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.
Similar content being viewed by others
References
Gerrard M, Cairo MS, Weston C, Auperin A, Pinkerton R, Lambilliote A, Sposto R, McCarthy K, Lacombe MJ, Perkins SL, Patte C, Committee FLIS (2008) Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141(6):840–847. doi:10.1111/j.1365-2141.2008.07144.x
Cairo MS, Gerrard M, Sposto R, Auperin A, Pinkerton CR, Michon J, Weston C, Perkins SL, Raphael M, McCarthy K, Patte C (2007) Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109(7):2736–2743. doi:10.1182/blood-2006-07-036665
Patte C, Auperin A, Gerrard M, Michon J, Pinkerton R, Sposto R, Weston C, Raphael M, Perkins SL, McCarthy K, Cairo MS, Committee FLIS (2007) Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109(7):2773–2780. doi:10.1182/blood-2006-07-036673
Woessmann W, Seidemann K, Mann G, Zimmermann M, Burkhardt B, Oschlies I, Ludwig WD, Klingebiel T, Graf N, Gruhn B, Juergens H, Niggli F, Parwaresch R, Gadner H, Riehm H, Schrappe M, Reiter A, Group BFM (2005) The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105(3):948–958. doi:10.1182/blood-2004-03-0973
Patte C, Auperin A, Michon J, Behrendt H, Leverger G, Frappaz D, Lutz P, Coze C, Perel Y, Raphael M, Terrier-Lacombe MJ (2001) The Societe Francaise d’Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97(11):3370–3379. doi:10.1182/blood.V97.11.3370
Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB (1997) Treatment of children and young adults with early-stage non-Hodgkin’s lymphoma. N Engl J Med 337(18):1259–1266. doi:10.1056/NEJM199710303371802
Pillon M, Arico M, Mussolin L, Mainardi C, Giraldi E, Garaventa A, Lombardi A, Santoro N, Carraro E, d’Amore ES, Rosolen A, Italian Association of Pediatric Hematology OAN-HLWG (2014) Mediastinal Burkitt lymphoma in childhood. Pediatr Blood Cancer 61(11):2127–2128. doi:10.1002/pbc.25127
Tsurusawa M, Mori T, Kikuchi A, Mitsui T, Sunami S, Kobayashi R, Takimoto T, Saito A, Watanabe T, Fujimoto J, Nakazawa A, Ohshima K, Horibe K, lymphoma committee of Japanese Pediatric Leukemia/Lymphoma Study G (2014) Improved treatment results of children with B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study. Pediatr Blood Cancer 61(7):1215–1221. doi:10.1002/pbc.24975
Cartron G, Trappe RU, Solal-Celigny P, Hallek M (2011) Interindividual variability of response to rituximab: from biological origins to individualized therapies. Clin Cancer Res 17(1):19–30. doi:10.1158/1078-0432.CCR-10-1292
Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP (1997) A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 100(5):1059–1070. doi:10.1172/JCI119616
Mishima Y, Terui Y, Mishima Y, Kuniyoshi R, Matsusaka S, Mikuniya M, Kojima K, Hatake K (2012) High reproducible ADCC analysis revealed a competitive relation between ADCC and CDC and differences between FcgammaRllla polymorphism. Int Immunol 24(8):477–483. doi:10.1093/intimm/dxs048
Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99(3):754–758
Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21(21):3940–3947. doi:10.1200/JCO.2003.05.013
Persky DO, Dornan D, Goldman BH, Braziel RM, Fisher RI, Leblanc M, Maloney DG, Press OW, Miller TP, Rimsza LM (2012) Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone. Haematologica 97(6):937–942. doi:10.3324/haematol.2011.050419
Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Leger-Falandry C, Cogliatti S, Fey M, Martinelli G, Stahel R, Lohri A, Ketterer N, Wernli M, Cerny T, Schmitz SF (2005) Single agent rituximab in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 16(10):1675–1682. doi:10.1093/annonc/mdi320
