HLH/LCH committee members of the Japan Children’s Cancer Group
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
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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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Conflict of interest
The authors declare that they have no conflict of interest.
Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58(9):817–25.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefGoogle Scholar
Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44(3):259–72.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar