Treatment algorithm

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ACUTE

single-system disease: bone involvement

1st line – surgery, radiation, and/or intralesional methylprednisolone

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ACUTE
|
single-system disease: bone involvement
|
unifocal disease in a non-CNS-risk bone (resectable)
1st line – 

surgery, radiation, and/or intralesional methylprednisolone

Unifocal bone disease occurs in a single bone only.

Simple curettage or biopsy will usually result in healing.[107]

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]

Intralesional instillation of methylprednisolone or radiation has been shown to be effective as either an adjunct to or an alternative to surgery.[108]

Primary options

methylprednisolone acetate: children and adults: consult specialist for guidance on intralesional dose

1st line – localized therapy and/or chemotherapy or targeted therapy

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ACUTE
|
single-system disease: bone involvement
|
unifocal disease in a non-CNS risk bone (unresectable)
1st line – 

localized therapy and/or chemotherapy or targeted therapy

Management will vary depending on disease and patient factors (including the size and location of the lesion, patient age and preference, etc.) and therefore an individualized approach is required to determine which of these treatments, alone or in combination, are suitable.

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]

Localized measures including surgical curettage, low-dose radiation therapy, and intralesional methylprednisolone may control the 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]

In patients with unresectable unifocal disease, chemotherapy may be used as an alternative, or required as an adjunct, to localized therapy. Cladribine, cytarabine, or a BRAF inhibitor (e.g., vemurafenib, dabrafenib) may be used in adults.[54][76] Vinblastine plus prednisone is the preferred regimen in children.[2] Selection of the appropriate therapeutic regimen should be made in conjunction with a specialist.

See local specialist protocol for dosing guidelines.

Primary options

methylprednisolone acetate

OR

vinblastine

and

prednisone

OR

cladribine injection

OR

cytarabine

OR

vemurafenib

OR

dabrafenib

1st line – chemotherapy or targeted therapy

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ACUTE
|
single-system disease: bone involvement
|
multifocal bone lesions, CNS-risk bone lesion, vertebra plana with soft-tissue extension, or bone lesion at risk of spontaneous fracture
1st line – 

chemotherapy or targeted therapy

Multifocal bone disease occurs in >1 bone. Central nervous system (CNS)-risk bones are the facial bones or bones of the anterior/middle cranial fossa (i.e., temporal, sphenoidal, ethmoidal, zygomatic, and orbital bones).[27]

Vinblastine plus prednisone is the recommended regimen in pediatric patients.[2] Cladribine, cytarabine, or a BRAF inhibitor (e.g., vemurafenib, dabrafenib) may be used in adults.[54][76] Selection of the appropriate therapeutic regimen should be made in conjunction with a specialist.

Patients with disease in CNS-risk bones should be monitored for the development of diabetes insipidus.

See local specialist protocol for dosing guidelines.

Primary options

vinblastine

and

prednisone

OR

cladribine injection

OR

cytarabine

OR

vemurafenib

OR

dabrafenib

Consider – radiation therapy

Back
ACUTE
|
single-system disease: bone involvement
|
multifocal bone lesions, CNS-risk bone lesion, vertebra plana with soft-tissue extension, or bone lesion at risk of spontaneous fracture
Consider – 

radiation therapy

Treatment recommended for SOME patients in selected patient group

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]

Consider – bracing or spinal fusion

Back
ACUTE
|
single-system disease: bone involvement
|
multifocal bone lesions, CNS-risk bone lesion, vertebra plana with soft-tissue extension, or bone lesion at risk of spontaneous fracture
Consider – 

bracing or spinal fusion

Treatment recommended for SOME patients in selected patient group

May be indicated in the presence of neurologic symptoms or instability of the cervical vertebrae.[73]

1st line – observation

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ACUTE
|
single-system disease: bone involvement
|
vertebra plana without soft-tissue extension or bone lesions at risk of spontaneous fracture
1st line – 

observation

Observation is usually all that is required, as the risk of biopsy in these patients outweighs the benefits.[2] Careful follow-up is recommended to exclude Ewing sarcoma.

single-system disease: skin involvement

1st line – observation

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ACUTE
|
single-system disease: skin involvement
|
asymptomatic
1st line – 

observation

Observation is adequate in most 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]

1st line – topical corticosteroid

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ACUTE
|
single-system disease: skin involvement
|
with symptomatic rash
1st line – 

topical corticosteroid

Topical corticosteroids, administered for 2 to 3 months, are first-line therapy.[2]

Primary options

betamethasone valerate topical: (0.05%; 0.1%) children and adults: apply sparingly to the affected area(s) once or twice daily

2nd line – alternative topical therapy

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ACUTE
|
single-system disease: skin involvement
|
with symptomatic rash
2nd line – 

alternative topical therapy

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] 

Primary options

tacrolimus topical: (0.03%) children ≥2 years of age and adults: apply to the affected area(s) twice daily

OR

imiquimod topical: (5%) children and adults: consult specialist for guidance on dose

3rd line – systemic therapy

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ACUTE
|
single-system disease: skin involvement
|
with symptomatic rash
3rd line – 

systemic therapy

Systemic therapy may be used if the patient does not respond to topical treatments.

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]

See local specialist protocol for dosing guidelines.

