International Journal of Hematology

, Volume 109, Issue 2, pp 206–213 | Cite as

Outcomes in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan

  • Ryu Yanagisawa
  • Yozo NakazawaEmail author
  • Kazuyuki Matsuda
  • Takahiro Yasumi
  • Hirokazu Kanegane
  • Shouichi Ohga
  • Akira Morimoto
  • Yoshiko Hashii
  • Masue Imaizumi
  • Yasuhiro Okamoto
  • Akiko M. Saito
  • Keizo Horibe
  • Eiichi Ishii
  • HLH/LCH committee members of the Japan Children’s Cancer Group
Original Article


Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein–Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.


HSCT HLH-2004 Epstein–Barr virus FHL EBV-HLH 



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) and by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED_16ek0109055h0003). The authors would like to thank Yūka Miyajima for assistance with drafting and translation 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 2018

Authors and Affiliations

  • Ryu Yanagisawa
    • 1
    • 2
    • 3
  • Yozo Nakazawa
    • 2
    Email author
  • Kazuyuki Matsuda
    • 4
  • Takahiro Yasumi
    • 5
  • Hirokazu Kanegane
    • 6
  • Shouichi Ohga
    • 7
  • Akira Morimoto
    • 8
  • Yoshiko Hashii
    • 9
  • Masue Imaizumi
    • 10
  • Yasuhiro Okamoto
    • 11
  • Akiko M. Saito
    • 3
  • Keizo Horibe
    • 3
  • Eiichi Ishii
    • 12
  • HLH/LCH committee members of the Japan Children’s Cancer Group
  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 Laboratory MedicineShinshu University HospitalMatsumotoJapan
  5. 5.Department of PediatricsKyoto University Graduate School of MedicineKyotoJapan
  6. 6.Department of Child Health and Development, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  7. 7.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  8. 8.Department of PediatricsJichi Medical University School of MedicineTochigiJapan
  9. 9.Department of PediatricsOsaka University Graduate School of MedicineSuitaJapan
  10. 10.Department of Hematology and OncologyMiyagi Children’s HospitalSendaiJapan
  11. 11.Department of PediatricsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  12. 12.Department of PediatricsEhime University Graduate School of MedicineToonJapan

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