Sandbox: Langerhans

Standard Treatment Options by Organ, Site, or System Involvement for Pediatric Patients

Treatment of Low-risk Disease (Single-system or Multisystem)

Isolated Skin Involvement

• Observation is recommended for all pediatric patients with isolated skin involvement of Langerhans cell histiocytosis.
• Therapy is suggested only for symptomatic disease that presents with either extensive rash, sever pain, skin ulceration, or bleeding.
• Medical therapies used for the treatment of isolated skin lesions of Langerhans cell histiocytosis include:

• Topical steroids
• Oral methotrexate (20 mg/m2) weekly for 6 months
• Oral thalidomide 50 mg to 200 mg each night
• Topical application of nitrogen mustard can be effective for cutaneous Langerhans cell histiocytosis that is resistant to oral therapies, but not for disease involving large areas of skin.
• Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB can be effective in skin Langerhans cell histiocytosis but its use is limited by the potential for late skin cancers.

Skull Involvement

• Curettage is the mainstay treatment for single skull lesions that involve the frontal, parietal, or occipital bones.
• In certain cases, curettage plus an injection of methylprednisolone may be used
• The use of low-dose radiation therapy is limited among pediatric patients due to severe side effects.
• Patients with isolated lesions to the mastoid, temporal, or orbital bones are treated with systemic therapy, as to prevent the development of diabetes insipidus among such patients.
• Comparison of diabetes insipidus incidence with no systemic therapy (40%) versus 6 months of vinblastine/prednisone (20%) strongly supports systemic treatment of of such bony lesions.

Vertebral or Femoral Bone Lesions at Risk for Collapse

• Observation is recommended for the management of a single vertebral body lesion that has no soft tissue extension into the extradural space.
• Low-dose radiation therapy may be used to try to promote resolution in an isolated vertebral body lesion or a large femoral neck lesion at risk of fracture
• Despite the low dose required (700–1,000 cGy), radiation therapy should be used with caution in the area of the thyroid gland, brain, or any growth plates.
• Patients with soft tissue extension from vertebral lesions are often treated successfully with chemotherapy.

Multiple Bone Lesions (Single-system Multifocal Bone Disease)

• The most commonly used systemic chemotherapy regimen is a combination of vinblastine and prednisone.
• Vinblastine treatment is recomended for 12 months. Weekly doses for the first 7 weeks, which is followed by a dose every 3 weeks for the rest of the management period.
• 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.

Multiple Bone Lesions in Combination with Skin, Lymph Node, or Diabetes Insipidus (Low-risk Multisystem Disease)

• Vinblastine AND prednisone combination therapy is the mainstay treatment for low-risk multisystem Langerhans cell histiocytosis.
• The same chemotherapy regimen of vinblastine and prednisone as described above is used for 12 months.
• Other chemotherapeutic agents used for the treatment of low-risk multisystem Langerhans cell histiocytosis include:

• Vincristine AND cytosine arabinoside AND prednisone
• Cladribine
• Pamidronate
• Zoledronate
• Alendronate

Treatment of High-risk Multisystem Disease

• The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months
• The mainstay therapy consists of vinblastine AND prednisone AND 6-mercaptopurine

Treatment of CNS Langerhans cell histiocytosis

• There are three types of Langerhans cell histiocytosis CNS lesions:

• Mass lesions or tumors in the cerebrum, cerebellum, or choroid plexus
• Mass lesions of the hypothalamic-pituitary axis that are always associated with diabetes insipidus
• Neurodegenerative syndrome

• Drugs that cross the blood-brain barrier, such as cladribine, or other nucleoside analogs, such as cytarabine, are used for active CNS Langerhans cell histiocytosislesions.
• Immunochemotherapeutic agents used for the treatment of Langerhans cell histiocytosis neurodegenerative syndrome include:

• Dexamethasone
• Cladribine
• Retinoic acid
• Intravenous immunoglobulin (IVIg)
• Infliximab
• Cytarabine
• Vincristine

Standard Treatment Options by Organ, Site, or System Involvement for Adult Patients

The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with Langerhans cell histiocytosis (LCH).

Most investigators have previously recommended treatment according to the guidelines given above for standard treatment of children with Langerhans cell histiocytosis. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children are not as well-tolerated when used in adults. Excessive neurologic toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial.

A consensus opinion reported on the evaluation and treatment of adult patients with LCH.[1] Discussion continues, however, particularly with regard to optimal first-line therapy with some experienced clinicians preferring to start with vinblastine and prednisone and others with alternative therapy, such as single-agent cytosine arabinoside or cladribine.

Treatment of pulmonary LCH It is difficult to judge the effectiveness of various treatments for pulmonary LCH because patients can recover spontaneously or have stable disease without treatment. Smoking cessation is mandatory because the apparent causal effect of smoking in pulmonary LCH.[2] It is not known if steroid therapy is efficacious in the treatment of adult pulmonary LCH because reported case series did not control for smoking cessation. Most adult patients with LCH have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking.[3] Some patients have been reported to respond to cladribine therapy.

