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Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia

Bone Marrow Transplantation volume 57, pages 874–880 (2022)Cite this article

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Abstract

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.

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Fig. 1: Current position of IgRT on HSCT and unrevealed points about the application.

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References

  1. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, et al. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med. 2020;172:229–39.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Penack O, Peczynski C, Mohty M, Yakoub-Agha I, Styczynski J, Montoto S, et al. How much has allogeneic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv. 2020;4:6283–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, et al. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021;106:1599–607.

    Article  CAS  PubMed  Google Scholar 

  4. Holmqvist AS, Chen Y, Wu J, Battles K, Bhatia R, Francisco L, et al. Assessment of late mortality risk after allogeneic blood or marrow transplantation performed in childhood. JAMA Oncol. 2018;4:e182453.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Patel SY, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Front Immunol. 2019;10:33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ueda M, Berger M, Gale RP, Lazarus HM. Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation. Blood Rev. 2018;32:106–15.

    Article  CAS  PubMed  Google Scholar 

  7. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17:57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126:573–81.

    Article  CAS  PubMed  Google Scholar 

  9. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138:563–79.

    Article  CAS  PubMed  Google Scholar 

  10. Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk. 2013;13:106–11.

    Article  CAS  PubMed  Google Scholar 

  11. Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1:e184169.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gudiol C, Lewis RE, Strati P, Kontoyiannis DP. Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: is there an excess risk for infection? Lancet Haematol. 2021;8:e216–28.

    Article  PubMed  Google Scholar 

  13. Hill JA, Giralt S, Torgerson TR, Lazarus HM. CAR-T—and a side order of IgG, to go?—immunoglobulin replacement in patients receiving CAR-T cell therapy. Blood Rev. 2019;38:100596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn JR, Devlin SM, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10:79.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl TM, et al. Cytokine release syndrome grade as a predictive marker for infections in patients with relapsed or refractory B-Cell acute lymphoblastic leukemia treated with chimeric antigen receptor T cells. Clin Infect Dis. 2018;67:533–40.

    Article  CAS  PubMed  Google Scholar 

  16. Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30.

    Article  CAS  PubMed  Google Scholar 

  17. Aguilar C, Malphettes M, Donadieu J, Chandesris O, Coignard-Biehler H, Catherinot E, et al. Prevention of infections during primary immunodeficiency. Clin Infect Dis. 2014;59:1462–70.

    Article  CAS  PubMed  Google Scholar 

  18. Oscier D, Dearden C, Eren E, Fegan C, Follows G, Hillmen P, et al. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. Br J Haematol. 2012;159:541–64.

    PubMed  Google Scholar 

  19. Compagno N, Cinetto F, Semenzato G, Agostini C. Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients. Haematologica. 2014;99:1101–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gale RP, Chapel HM, Bunch C, Rai KR, Foon K, Courter SG, et al. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med. 1988;319:902–7.

    Article  PubMed  Google Scholar 

  21. Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet. 1994;343:1059–63.

    Article  CAS  PubMed  Google Scholar 

  22. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma. 2009;50:764–72.

    Article  CAS  PubMed  Google Scholar 

  23. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma (version 3.2022). https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.

  24. NCCN Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma (version 1.2022). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf.

  25. NCCN: Cancer and COVID-19 Vaccination. (version 5.0). 2022. https://www.nccn.org/docs/default-source/covid-19/2021_covid-19_vaccination_guidance_v5-0.pdf?sfvrsn=b483da2b_74.

  26. Shao Z, Feng Y, Zhong L, Xie Q, Lei M, Liu Z, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19: a multicenter retrospective cohort study. Clin Transl Immunol. 2020;9:e1192.

    Article  CAS  Google Scholar 

  27. Mazeraud A, Jamme M, Mancusi RL, Latroche C, Megarbane B, Siami S, et al. Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022;10:158–66.

    Article  CAS  PubMed  Google Scholar 

  28. Vandeberg P, Cruz M, Diez JM, Merritt WK, Santos B, Trukawinski S, et al. Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma. Transfusion. 2021;61:1705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ali S, Uddin SM, Shalim E, Sayeed MA, Anjum F, Saleem F, et al. Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial. EClinicalMedicine. 2021;36:100926.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021;27:2012–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2021;384:619–29.

    Article  CAS  PubMed  Google Scholar 

  32. Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: a systematic review and meta-analysis. JAMA. 2021;325:1185–95.

    Article  CAS  PubMed  Google Scholar 

  33. Norlin AC, Sairafi D, Mattsson J, Ljungman P, Ringdén O, Remberger M. Allogeneic stem cell transplantation: low immunoglobulin levels associated with decreased survival. Bone Marrow Transplant. 2008;41:267–73.

    Article  CAS  PubMed  Google Scholar 

  34. Arai Y, Yamashita K, Mizugishi K, Kondo T, Kitano T, Hishizawa M, et al. Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transplant. 2014;49:859–61.

