Treatment of Relapsed and Refractory Langerhans Cell Histiocytosis in Children

  • Oussama Abla
  • Carlos Rodriguez-Galindo
  • Paul Veys
Chapter

Abstract

Approximately 50% of patients with multisystem (MS) Langerhans cell histiocytosis (LCH) are refractory to initial treatment or develop reactivation of their disease within 5 years, and the treatment of these patients has been a challenge and their outcome is very poor. Treatment failures in patients with low-risk LCH are not associated with mortality but with morbidity, and their optimal treatment is not well defined. Nucleoside analogues such as cladribine and clofarabine have an excellent activity in treating resistant MS-LCH, and patients with very high-risk LCH despite multiple salvage therapies can be possibly cured with haematopoietic stem cell transplant. BRAF-V600E inhibitors, such as vemurafenib and dabrafenib, have proven to be effective in relapsed/refractory MS-LCH. However, larger studies are needed to define the best dose and duration of these drugs and to better identify the toxicity profile in children with LCH. The effect of these drugs on future reactivations and late sequelae needs to be well defined, as well. Future trials will most likely examine the combination of BRAF or BRAF/MEK inhibitors with chemotherapy in relapsed/refractory MS patients.

Keywords

Relapsed LCH Treatment Nucleoside analogues HSCT Targeted therapies 

References

  1. 1.
    Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–23.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, et al. Histiocyte Society. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121(25):5006–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Minkov M, Steiner M, , Pötschger U, Aricò M, Braier J, Donadieu J, et al International LCH study group. Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 2008; 153(5):700-705., e1-e2.PubMedCrossRefGoogle Scholar
  4. 4.
    Gadner H, Grois N, Pötschger U, Minkov M, Aricò M, Braier J, et al. Histiocyte Society. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008;111(5):2556–62.PubMedCrossRefGoogle Scholar
  5. 5.
    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(5):728–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Minkov M, Grois N, Heitger A, Pötschger U, Westermeier T, Gadner H, DAL-HX Study Group. Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med Pediatr Oncol. 2002;39:581–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Lindahl LM, Fenger-Grøn M, Iversen L. Topical nitrogen mustard therapy in patients with Langerhans cell histiocytosis. Br J Dermatol. 2012;166:642–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Hoeger P, Nanduri V, Harper J, Atherton D, Pritchard J. Long term follow up of topical mustine treatment for cutaneous Langerhans cell histiocytosis. Arch Dis Child. 2000;82:483–7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Morren M, Vanden Broecke K, Vangeebergen L, Sillevis-Smitt JH, Van Den Berghe P, Hauben E, et al. Diverse Cutaneous presentations of Langerhans cell Histiocytosis in children: a retrospective cohort study. Pediatr Blood Cancer. 2016;63:486–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Dodd E, Hook K. Topical Imiquimod for the treatment of childhood cutaneous Langerhans cell Histiocytosis. Pediatr Dermatol. 2016;33:e184–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Okane D, Jenkinson H, Carson J. Langerhans cell histiocytosis associated with breast carcinoma successfully treated with topical imiquimod. Clin Exp Dermatol. 2009;34:e829–32.CrossRefGoogle Scholar
  12. 12.
    Kwon OS, Cho KH, Song KY. Primary Cutaneous Langerhans cell Histiocytosis treated with Photochemotherapy. J Dermatol. 1997;24:54–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Do JE, Lee JY, Kim YC. Successful treatment of cutaneous Langerhans cell histiocytosis with targeted narrowband ultraviolet B phototherapy in an infant. Clin Exp Dermatol. 2009;34:e280–1.PubMedCrossRefGoogle Scholar
  14. 14.
    Ness MJ, Lowe GC, Davis DMR, Hand JL. Narrowband ultraviolet B light in Langerhans cell histiocytosis: a case report. Pediatr Dermatol. 2014;31:e10–2.PubMedCrossRefGoogle Scholar
  15. 15.
    Failla V, Wauters O, Caucanas M, Nikkels-Tassoudji N, Nikkels AF. Photodynamic therapy for multi-resistant cutaneous Langerhans cell histiocytosis. Rare Tumors. 2010;2:e34.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Steen AE, Steen KH, Bauer R, Bieber T. Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol. 2001;145:137–40.PubMedCrossRefGoogle Scholar
  17. 17.
