Approach

Choice of therapy depends on the age of the patient, whether the patient has single-system or multisystem disease, and which organs are affected.

Chemotherapeutic agents are the mainstay of treatment for multisystem disease, single-system disease affecting special sites (e.g., central nervous system [CNS]), and single-system disease affecting risk organs in children (spleen, liver, hematopoietic system).[2][54]

Single-system disease can usually be managed with observation or localized treatment.

Systemic therapy in children

Induction regimens containing vinblastine and prednisone are first line in children.[2][68] Response is assessed after the first 6 weeks of treatment. Further intensive courses may be used if there is residual disease activity.

Induction chemotherapy is followed by maintenance chemotherapy. High-risk patients are treated with vinblastine, prednisone, and mercaptopurine, and low-risk patients continue treatment with vinblastine and prednisone, for a total duration of ≤12 months.[2][68]

The goal of therapy is to reduce mortality, prevent disease reactivation, and prevent development of complications (e.g., diabetes insipidus secondary to pituitary involvement, pathologic fracture secondary to vertebra plana).

Chemotherapy is indicated for children with:[2]

  • Multisystem disease

  • Single-system disease involving the liver, spleen, or hematopoietic system. Involvement of these risk organs is associated with increased mortality

  • Brain or meningeal lesions. Radiographic response has been reported in a small number of children treated with vinblastine plus prednisone or cladribine (with or without cytarabine)[69][70][71][72]

  • Active pituitary disease, indicated by thickening of the pituitary stalk, a mass lesion of hypothalamic-pituitary axis with local neurologic signs (e.g., visual field loss), or a mass lesion of hypothalamic-pituitary axis whose volume is increasing on sequential MRI scans

  • Lesions in CNS-risk bones. CNS-risk bones are the facial bones and the bones of the anterior/middle cranial fossa (i.e., temporal, sphenoidal, ethmoidal, zygomatic, and orbital bones). If lesions are present, the patient has a higher risk of developing CNS disease[27]

  • Multifocal bone involvement

  • Vertebra plana with soft-tissue extension, or other bone lesions at risk of spontaneous fracture. Bracing or spinal fusion may be indicated in the presence of neurologic symptoms or instability of the cervical vertebrae.[73] Low-dose radiation therapy may also be used for bone lesions in an emergency, such as for optic nerve or spinal cord compression.

Systemic therapy in adults

Systemic therapy should be considered for adults with:[54]

  • Multisystem disease

  • Single-system disease with multifocal lesions

  • Single-system disease of the CNS, liver, spleen, or bone marrow

  • Vertebral lesions with intraspinal soft-tissue extension

  • Lesions of the orbit, sphenoid, mastoid, or temporal bones with soft-tissue extension.

Selection of the appropriate therapeutic regimen should be made in conjunction with a specialist. Cladribine, cytarabine, or a BRAF inhibitor (e.g., vemurafenib, dabrafenib) may be used.

In one retrospective study, both cladribine and cytarabine were associated with lower relapse rates and lower toxicity in adults, compared with vinblastine plus prednisone.[74] Response is evaluated after 2 or 3 cycles of chemotherapy. Maintenance therapy is continued for a maximum of 6 months (cladribine) or up to 12 months (cytarabine).[54][75]

For adult patients with the BRAF V600E mutation and critical organ involvement (e.g., CNS, liver), or severe symptomatic disease, targeted therapy with vemurafenib or dabrafenib may be preferred. Studies have reported partial response in 50% to 75% of patients, and complete response in 33% to 50%, in patients treated with BRAF inhibitors.[76][77] Further large studies are needed.

Bone involvement

Systemic therapy is indicated for multifocal bone lesions, lesions in CNS-risk bones, and lesions with soft-tissue extension that risk compromising critical anatomic structures.

Localized measures including surgical curettage, low-dose radiation therapy, and intralesional methylprednisolone may control unifocal disease.[78]

In adults, radiation therapy may be used for unresectable lesions (involving anatomically high-risk sites such as the odontoid peg), for recurrent or progressive lesions, or as an adjuvant treatment following marginal or incomplete resection.[54]

In children, low-dose radiation therapy (6-8 Gy) for bone lesions is restricted to emergency situations such as optic nerve or spinal cord compression, because it is associated with short-term and long-term morbidity.[79] Some clinicians use radiation therapy in older children or adolescents who are at risk of a pathologic fracture due to lesions of a single vertebra or of the greater trochanter of the femur.[2][80]

Resection of lesions <2 cm may be considered in children, in combination with diagnostic biopsy. Partial curettage and biopsy may be considered for children with lesions of size 2 to 5 cm. Radical excision of lesions >5 cm in children, and extensive bone resection in adults, is not recommended because it may increase the size of the defect, increase healing time, and cause permanent skeletal defects.[2][54] Chemotherapy may be more suitable for these patients.

Observation is usually sufficient for patients with vertebra plana without a soft-tissue mass, because the risk of biopsy in these patients outweighs the benefits.[2] Careful follow-up is recommended to exclude Ewing sarcoma.

