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International Journal of Hematology

, Volume 109, Issue 5, pp 612–617 | Cite as

Factors predicting the recurrence of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol

  • Ryu Yanagaisawa
  • Kazuyuki Matsuda
  • Shouichi Ohga
  • Hirokazu Kanegane
  • Akira Morimoto
  • Yasuhiro Okamoto
  • Akira Ohara
  • Keitaro Fukushima
  • Manabu Sotomatsu
  • Keiko Nomura
  • Akiko M. Saito
  • Keizo Horibe
  • Eiichi Ishii
  • Yozo NakazawaEmail author
Original Article
  • 123 Downloads

Abstract

Epstein–Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is highly prevalent in Japan. To date, no standard treatment for EBV–HLH has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. The present prospective study recruited 27 children with EBV–HLH who were also part of the HLH-2004 study. EBV load in the peripheral blood was monitored at diagnosis and 2, 4, and 8 weeks after treatment initiation. Additionally, T-cell receptor (TCR) clonality and other laboratory data were evaluated. TCR clonality was positive in 14 patients at diagnosis. Seven of 27 patients experienced recurrences after treatment. No correlation was noted among any clinical data at diagnosis of patients with and without recurrence. However, the recurrence rate was significantly higher in patients aged < 2 years and/or those with a high plasma EBV load of > 103 copies/mL 2 weeks after treatment than that in patients without these factors. These findings suggest that a younger age or a high EBV load in plasma at the early phase of treatment is a factor predicting a recurrence and helps guide the intensity of subsequent treatment phases for children with EBV–HLH.

Keywords

Hemophagocytic lymphohistiocytosis EBV DNA HLH-2004 protocol 

Notes

Acknowledgements

This work was supported by a Grant-in-Aid for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan (H20-GanRinsho-Ippan-017), by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED_16ek0109055h0003 and AMED_18ck0106462h0001), and by the Japan Leukemia Research Fund. The authors would like to thank Yūka Miyajima for assistance with preparation of the manuscript as well as secretarial assistance. The authors also thank Enago (http://www.enago.jp) for the English language review.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Imashuku S. Clinical features and treatment strategies of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44:259–72.CrossRefGoogle Scholar
  2. 2.
    Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47.CrossRefGoogle Scholar
  3. 3.
    Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86:58–65.CrossRefGoogle Scholar
  4. 4.
    Kasahara Y, Yachie A. Cell type specific infection of Epstein-Barr virus (EBV) in EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Crit Rev Oncol Hematol. 2002;44:283–94.CrossRefGoogle Scholar
  5. 5.
    Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58:817–25.CrossRefGoogle Scholar
  6. 6.
    Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19:2665–73.CrossRefGoogle Scholar
  7. 7.
    Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130:2728–38.CrossRefGoogle Scholar
  8. 8.
    Henter JI, Samuelsson-Horne A, Arico 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.CrossRefGoogle Scholar
  9. 9.
    Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118:4577–84.CrossRefGoogle Scholar
  10. 10.
    Ohga S, Kudo K, Ishii E, Honjo S, Morimoto A, Osugi Y, et al. Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Pediatr Blood Cancer. 2010;54:299–306.Google Scholar
  11. 11.
    Shiraishi A, Ohga S, Doi T, Ishimura M, Takimoto T, Takada H, et al. Treatment choice of immunotherapy or further chemotherapy for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2012;59:265–70.CrossRefGoogle Scholar
  12. 12.
    Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A, et al. Prognostic factors of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group. Pediatr Blood Cancer. 2014;61:1257–62.CrossRefGoogle Scholar
  13. 13.
    Imashuku S, Teramura T, Kuriyama K, Kitazawa J, Ito E, Morimoto A, et al. Risk of etoposide-related acute myeloid leukemia in the treatment of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis. Int J Hematol. 2002;75:174–7.CrossRefGoogle Scholar
  14. 14.
    Yanagisawa R, Nakazawa Y, Matsuda K, Yasumi T, Kanegane H, Ohga S, et al. Outcome in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan. Int J Hematol. 2019;109:206–13.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    Matsuda K, Nakazawa Y, Yanagisawa R, Honda T, Ishii E, Koike K. Detection of T-cell receptor gene rearrangement in children with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis using the BIOMED-2 multiplex polymerase chain reaction combined with GeneScan analysis. Clin Chim Acta. 2011;412:1554–8.CrossRefGoogle Scholar
  17. 17.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRefGoogle Scholar
  18. 18.
    Kimura H, Hoshino Y, Hara S, Nishikawa K, Sako M, Hirayama M, et al. Viral load in Epstein–Barr virus-associated hemophagocytic syndrome. Microbiol Immunol. 2002;46:579–82.CrossRefGoogle Scholar
  19. 19.
    Imashuku S, Hibi S, Tabata Y, Itoh E, Hashida T, Tsunamoto K, et al. Outcome of clonal hemophagocytic lymphohistiocytosis: analysis of 32 cases. Leuk Lymphoma. 2000;37:577–84.CrossRefGoogle Scholar
  20. 20.
    Kanakry JA, Hegde AM, Durand CM, Massie AB, Greer AE, Ambinder RF, et al. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood. 2016;127:2007–17.CrossRefGoogle Scholar
  21. 21.
    Teramura T, Tabata Y, Yagi T, Morimoto A, Hibi S, Imashuku S. Quantitative analysis of cell-free Epstein-Barr virus genome copy number in patients with EBV-associated hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2002;43:173–9.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Ryu Yanagaisawa
    • 1
    • 2
    • 3
  • Kazuyuki Matsuda
    • 4
  • Shouichi Ohga
    • 5
  • Hirokazu Kanegane
    • 6
  • Akira Morimoto
    • 7
  • Yasuhiro Okamoto
    • 8
  • Akira Ohara
    • 9
  • Keitaro Fukushima
    • 10
  • Manabu Sotomatsu
    • 11
  • Keiko Nomura
    • 12
  • Akiko M. Saito
    • 3
  • Keizo Horibe
    • 3
  • Eiichi Ishii
    • 13
  • Yozo Nakazawa
    • 2
    Email author
  1. 1.Division of Blood TransfusionShinshu University HospitalMatsumotoJapan
  2. 2.Department of PediatricsShinshu University School of MedicineMatsumotoJapan
  3. 3.Clinical Research CenterNational Hospital Organization Nagoya Medical CenterNagoyaJapan
  4. 4.Department of Clinical Laboratory Sciences, School of Health SciencesShinshu UniversityMatsumotoJapan
  5. 5.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  6. 6.Department of Child Health and Development, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  7. 7.Department of PediatricsJichi Medical University School of MedicineShimotsukeJapan
  8. 8.Department of PediatricsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  9. 9.Department of PediatricsToho UniversityTokyoJapan
  10. 10.Department of PediatricsDokkyo Medical UniversityMibuJapan
  11. 11.Department of PediatricsGunma Children’s Medical CenterShibukawaJapan
  12. 12.Department of Pediatrics, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  13. 13.Department of PediatricsEhime University Graduate School of MedicineToonJapan

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