Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Hematology
Published in: Annals of Hematology 9/2016

01-09-2016 | Original Article

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

Authors: Birgit Burkhardt, Deniz Yavuz, Martin Zimmermann, Jutta Schieferstein, Edita Kabickova, Andishe Attarbaschi, Jasmin Lisfeld, Alfred Reiter, Olga Makarova, Jennifer Worch, Bettina R. Bonn, Christine Damm-Welk

Published in: Annals of Hematology | Issue 9/2016

Login to get access

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.

Literature
  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 View ArticlePubMed
  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 PubMedPubMed Central
  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 PubMedPubMed Central
  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 View ArticlePubMed
  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 View ArticlePubMed
  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/​NEJM199710303371​802 View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMedPubMed Central
  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 View ArticlePubMed
  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):754–758View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMedPubMed Central
  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 View ArticlePubMed
  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 View ArticlePubMed
  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):198–202PubMed
  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 View ArticlePubMed
  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):1127–1130View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMed
  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):315–321View ArticlePubMed
  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 View ArticlePubMed
  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):998–999View ArticlePubMed
  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 View ArticlePubMed
  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 View ArticlePubMedPubMed Central
  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 View ArticlePubMed
  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 View ArticlePubMed
  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):919–922View Article
  30. Clynes R (2007) IVIG therapy: interfering with interferon-gamma. Immunity 26(1):4–6. doi:10.​1016/​j.​immuni.​2007.​01.​006 View ArticlePubMed
  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 View ArticlePubMed
  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
  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 View ArticlePubMed
  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):332–339PubMed
  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):55–59View ArticlePubMed
  36. Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. John Wiley, New York, pp. 163–188
  37. Armitage P (1955) Test for linear trends in proportions and frequencies. Biometrics 11:375–386View Article
  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 View ArticlePubMedPubMed Central
  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 View ArticlePubMed
  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 View ArticlePubMed
  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):817–826View ArticlePubMed
  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 View ArticlePubMed
Metadata
Title
Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia
Authors
Birgit Burkhardt
Deniz Yavuz
Martin Zimmermann
Jutta Schieferstein
Edita Kabickova
Andishe Attarbaschi
Jasmin Lisfeld
Alfred Reiter
Olga Makarova
Jennifer Worch
Bettina R. Bonn
Christine Damm-Welk
Publication date
01-09-2016
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 9/2016
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-016-2731-x

Other articles of this Issue 9/2016

Annals of Hematology 9/2016 Go to the issue

Letter to the Editor

Congenital dyserythropoietic anemia associated to a GATA1 mutation aggravated by pyruvate kinase deficiency

Review Article

Venous thromboembolism following hematopoietic stem cell transplantation—a systematic review and meta-analysis

Letter to the Editor

Long-term follow-up of non-syphilitic paroxysmal cold hemoglobinuria in an adult

Original Article

The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis

Original Article

Etiopathological mechanisms and clinical characteristics of hyperhemolysis syndrome in Spanish patients with thalassemia

Letter to the Editor

Rhodotorula mucilaginosa as a cause of recurrent pulmonary infection and liver infiltration in a patient with CLL

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits