Intensification of induction therapy and prolongation of maintenance therapy did not improve the outcome of pediatric Langerhans cell histiocytosis with single-system multifocal bone lesions: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study

  • Akira Morimoto
  • Yoko Shioda
  • Toshihiko Imamura
  • Kazuko Kudo
  • Toshiyuki Kitoh
  • Hiroshi Kawaguchi
  • Hiroaki Goto
  • Yoshiyuki Kosaka
  • Yukiko Tsunematsu
  • Shinsaku Imashuku
  • On behalf of the Japan LCH Study Group
Original Article
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Abstract

Langerhans cell histiocytosis (LCH) with single-system (SS) multifocal bone (MFB) lesions is rarely fatal, but patients may experience relapses and develop LCH-associated sequelae. To evaluate effect on outcomes of pediatric multifocal LCH, we tested a treatment protocol modified from the Japan Langerhans Cell Histiocytosis Study Group (JLSG)-96 study. We assessed the outcomes of all consecutive newly diagnosed pediatric patients with LCH with SS-MFB lesions who were treated with JLSG-02 protocol in 2002–2009. JLSG-02 was modified from JLSG-96 as follows: increased prednisolone dosage at the induction phase and extension of maintenance therapy duration from 24 to 48 weeks. In total, 82 patients with a median follow-up duration of 8.0 years were eligible for analysis. At 6 weeks, 92.7% responded to induction; however, 27.6% of responders experienced relapses. In total, 4.8% developed central nervous system-related sequelae, including central diabetes insipidus and neurodegeneration, which were associated with relapse. None of the patients died. The 5-year event-free survival rates were not different between JLSG-02 and -96 cohort (66.7 vs. 65.1%; p = 0.697). Modification of previous treatment protocol did not contribute to improvement of outcomes in LCH with SS-MFB lesions.

Keywords

Langerhans cell Histiocytosis Multifocal bone disease Chemotherapy Central diabetes insipidus Neurodegeneration 

Notes

Acknowledgements

The authors thank all physicians who participated in the JLSG-02 study. We also thank Ms. Yasuko Hashimoto for secretarial assistance. This work was supported by the Ministry of Health, Labor, and Welfare, Japan (Grant number: Research on Measures for Intractable Disease H24-General-076 and H-26-General-068) and the Japan Agency for Medical Research and Development (Grant number: 15ek0109055h0202 and 16ek0109055h0203).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

