Treatment of Childhood LCH
Standard Treatment Options by Organ, Site or System Involvement
Treatment of low-risk disease (single-system or multisystem)
Treatment of high-risk multisystem disease
Treatment of CNS disease
Reactivation of single-system and multisystem LCH
Treatment Options for Childhood LCH No Longer Considered Effective
Assessment of Response to Treatment
Current Clinical Trials
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 6 months for patients who require chemotherapy for bone, skin, or lymph node involvement. For patients with liver, spleen, bone marrow, or lung involvement, treatment is 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%) than the LCH-I and LCH-II trials, in which patients received 6 months of treatment and had a 50% chance of relapse. Future trials will assess whether even longer duration of therapy will reduce the incidence of reactivations and late effects.
It is preferable that LCH patients 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
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.Treatment of low-risk disease (single-system or multisystem)
Isolated skin involvement
- Topical steroids, although topical steroid creams are rarely effective.
- Oral methotrexate (20 mg/m2) weekly for 6 months.
- Oral thalidomide 50 mg to 200 mg nightly.
- 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.[5,6]
- Psoralen and long-wave ultraviolet radiation (PUVA).
- Curettage only, curettage plus injection of methylprednisolone, or radiation therapy may be used.[8,9]; [Level of evidence: 3iiiA] LCH bone lesions may not need complete excision, as this only increases healing time and the risk of long-term complications.
The purpose of treating patients with skull lesions in the mastoid, temporal, or orbital bones is to decrease the chance of developing diabetes insipidus and other long-term problems, although the efficacy of this, and the optimal length of therapy, have yet to be proven in a prospective trial.
- Twelve months of vinblastine and prednisone (based upon comparative results noted above regarding DAL-HX trials versus the LCH-I and LCH-II studies): 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.
- There is some controversy about whether systemic therapy is required for the first presentation with unifocal bone even in the central nervous system (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 (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [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 treatment to prevent diabetes insipidus in patients with LCH of the mastoid, temporal, or orbital bones.[13,14] It should be noted, however, that the DAL HX studies used more drugs and treated for a duration of 12 months. Nonetheless, the CNS study group of the Histiocyte Society believes prevention of the potentially devastating consequences of CNS and endocrine disease with relatively low-toxicity chemotherapy is worthwhile; acknowledging that the overall level of evidence is low (Level of evidence: 3iii) and that prospective trials are needed.
- Radiation therapy is indicated for patients with bone lesions of the vertebrae or femoral neck, which are at risk of collapse or fracture.[15,16] Low-dose radiation therapy may be used to try to promote resolution in an isolated vertebral or 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.
- When instability of the cervical vertebrae and neurologic symptoms are present, bracing or spinal fusion may be needed. Patients with soft tissue extension from the vertebral lesions are often treated successfully with chemotherapy.[Level of evidence: 3iiDiii]
- 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 a historical reactivation rate of 50% to 80% with surgery alone, or with a single-drug treatment regimen has been reported. A comprehensive review of the DAL and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years.[Level of evidence: 3iii] Most disease reactivations were in bone, skin, or other nonrisk locations.
- Pamidronate is also 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. The majority received six courses 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.
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 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).[11,14] In the LCH-II and HISTSOC-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, has shown 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 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.
The important finding of this study was the decreased mortality compared with previous JLSG studies and to the LCH-II study, and was attributed to the early move to salvage therapy for patients with nonresponsive disease, improved salvage therapy, and better supportive care.
- The LCH-III study randomized risk organ–affected patients to either velban/prednisone/6-mercaptopurine or velban/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.
Patients without risk-organ involvement who were randomized to 12 months of velban/prednisone had a lower 5-year reactivation rate (37%) than 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).
Although CNS LCH arises initially at areas where the blood brain barrier is deficient, drugs that cross the blood-brain barrier, such as cladribine (2-CdA), or other nucleoside analogs, such as cytarabine, seem to be the best option for active CNS LCH lesions.
- Treatment of mass lesions with cladribine (2-CdA) has been effective in 13 reported cases.[27,28]; [Level of evidence: 3iiiDiii] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of 2-CdA ranged from 5 mg/m2 to 13 mg/m2 given at varying frequencies.[Level of evidence: 3iiiDiii]
- LCH patients with mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter may respond to chemotherapy.[30,31] 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.
- For treatment of symptoms of LCH CNS neurodegenerative syndrome, dexamethasone, 2-CdA, retinoic acid, intravenous immunoglobulin (IVIg), infliximab, and cytarabine with or without vincristine have been used.[Level of evidence: 3iiiDiii]; [32-36] Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks per month for 1 year. IVIg (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 1 year. Magnetic resonance imaging (MRI) findings were stable but clinical efficacy was difficult to judge as patients were reported to have no progression in their neurologic symptoms. A study using cytarabine with or without vincristine reported improvement in the clinical and MRI findings.[Level of evidence: 3iiiC] Seven of eight patients have been followed for more than 2 years after stopping therapy and have had stable neurologic and radiographic findings.
In the Japan LCH Study Group-96 Protocol study 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 experience on Histiocyte Society studies.
Reactivation of LCH after complete response has been reported; usually occurring within the first 9 to 12 months after stopping treatment. The percentage of patients with reactivations was 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for patients with risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% develop diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses. The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.
A comprehensive review of the DAL and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44%, again within 2 years of the second remission. Involvement of the risk organs in these reactivations only occurred in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.
The percentage of reactivations in multisystem disease was identical in the Japanese trial, [Level of evidence: 1iiA] and the LCH-II trial  (45% and 46%, respectively). There was not a statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased rapid response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, reduced mortality for patients with high-risk multisystem LCH.Treatment Options for Childhood LCH No Longer Considered Effective
Treatments for LCH in any location which have been used in the past but are no longer recommended 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, 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 an isolated lytic bone lesion. Technetium bone scans remain positive in healing bone. PET scans may be helpful in following the response to therapy since intensity of the PET image diminishes with healing of a bone or other lesion.
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.References
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