Lung transplantation may be necessary for adults with extensive pulmonary destruction from LCH.[4] This multicenter study reported 54% survival at 10 years posttransplant, with 20% of patients having recurrent LCH that did not impact survival; longer follow-up of these patients is needed. Another study confirmed an approximate 50% survival at 10 years and improved hemodynamic changes associated with pulmonary arterial hypertension, but did not alter pulmonary function testing or incidence of pulmonary edema.[5] The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans.[6]

Treatment of bone LCH As in children, adults with single-bone lesions should undergo curettage of the lesion followed by observation, with or without intralesional corticosteroids. Extensive or radical surgery leading to loss of function and disfigurement is contraindicated at any site, including the teeth or jaw bones. Systemic chemotherapy will cause bone lesions to regress and the involved teeth and jaw bones cannot reform. For those failing chemotherapy, low-dose radiation therapy may be indicated and should be tried before any radical surgery that leads to extensive loss of function and disfigurement. Radiation therapy is also indicated for impending neurological deficits from vertebral body lesions or visual problems from orbital lesions. A German cooperative radiation therapy group reported on a series of 98 adult patients with LCH, most of whom (60 of 98) had only bone lesions, and 24 had multisystem disease including bone, treated with radiation therapy.[7][Level of evidence: 3iiiDiv] Of 89 evaluable patients, 77% achieved a complete remission, 9% developed an infield recurrence, and 15.7% (14 of 89) experienced a progression outside the radiation field(s). A retrospective analysis of 80 patients treated with radiation therapy alone reported a 77% complete remission rate and a 12.5% partial remission rate, with 80% long-term control noted in adults. No adverse late effects were reported.[8]

A variety of chemotherapy regimens, including cladribine, have been published in the treatment of a relatively limited number of patients. (Refer to the Chemotherapy section of this summary for more information.)

Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[9-11] Successful use of oral bisphosphonates have also been described and may be a useful and relatively less toxic way of treating adult bone LCH.[12] Because of the increased toxicity of chemotherapy in adults, bisphosphonate therapy could be used before chemotherapy in multifocal bone disease. Response of other organs, such as skin and soft tissue, to bisphosphonate therapy has been reported.[13]

Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients who had disease resistant to standard chemotherapy treatment.[14]

Treatment of single-system skin disease Localized lesions can be treated by surgical excision, but as with bone, mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to available therapy. Topical therapies are described in greater detail in the childhood isolated skin involvement section of this summary and include topical or intralesional corticosteroid, topical tacrolimus, imiquimod, psoralen and long-wave ultraviolet A radiation (PUVA), and UVB.[15] Therapies such as PUVA/UVB may be more useful in adults when consideration of long-term toxicity may be less.[16-18] Systemic therapy for severe skin LCH includes oral methotrexate, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide.[19,20] Recurrences after stopping treatment may occur but may respond to re-treatment. Oral isotretinoin has achieved remission in some refractory cases of skin LCH in adults.[21] Chemotherapy for the treatment of single-system and multisystem disease Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.

A single-center, retrospective review of 58 adult patients with LCH reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine. Patients treated with vinblastine/prednisone had the worst outcome, with 84% not responding within 6 weeks or relapsing within a year. The no-response/relapse rate was 59% for cladribine and 21% for cytarabine. Grade 3 or 4 neurologic toxic effects occurred in 75% of patients treated with vinblastine. Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients receiving cytarabine.[22] Etoposide has been used with some success in single-system and multisystem LCH. Use of prolonged oral etoposide in adults with skin LCH has been reported with minimal toxicity, while 3-day courses of intravenous etoposide (100 mg/m2/day) achieved complete remission in a small number of patients with resistant single-system and multisystem disease.[23] Another study at the same center found that azathioprine was the most successful drug for localized disease in adults, with the addition of etoposide for refractory and multisystem disease.[24] For patients who do not respond to front-line therapy with etoposide, cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system (CNS) disease.[25,26] The first study that used cladribine to treat refractory and recurrent skin LCH disease reported on three patients (aged 33, 51, and 57 years) who received two to four courses of cladribine at 0.7 mg/kg intravenously over 2 hours/day for 5 days.[25] In a series of five adults (one untreated and four with refractory LCH treated with cladribine at the same dose noted above), three patients achieved a complete remission and two patients achieved a partial remission.[26] An adult lymphoma treatment regimen, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (MACOP-B), was used in three patients with multisystem LCH and four with single-system multifocal bone LCH from 1995 to 2007.[27] Total duration of therapy was 12 weeks; response was seen in all patients, two with partial response and five with complete response. Three recurrences were seen after stopping therapy.[27] Despite the small number of patients and the retrospective nature of the study, MACOP-B may be useful as salvage therapy in adult patients with LCH and deserves further study.[28] Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[9-11] A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor-alpha inhibitor.[29] A report of stereotactic radiosurgery for the treatment of pituitary LCH in adults showed efficacy in reducing the masses.[30] However, radiation therapy is not considered the standard of care for children with pituitary involvement. Systemic chemotherapy with cytarabine and cladribine have been the preferred treatments.[31,32] Targeted therapies for the treatment of single-system and multisystem disease New targeted therapies under investigation include the following:

Tyrosine kinase inhibitors: Imatinib mesylate has been effective in the treatment of four adult patients with LCH who had skin, lung, bone, and/or CNS involvement.[33,34] Another adult patient with LCH did not respond to imatinib mesylate.[35] RAS pathway inhibitors: The finding that most patients with LCH have BRAF and other RAS pathway mutations has led to several anecdotal reports of responses to vemurafenib, a BRAF V600E inhibitor, in adult patients with LCH, Erdheim-Chester (ECD) disease, or mixed ECD/LCH.[36,37] A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing. NCT01677741 is one such trial.