the prevalence of V158F FCGR3A polymorphism and genotype-specific rituximab outcomes.
RESULTS: Sixty publications met the selection criteria. FCGR3A V158F prevalence varied across interventional (19-48%) and observational studies (1-90%) with a median estimate of 39%. The prevalence ranged 30-82% for Neuromyelitis Optica Spectrum Disorder (NMOSD) specifically. Eight cancer studies demonstrated inferior rituximab outcomes among patients with the polymorphism, while three studies reported no association. In autoimmune diseases, a meta-analysis showed reduced odds of rituximab response in patients with the polymorphism. Across 3 NMOSD studies, the presence of polymorphism was associated with a higher relapse risk, more frequent rituximab dose escalation, and greater treatment discontinuation; one small study showed no association.
CONCLUSIONS: Across cancers and autoimmune diseases, the FCGR3A polymorphism is associated with attenuated rituximab effectiveness, reflecting variability in Fc receptor-dependent mechanisms of B-cell depletion. In NMOSD, where relapses can result in severe and irreversible neurological disability, reduced treatment effectiveness may have important clinical consequences. In this context, B-cell-depleting therapies whose efficacy is not influenced by FCGR3A status may provide more consistent pharmacodynamic effects. These findings underscore the relevance of glycoengineering of monoclonal antibodies when considering therapies for NMOSD.
METHODS: A literature review was conducted through August 2025, supplemented by structured large-language-model searching, hand searches of clinical trials registries, clinical guidelines, and health technology assessment submissions. Evidence across populations, diseases, and study designs was included to characterize the prevalence of V158F FCGR3A polymorphism and genotype-specific rituximab outcomes.
RESULTS: Sixty publications met the selection criteria. FCGR3A V158F prevalence varied across interventional (19-48%) and observational studies (1-90%) with a median estimate of 39%. The prevalence ranged 30-82% for Neuromyelitis Optica Spectrum Disorder (NMOSD) specifically. Eight cancer studies demonstrated inferior rituximab outcomes among patients with the polymorphism, while three studies reported no association. In autoimmune diseases, a meta-analysis showed reduced odds of rituximab response in patients with the polymorphism. Across 3 NMOSD studies, the presence of polymorphism was associated with a higher relapse risk, more frequent rituximab dose escalation, and greater treatment discontinuation; one small study showed no association.
CONCLUSIONS: Across cancers and autoimmune diseases, the FCGR3A polymorphism is associated with attenuated rituximab effectiveness, reflecting variability in Fc receptor-dependent mechanisms of B-cell depletion. In NMOSD, where relapses can result in severe and irreversible neurological disability, reduced treatment effectiveness may have important clinical consequences. In this context, B-cell-depleting therapies whose efficacy is not influenced by FCGR3A status may provide more consistent pharmacodynamic effects. These findings underscore the relevance of glycoengineering of monoclonal antibodies when considering therapies for NMOSD.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
CO32
Topic
Clinical Outcomes
Disease
SDC: Rare & Orphan Diseases, SDC: Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)