Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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

    Article  CAS  PubMed  Google Scholar 

  2. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. 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

    CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  Google Scholar 

  30. Clynes R (2007) IVIG therapy: interfering with interferon-gamma. Immunity 26(1):4–6. doi:10.1016/j.immuni.2007.01.006

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    CAS  PubMed  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. John Wiley, New York, pp. 163–188

    Google Scholar 

  37. Armitage P (1955) Test for linear trends in proportions and frequencies. Biometrics 11:375–386

    Article  Google Scholar 

  38. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. 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

    Article  CAS  PubMed  Google Scholar 

  41. 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

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Birgit Burkhardt.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-016-2731-x

Keywords

Navigation