    Womer RB, Anunciato KR, Chehrenama M. Oral methotrexate and alternate-day prednisone for low-risk Langerhans cell histiocytosis. Med Pediatr Oncol. 1995;25:70–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Carstensen H. Methotrexate and 6-mercaptopurine in the treatment of Langerhans cell histiocytosis (LCH). J Invest Dermatol. 2001;117:1020.Google Scholar
  19. 19.
    Bank MI, Rengtved P, Carstensen H, Peterson BL. P53 expression in biopsies from children with Langerhans cell Histiocytosis. J Pediatr Hematol Oncol. 2002;24:733–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Sander C, Kaatz M, Elsner P. Successful treatment of Cutaneous Langerhans cell Histiocytosis with thalidomide. Dermatology. 2004;208:149–52.PubMedCrossRefGoogle Scholar
  21. 21.
    Munn SE, Olliver L, Boradbent V, Pritchard J. Use of Indomethacin in Langerhans cell histiocytosis. Med Pediatr Oncol. 1999;32:247–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Braier J, Rosso D, Pollono D, Rey G, Lagomarsino E, Latella A, et al. Symptomatic bone Langerhans cell Histiocytosis treated at diagnosis or after reactivation with Indomethacin alone. J Pediatr Hematol Oncol. 2014;11:e280. (Epub ahead of print)CrossRefGoogle Scholar
  23. 23.
    Shaw NJ, Bishop NJ. Bisphosphonate treatment of bone disease. Arch Dis Child. 2005;90:494–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Farran RP, Zaretski E, Egeler RM. Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol. 2001;23:54–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Elomaa I, Blomqvist C, Porkka L, Holmström T. Experiences of clodronate treatment of multifocal eosinophilic granuloma of bone. J Intern Med. 1989;225:59–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Arzoo K, Sadeghi S, Pullarkat V. Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. N Engl J Med. 2001;345:225.PubMedCrossRefGoogle Scholar
  27. 27.
    Kamizono J, Okada Y, Shirahata A, Tanaka Y. Bisphosphonate induces remission of refractory osteolysis in langerhans cell histiocytosis. J Bone Miner Res. 2002;17:1926–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Montella L, Merola C, Merola G, Petillo L, Palmieri G. Zoledronic acid in treatment of bone lesions by Langerhans cell histiocytosis. J Bone Miner Metab. 2009;27:110–3.PubMedCrossRefGoogle Scholar
  29. 29.
    da Costa CE, Annels NE, Faaij CM, Forsyth RG, Hogendoorn PC, Egeler RM. Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis. J Exp Med. 2005;201:687–93.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    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. 2011;56:110–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Chellapandian D, Makras P, Kaltsas G, van den Bos C, Naccache L, Rampal R, et al. Bisphosphonates in Langerhans cell histiocytosis: An international retrospective case series. Mediterr J Hematol Infect Dis. 2016;8(10):e2016033. (E-pub ahead of print)PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    King AE, Umland EM. Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy. 2008;28:667–77.PubMedCrossRefGoogle Scholar
  33. 33.
    Lockridge L, Papac RJ, Perazella MA. Pamidronate-associated nephrotoxicity in a patient with Langerhans histiocytosis. Am J Kidney Dis. 2002;40:E2.PubMedCrossRefGoogle Scholar
  34. 34.
    Fraunfelder PW, Fraunfelder FT. Bisphosphonates and ocular inflammation. New Engl J Med. 2003;348:1187–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Carroll C, Collier A, Malempati S, Whitlock J. Intermediate-dose methotrexate for recurrent Langerhans cell histiocytosis: a retrospective analysis. In: Proceedings of the 24th Annual Meeting of the Histiocyte Society, Ocotober 1–3, Berlin; 2008.Google Scholar
  36. 36.
    Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211(4):669–83.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Egeler R, Dekraker J, Voute P. Cytosine-arabinoside, Vincristine, and prednisone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction – experience at a single institution. Med Pediatr Oncol. 1993;21:265–70.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Cantu MA, Lupo PJ, Bilgi M, Hicks MJ, Allen CE, McClain KL. Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PLoS One. 2012;7:e43257.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Simko SJ, McClain KL, Allen CE. Up-front therapy for LCH: is it time to test an alternative to vinblastine/prednisone? Br J Haematol. 2015;169:299–301.PubMedCrossRefGoogle Scholar
  41. 41.
    Santana VM, Mirro J, Kearns C, Schell M, Crom W, Blakely RL. 2-chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol. 1992;10:364–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Robertson LE, Chubb S, Meyn RE, Story M, Ford R, Hittelman WN, et al. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-a’-D-arabinosyl-2-fluoroadenine. Blood. 1993;81:143–50.PubMedGoogle Scholar
  43. 43.
    Carrera CJ, Terai C, Lotz M, Curd JG, Piro LD, Beutler E, et al. Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitor and in vivo. J Clin Invest. 1990;86:1480–8.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Saven A, Burian C. Cladribine activity in adult Langerhans cell histiocytosis. Blood. 1999;93:4125–30.PubMedGoogle Scholar
  45. 45.
    Rodriguez-Galindo C, Kelly P, Jeng M, Presbury GG, Rieman M, Wang W. Treatment of children with Langerhans cell Histiocytosis with 2-chlorodeoxyadenosine. Am J Hematol. 2002;69:179–84.PubMedCrossRefGoogle Scholar
  46. 46.
    Mottl H, Stary J, Chanova M, Nekolna M, Drahokoupilova E, Smelhaus V. Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma. 2006;47:1881–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Weitzman S, Wayne AS, Arceci R, Lipton JM, Whitlock JA, De Rossi G. Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the Histiocyte Society and review of the literature. Med Pediatr Oncol. 1999;33:4761–481.CrossRefGoogle Scholar
  48. 48.
    Stine KC, Saylors RL, Saccente S, McClain KL, Becton DL. Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004;43:81–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol. 2003;25:575–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Weitzman S, Braier J, Donadieu J, Egeler RM, Grois N, Ladisch S, et al. 2-Chlorodeoxyadenosine (2-CDA) as salvage therapy for Langerhans cell histiocytosis (LCH). Results of the LCH-98 protocol of the Histiocyte Society. Pediatr Blood Cancer. 2009;53:1271–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Joshi S, Parisi M, Smogorzevska E, et al. Long term immunodeficiency in a patient with Langerhans cell histiocytosis treated with 2-Chlorodeoxyadenosine. Med Pediatr Oncol. 1999;33:523.Google Scholar
  52. 52.
    Tetrault SA, Saven A. Delayed onset of autoimmune hemolytic anemia complicating cladribine therapy for Waldenstrom cryoglobulinemia. Leuk Lymphoma. 2000;37:125–30.CrossRefGoogle Scholar
  53. 53.
    Grey MR, Flanagan NG, Kelsey PR. Severe skin rash in two consecutive patients treated with 2-chlorodeoxyadenosine for hairy cell leukemia. Clin Lab Haematol. 2000;22:111–3.PubMedCrossRefGoogle Scholar
  54. 54.
    Choi SW, Bangaru BS, Wu CD, Finlay JL. Gastrointestinal involvement in disseminated Langerhans cell histiocytosis (LCH) with durble complete response to 2-chlorodeoxyadenosine and high-dose cytarabine. J Pediatr Hematol Oncol. 2003;25:503–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W. Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamics and molecular interactions. Blood. 1996;87:256–64.PubMedGoogle Scholar
  56. 56.
    Bernard F, Thomas C, Bertrand Y, Munzer M, Landman Parker J, Ouache M, et al. Multi-centre pilot study of 2- chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer. 2005;41:2682–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Apollonsky N, Lipton JM. Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol. 2009;31:53–6.PubMedCrossRefGoogle Scholar
  58. 58.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rosso D, Amaral D, Latella A, Chantada G, Braier JL. Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Hematol. 2015; doi: 10.1111/bjh.13475.
  60. 60.
    Jeha S, Razzouk B, Rytting M, Rheingold S, Albano E, Kadota R, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Oncol. 2009;27:4392–7.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bonate PL, Arthaud L, Cantrell WR, Stephenson K, Secrist JA, Weitman S. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov. 2006;5:855–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Simko SJ, Tran HD, Jones J, Bilgi M, Beaupin LK, Coulter D, et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer. 2014;61:479–87.PubMedCrossRefGoogle Scholar
  63. 63.
    Abraham A, Alsultan A, Jeng M, Rodriguez-Galindo C, Campbell PK. Clofarabine salvage therapy for refractory high-risk Langerhans cell histiocytosis. Pediatr Blood Cancer. 2013;60:E19–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Rodriguez-Galindo C, Jeng M, Khuu P, McCarville MB, Jeha S. Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer. 2008;51:703–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Maria Postini A, del Prever AB, Pagano M, Rivetti E, Berger M, Asaftei SD, et al. Langerhans cell histiocytosis: 40 years’ experience. J Pediatr Hemato Oncol. 2012;34:353–8.CrossRefGoogle Scholar
  66. 66.
    Ringden O, Ahstrom L, Lonnqvist B, Baryd I, Svedmyr E, Gahrton G. Allogeneic bone marrow transplantation in a patient with chemotherapy-resistant progressive histiocytosis X. New Engl J Med. 1987;316:733–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Ringden O, Lonnqvist B, Holst M. 12-year follow-up of allogeneic bone-marrow transplant for Langerhans cell histiocytosis. The Lancet. 1997;349:476.CrossRefGoogle Scholar
  68. 68.
    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 Transplant. 2005;36:215–25.PubMedCrossRefGoogle Scholar
  69. 69.
    Chiesa R, Veys P. Reduced intensity conditioning in paediatric haematopoietic cell transplantation. In: Thomas AE, Halsey C, editors. Controversies in Paediatric and Adolescent Haematology. Basel/Switzerland: Karger; 2014. p. 116–34.Google Scholar
  70. 70.
    Cooper N, Rao K, Goulden N, Webb D, Amrolia P, Veys P. The use of reduced intensity stem cell transplantation in haemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis. Bone Marrow Transplant. 2008;42(Suppl. 2):S47–50.PubMedCrossRefGoogle Scholar
  71. 71.
    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. Pediatric Transplant. 2010;14:E4–E10.CrossRefGoogle Scholar
  72. 72.
    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 Transplant. 2010;45:901–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al. Acute Leukaemia working Party of the European Group for blood and marrow transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119:1599–606.PubMedCrossRefGoogle Scholar
  74. 74.
    Veys PA, Nanduri V, Baker KS, Bandini G, Biondi A, Dalissier A, et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol. 2015;169:711–8.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116:5824–31.PubMedCrossRefGoogle Scholar
  76. 76.
    Terrell CE, Jordan MB. Mixed hematopoietic or T-cell chimerism above a minimal threshold restores perforin-dependent immune regulation in perforin-deficient mice. Blood. 2013;122:2618–21.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ardeshna K, Hollifield J, Chessells JM, Veys P, Webb DKH. Outcome for children after failed transplant for primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2001;115:949–52.PubMedCrossRefGoogle Scholar
  78. 78.
    Lang P, Teltschik HM, Feuchtinger T, Müller I, Pfeiffer M, Schumm M, et al. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol. 2014;165:688–98.PubMedCrossRefGoogle Scholar
  79. 79.
    Bernardo ME, Piras E, Vacca A, Giorgiani G, Zecca M, Bertaina A, et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. 2012;120:473–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Aricò M. Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy. Br J Haematol. 2016;23. [Epub ahead of print]. ReviewGoogle Scholar
  81. 81.
    Zinn DJ, Grimes AB, Lin H, Eckstein O, Allen CE, McClain KL. Hydroxyurea: a new old therapy for Langerhans cell histiocytosis. Blood. 2016; doi:10.1182–06721993.Google Scholar
  82. 82.
    Charles P, Elliot MJ, Davis D, Potter A, Kalden JR, Antoni C, et al. Regulation of cytokines, cytokine inhibitors and acute phase proteins following anti-TNFα therapy in rheumatoid arthritis. J Immunol. 1999;163:1521–8.PubMedGoogle Scholar
  83. 83.
    Rizzo F, Cives M, Simone V, Silvestris F. New insights into the molecular pathogenesis of Langerhans cell Histiocytosis. Oncologist. 2014;19:151–63.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Claudon A, Dietamann JL, Hamman DCA, Hassler P. Interest in thalidomide in cutaneo-mucous and hypothalamo-hypophyseal involvement of Langerhans cell histiocytosis. Rev Med Intern. 2002;23:651–6.CrossRefGoogle Scholar
  85. 85.
    Montero AJ, Diaz-Montero CM, Malpica A, Ramirez PT, Kavanagh JJ. Langerhans cell histiocytosis of the female genital tract: a literature review. Int J Gynecol Cancer. 2003;13:381–8.PubMedCrossRefGoogle Scholar
  86. 86.
    McClain K, Kozinetz C. A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007;48:44–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Broekart SMC, Metzler G, Burgdorf W, Rocken M, Schaller M. Multisystem Langerhans cell histiocytosis: successful treatment with thalidomide. Am J Clin Dermatol. 2007;8:311–4.CrossRefGoogle Scholar
  88. 88.
    Szturz P, Adam Z, Rehák Z, Koukalová R, Slaisová R, Stehlíková O, et al. Lenalidomide proved effective in multisystem Langerhans cell histiocytosis. Acta Oncol. 2012;51:412–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Ibrahim I, Naina H. Treatment of recurrent Langerhans cell histiocytosis of the vulva with Lenalidomide. J Clin Oncol. 2013;31:e16555.Google Scholar
  90. 90.
    Adam Z, Pour L, Krejčí M, Zahradová L, Szturz P, Koukalová R, et al. The effect of lenalidomide on rare blood disorders: Langerhans cell histiocytosis, multicentric Castleman disease, POEMS syndrome. Erdheim-Chester disease and angiomatosis. Vnitr Lek. 2012;58:856.PubMedGoogle Scholar
  91. 91.
    Adam Z, Rehák Z, Koukalová R, Szturz P, Krejčí M, Pour L, et al. Lenalidomide induced therapeutic response in a patient with aggressive multi-system Langerhans cell histiocytosis resistant to 2-chlorodeoxyadenosine and early relapsing after high-dose BEAM chemotherapy with autologous peripheral blood stem cell transplantation. Vnitr Lek. 2012;58:62.PubMedGoogle Scholar
  92. 92.
    Uppuluri R, Ramachandrakurup S, Subburaj D, Bakane A, Raj R. Excellent remission rates with limited toxicity in relapsed/refractory Langerhans cell histiocytosis with pulse dexamethasone and lenalidomide in children. Pediatr Blood Cancer. 2017;64:110–2.PubMedCrossRefGoogle Scholar
  93. 93.
    Henter J, Karlen J, Calming U, Bernstrand C, Andersson U, Fadeel B. Successful treatment of Langerhans cell histiocytosis with Etanercept. New Engl J Med. 2001;345:1577–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Chohan G, Barnett Y, Gibson J, Reddel S, Barnett M. Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg And Psych. 2012;83:574–8.CrossRefGoogle Scholar
  95. 95.
    Rodriguez H, Garcia I, Alba A, Igea F. Infliximab-induced reactivated Langerhans cell histiocytosis in a patient with ulcerative colitis. Inflamm Bowel Dis. 2009;15:1286–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Mahe E, Descamps V, Grossin M, Fraitag S, Crickx B. CD30+ T-cell lymphoma in a patient with psoriasis treated with cyclosporine and infliximab. Br J Dermatol. 2003;149:170–3.PubMedCrossRefGoogle Scholar
  97. 97.
    Appel S, Boehmler A, Grunebach F, Müller MR, Rupf A, Weck MM, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34 (+) peripheral blood progenitor cells. Blood. 2004;103:538–44.PubMedCrossRefGoogle Scholar
  98. 98.
