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Langerhans Cell Histiocytosis Treatment (PDQ®)

  • Last Modified: 02/03/2014

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Treatment of Recurrent, Refractory, or Progressive Childhood LCH

Recurrent Low-Risk Organ Involvement
Refractory High-Risk Organ Involvement

Recurrent Low-Risk Organ Involvement

The optimal therapy for patients with relapsed or recurrent Langerhans cell histiocytosis (LCH) has not been determined. Several regimens exist. Patients with recurrent bone disease who reoccur months after stopping vinblastine and prednisone can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is no active disease or very little evidence of active disease, treatment can be changed to every 3 weeks with the addition of oral mercaptopurine nightly.[1] An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside.[2] Cladribine (2-CdA) at 5 mg/m2/day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH) with very little toxicity as long as the therapy was limited to a maximum of six courses.[3]

A phase II trial of thalidomide for LCH patients (ten low-risk patients; six high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (four out of ten) and partial (three out of ten) responses for the low-risk patients. Complete remission was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of bone lesion, but then worsening of a skin rash that was partially resolved. However, dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide.[4]

Indomethacin and bisphosphonates have also been used for recurrent LCH.[5-8]

Refractory High-Risk Organ Involvement

A new treatment plan is indicated when a patient with multisystem involvement shows progressive disease after 6 weeks of standard treatment, or has not had a partial response by 12 weeks. Data from the German-Austrian-Dutch Group studies have shown that these children have only a 10% chance of surviving.[9] Results of the LCH-II trial revealed that patients treated with vinblastine/prednisone who did not respond well by 6 weeks had a 27% chance of survival.[10][Level of evidence: 1iiA] Those treated with vinblastine/prednisone/etoposide with a good response at 6 weeks had a 52% chance of survival. Reports about the use of 2-CdA and 2’-deoxycoformycin as salvage therapies for LCH have been published.[3,11]; [12][Level of evidence: 3iiiDiv] In this trial, these drugs were more often effective for patients with bone, skin, or lymph node involvement. Only one-third of patients with LCH of the liver, bone marrow, spleen, or lung responded.[11] Another study demonstrated that patients with multiple reactivations or high-risk disease could be effectively treated with continuous infusion 2-CdA for 3 days.[13] Seven of ten patients on this trial required no more therapy. A total of six patients with multiorgan LCH that was resistant to other agents, including 2-CdA, have been reported to respond to treatment with clofarabine.[14,15][Level of evidence: 3iiiDii]

Patients with refractory high-risk organ (liver, spleen, or bone marrow) involvement and resistant multisystem low-risk organ involvement have been treated with an intensive acute myeloid leukemia–like protocol. Prompt change of therapy to cladribine (2-CdA) and/or cytosine arabinoside may provide an improvement in overall survival (OS).[16]; [17][Level of evidence: 3iiiDii]; [18][Level of evidence: 3iiiDiv] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed.

Hematopoietic stem cell transplantation (HSCT) has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[19-22] The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just prior to HSCT, may reduce toxic deaths and improve outcome.[23]

  1. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001.  [PUBMED Abstract]

  2. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993.  [PUBMED Abstract]

  3. Weitzman S, Braier J, Donadieu J, et al.: 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer 53 (7): 1271-6, 2009.  [PUBMED Abstract]

  4. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.  [PUBMED Abstract]

  5. Munn SE, Murray S, Chu AC: Adult langerhans cell histiocytosis: A review of 46 cases. [Abstract] Med Pediatr Oncol 38 (3): 222, 2001. 

  6. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001.  [PUBMED Abstract]

  7. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011.  [PUBMED Abstract]

  8. Sivendran S, Harvey H, Lipton A, et al.: Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series. Int J Hematol 93 (6): 782-6, 2011.  [PUBMED Abstract]

  9. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.  [PUBMED Abstract]

  10. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.  [PUBMED Abstract]

  11. Weitzman S, Wayne AS, Arceci R, et al.: 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 33 (5): 476-81, 1999.  [PUBMED Abstract]

  12. Mottl H, Starý J, Chánová M, et al.: Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma 47 (9): 1881-4, 2006.  [PUBMED Abstract]

  13. Stine KC, Saylors RL, Saccente S, et al.: Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (1): 81-4, 2004.  [PUBMED Abstract]

  14. Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008.  [PUBMED Abstract]

  15. Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013.  [PUBMED Abstract]

  16. Bernard F, Thomas C, Bertrand Y, 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 41 (17): 2682-9, 2005.  [PUBMED Abstract]

  17. Apollonsky N, Lipton JM: Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol 31 (1): 53-6, 2009.  [PUBMED Abstract]

  18. Imamura T, Sato T, Shiota Y, et al.: Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan. Int J Hematol 91 (4): 646-51, 2010.  [PUBMED Abstract]

  19. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003.  [PUBMED Abstract]

  20. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001.  [PUBMED Abstract]

  21. Caselli D, Aricò M; EBMT Paediatric Working Party.: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008.  [PUBMED Abstract]

  22. Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010.  [PUBMED Abstract]

  23. Steiner M, Matthes-Martin S, Attarbaschi A, et al.: Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 36 (3): 215-25, 2005.  [PUBMED Abstract]