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

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Abstract

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.

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References

  1. Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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(1):58–65.

    Article  PubMed  Google Scholar 

  3. Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58(9):817–25.

    Article  CAS  PubMed  Google Scholar 

  4. 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(7):1257–62.

    Article  CAS  PubMed  Google Scholar 

  5. 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(17):4577–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergsten E, Horne A, Arico 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(25):2728–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.

    Article  PubMed  Google Scholar 

  8. Murata Y, Yasumi T, Shirakawa R, Izawa K, Sakai H, Abe J, et al. Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein. Blood. 2011;118(5):1225–30.

    Article  CAS  PubMed  Google Scholar 

  9. Shibata H, Yasumi T, Shimodera S, Hiejima E, Izawa K, Kawai T, et al. Human CTL-based functional analysis shows the reliability of a munc13-4 protein expression assay for FHL3 diagnosis. Blood. 2018;131(18):2016–25.

    Article  CAS  PubMed  Google Scholar 

  10. Yanagisawa R, Nakazawa Y, Matsuda K, Morimoto A, Ishii E, HLH/LCH committee of Japan Pediatric Leukemia/Lymphoma Study Group. Significance of molecular monitoring in children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2015; 62(S1):S17.

    Google Scholar 

  11. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.

    Article  CAS  PubMed  Google Scholar 

  12. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44(3):259–72.

    Article  PubMed  Google Scholar 

  13. 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(10):2665–73.

    Article  CAS  PubMed  Google Scholar 

  14. 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(3):283–94.

    Article  PubMed  Google Scholar 

  15. 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(2):265–70.

    Article  PubMed  Google Scholar 

  16. Su IJ, Wang CH, Cheng AL, Chen RL. Hemophagocytic syndrome in Epstein-Barr virus-associated T-lymphoproliferative disorders: disease spectrum, pathogenesis, and management. Leuk Lymphoma. 1995;19(5–6):401–6.

    Article  CAS  PubMed  Google Scholar 

  17. Al Asad O, Salam A, Mannem S, Ninan M, Markowitz A, Jana B. Alternative therapy for Epstein–Barr virus related hemophagocytic lymphohistiocytosis. Case Rep Oncol Med. 2015; 2015:508387.

    PubMed  PubMed Central  Google Scholar 

  18. Balamuth NJ, Nichols KE, Paessler M, Teachey DT. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29(8):569–73.

    Article  PubMed  Google Scholar 

  19. Beutel K, Gross-Wieltsch U, Wiesel T, Stadt UZ, Janka G, Wagner HJ. Infection of T lymphocytes in Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediatr Blood Cancer. 2009;53(2):184–90.

    Article  PubMed  Google Scholar 

  20. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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(2):174–7.

    Article  PubMed  Google Scholar 

Download references

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) 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 (http://www.enago.jp) for the English language review.

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Authors and Affiliations

  1. Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan

    Ryu Yanagisawa

  2. Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan

    Ryu Yanagisawa & Yozo Nakazawa

  3. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Ryu Yanagisawa, Akiko M. Saito & Keizo Horibe

  4. Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan

    Kazuyuki Matsuda

  5. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takahiro Yasumi

  6. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Hirokazu Kanegane

  7. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shouichi Ohga

  8. Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan

    Akira Morimoto

  9. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan

    Yoshiko Hashii

  10. Department of Hematology and Oncology, Miyagi Children’s Hospital, Sendai, Japan

    Masue Imaizumi

  11. Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Yasuhiro Okamoto

  12. Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan

    Eiichi Ishii

Authors
  1. Ryu Yanagisawa
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  2. Yozo Nakazawa
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  3. Kazuyuki Matsuda
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  4. Takahiro Yasumi
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  5. Hirokazu Kanegane
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  6. Shouichi Ohga
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  7. Akira Morimoto
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  8. Yoshiko Hashii
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  9. Masue Imaizumi
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  10. Yasuhiro Okamoto
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  11. Akiko M. Saito
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  12. Keizo Horibe
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  13. Eiichi Ishii
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HLH/LCH committee members of the Japan Children’s Cancer Group

Corresponding author

Correspondence to Yozo Nakazawa.

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The authors declare that they have no conflict of interest.

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Yanagisawa, R., Nakazawa, Y., Matsuda, K. et al. Outcomes in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan. Int J Hematol 109, 206–213 (2019). https://doi.org/10.1007/s12185-018-02572-z

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  • DOI: https://doi.org/10.1007/s12185-018-02572-z

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