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Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein–Barr virus infection: a retrospective analysis of a single center

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Abstract

Background

This study aimed to evaluate the feasibility and clinical effect of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for the treatment of pediatric patients with chronic active Epstein–Barr virus infection (CAEBV).

Methods

Children with CAEBV who did not have matched donors and underwent haplo-HSCT in Beijing Children’s Hospital, Capital Medical University, from October 2016 to June 2020 were analyzed retrospectively. Data relating to the clinical manifestations, engraftment, and prognosis of the children were extracted from medical records.

Results

Twenty-five patients, including 16 males and 9 females, with an onset age of 5.0 ± 2.6 years and a transplantation age of 6.9 ± 2.9 years, were enrolled in this study. The mean time from diagnosis to transplantation was 3.8 (2.0–40.2) months. The mean observation time was 19.0 ± 12.0 months. Three patients received the reduced intensity conditioning regimen, and the remaining patients all received the modified myeloablative conditioning regimen. By the end of the follow-up, 23 patients were characterized by disease-free survival (DFS), 22 were characterized by event-free survival (EFS), and two died. One of the patients died of thrombotic microangiopathy (TMA), and another died of graft versus host disease (GVHD); this patient discontinued the treatment for economic reasons. The 3-year overall survival (OS) rate was estimated to be 92.0% ± 5.4%, and the 3-year EFS rate was estimated to be 87.4% ± 6.8%. All active patients survived after HSCT event-free. Acute GVHD degrees 1–3 were observed in ten patients (40.0%), and degree IV was observed in six (24.0%), who were all cured except for one patient. Chronic GVHD was observed in nine (36.0%), and most of these cases were mild. The incidence of TMA and veno-occlusive disease (VOD) was 28.0% and 4.0%.

Conclusions

Haploidentical hematopoietic stem cell transplantation is safe and effective in the treatment of pediatric CAEBV and can be used as an alternative therapy without matched donors or emergency transplantation. Patients with active disease before HSCT also benefited from haplo-HSCT. Haplo-HSCT requires careful monitoring for complications, such as GVHD and TMA. Early detection of TMA and timely treatment can reduce mortality and can improve the survival rate.

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Data availability statement

The data that support the findings of this study are available on request from the corresponding author.

References

  1. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from burkitt’s lymphoma. Lancet. 1964;1:702–3.

    Article  CAS  Google Scholar 

  2. Kawa K. Epstein-Barr virus–associated diseases in humans. Int J Hematol. 2000;71:108–17.

    CAS  PubMed  Google Scholar 

  3. Kimura H, Cohen JI. Chronic active epstein-barr virus disease. Front Immunol. 2017;8:1867.

    Article  Google Scholar 

  4. Bollard CM, Cohen JI. How I treat T-cell chronic active Epstein-Barr virus disease. Blood. 2018;131:2899–905.

    Article  CAS  Google Scholar 

  5. Sawada A, Inoue M, Kawa K. How we treat chronic active Epstein-Barr virus infection. Int J Hematol. 2017;105:406–18.

    Article  CAS  Google Scholar 

  6. Okano M. Recent concise viewpoints of chronic active Epstein-Barr virus infection. Curr Pediatr Rev. 2015;11:5–9.

    Article  Google Scholar 

  7. Okano M, Kawa K, Kimura H, Yachie A, Wakiguchi H, Maeda A, et al. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am J Hematol. 2005;80:64–9.

    Article  Google Scholar 

  8. Ohshima K, Kimura H, Yoshino T, Kim CW, Ko YH, Lee SS, et al. Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD. Pathol Int. 2008;58:209–17.

    Article  CAS  Google Scholar 

  9. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  Google Scholar 

  10. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the mount sinai acute GVHD international consortium. Biol Blood Marrow Transplant. 2016;22:4–10.

    Article  Google Scholar 

  11. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21:389-401.e1.

    Article  Google Scholar 

  12. Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:918–26.

    Article  CAS  Google Scholar 

  13. Bonifazi F, Barbato F, Ravaioli F, Sessa M, Defrancesco I, Arpinati M, et al. Diagnosis and treatment of VOD/SOS After allogeneic hematopoietic stem cell transplantation. Front Immunol. 2020;11:489.

    Article  CAS  Google Scholar 

  14. Hamidieh AA, Pourpak Z, Hosseinzadeh M, Fazlollahi MR, Alimoghaddam K, Movahedi M, et al. Reduced-intensity conditioning hematopoietic SCT for pediatric patients with LAD-1: clinical efficacy and importance of chimerism. Bone Marrow Transplant. 2012;47:646–50.

    Article  CAS  Google Scholar 

  15. Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73.

    Article  CAS  Google Scholar 

  16. Ma H, Zhang L, Wei A, Jun Y, Dong W, Qing Z, et al. Outcome of L-DEP regimen for treatment of pediatric chronic active Epstein-Barr virus infection. Orphanet J Rare Dis. 2021;16:269.

    Article  Google Scholar 

  17. Mahlaoui N, Ouachée-Chardin M, de Saint BG, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120:e622–8.

    Article  Google Scholar 

  18. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9.

    Article  Google Scholar 

  19. Jia C, Wang B, Zhu G, Zhang R, Wang K, Yan Y, et al. Haploidentical hematopoietic stem cell transplantation using reduced-intensity conditioning for pediatric patients with familial hemophagocytic lymphohistiocytosis. Pediatr Investig. 2019;2:216–21.

