Standard Treatment Options by Organ, Site or System Involvement
        Skin involvement only
        Single skull lesions of the frontal, parietal or occipital regions, or single lesions of any other bone
        Skull lesions in the mastoid, temporal or orbital bones
        Multiple bone lesions; or combinations of skin, lymph node or pituitary gland with or without bone lesions
        Spleen, liver, bone marrow or lung (may or may not include skin, bone, lymph node or pituitary gland)
        Vertebral or femoral bone lesions at risk for collapse
        Central nervous system
        Multisystem disease
Treatment Options for Childhood Langerhans Cell Histiocytosis No Longer Considered Effective
Treatment Options Under Clinical Evaluation for Childhood Langerhans Cell Histiocytosis
        LCH-III trial
Current Clinical Trials

Treatment of Langerhans cell histiocytosis (LCH) may include surgery, oral, topical and intravenous medications and chemotherapy, or radiation therapy depending on the site and extent of disease. The recommended duration of therapy is 6 months for patients who require chemotherapy for bone, skin, or lymph node LCH and 12 months if the liver, spleen, bone marrow, or lungs are involved. It is preferable that LCH patients be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly and to ensure optimal care.

The standard treatment of LCH is best chosen based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In such cases therapy recommendations are based upon case series which lack the evidence-based strength of the trials.

• Observation.



• Topical steroids.[1] (Although topical steroid creams are rarely effective.)



• Oral methotrexate (20 mg/m2) weekly for 6 months.[2]



• Oral thalidomide 50 mg to 200 mg nightly.[3]



• Topical application of nitrogen mustard is effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[4]



• Psoralen and long-wave ultraviolet radiation .[5]

• Curettage only or curettage plus injection of methylprednisolone.[6]

The purpose of treating these patients is to decrease the chances of developing diabetes insipidus (DI).[7]

• Six months of vinblastine and prednisone: Weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. Daily prednisone (40 mg/m2) for 4 weeks then tapered over 2 weeks. Afterwards prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.[7]



• Ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage.[8] None of these patients developed DI. However, when comparing the incidence rates of DI in patients who received little or no chemotherapy (20%–50% incidence of DI) versus DI incidence rates reported by the German-Austrian-Dutch (DAL) Group HX-83 trial (10% incidence of DI in patients treated for LCH), it appears that the weight of evidence from the DAL HX-83 trial supports treatment to prevent DI in patients with the mastoid, temporal, or orbital bones.[9,10]

• Vinblastine and prednisone: Six months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. Prednisone (40 mg/m2) is given daily for 4 weeks then tapered over 2 weeks. Afterwards prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections. A short (< 6 months) treatment course with only a single agent (e.g., prednisone) is not sufficient, and the number of relapses is higher. An 18% reactivation rate with a multidrug regimen for 6 months versus an historical reactivation rate of 50% to 80% with surgery alone, or with a single-drug treatment regimen has been reported.[11]

• The standard therapy length used for LCH in the spleen, liver, bone marrow or lung (high-risk organs) is based upon LCH-I, LCH-II, and the DAL-HX 83 studies and varies from 6 months (LCH-I and LCH-II) to 1 year (DAL-HX-83).[7,10] The LCH-II study was a randomized trial to compare treatment of patients with velban/prednisone/mercaptopurine or velban/etoposide/prednisone/mercaptopurine.[12] There outcomes of response at 6 weeks, 5 year probability of survival, relapses, and permanent consequences had no statistical difference between the two treatments. Hence, etoposide has not been used in subsequent Histiocyte Society trials. There was reduced mortality of patients with risk organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I to LCH-II trials suggested that increased treatment intensity promoted additional early responses and reduced mortality.

• Radiation therapy is indicated for patients with bone lesions of the vertebrae or femoral neck, which are at risk of collapse.[13,14] Certain skull lesions, not in the central nervous system (CNS)-risk region, could be considered for radiation therapy. When instability of the cervical vertebrae and neurologic symptoms are present, bracing or spinal fusion may be needed.[15]

• Treatment of mass lesions with cladribine (2-CdA) has been effective in 13 reported cases.[16-18] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of 2-CdA ranged from 5–13 mg/m2 given at varying frequencies.[18]



• For treatment of symptoms of LCH CNS neurodegenerative syndrome, dexamethasone, 2-CdA, retinoic acid and intravenous immunoglobulin (IVIgG) have been used.[18-20] Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks a month for 1 year.[19] Intravenous immunoglobulin (400 mg/m2) was given monthly and chemotherapy consisting of oral prednisolone with or without oral or intravenous methotrexate and oral 6-mercaptopurine were given for at least one year.[20] Magnetic resonance imaging findings were stable but clinical efficacy was difficult to judge as patients were reported to have no progression in their neurologic symptoms.

• The Japan Langerhans Cell Histiocytosis Study Group (JLSG) reported 5-year response and overall survival rates of 78% and 95% respectively for patients with multisystem disease treated on the JLSG-96 trial (induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy). If patients had a poor response to this initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, vincristine and prednisolone).[21]



• Results from the LCH-II trial for multisystem LCH showed a 5-year survival rate of 74% for patients treated with vinblastine/prednisone/mercaptopurine, versus a 79% 5-year survival rate for those patients who had etoposide added to the vinblastine/prednisone/mercaptopurine regimen.[12] No salvage regimen was recommended as part of the LCH-II trial.



