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Systemic therapy

Author(s): Euro Histio Net Work Group for LCH Guidelines for adults (see introduction page), Created: 2012/07/26, last update: 2013/08/18

Front line treatment

Systemic therapy should be considered in case of the following disease category:

There is no standard first line therapy like in pediatric LCH. Vinblastine/prednisolone is mentioned in various chemotherapeutic manuals, but has never been proven effective for adults in a prospective study. An international trial failed because of low recruitment rate. Due to lower risk of neurotoxicity and frequently observed unacceptable steroid induced side effects some experts prefer monotherapy with cladribine, cytarabine or etoposide [Chu 2011]. In a retrospective study evaluating 58 adult patients with bone lesions the authors observed a clear superiority of cytarabine especially to vinblastine/prednisolone but even to 2-CDA in terms of response and toxicity [Cantu et al 2012]. Intensive combination chemotherapies (e.g. MACOP-B) are effective [Derenzini et al 2010] but should be used only in rare cases of an aggressive LCH form [Szturz et al 2010]. (Grade C1 *)

Until recently, most experts started with 2-CDA in case of risk organ or tumorous cerebral involvement, but cytarabine may be a reasonable alternative. (Grade C2 *)

Some investigators have used bisphosphonates for multifocal bone disease, but patients have to be advised to the risk of osteonecrosis of the jaw and its prevention [Montella et al 2009]. COX-Inhibitors might be more than analgetic drugs and regression of LCH was observed [Reichle et al 2005]. (Grade C2 *).

The grade of recommended systemic first line therapy is listed in table 5.

Evaluation of response

Evaluation is done after 2 to 3 cycles of chemotherapy. If there is disease progression or reactivation, complete evaluation as recommended in the previous section has to be performed. (Grade D2 *)

Maintenance therapy

Etoposide or 2-CDA are usually administered up to 6 months. Cytarabine can be given at low dose monthly up to a year in most patients (6-12 cycles). (Grade D2 *)

Salvage therapy

Refractory disease should be treated with drugs not used for the first course. In case of further progression, especially in CNS involvement cytarabine may be added to 2-CDA (both drugs cross the blood brain barrier) [McClain 2005]. Some cases with response to tyrosine kinase inhibitors (imatinib) have been reported [Montella/Insabato/Palmieri 2004; Janku et al 2010]. In the rare case of a most aggressive course of disease hematopoietic stem cell transplant has been performed successfully as well [Ingram et al 2006; Xicoy et al 2006]. Clofarabine has been effective for refractory childhood LCH [Rodriguez-Galindo et al 2008]. (Grade C2 *)


Table 5: First line systemic therapy


Mild symptoms, no risk organs involved

Grade *

  • Methotrexate 20 mg per week p.o/i.v.


  • Azathioprine 2 mg/kg/d p.o


  • Thalidomide 100mg/d p.o in skin or soft tissue multifocal single system LCH


Additionally in multifocal bone LCH

Grade *

  • Zoledronic acid 4 mg i.v.


q 1 (- 6) month (depending on extent and response)


Symptomatic, MS-LCH, no risk organs involved

Grade *

  • Cytarabine 100 mg/m² d1-5 q4w i.v.


  • Etoposide 100 mg/m² d1-5 q4w i.v.


  • Vinblastin/Prednisolone (like in pediatric studies)


MS-LCH, risk organs involved

Grade *

  • 2-CDA 6 mg/m² d1-5 q4w s.c./i.v.


* Grades of recommendation see here.


[Chu 2011] Chu A: Dermatological Aspects and Presentation of an Adult Clinic . Oral Presentation at the Annual Meeting of the Histiocyte Society Vienna 2011

[Cantu et al 2012] 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 [PMID: 22916233]

[Derenzini et al 2010] Derenzini E, Fina MP, Stefoni V, Pellegrini C, Venturini F, Broccoli A, Gandolfi L, Pileri S, Fanti S, Lopci E, Castellucci P, Agostinelli C, Baccarani M, Zinzani PL: MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010, 21: 1173 [PMID: 19861578]

[Szturz et al 2010] Szturz P, Adam Z, Rehák Z, Koukalová R, Kodet R, Nebeský T, Neubauer J, Moulis M, Smardová L, Mayer J: [Lymphoma-like course in aggressive adult multisystem Langerhans cell histiocytosis and the benefit of PET/CT imaging in evaluation of diffuse metabolic activity of lung parenchyma]. [Article in Czech]. Vnitr Lek 2010, 56: 1177-93. [PMID: 21250497]

[Montella et al 2009] Montella L, Merola C, Merola G, Petillo L, Palmieri G: Zoledronic acid in treatment of bone lesions by Langerhans cell histiocytosis. Journal of bone and mineral metabolism 2009, 27: 110 [PMID: 19018458]

[Reichle et al 2005] Reichle A, Vogt T, Kunz-Schughart L, Bretschneider T, Bachthaler M, Bross K, Freund S, Andreesen R: Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans' cell histiocytosis of adults. British journal of haematology 2005, 128: 730 [PMID: 15725096]

[McClain 2005] McClain KL: Drug therapy for the treatment of Langerhans cell histiocytosis. Expert opinion on pharmacotherapy 2005, 6: 2435 [PMID: 16259575]

[Montella/Insabato/Palmieri 2004] Montella L, Insabato L, Palmieri G: Imatinib mesylate for cerebral Langerhans'-cell histiocytosis. The New England journal of medicine 2004 Sep 2; 351: 1034 [PMID: 15342818]

[Janku et al 2010] Janku F, Amin HM, Yang D, Garrido-Laguna I, Trent JC, Kurzrock R: Response of histiocytoses to imatinib mesylate: fire to ashes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010 Nov 1; 28:e633 [PMID: 20733125]

[Ingram et al 2006] Ingram W, Desai SR, Gibbs JS, Mufti G: Reduced-intensity conditioned allogeneic haematopoietic transplantation in an adult with Langerhans' cell histiocytosis and thrombocytopenia with absent radii. Bone marrow transplantation 2006, 37: 713 [PMID: 16489360]

[Xicoy et al 2006] Xicoy B, Ribera JM, Batlle M, Feliu E: [Sustained remission in an adult patient with Langerhans cell histiocytosis following T-cell depleted allogenic cell transplantation]. Medicina clinica 2006 Nov 11; 127: 716 [PMID: 17169302]

[Rodriguez-Galindo et al 2008] Rodriguez-Galindo C, Jeng M, Khuu P, McCarville MB, Jeha S: Clofarabine in refractory Langerhans cell histiocytosis. Pediatric blood & cancer 2008, 51: 703 [PMID: 18623218]