Prognostic Impact of Fc Gamma-Receptor Polymorphisms and Efficacy of Rituximab in Children and Adolescents with Mature Aggressive B-NHL

Abstract 1547

Recent studies in adult lymphoma patients indicated a correlation of polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and response to rituximab or outcome. FcγRIIIa is expressed on natural killer (NK) cells and macrophages representing the most important antibody-dependent cellular cytotoxicity (ADCC) effector cells. It is reported that the FcγRIIIa-158 valine (V) isotype has a higher affinity to human immunoglobulin G1 than the phenylalanine (F) isotype and that cells with FcγRIIIa-158V mediate ADCC more efficiently. Besides FCGR3A, a polymorphism of FCGR2A resulting in either histidine (H) or arginine (R) at amino acid position 131 was analyzed in clinical trials for its prognostic impact on rituximab response but the results remained inconclusive.

The trial B-NHL BFM Rituximab tested the efficacy of rituximab in pediatric patients (pts) with mature aggressive B-NHL. In this context the impact of FCGR-polymorphisms was analyzed in the current project.

Patients were registered and treated according to protocol B-NHL BFM Rituximab with a single dose rituximab (375 mg/m² n= 88 and 700 mg/m² n=40) at day one, rituximab response evaluation at day five, followed by standard chemotherapy. The FCGR3A-158V/F polymorphism and the FCGR2A-131H/R polymorphism were assessed.

Of a total of 128 pts, 105 were evaluable for rituximab response at day 5 with 47 responders and 58 non-responders (response rate 45%).

Rituximab response rate was 26% and therefore significantly lower in pts with FcγRIIa-131R/R isotype (n=23, 6 responders) compared to the response for FcγRIIa-131H isotype carriers (H/H n=34, 19 responders and H/R n= 45, 22 responders; response rate 52%). Concerning the FCGR3A polymorphism, the F/F genotype was highly significantly associated with favorable response rate of 70% (F/F n=33, 23 responders) compared to the response rate in FcγRIIIa-158V isotype carriers (V/V n=9, 2 responders and V/F n=63, 22 responders; response rate 33%). Response rate for FCGR3A-158F/F genotype was favorable for both, low-risk-R2 (14/21 responders) and higher-risk-R3/R4 (9/12 responders) pts.

In the current context of rituximab response evaluation after an upfront window, the FcγRIIIa-158 phenylalanine (F) isotype is associated with favorable response in pediatric pts with aggressive B-NHL, but not the high-affinity FcγRIIIa-158 valine isotype. These are conflicting results compared to published data for lymphoma trials in adults and the in vitro data on FcγRIIIa-158. This raises the question whether ADCC is a relevant mechanism of action in the current patient population or whether other factors might impact the interaction of NK cells, macrophages, neutrophils and lymphoma cells.