• The percentage of reactivations was nearly the same in the Japanese trial [21], and the LCH-II trial [12] (45% vs. 46%, respectively). Both studies concluded that intensified treatment increased rapid response and reduced mortality.

Treatments for LCH in any location which have been used in the past but are no longer recommended include cyclosporine [22] and interferon-alpha.[23] Extensive surgery is also not indicated. Curettage of a circumscribed skull lesion may be sufficient if the lesion in not in the temporal, mastoid, or orbital areas (CNS-risk). Patients with disease in these particular sites are recommended to receive 6 months of systemic therapy with vinblastine and prednisone. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated as chemotherapy can heal bone or skin lesions.

Treatment regimens for LCH patients with multisystem high-risk or low-risk organ disease, multiple bone, or CNS-risk lesions were studied by the Histiocyte Society on LCH-III. This trial is now closed to accrual, however, important treatment tenets of this trial were the following:

• High-risk organ involvement: Patients with high-risk organ disease were randomly assigned to receive either vinblastine/prednisone/6-mercaptopurine alone, or in combination with methotrexate intravenously during induction therapy and orally during the maintenance phase.



• Low-risk organ involvement: Those patients with a single bone lesion and skin, lymph node, or pituitary gland involvement were randomized to 6 or 12 months of treatment with vinblastine and prednisone.



• CNS-risk site involvement: Special sites were designated CNS-risk because of the recognition that patients with multifocal bone disease and those patients with disease at the base of the skull are at high risk for CNS involvement. CNS-risk patients were treated with systemic therapy, not just local therapy or single-drug administration. These special anatomic sites and multifocal bone disease were treated with vinblastine and prednisone for 6 months.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Lau L, Krafchik B, Trebo MM, et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46 (1): 66-71, 2006.  [PUBMED Abstract]
   
   
2. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001.  [PUBMED Abstract]
   
   
3. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.  [PUBMED Abstract]
   
   
4. Hoeger PH, Nanduri VR, Harper JI, et al.: Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis. Arch Dis Child 82 (6): 483-7, 2000.  [PUBMED Abstract]
   
   
5. Kwon OS, Cho KH, Song KY: Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy. J Dermatol 24 (1): 54-6, 1997.  [PUBMED Abstract]
   
   
6. Nauert C, Zornoza J, Ayala A, et al.: Eosinophilic granuloma of bone: diagnosis and management. Skeletal Radiol 10 (4): 227-35, 1983.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. Woo KI, Harris GJ: Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg 19 (6): 429-39, 2003.  [PUBMED Abstract]
   
   
9. Dunger DB, Broadbent V, Yeoman E, et al.: The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 321 (17): 1157-62, 1989.  [PUBMED Abstract]
   
   
10. Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. Nesbit ME, Kieffer S, D'Angio GJ: Reconstitution of vertebral height in histiocytosis X: a long-term follow-up. J Bone Joint Surg Am 51 (7): 1360-8, 1969.  [PUBMED Abstract]
    
    
14. Womer RB, Raney RB Jr, D'Angio GJ: Healing rates of treated and untreated bone lesions in histiocytosis X. Pediatrics 76 (2): 286-8, 1985.  [PUBMED Abstract]
    
    
15. Mammano S, Candiotto S, Balsano M: Cast and brace treatment of eosinophilic granuloma of the spine: long-term follow-up. J Pediatr Orthop 17 (6): 821-7, 1997 Nov-Dec.  [PUBMED Abstract]
    
    
16. Büchler T, Cervinek L, Belohlavek O, et al.: Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer 44 (3): 286-8, 2005.  [PUBMED Abstract]
    
    
17. Watts J, Files B: Langerhans cell histiocytosis: central nervous system involvement treated successfully with 2-chlorodeoxyadenosine. Pediatr Hematol Oncol 18 (3): 199-204, 2001 Apr-May.  [PUBMED Abstract]
    
    
18. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008.  [PUBMED Abstract]
    
    
19. Idbaih A, Donadieu J, Barthez MA, et al.: Retinoic acid therapy in "degenerative-like" neuro-langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer 43 (1): 55-8, 2004.  [PUBMED Abstract]
    
    
20. Imashuku S, Ishida S, Koike K, et al.: Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 26 (11): 735-9, 2004.  [PUBMED Abstract]
    
    
21. Morimoto A, Ikushima S, Kinugawa N, 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 107 (3): 613-9, 2006.  [PUBMED Abstract]
    
    
22. Minkov M, Grois N, Broadbent V, et al.: Cyclosporine A therapy for multisystem langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 482-5, 1999.  [PUBMED Abstract]
    
    
23. Lukina EA, Kuznetsov VP, Beliaev DL, et al.: [The treatment of histiocytosis X (Langerhans-cell histiocytosis) with alpha-interferon preparations] Ter Arkh 65 (11): 67-70, 1993.  [PUBMED Abstract]
    
    

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