    Article  CAS  PubMed  Google Scholar 

  35. Frangoul H, Min E, Wang W, Chandrasekhar R, Calder C, Evans M, et al. Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT. Bone Marrow Transplant. 2013;48:1456–9.

    Article  CAS  PubMed  Google Scholar 

  36. Winston DJ, Ho WG, Lin CH, Bartoni K, Budinger MD, Gale RP, et al. Intravenous immune globulin for prevention of cytomegalovirus infection and interstitial pneumonia after bone marrow transplantation. Ann Intern Med. 1987;106:12–8.

    Article  CAS  PubMed  Google Scholar 

  37. Bass EB, Powe NR, Goodman SN, Graziano SL, Griffiths RI, Kickler TS, et al. Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis. Bone Marrow Transplant. 1993;12:273–82.

    CAS  PubMed  Google Scholar 

  38. Sullivan KM, Kopecky KJ, Jocom J, Fisher L, Buckner CD, Meyers JD, et al. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med. 1990;323:705–12.

    Article  CAS  PubMed  Google Scholar 

  39. Cordonnier C, Chevret S, Legrand M, Rafi H, Dhédin N, Lehmann B, et al. Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med. 2003;139:8–18.

    Article  CAS  PubMed  Google Scholar 

  40. Ahn H, Tay J, Shea B, Hutton B, Shorr R, Knoll GA, et al. Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transfusion. 2018;58:2437–52.

    Article  PubMed  Google Scholar 

  41. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2009;27:770–81.

    Article  CAS  PubMed  Google Scholar 

  42. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2008;4:CD006501.

    Google Scholar 

  43. Pasic I, Alanazi W, Dranitsaris G, Lieberman L, Viswabandya A, Kim DDH, et al. Subcutaneous immunoglobulin in allogeneic hematopoietic cell transplant patients: a prospective study of feasibility, safety, and healthcare resource use. Hematol Oncol Stem Cell Ther. 2021. https://doi.org/10.1016/j.hemonc.2021.01.001.

  44. Howell JE, Gulbis AM, Champlin RE, Qazilbash MH. Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. Am J Hematol. 2012;87:172–4.

    Article  CAS  PubMed  Google Scholar 

  45. Derman BA, Schlei Z, Parsad S, Mullane K, Knoebel RW. Changes in intravenous immunoglobulin usage for hypogammaglobulinemia after implementation of a stewardship program. JCO Oncol Pract. 2021;17:e445–3.

    Article  PubMed  Google Scholar 

  46. Bhella S, Majhail NS, Betcher J, Costa LJ, Daly A, Dandoy CE, et al. Choosing Wisely BMT: American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant Group’s list of 5 tests and treatments to question in blood and marrow transplantation. Biol Blood Marrow Transplant. 2018;24:909–13.

    Article  PubMed  Google Scholar 

  47. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. NCCN Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections (version 1.2021) https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf.

  49. Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians (version October 01.2021). https://www.fredhutch.org/content/dam/www/research/patient-treatment-and-support/ltfu/LTFU_HSCT_guidelines_physicians.pdf.

  50. Jolles S, Michallet M, Agostini C, Albert MH, Edgar D, Ria R, et al. Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. Eur J Haematol. 2021;106:439–49.

    Article  CAS  PubMed  Google Scholar 

  51. The Japan Society for Hematopoietic Cell Transplantation. Post-transplant infectious control guidelines (version 4.2017). (in Japanese) https://www.jstct.or.jp/uploads/files/guideline/01_01_kansenkanri_ver04.pdf.

  52. Otani IM, Lehman HK, Jongco AM, Tsao LR, Azar A, Tarrant T, et al. Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a work group report of the AAAAI primary immunodeficiency and altered immune response committees. J Allergy Clin Immunol. 2022. https://doi.org/10.1016/j.jaci.2022.01.025.

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Author notes

  1. These authors contributed equally: Akihiro Ohmoto, Shigeo Fuji.

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Akihiro Ohmoto

  2. Department of Hematology, Osaka International Cancer Institute, Osaka, Japan

    Shigeo Fuji

  3. Stem Cell Transplant and CART Therapy, VA Tennessee Valley Healthcare System, Nashville, TN, USA

    Kendall C. Shultes

  4. Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Bipin N. Savani

  5. Department of Medicine II, Würzburg University Medical Centre, Würzburg, Germany

    Hermann Einsele

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AO and SF designed the outline for the paper and wrote the first draft; KCS, BNS and HE critically reviewed and revised the paper; all authors reviewed the final paper and agreed with its content.

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Correspondence to Shigeo Fuji.

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SF received a research grant from CSL Behring K.K.

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Ohmoto, A., Fuji, S., Shultes, K.C. et al. Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia. Bone Marrow Transplant 57, 874–880 (2022). https://doi.org/10.1038/s41409-022-01680-z

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