Kim DH, Jung HD, Kim JG, Lee JJ, Yang DH, Park YH, Do YR, Shin HJ, Kim MK, Hyun MS, Sohn SK (2006) FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 108(8):2720–2725. doi:10.1182/blood-2006-01-009480
Zhang W, Wang X, Li J, Duan MH, Zhou DB (2010) Fcgamma receptor IIIA polymorphisms and efficacy of rituximab therapy on Chinese diffuse large B-cell lymphoma. Chin Med J 123(2):198–202
Cornec D, Tempescul A, Querellou S, Hutin P, Pers JO, Jamin C, Bendaoud B, Berthou C, Renaudineau Y, Youinou P (2012) Identification of patients with indolent B cell lymphoma sensitive to rituximab monotherapy. Ann Hematol 91(5):715–721. doi:10.1007/s00277-011-1369-y
Carlotti E, Palumbo GA, Oldani E, Tibullo D, Salmoiraghi S, Rossi A, Golay J, Pulsoni A, Foa R, Rambaldi A (2007) FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin’s lymphoma patients treated with sequential CHOP and rituximab. Haematologica 92(8):1127–1130
Farag SS, Flinn IW, Modali R, Lehman TA, Young D, Byrd JC (2004) Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 103(4):1472–1474. doi:10.1182/blood-2003-07-2548
Dornan D, Spleiss O, Yeh RF, Duchateau-Nguyen G, Dufour A, Zhi J, Robak T, Moiseev SI, Dmoszynska A, Solal-Celigny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Rossiev VA, Bence-Bruckler I, Geisler CH, Montillo M, Wenger MK, Weisser M (2010) Effect of FCGR2A and FCGR3A variants on CLL outcome. Blood 116(20):4212–4222. doi:10.1182/blood-2010-03-272765
Galimberti S, Palumbo GA, Caracciolo F, Benedetti E, Pelosini M, Brizzi S, Ciabatti E, Fazzi R, Stelitano C, Quintana G, Conte E, Tibullo D, Di Raimondo F, Petrini M (2007) The efficacy of rituximab plus hyper-CVAD regimen in mantle cell lymphoma is independent of FCgammaRIIIa and FCgammaRIIa polymorphisms. J Chemother 19(3):315–321
Pennell NM, Bhanji T, Zhang L, Seth A, Sawka CA, Berinstein NL (2008) Lack of prognostic value of FCGR3A-V158F polymorphism in non-Hodgkin’s lymphoma. Haematologica 93(8):1265–1267. doi:10.3324/haematol.12638
Mitrovic Z, Aurer I, Radman I, Ajdukovic R, Sertic J, Labar B (2007) FCgammaRIIIA and FCgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma. Haematologica 92(7):998–999
Varoczy L, Zilahi E, Gyetvai A, Kajtar B, Gergely L, Sipka S, Illes A (2012) Fc-gamma-receptor IIIa polymorphism and gene expression profile do not predict the prognosis in diffuse large B-cell lymphoma treated with R-CHOP protocol. Pathol Oncol Res 18(1):43–48. doi:10.1007/s12253-011-9414-7
Ahlgrimm M, Pfreundschuh M, Kreuz M, Regitz E, Preuss KD, Bittenbring J (2011) The impact of Fc-gamma receptor polymorphisms in elderly patients with diffuse large B-cell lymphoma treated with CHOP with or without rituximab. Blood 118(17):4657–4662. doi:10.1182/blood-2011-04-346411
Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M (2010) Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28(29):4480–4484. doi:10.1200/JCO.2010.28.4786
Paiva M, Marques H, Martins A, Ferreira P, Catarino R, Medeiros R (2008) FcgammaRIIa polymorphism and clinical response to rituximab in non-Hodgkin lymphoma patients. Cancer Genet Cytogenet 183(1):35–40. doi:10.1016/j.cancergencyto.2008.02.001
Levy D, Bellesso M, Oliveira-Souza P, Maciel FV, Pereira J, Bydlowski SP (2011) The H/R FcgammaRIIA-131 polymorphism and survival in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP: a study in a genetically mixed population. Clinics (Sao Paulo) 66(5):919–922