    Article  Google Scholar 

  20. Okamura T, Kishimoto T, Inoue M, Honda M, Yamashita N, Wakiguchi H, et al. Unrelated bone marrow transplantation for Epstein-Barr virus-associated T/NK-cell lymphoproliferative disease. Bone Marrow Transplant. 2003;31:105–11.

    Article  CAS  Google Scholar 

  21. Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y, Kojima S, et al. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood. 2012;119:673–86.

    Article  CAS  Google Scholar 

  22. Sato E, Ohga S, Kuroda H, Yoshiba F, Nishimura M, Nagasawa M, et al. Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan. Am J Hematol. 2008;83:721–7.

    Article  Google Scholar 

  23. Arai A. Advances in the study of chronic active Epstein-Barr Virus infection: clinical features under the 2016 WHO classification and mechanisms of development. Front Pediatr. 2019;7:14.

    Article  Google Scholar 

  24. Fujiwara S, Nakamura H. Chronic active Epstein-Barr Virus infection: is it immunodeficiency, malignancy, or both? Cancers (Basel). 2020;12:3202.

    Article  CAS  Google Scholar 

  25. Kawa K, Sawada A, Sato M, Okamura T, Sakata N, Kondo O, et al. Excellent outcome of allogeneic hematopoietic SCT with reduced-intensity conditioning for the treatment of chronic active EBV infection. Bone Marrow Transplant. 2011;46:77–83.

    Article  CAS  Google Scholar 

  26. Gotoh K, Ito Y, Shibata-Watanabe Y, Kawada J, Takahashi Y, Yagasaki H, et al. Clinical and virological characteristics of 15 patients with chronic active Epstein-Barr virus infection treated with hematopoietic stem cell transplantation. Clin Infect Dis. 2008;46:1525–34.

    Article  CAS  Google Scholar 

  27. Yang J, Zhu GH, Wang B, Zhang R, Jia CG, Yan Y, et al. Haploidentical hematopoietic stem cell transplantation for xiap deficiency: a single-center report. J Clin Immunol. 2020;40:893–900.

    Article  CAS  Google Scholar 

  28. Leon Rodriguez E, Rivera Franco MM, Perez Alvarez SI. Reduced BUCY 2 and G-CSF-primed bone marrow associates with low graft-versus-host-disease and transplant-related mortality in allogeneic HSCT. Ann Hematol. 2017;96:1525–31.

    Article  CAS  Google Scholar 

  29. Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107:3065–73.

    Article  CAS  Google Scholar 

  30. Chang YJ, Huang XJ. Haploidentical bone marrow transplantation without T-cell depletion. Semin Oncol. 2012;39:653–63.

    Article  Google Scholar 

  31. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44:294–304.

    Article  Google Scholar 

  32. Epperla N, Li A, Logan B, Fretham C, Chhabra S, Aljurf M, et al. Incidence, risk factors for and outcomes of transplant-associated thrombotic microangiopathy. Br J Haematol. 2020;189:1171–81.

    Article  CAS  Google Scholar 

  33. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011;118:1452–62.

    Article  CAS  Google Scholar 

  34. Xiao H, Hu B, Luo R, Hu H, Zhang J, Kuang W, et al. Chronic active Epstein-Barr virus infection manifesting as coronary artery aneurysm and uveitis. Virol J. 2020;17:166.

    Article  CAS  Google Scholar 

  35. Xiao H, Hu B, Luo R, Hu H, Zhang J, Kuang W, et al. Cardiovascular complications associated with chronic active Epstein-Barr virus infection. Pediatr Cardiol. 2009;30:274–81.

    Article  Google Scholar 

  36. Kernan NA, Grupp S, Smith AR, Arai S, Triplett B, Antin JH, et al. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018;181:816–27.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all of the patients and their families for their kind cooperation. We thank all of the members of clinical team who provided care for patients. This work was supported by Beijing Municipal Science & Technology Commission (No. Z171100001017050) and National Science and Technology Key Projects (No. 2017ZX09304029001).

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    Authors and Affiliations

    1. Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Department of Hematology and Oncology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Nanlishi Road No. 56, Beijing 100045, China

      Yan-Hui Luo, Jun Yang, Ang Wei, Guang-Hua Zhu, Bin Wang, Rui Zhang, Chen-Guang Jia, Yan Yan, Kai Wang, Sidan Li, Xuan Zhou, Mao-Quan Qin & Tian-You Wang

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    Contributions

    YHL, JY and AW contributed equally to this paper. YHL and AW designed and performed the literature search and drafted the manuscript. YHL and AW contributed equally to this work. BW, GHZ, RZ, CGJ, YY, KW, XZ and SDL analyzed the data, and verified and discussed the studies. JY, TYW and MQQ amended the paper, designed the research, proofread the manuscript, supervised and approved the study.

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    Correspondence to Tian-You Wang.

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    No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

    Ethics approval and consent to participate

    This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Beijing Children’s Hospital, Capital Medical University ([2021]-A-123-R). Informed consent to participate in the study have been obtained from their parent or legal guardian in the case of children under 16.

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    Luo, YH., Yang, J., Wei, A. et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein–Barr virus infection: a retrospective analysis of a single center. World J Pediatr 17, 626–636 (2021). https://doi.org/10.1007/s12519-021-00470-9

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