Skin involvement

Observation is adequate in most asymptomatic cases. Long-term monitoring for progression to multisystem disease is recommended. In one institutional series, 40% of patients with presumed skin-only LCH had multisystem disease, and one half of these patients had risk organ involvement. Risk of multisystem involvement was significantly higher if the patient was >18 months of age at diagnosis of skin LCH.[81]

Surgical excision is the treatment of choice for isolated skin nodules, but extensive surgery should be avoided.[2]

Patients with a rash that is symptomatic should receive initial treatment with topical corticosteroids.[2]

If response to topical corticosteroids is inadequate, alternative local treatments include topical nitrogen mustard, topical tacrolimus, topical imiquimod, and phototherapy with psoralen plus ultraviolet A (PUVA).

  • Topical nitrogen mustard has been shown to be effective in children, although availability is limited in many countries, and it requires application by trained clinicians.[2][54][82]

  • Topical tacrolimus is an alternative option.[42] Topical tacrolimus should not be used in children ages <2 years.

  • Case reports of successful treatment with topical imiquimod in adults and children have been published.[83][84]

  • PUVA has been used successfully to treat adults with LCH of the skin.[85][86] It is contraindicated in penile disease, and is unsuitable for treating the scalp or intertriginous areas.[54] Reports of PUVA use in children are lacking. Guidelines suggest its use may be considered in children with severe disease.[2]

If systemic therapy is needed, options include oral methotrexate, azathioprine (or mercaptopurine), thalidomide, hydroxyurea, and corticosteroids (with or without vinblastine).

  • Methotrexate has been used successfully to treat adult patients with LCH.[87] Guidelines advise it can be used in children when local therapy is ineffective, or an extensive area of skin is affected.[2]

  • Guidelines and experts advise azathioprine (or mercaptopurine) may be used in adults with single-system skin LCH.[54][80] Trials of azathioprine use in children are lacking. Guidelines suggest its use may be considered in children with severe disease.[2]

  • Methotrexate and azathioprine (or mercaptopurine) may be given in combination.[54][80]

  • Oral thalidomide has been shown to induce remission in adult patients with low-risk LCH involving the skin.[88][89] Trials of thalidomide use in children are lacking. Guidelines suggest its use may be considered in children with severe disease.[2] Lenalidomide is an alternative option.

  • Hydroxyurea has been used successfully to induce complete or partial remission in pediatric and adult patients with refractory LCH involving the skin.[90]

  • Systemic therapy with corticosteroids, with or without vinblastine, may be used in pediatric cases when local therapy is ineffective or an extensive area of skin is affected.[2]

Lymph node involvement

Excisional biopsy is usually sufficient to treat isolated lymph node involvement.[2] Extensive surgery should be avoided.[54] Spontaneous regression has been reported.[91]

Single-system pulmonary LCH

Patients who are asymptomatic or who have mild symptoms may not require treatment, but should be closely monitored.[54]

Smoking cessation often results in partial or complete remission.[2] Exposure to passive smoking should be avoided. Vaping or use of other inhaled substances (e.g., marijuana) should be avoided.

Systemic corticosteroids are indicated for symptomatic patients.[54] Progressive lung disease is usually treated with chemotherapy (cladribine).[54][92] Vinblastine and prednisone is an alternative in children.[2]

Lung transplantation may be required if the patient has severe respiratory failure or major pulmonary hypertension.[54]

Pituitary involvement

Systemic therapy is not usually required for isolated diabetes insipidus (DI), unless there is active pituitary disease. Most cases are irreversible at the time of presentation.[71]

Replacement therapy with desmopressin is usually required for patients with DI.[2]

Growth hormone (GH) replacement therapy can be prescribed for children with GH deficiency. Risk of GH deficiency in patients with DI is 35% at 5 years and 54% at 10 years.[93]

Adequate replacement of other pituitary hormones should be started as soon as pituitary insufficiency is detected.[54]

Neurodegenerative disease

Some treatments appear to stabilize clinical and radiographic disease in a small number of patients, but an obvious clinical improvement has not been seen in practice. These regimens include intravenous immune globulin plus prednisone with or without mercaptopurine and methotrexate, given for 12 months; tretinoin, given for 12 months; cladribine; and cytarabine with or without vincristine.[69][94][95][96]

Targeted therapy with a BRAF inhibitor may be preferred in the presence of mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway.[97]

Relapsed or refractory disease

There are no standard salvage regimens for patients with relapsed/reactivated or refractory disease. Selection of the appropriate chemotherapeutic regimen should be made in conjunction with a specialist.

For children with high-risk refractory disease, the most successful published salvage regimen is a combination of cladribine plus cytarabine. In one phase 2 study, a response rate of 92% was achieved in 27 very high-risk young patients (median age at diagnosis 0.7 years).[98]

In adults, refractory disease may be treated with an alternative chemotherapeutic regimen or with a BRAF inhibitor.[54][76][99] Improvement in bone disease refractory to chemotherapy and radiation therapy has been reported with zoledronic acid.[100] Among patients with a BRAF V600E or other MAPK-ERK pathway mutations (KRAS, MEK, etc.), targeted agents like BRAF inhibitors may be utilized following reports of efficacy.[54][76][77][101][102]

Allogeneic hematopoietic stem cell transplant (HSCT) has been performed in high-risk pediatric and adult patients (i.e., those with risk-organ involvement), achieving good disease control but with high treatment-related toxicity.[103][104][105][106] One retrospective study reported a 3-year survival rate of 73% for patients who underwent allogeneic HSCT after the year 2000.[104] The role of HSCT in the era of targeted therapies is uncertain.

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