References

  1. 1.
    Morimoto A, Oh Y, Shioda Y, Kudo K, Imamura T. Recent advances in Langerhans cell histiocytosis. Pediatr Int. 2014;56:451–61.CrossRefPubMedGoogle Scholar
  2. 2.
    Berres ML, Merad M, Allen CE. Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to histiocytosis X? Br J Haematol. 2015;169:3–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Guyot-Goubin A, Donadieu J, Barkaoui M, Bellec S, Thomas C, Clavel J. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000–2004. Pediatr Blood Cancer. 2008;51:71–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Kim BE, Koh KN, Suh JK, Im HJ, Song JS, Lee JW, et al. Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party. J Pediatr Hematol Oncol. 2014;36:125–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Jubran RF, Marachelian A, Dorey F, Malogolowkin M. Predictors of outcome in children with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2005;45:37–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Pollono D, Rey G, Latella A, Rosso D, Chantada G, Braier J. Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007;48:696–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Haupt R, Nanduri V, Calevo MG, Bernstrand C, Braier JL, Broadbent V, et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer. 2004;42:438–44.CrossRefPubMedGoogle Scholar
  8. 8.
    Minkov M, Grois N, Heitger A, Pötschger U, Westermeier T, Gadner H. Treatment of multisystem Langerhans cell histiocytosis. Results of the DAL-HX 83 and DAL-HX 90 studies. DAL-HX Study Group. Klin Padiatr. 2000;212:139–44.CrossRefPubMedGoogle Scholar
  9. 9.
    Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138:728–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Gadner H, Grois N, Pötschger U, Minkov M, Aricò M, Braier J, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008;111:2556–62.CrossRefPubMedGoogle Scholar
  11. 11.
    Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121:5006–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Morimoto A, Ikushima S, Kinugawa N, Ishii E, Kohdera U, Sako M, et al. Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer. 2006;107:613–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Morimoto A, Shioda Y, Imamura T, Kudo K, Kawaguchi H, Sakashita K, et al. Intensified and prolonged therapy comprising cytarabine, vincristine and prednisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study. Int J Hematol. 2016;104:99–109.CrossRefPubMedGoogle Scholar
  14. 14.
    Titgemeyer C, Grois N, Minkov M, Flucher-Wolfram B, Gatterer-Menz I, Gadner H. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001;37:108–14.CrossRefPubMedGoogle Scholar
  15. 15.
    Haupt R, Minkov M, Astigarraga I, Schäfer E, Nanduri V, Jubran R, et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013;60:175–84.CrossRefPubMedGoogle Scholar
  16. 16.
    Imashuku S, Shioda Y, Kobayashi R, Hosoi G, Fujino H, Seto S, et al. Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group. Haematologica. 2008;93:615–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Grois N, Fahrner B, Arceci RJ, Henter JI, McClain K, Lassmann H, et al. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr. 2010;156:873–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Grois N, Pötschger U, Prosch H, Minkov M, Arico M, Braier J, et al. Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer. 2006;46:228–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Morimoto A, Kobayashi R, Maeda M, Asami K, Bessho F, Imashuku S. Impact of reactivation on the sequelae of multi-system Langerhans cell histiocytosis patients. Pediatr Blood Cancer. 2008;50:931–2.CrossRefPubMedGoogle Scholar
  20. 20.
    Minkov M, Steiner M, Pötschger U, Aricò M, Braier J, Donadieu J, et al. Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr. 2008;153:700–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Morimoto A, Shioda Y, Imamura T, Kanegane H, Sato T, Kudo K, et al. Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer. 2001;56:110–5.CrossRefGoogle Scholar
  22. 22.
    Imashuku S, Shioda Y, Morimoto A. CNS-directed prophylactic approach to Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2017;39:321–2.CrossRefPubMedGoogle Scholar
  23. 23.
    Diamond EL, Subbiah V, Lockhart AC, Blay JY, Puzanov I, Chau I, et al. Vemurafenib for BRAF V600-mutant Erdheim–Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET study. JAMA Oncol. 2018;4:384–8.  https://doi.org/10.1001/jamaoncol.2017.5029.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Akira Morimoto
    • 1
  • Yoko Shioda
    • 2
  • Toshihiko Imamura
    • 3
  • Kazuko Kudo
    • 4
  • Toshiyuki Kitoh
    • 5
  • Hiroshi Kawaguchi
    • 6
  • Hiroaki Goto
    • 7
  • Yoshiyuki Kosaka
    • 8
  • Yukiko Tsunematsu
    • 9
  • Shinsaku Imashuku
    • 10
  • On behalf of the Japan LCH Study Group
  1. 1.Department of PediatricsJichi Medical UniversityShimotsukeJapan
  2. 2.Pediatric Cancer CenterNational Center for Child Health and DevelopmentTokyoJapan
  3. 3.Department of PediatricsKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
  4. 4.Department of PediatricsFujita Health University School of MedicineToyoakeJapan
  5. 5.Laboratory of PediatricsAichi Gakuin University School of PharmacyNagoyaJapan
  6. 6.Department of PediatricsHiroshima University Graduate School of Biomedical and Health SciencesHiroshimaJapan
  7. 7.Division of Hematology/OncologyKanagawa Children’s Medical CenterYokohamaJapan
  8. 8.Department of Hematology and Oncology, Children’s Cancer CenterHyogo Prefectural Kobe Children’s HospitalKobeJapan
  9. 9.Department of Pediatrics and Adolescent MedicineJuntendo University School of MedicineTokyoJapan
  10. 10.Department of Laboratory MedicineUji-Tokushukai Medical CenterUjiJapan

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