    Caponetti G, Miranda R, Althof P, Dobesh RC, Sanger WG, Medeiros LJ, et al. Immunohistochemical and molecular cytogenetic evaluation of potential targets for tyrosine kinase inhibitors in Langerhans cell histiocytosis. Hum Pathol. 2012;43:2223–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Janku F, Amin H, Yang D, Garrido-Laguna I, Trent J, Kurzrock R. Response of Histiocytoses to Imatinib Mesylate: fire to ashes. J Clin Oncol. 2010;28:E633–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Montella L, Insabato L, Palmieri G. Imatinib mesylate for cerebral Langerhans cell histiocytosis. N Engl J Med. 2004;351:1034–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Wagner C, Mohme H, Kromer-Olbrisch T, Stadler R, Goerdt S, Kurzen H. Langerhans cell histiocytosis: treatment failure with Imatinib. Arch Dermatol. 2009;145:949–50.PubMedCrossRefGoogle Scholar
  102. 102.
    Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, et al. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014;9:e100880.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Morgensztern D, McLeod HL. PI3K/AKT/mTOR pathway as a target for cancer therapy. Anti-Cancer Drugs. 2005;16:797–803.PubMedCrossRefGoogle Scholar
  104. 104.
    Brown RE. Brief communication: morphoproteomic analysis of osteolytic Langerhans cell histiocytosis with therapeutic implications. Ann Clin Lab Sci. 2005;35:131–6.PubMedGoogle Scholar
  105. 105.
    van de Laar L, Buitenhuis M, Wensveen FM, Janssen HL, Coffer PJ, Woltman AM. Human CD34-derived myeloid dendritic cell development requires intact phosphatidylinositol 3-kinase protein kinase B mammalian target of rapamycin signaling. J Immunol. 2010;184:6600–11.PubMedCrossRefGoogle Scholar
  106. 106.
    Arceci RJ, Allen CE, Dunkel IJ, Jacobsen E, Whitlock J, Vassallo R, et al. A phase IIa study of afuresertib, an oral pan-AKT inhibitor, in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2016; doi: 10.1002/pbc.26325. (epub ahead of print)
  107. 107.
    Heritier S, Emile JF, Barkaoui MA, Thomas C, Fraitag S, Boudjemaa S, et al. BRAF mutation correlates with high-risk Langerhans cell Histiocytosis and increased resistance to first-line therapy. J Clin Oncol. 2016;34:3023–30.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Tolédano D, et al. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAFV600E-mutated Erdheim-Chester disease. J Clin Oncol. 2015;33:411–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Euskirchen P, Haroche J, Emile JF, Buchert R, Vandersee S, Meisel A. Complete remission of critical neurohistiocytosis by vemurafenib. Neurol Neuroimmunol & Neuroinflamm. 2015;2:e78.CrossRefGoogle Scholar
  110. 110.
    Charles J, Beani JC, Fiandrino G, Busser B. Major response to vemurafenib in a patient with severe cutaneous Langerhans cell histiocytosis. J Am Acad Dermatol. 2014;71:e97–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Bubolz AM, Weissinger SE, Stenzinger A, Arndt A, Steinestel K, Brüderlein S, et al. Potential clinical implications of BRAF mutations in histiocytic proliferations. Oncotarget. 2014;5:4060–70.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Hyman D, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple non-melanoma cancers with BRAF V600E mutations. New Engl J Med. 2015;373:726–36.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Heritier S, Jehanne M, Leverger G, Emile JF, Alvarez JC, Haroche J, et al. Vemurafenib use in an infant for high-risk Langerhans cell histiocytosis. JAMA Oncol. 2015;1:836–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Donadieu J, Armari-Alla C, Templier I, et al. First use of vemurafenib in children LCH with neurodegenerative LCH. In: 30th Annual Histiocyte Society Meeting. Toronto, October 28–30, 2014. Abstract 3, p. 35.Google Scholar
  115. 115.
    Donadieu J, Visser J, Sieni E, et al. Vemurafenib in children with refractory LCH: 21 Patients treated in France, UK, Italy And Lebanon. In: 32 Annual Histiocyte Society Meeting. Dublin, October 17–19, 2016. Abstract 3, p. 38.Google Scholar
  116. 116.
    Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harbouring the BRAF V600E mutation. Blood. 2013;121:1495–500.PubMedCrossRefGoogle Scholar
  117. 117.
