Treatment of Childhood LCH
Depending on the site and extent of disease, treatment of Langerhans cell histiocytosis (LCH) may include surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 12 months for patients who require chemotherapy for single-system bone, skin, or lymph node involvement. For patients with both high-risk and low-risk multisystem disease, the reactivation rate following 6 months of therapy was as high as 50% on the LCH-I and LCH-II trials.. Based upon data from the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group trials, which treated patients for 1 year and had fewer relapses (29%), the LCH-III trial was designed to give 12 months of chemotherapy for all high-risk multisystem patients and to randomly assign low-risk multisystem patients to either 6 months or 12 months of therapy. In patients with low-risk or high-risk disease who received 12 months of therapy, the reactivation rate was significantly reduced to approximately 30%. The LCH-IV trial will assess whether extending the duration of therapy further will reduce the incidence of reactivations and late effects. Although the LCH-IV study is open in several European centers, it is not open in the United States.
It is preferable that patients with LCH be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly, utilizing evidence-based recommendations and to ensure optimal care. Information about clinical trials for LCH in children is available from the Histiocyte Society Web site.
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.
- Oral methotrexate (20 mg/m2) weekly for 6 months.
- Oral thalidomide 50 mg to 200 mg nightly. 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]
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]; [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. 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. 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. 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.
- Patients with soft tissue extension from vertebral lesions are often treated successfully with chemotherapy,[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.
- When instability of the cervical vertebrae and/or neurologic symptoms are present, bracing, or rarely, spinal fusion may be needed. Patients with soft tissue extension from the vertebral lesions are often treated successfully with chemotherapy.[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. 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.
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.
- Other chemotherapy regimens have also been effective, including the following:
- Vincristine, cytosine arabinoside, and prednisone in combination. 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. 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. 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.[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.
- 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). 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.
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.
- 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.
Treatment of CNS disease
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]; [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.[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]; [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. 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. 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.[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.
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.
Treatment Options for Childhood LCH No Longer Considered Effective
Treatments that have been used in the past but are no longer recommended for pediatric patients with LCH in any location include cyclosporine  and interferon-alpha. 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 these lesions can be healed by chemotherapy.
Radiation therapy use in LCH has been significantly reduced in pediatric patients, and even low-dose radiation therapy should be limited to single-bone vertebral body lesions or other single-bone lesions compressing the spinal cord or optic nerve that do not respond to chemotherapy.
Assessment of Response to Treatment
Response assessment remains one of the most difficult areas in LCH therapy unless there is a specific area that can be followed clinically or with sonography, computed tomography (CT), or MRI scans of areas such as the skin, hepato/splenomegaly, and other mass lesions. Clinical judgment including evaluation of pain and other symptoms remains important.
Bone lesions may take many months to heal and are difficult to evaluate on plain radiographs, although sclerosis around the periphery of a bone lesion suggests healing. CT or MRI scans are useful in assessing response of a soft tissue mass associated with a bone lesion, but is not particularly helpful in lytic bone lesions. Technetium bone scans remain positive in healing bone. Positron emission tomography (PET) scans may be helpful in following the response to therapy since intensity of the PET image diminishes with response of lesions and healing of bone.
For children or adults with lung LCH, pulmonary function testing and high resolution CT scans are sensitive methods for detecting disease progression. Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease and somatostatin analogue scintigraphy may be useful in this regard.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
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