Sandbox: Langerhans
Standard Treatment Options by Organ, Site or System Involvement for Pediatric Patients
The standard treatment for 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 that lack the evidence-based strength of the trials.
Treatment of low-risk disease (single-system or multisystem) Isolated skin involvement Observation. Observation is recommended for all pediatric patients with skin-only LCH. Therapy is suggested only for symptomatic disease such as extensive rashes, pain, ulceration, or bleeding. Topical steroids. Medium to high potency steroids are effective but the effect is usually not long lasting.[3] Oral methotrexate (20 mg/m2) weekly for 6 months.[4] Oral thalidomide 50 mg to 200 mg nightly.[5] Oral thalidomide may be effective for both pediatric and adult patients. Topical application of nitrogen mustard can be effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[6,7] Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB can be effective in skin LCH but its use is limited by the potential for late skin cancers, especially in patients with light skin tones.[8,9] Skeletal involvement Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone
Curettage only is the recommended therapy, when possible for isolated bone lesions; curettage plus injection of methylprednisolone may be used. Low-dose radiation therapy is effective but its use is limited in pediatric patients to lesions that threaten organ function.[10,11]; [12][Level of evidence: 3iiiA] LCH bone lesions may not need complete excision, because this may increase healing time and the risk of long-term complications. Skull lesions in the mastoid, temporal, or orbital bones
The purpose of treating patients with isolated skull lesions in the mastoid, temporal, or orbital bones is to decrease the chance of developing diabetes insipidus and other long-term problems.[13] Comparison of diabetes insipidus incidence with no systemic therapy (40%) versus 6 months of vinblastine/prednisone (20%) strongly supports treatment of the central nervous system (CNS)–risk bones even when it occurs in a single site.[14] However, the efficacy of therapy and the optimal length of therapy have yet to be proven in a prospective trial.
Twelve months of vinblastine and prednisone as per the LCH-III study results: 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. Afterward prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.[2,13] There is some controversy about whether systemic therapy is required for the first presentation with unifocal bone LCH even in the CNS risk bones. Ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage.[15] None of these patients developed diabetes insipidus. However, when comparing the incidence rates of diabetes insipidus in patients who received little or no chemotherapy (20%–50% incidence of diabetes insipidus) versus diabetes insipidus incidence rates reported by the German-Austrian-Dutch (DAL) Group HX-83 trial (10% incidence of diabetes insipidus in patients treated for LCH), it appears that the weight of evidence from the DAL HX-83 trial supports chemotherapy treatment to prevent diabetes insipidus in patients with LCH of the mastoid, temporal, or orbital bones.[16,17] It should be noted, however, that the DAL HX studies used more drugs and treated patients for a duration of 12 months. Vertebral or femoral bone lesions at risk for collapse
A single vertebral body lesion without soft tissue extension to the extradural space may be observed only. 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 for fracture, where chemotherapy is not usually indicated (single bone lesion). 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.[18] Patients with soft tissue extension from vertebral lesions are often treated successfully with chemotherapy,[19][Level of evidence: 3iiDiii] but prolonged therapy does not appear to be needed beyond the period required to reduce the mass and any risk to the spinal cord. The risk of reactivation of a single bone lesion was only 9% in one large retrospective series.[20] When instability of the cervical vertebrae and/or neurologic symptoms are present, bracing, or rarely, spinal fusion may be needed.[21] Patients with soft tissue extension from the vertebral lesions are often treated successfully with chemotherapy.[19][Level of evidence: 3iiDiii] Multiple bone lesions (single-system multifocal bone)
The most commonly used systemic chemotherapy regimen is the combination of vinblastine and prednisone. Based on the results of the HISTSOC-LCH-III (NCT00276757) trial, 12 months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks is used for good responders.[2] 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. A reactivation rate of 18% was reported with a multidrug treatment regimen that was used for 6 months versus a historical reactivation rate of 50% to 80% with surgery alone or with a single-drug treatment regimen.[22] Multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH)
Vinblastine and prednisone in combination. Based on the results of the randomized HISTSOC-LCH-III (NCT00276757) trial, the same chemotherapy regimen of vinblastine and prednisone as described above is used for 12 months. Patients without risk-organ involvement who were randomly assigned to 12 months of vinblastine/prednisone had a lower 5-year reactivation rate (37%) than did patients who received only 6 months of treatment (54%; P = .03) and patients treated with historical 6-month schedules (52% [LCH-I] and 48% [LCH-II]; P < .001). Most disease reactivations were in bone, skin, or other nonrisk locations.[2] Other chemotherapy regimens have also been effective, including the following: Vincristine, cytosine arabinoside, and prednisone in combination.[23] This combination has been proven to be an effective frontline or salvage therapy. However, prednisone is given for a much shorter duration than was originally published; currently, prednisone is given for 4 to 6 weeks during the induction phase and then for 5 days every 3 weeks with a single dose of vincristine and 5 days of cytosine arabinoside during maintenance. Cladribine. Cladribine given at 5 mg/m2/day for 5 days every 3 weeks for two to six cycles can be an effective salvage therapy for recurrent bone or low-risk multisystem disease. More than six cycles is not recommended because of the risk of cumulative cytopenias. Pamidronate can also be effective for treating LCH bone lesions.[24] A nationwide survey from Japan described 16 children treated with bisphosphonates for bone LCH. All had bone disease; none had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg/course given at 4-week intervals. In 12 of 16 patients, all active lesions including skin (n = 3) and soft tissues (n = 3) resolved. Eight remained disease free at a median of 3.3 years.[25] Other bisphosphonates, such as zoledronate and oral alendronate, have been used to successfully treat bone LCH. Treatment of high-risk multisystem disease Spleen, liver, and bone marrow (may or may not include skin, bone, lymph node, lung, or pituitary gland) The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months based upon the DAL-HX-83 and HISTSOC-LCH-III (NCT00276757) studies.[13,17] In the Histiocyte Society LCH-II and LCH-III studies, the standard arm consisted of vinblastine and prednisone as described above under multifocal bone, but 6-mercaptopurine was added to the continuation phase of the protocol. The LCH-II study was a randomized trial to compare treatment of patients with vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[26][Level of evidence: 1iiA] There was no statistical significance in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials. Late review of the results, however, reported reduced mortality of patients with risk-organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I trial with patients in the LCH-II trial suggested that increased treatment intensity promoted additional early responses and reduced mortality.
It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.[27]
The LCH-III study randomly assigned risk organ–affected patients to either vinblastine/prednisone/6-mercaptopurine or vinblastine/prednisone/6-mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[2] The response rates at 6 and 12 weeks and overall survival were not improved; however, there were significantly increased grade 3 and grade 4 toxicities in patients who received methotrexate. An important finding of the LCH-III study was that the mortality of patients with high-risk LCH on both arms of the study was significantly reduced compared with the earlier LCH-II study, even though the standard arm utilizes the same drugs. Possible explanations for reduced mortality include the following:
A second 6-week induction phase of weekly vinblastine with prednisone given for 3 days per week. This reinduction phase was given to all patients who did not achieve a status of no active disease by the end of the 6-week induction phase, before going onto the every-3-weeks maintenance courses. The rate of no active disease increased after the second induction phase and this course may have played a significant role in the reduced mortality rate. Better supportive care. Earlier change to an effective salvage strategy for nonresponsive lesions. It should be noted that although survival was improved in the LCH-III study, only 60% of patients had no active disease in risk organs after a year of therapy and 25% to 29% of patients relapsed.
The Japan LCH 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 (6-week induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate). If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[28] Similar to the LCH-III study, the important finding of this study was the decreased mortality compared with previous JLSG studies and to the LCH-II study. This was attributed to the early change to a more effective salvage therapy for patients with nonresponsive disease, as well as better supportive care.[28]
Some patients develop a “macrophage activation” of their marrow. This may be confusing to clinicians who may think the patient has hemophagocytic lymphohistiocytosis and LCH. The best therapy for this life-threatening manifestation is not clear, because it tends not to respond well to standard hemophagocytic lymphohistiocytosis therapy. Clofarabine, anti-CD52 antibody alemtuzumab, or reduced-intensity allogeneic stem cell transplant could be considered.[29] Treatment of CNS disease CNS lesions There are three types of LCH 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 and are often associated with other endocrinopathies. Neurodegenerative syndrome. T2 fluid attenuated inversion recovery (FLAIR) hyperintense signals are present, most often in the cerebellar white matter, pons, basal ganglia, and sometimes, in the cerebrum. Drugs that cross the blood-brain barrier, such as cladribine, or other nucleoside analogs, such as cytarabine, are used for active CNS LCH lesions.
Treatment of mass lesions with cladribine has been effective in 13 reported cases.[30,31]; [32][Level of evidence: 3iiiDiii] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of cladribine ranged from 5 mg/m2 to 13 mg/m2, given at varying frequencies.[32][Level of evidence: 3iiiDiii] Patients with LCH and mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter, may also respond to standard LCH chemotherapy.[33,34] Treatment with vinblastine with or without corticosteroids for patients with CNS mass lesions (20 patients; mainly pituitary) demonstrated an objective response in 15 patients, with 5 of 20 patients demonstrating a complete response and 10 of 20 patients demonstrating a partial response. CNS neurodegenerative syndrome Drugs used in active LCH, such as dexamethasone and cladribine, along with other agents, such as retinoic acid, intravenous immunoglobulin (IVIg), infliximab, and cytarabine with or without vincristine have been used in small numbers of patients with mixed results. Many of these agents may result in the complete or partial resolution of radiographic findings, but definitive clinical response rates have not been rigorously defined.[35-39]; [32][Level of evidence: 3iiiDiii]
Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks per month for 1 year.[35] Patients were reported to have stable clinical status. IVIg (400 mg/m2) was given monthly with chemotherapy consisting of oral prednisolone with or without oral or intravenous methotrexate and oral 6-mercaptopurine for at least 1 year.[36] Magnetic resonance imaging (MRI) findings were stable but clinical efficacy was difficult to judge because patients were reported to have no progression in their neurologic symptoms. A study using cytarabine with or without vincristine for up to 24 months reported improvement in the clinical and MRI findings in some patients and stabilization of disease in the others.[38][Level of evidence: 3iiiC] Seven of eight patients have been followed for more than 8 years after stopping therapy and have had stable neurologic and radiographic findings. In the Japan LCH Study Group-96 Protocol, cytarabine failed to prevent the onset of neurodegenerative syndrome. Patients received cytarabine 100 mg/m2 daily on days 1 to 5 during induction and 150 mg/m2 on day 1 of each maintenance cycle (every 2 weeks for 6 months). Three of 91 patients developed neurodegenerative disease, which is similar to the rate experienced on the Histiocyte Society studies.[28] Perhaps the most important aspect of therapy for neurodegenerative disease is the early recognition of clinical neurodegeneration and institution of therapy. Studies combining MRI findings together with cerebrospinal fluid markers of demyelination, to identify patients who require therapy, even before onset of clinical symptoms, are currently underway in several countries.
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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.