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Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma

Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma
Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: Hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.

2473-9529
2935-2944
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Davies, Andrew
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Rose-Zerilli, Matthew
08b3afa4-dbc2-4c0d-a852-2a9f33431199
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Davies, Andrew
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Rose-Zerilli, Matthew
08b3afa4-dbc2-4c0d-a852-2a9f33431199

Strefford, Jonathan, Cragg, Mark, Davies, Andrew, Parker, Helen and Rose-Zerilli, Matthew (2021) Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma. Blood Advances, 5 (15), 2935-2944. (doi:10.1182/bloodadvances.2020003985).

Record type: Article

Abstract

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: Hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.

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Strefford_FCGR_SNP_20November20_accepted - Accepted Manuscript
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Accepted/In Press date: 22 March 2021
Published date: 10 August 2021
Additional Information: Acknowledgments The authors thank all patients who participated in and clinicians who contributed to the study; and the Experimental Cancer Medicine Centre (ECMC)–funded University of Southampton Faculty of Medicine Human Tissue Bank (Human Tissue Authority license 12009) for sample storage. Editorial support under the direction of Malgorzata Nowicka was provided by Zoe Toland and Louise Profit of Ashfield MedComms, an Ashfield Health company, and funded by F. Hoffmann-La Roche Ltd. This work was supported by funding from Bloodwise (grant 12050 and 12036) and Cancer Research United Kingdom (grants A18087, A24721, A25139, and A15581) (M.S.C.), NC3R CRACKIT (grant 15402-106217) (J.C.S. and M.S.C.), and F. Hoffmann-La Roche Ltd. GALLIUM was sponsored by F. Hoffmann-La Roche Ltd and GOYA was sponsored by F. Hoffmann-La Roche Ltd with the scientific support of the Fondazione Italiana Linfomi.

Identifiers

Local EPrints ID: 449591
URI: http://eprints.soton.ac.uk/id/eprint/449591
ISSN: 2473-9529
PURE UUID: 917cb593-8738-4027-a157-14ed617cf3f1
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350

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Date deposited: 08 Jun 2021 16:32
Last modified: 26 Nov 2021 02:56

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Contributors

Author: Mark Cragg ORCID iD
Author: Andrew Davies ORCID iD
Author: Helen Parker ORCID iD

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