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


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.


Hemophagocytic lymphohistiocytosis EBV DNA HLH-2004 protocol 



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 ( for the English language review.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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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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