Clynes R (2007) IVIG therapy: interfering with interferon-gamma. Immunity 26(1):4–6. doi:10.1016/j.immuni.2007.01.006
Manches O, Lui G, Chaperot L, Gressin R, Molens JP, Jacob MC, Sotto JJ, Leroux D, Bensa JC, Plumas J (2003) In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 101(3):949–954. doi:10.1182/blood-2002-02-0469
Lisfeld J, Burkhardt B, Meinhardt A, Zimmermann M, Kabıckova E, Bielack S, Kontny U, Gnekow A, Sauerbrey A, Reiter A (2012) Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia: dose-escalation does not increase the response rate. Br J Haematol 112(Suppl. 2012):Abstract 6
Meinhardt A, Burkhardt B, Zimmermann M, Borkhardt A, Kontny U, Klingebiel T, Berthold F, Janka-Schaub G, Klein C, Kabickova E, Klapper W, Attarbaschi A, Schrappe M, Reiter A, Berlin-Frankfurt-Munster g (2010) Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia. J Clin Oncol 28(19):3115–3121. doi:10.1200/JCO.2009.26.6791
Murphy SB (1980) Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 7(3):332–339
Jiang XM, Arepally G, Poncz M, McKenzie SE (1996) Rapid detection of the Fc gamma RIIA-H/R 131 ligand-binding polymorphism using an allele-specific restriction enzyme digestion (ASRED). J Immunol Methods 199(1):55–59
Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. John Wiley, New York, pp. 163–188
Armitage P (1955) Test for linear trends in proportions and frequencies. Biometrics 11:375–386
Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A (2013) A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol 6:1. doi:10.1186/1756-8722-6-1
Nishio M, Endo T, Fujimoto K, Yamamoto S, Obara M, Yamaguchi K, Takeda Y, Goto H, Kasahara I, Sato N, Koike T (2009) FCGR3A-158V/F polymorphism may correlate with the levels of immunoglobulin in patients with non-Hodgkin’s lymphoma after rituximab treatment as an adjuvant to autologous stem cell transplantation. Eur J Haematol 82(2):143–147. doi:10.1111/j.1600-0609.2008.01174.x
Capuano C, Romanelli M, Pighi C, Cimino G, Rago A, Molfetta R, Paolini R, Santoni A, Galandrini R (2015) Anti-CD20 therapy acts via FcgammaRIIIA to diminish responsiveness of human natural killer cells. Cancer Res 75(19):4097–4108. doi:10.1158/0008-5472.CAN-15-0781
Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, Lin WY, Hu Z, Lu Y, Chen Y, Wu Y, Meng YG, Gribling P, Lin Z, Nguyen K, Tran T, Zhang Y, Rosen H, Martin F, Chan AC (2005) Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 174(2):817–826
Okroj M, Osterborg A, Blom AM (2013) Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev 39(6):632–639. doi:10.1016/j.ctrv.2012.10.008
Acknowledgments
The authors thank Gabriele Buck (cytomorphology), Bettina Paul, and Ulrike Meyer (data management) for their expert work. We also thank the physicians, radiologists, nurses, and data managers at the participating hospitals who cared for the children and supplied the data. This work was supported by “Forschungshilfe Peiper”, Giessen, Germany. EK was supported by a project of the Czech Ministry of Health: project for conceptual development of research organization 00064203.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Rights and permissions
About this article
Cite this article
Burkhardt, B., Yavuz, D., Zimmermann, M. et al. Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia. Ann Hematol 95, 1503–1512 (2016). https://doi.org/10.1007/s00277-016-2731-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-016-2731-x