    Gandolfi L, Adamo S, Pileri A, Broccoli A, Argnani L, Zinzani PL. Multisystemic and Multiresistant Langerhans cell Histiocytosis: a case treated with BRAF inhibitor. J Natl Compr Cancer Net. 2015;13:715–8.CrossRefGoogle Scholar
  118. 118.
    da Rocha DS, Salmonson T, van Zwieten-Boot B, Jonsson B, Marchetti S, Schellens JH, et al. The European medicines agency review of vemurafenib (Zelboraf) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for human use. Eur J Cancer. 2013;49:1654–61.CrossRefGoogle Scholar
  119. 119.
    Lipowicz S, Chagnon S, Saiag P. Rapidly growing pancreatic ductal adenocarcinoma in a patient with metastatic melanoma and harbouring CDKN2A germline mutation: a new vemurafenib-induced malignancy? Melanoma Res. 2013;23:241.PubMedCrossRefGoogle Scholar
  120. 120.
    Yeh EA, Leary S, Longoni G, et al. Clinical and Radiographic Improvement of Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) Following Dabrafenib. The 68th Annual American Academy of Neurology Annual Meeting, April 15–21, Vancouver. 2016.Google Scholar
  121. 121.
    Zhang W. BRAF inhibitors: the current and the future. Curr Opinion Pharmacol. 2015;23:68–73.CrossRefGoogle Scholar
  122. 122.
    Diamond E, Durham B, Haroche J, Yao Z, Ma J, Parikh SA, et al. Diverse and targetable Kinase alterations drive Histiocytic Neoplasms. Cancer Discov. 2016;6:154–65.PubMedCrossRefGoogle Scholar
  123. 123.
    Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29:3085–96.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.PubMedCrossRefGoogle Scholar
  125. 125.
    Jhaveri KD, Sakhiya V, Fishbane S. Nephrotoxicity of the BRAF inhibitors Vemurafenib and Dabrafenib. JAMA Oncol. 2015;1(8):1133–4. doi: 10.1001/jamaoncol.2015.1713.PubMedCrossRefGoogle Scholar
  126. 126.
    Bronte E, Bronte G, Novo G, Bronte F, Bavetta MG, Lo RG. What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment. Oncotarget. 2015;6:35589–601. doi: 10.18632/oncotarget.5853.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Niro A, Strippoli S, Alessio G, Sborgia L, Recchimurzo N, Guida M. Ocular toxicity in metastatic melanoma patients treated with mitogen-activated protein kinase kinase inhibitors: a case series. Am J Ophthalmol. 2015;160:959–67. doi: 10.1016/j.ajo.2015.07.035. e1. Epub 2015 Jul 29PubMedCrossRefGoogle Scholar
  128. 128.
    Jordan M, McClain K, Yan X, Hicks J, Jaffe R. Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2005;44:251–4.PubMedCrossRefGoogle Scholar
  129. 129.
    Seo J, Cho T, Kim S, Nassour I, Kim HJ, Lim YJ, et al. Prognostic significance of gelsolin and MMP12 in Langerhans cell histiocytosis. Korean J Hematol. 2012;47:267–72.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Kis-Toth K, Bacskai I, Gogolak P, Mazlo A, Szatmari I, Rajnavolgyi E. Monocyte-derived dendritic cell subpopulations use different types of matrix metalloproteinase inhibited by GM6001. Immunobiology. 2013;218:1361–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Bechan GI, Lee DW, Zajonc DM, Heckel D, Xian R, Throsby M, et al. Phage display generation of a novel human anti-CD1A monoclonal antibody with potent cytolytic activity. Br J Haematol. 2012;159:299–310.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Oussama Abla
    • 1
  • Carlos Rodriguez-Galindo
    • 2
  • Paul Veys
    • 3
  1. 1.Department of Pediatrics, Division of Hematology/OncologyHospital for Sick Children, University of TorontoTorontoCanada
  2. 2.Departments of Global Pediatric Medicine and Oncology, St. Jude Children’s Research HospitalMemphisUSA
  3. 3.Blood and Bone Marrow Transplantation Unit, Great Ormond Street Hospital for ChildrenLondonUK

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