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Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis

  • Kazuko KudoEmail author
  • Miho Maeda
  • Nobuhiro Suzuki
  • Hirokazu Kanegane
  • Shouichi Ohga
  • Eiichi Ishii
  • Yoko Shioda
  • Toshihiko Imamura
  • Shinsaku Imashuku
  • Yukiko Tsunematsu
  • Mikiya Endo
  • Akira Shimada
  • Yuuki Koga
  • Yoshiko Hashii
  • Maiko Noguchi
  • Masami Inoue
  • Ken Tabuchi
  • Akira Morimoto
  • The Histiocytosis study group of the Japanese Society of Pediatric Hematology/Oncology
Original Article

Abstract

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9–5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

Keywords

Refractory Langerhans cell histiocytosis (LCH) Hematopoietic stem cell transplantation (HSCT) Reduced-intensity conditioning (RIC) 

Notes

Acknowledgements

We thank all participating doctors and patients who were involved in the Japanese Hematopoietic Cell Transplantation Registry. This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) of the Japan Agency for Medical Research and Development under grant number 18ek0510023h0002.

Author contributions

KK and AM designed the research, analyzed the data, and wrote the manuscript. MM, NS, HK, SO, EI, YS, TI, SI, YT, ME, AS, YK, YH, MN, MI, and KT collected and managed the clinical data and discussed the results.

Compliance with ethical standards

Conflict of interest

We have no conflicts of interest with regard to this manuscript.

References

  1. 1.
    Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell histiocytosis. Blood. 2015;126(1):26–35.CrossRefGoogle Scholar
  2. 2.
    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(5):2556–62.CrossRefGoogle Scholar
  3. 3.
    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(25):5006–14.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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(1):99–109.CrossRefGoogle Scholar
  6. 6.
    Ringden O, Ahstrom L, Lonnqvist B, Båryd I, Svedmyr E, Gahrton G. Allogeneic bone marrow transplantation in a patient with chemotherapy-resistant progressive histiocytosis X. N Engl J Med. 1987;316:733–5.CrossRefGoogle Scholar
  7. 7.
    Kinugawa N, Imashuku S, Hirota Y, Yamada K, Yamamoto A, Akazai A, et al. Hematopoietic stem cell transplantation (HSCT) for Langerhans cell histiocytosis (LCH) in Japan. Bone Marrow Transpl. 1999;24:935–8.CrossRefGoogle Scholar
  8. 8.
    Steiner M, Matthes-Martin S, Attarbaschi A, Minkov M, Grois N, Unger E, et al. Improved outcome of treatment- resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transpl. 2005;36:215–25.CrossRefGoogle Scholar
  9. 9.
    Steiner M, Matthes-Martin S, Attarbaschi A, Lawitschka A, Minkov M, Mittheisz E, et al. Importance of allogeneic T-cells for disease control after stem cell transplantation for high-risk Langerhans cell histiocytosis. Haematologica. 2007;92:e3–4.CrossRefGoogle Scholar
  10. 10.
    Kudo K, Ohga S, Morimoto A, Ishida Y, Suzuki N, Hasegawa D, et al. Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transpl. 2010;45(5):901–6.CrossRefGoogle Scholar
  11. 11.
    Veys PA, Nanduri V, Baker KS, He W, Bandini G, Biondi A, et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol. 2015;169(5):711–8.CrossRefGoogle Scholar
  12. 12.
    Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86(3):269–74.CrossRefGoogle Scholar
  13. 13.
    Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103(1):3–10.CrossRefGoogle Scholar
  14. 14.
    Hatakeyama N, Hori T, Yamamoto M, Inazawa N, Hirako Y, Tsutsumi H, et al. Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced-intensity conditioning cord blood transplantation. Pediatr Transpl. 2010;14(3):E4–10.CrossRefGoogle Scholar
  15. 15.
    Washio K, Muraoka M, Kanamitsu K, Oda M, Shimada A. A case of refractory Langerhans cell histiocytosis complicated with hemophagocytic lymphohistiocytosis rescued by cord blood transplantation with reduced-intensity conditioning. Acta Med Okayama. 2017;71(3):249–54.PubMedGoogle Scholar
  16. 16.
    Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15(12):1628–33.CrossRefGoogle Scholar
  17. 17.
    Morimoto A, Shioda Y, Imamura T, Kudo K, Kitoh T, Kawaguchi H, et al. 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. Int J Hematol. 2018;108(2):192–8.CrossRefGoogle Scholar
  18. 18.
    Donadieu J, Bernard F, van Noesel M, Barkaoui M, Bardet O, Mura R, et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood. 2015;126(12):1415–23.CrossRefGoogle Scholar
  19. 19.
    Heisig A, Sörensen J, Zimmermann SY, Schöning S, Schwabe D, Kvasnicka HM, et al. Vemurafenib in Langerhans cell histiocytosis: report of a pediatric patient and review of the literature. Oncotarget. 2018;9(31):22236–40.CrossRefGoogle Scholar
  20. 20.
    McClain KL, Picarsic J, Chakraborty R, Zinn D, Lin H, Abhyankar H, et al. CNS Langerhans cell histiocytosis: common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer. 2018;124(12):2607–20.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Kazuko Kudo
    • 1
    Email author
  • Miho Maeda
    • 2
  • Nobuhiro Suzuki
    • 3
  • Hirokazu Kanegane
    • 4
  • Shouichi Ohga
    • 5
  • Eiichi Ishii
    • 6
  • Yoko Shioda
    • 7
  • Toshihiko Imamura
    • 8
  • Shinsaku Imashuku
    • 9
  • Yukiko Tsunematsu
    • 10
  • Mikiya Endo
    • 11
  • Akira Shimada
    • 12
  • Yuuki Koga
    • 5
  • Yoshiko Hashii
    • 13
  • Maiko Noguchi
    • 14
  • Masami Inoue
    • 15
  • Ken Tabuchi
    • 16
  • Akira Morimoto
    • 17
  • The Histiocytosis study group of the Japanese Society of Pediatric Hematology/Oncology
  1. 1.Department of PediatricsFujita Health University School of MedicineToyoakeJapan
  2. 2.Department of PediatricsNippon Medical SchoolTokyoJapan
  3. 3.Hokkaido GovernmentSapporoJapan
  4. 4.Department of Child Health and Development, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  5. 5.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  6. 6.Department of PediatricsEhime University Graduate School of MedicineToonJapan
  7. 7.Children’s Cancer Center, National Center for Child Health and DevelopmentTokyoJapan
  8. 8.Department of PediatricsKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
  9. 9.Department of Laboratory MedicineUji-Tokushukai Medical CenterUjiJapan
  10. 10.Department of PediatricsJuntendo University School of MedicineTokyoJapan
  11. 11.Department of PediatricsIwate Medical UniversityMoriokaJapan
  12. 12.Department of Pediatric Hematology/OncologyOkayama University, Graduate School of MedicineOkayamaJapan
  13. 13.Department of PediatricsOsaka University Graduate School of MedicineSuitaJapan
  14. 14.Department of PediatricsNational Kyushu Cancer CenterFukuokaJapan
  15. 15.Department of Hematology/OncologyOsaka Women’s and Children’s HospitalIzumiJapan
  16. 16.Division of Pediatrics, Tokyo Cancer RegistryTokyo Metropolitan Cancer and Infectious Disease Center Komagome HospitalTokyoJapan
  17. 17.Department of PediatricsJichi Medical University of MedicineShimotsukeJapan

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