Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia

Abstract

Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.

FC gamma receptor polymorphisms in patients with immune thrombocytopenia

“…Over the last two decades, a number of groups have investigated the frequencies and clinical significance of variant alleles in FCGR2A and FCGR3A in several disease populations [33]. FCGR2A polymorphism has been associated with different diseases like heparininduced thrombocytopenia [24,25], SLE [28,29,34], bacterial infection [35] and response to rituximab-based treatment in lymphoma patients [36,37]. Our results did not confirm significant difference in genotype distribution or allele frequencies for FCGR2A polymorphisms in patients with ITP and control subjects.…”

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1–2 trial

“…The valine allotype displays a higher affinity for immunoglobulin G1 than the wild-type phenylalanine, resulting in increased antibody-dependent cytotoxicity, 12 thereby increasing response rates for monoclonal antibodies such as rituximab in some studies. 27,28 Interestingly, we observed the opposite relationship: a lower complete response rate among subjects with one or more variant valine alleles. As an antibody-drug conjugate, Brentuximab vedotin is thought to exert cytotoxicity primarily through selective delivery of a microtubule disrupting agent to CD30 positive cells, 29 a mechanism independent of antibody-dependent cellular cytotoxicity.…”

PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody

“…Indeed, TA-targeting mAbs have the unique capacity to specifically target cancer cells and to kill them through FcgR-dependent mechanisms, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). FcgR polymorphisms have been associated with differential clinical outcome in patients treated with trastuzumab 3,4 or rituximab, 5 supporting the importance of FcgR-mediated mechanisms. Moreover, the demonstration that rituximab immunotherapy elicits a lymphoma-specific T cell response also suggests that immunotherapy with TA-targeting mAbs can result in the induction of a specific cellular immune response against tumorassociated antigens.…”