Primary options

methotrexate

OR

azathioprine

OR

mercaptopurine

OR

methotrexate

-- AND --

azathioprine

or

mercaptopurine

OR

thalidomide

OR

lenalidomide

OR

hydroxyurea

OR

prednisone

OR

prednisone

and

vinblastine

1st line – surgical excision

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ACUTE
|
single-system disease: skin involvement
|
with isolated skin nodules
1st line – 

surgical excision

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

single-system disease: isolated lymph node involvement

1st line – excisional biopsy

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ACUTE
|
single-system disease: isolated lymph node involvement
1st line – 

excisional biopsy

Usually sufficient to treat isolated lymph node involvement.[109] Extensive surgery should be avoided.[54] Spontaneous regression has been reported.[91]

single-system disease: lung involvement

1st line – observation

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ACUTE
|
single-system disease: lung involvement
|
asymptomatic or mild symptoms
1st line – 

observation

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

Plus – smoking cessation

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ACUTE
|
single-system disease: lung involvement
|
asymptomatic or mild symptoms
Plus – 

smoking cessation

Treatment recommended for ALL patients in selected patient group

Smoking cessation in adolescents and adults 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.

1st line – oral corticosteroid

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ACUTE
|
single-system disease: lung involvement
|
moderate or severe symptoms
1st line – 

oral corticosteroid

Systemic corticosteroids are indicated for patients with moderate or severe symptoms.[54]

Primary options

prednisone: 1 mg/kg orally once daily for 1 month, then taper gradually according to response

2nd line – chemotherapy

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ACUTE
|
single-system disease: lung involvement
|
moderate or severe symptoms
2nd line – 

chemotherapy

Progressive lung disease is usually treated with chemotherapy (cladribine).[54][92] Vinblastine and prednisone is an alternative in children.[2]

See local specialist protocol for dosing guidelines.

Primary options

cladribine injection

OR

vinblastine

and

prednisone

Consider – lung transplantation

Back
ACUTE
|
single-system disease: lung involvement
|
moderate or severe symptoms
Consider – 

lung transplantation

Treatment recommended for SOME patients in selected patient group

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

single-system disease: CNS involvement

1st line – chemotherapy or targeted therapy

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ACUTE
|
single-system disease: CNS involvement
1st line – 

chemotherapy or targeted therapy

Systemic therapy is indicated in children and adults with brain or meningeal lesions and those with active pituitary disease.[2][54]

Systemic therapy is not usually required for isolated diabetes insipidus unless there is active pituitary disease.

Active pituitary disease is 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 magnetic resonance imaging scans.[2]

Selection of the appropriate therapeutic regimen should be made in conjunction with a specialist. Radiographic response has been reported in a small number of children with intracranial lesions treated with vinblastine plus prednisone, or cladribine.[69][70][71][72] Cladribine or cytarabine may be used in adults. If the patient has the BRAF V600E mutation, targeted therapy with vemurafenib or dabrafenib may be preferred.[76][77]

See local specialist protocol for dosing guidelines.

Primary options

vinblastine

and

prednisone

OR

cladribine injection

OR

cytarabine

OR

vemurafenib

OR

dabrafenib

Consider – endocrine replacement therapy

Back
ACUTE
|
single-system disease: CNS involvement
Consider – 

endocrine replacement therapy

Treatment recommended for SOME patients in selected patient group

Replacement therapy with desmopressin is usually required for patients with diabetes insipidus.[2] Growth hormone (GH) replacement therapy can be prescribed for children with GH deficiency.[93] Adequate replacement of other pituitary hormones should be started as soon as pituitary insufficiency is detected.[54]

single-system disease: neurodegenerative disease

1st line – chemotherapy or targeted therapy

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ACUTE
|
single-system disease: neurodegenerative disease
1st line – 

chemotherapy or targeted therapy

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.[97]

See local specialist protocol for dosing guidelines.

Primary options

immune globulin (human)

and

prednisone

OR

immune globulin (human)

and

prednisone

and

mercaptopurine

and

methotrexate

OR

tretinoin

OR

cytarabine

OR

cytarabine

and

vincristine

OR

cladribine injection

OR

vemurafenib

OR

dabrafenib

multisystem disease

1st line – chemotherapy

Back
ACUTE
|
multisystem disease
|
children: risk-organ positive
1st line – 

chemotherapy

Risk organs are the liver, spleen, and hematopoietic system.[2]

Selection of the appropriate chemotherapeutic regimen should be made in conjunction with a specialist; however, the following protocol is widely used.

Vinblastine plus prednisone are given as induction chemotherapy, and 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, with vinblastine, prednisone, and mercaptopurine, 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).

See local specialist protocol for dosing guidelines.

Primary options

vinblastine

and

prednisone

and

mercaptopurine

1st line – chemotherapy

Back
ACUTE
|
multisystem disease
|
children: risk-organ negative
1st line – 

chemotherapy

Risk organs are the liver, spleen, and hematopoietic system.[2]

Selection of the appropriate chemotherapeutic regimen should be made in conjunction with a specialist; however, the following protocol is widely used.

Vinblastine plus prednisone are given as induction chemotherapy, and 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, with vinblastine, prednisone, and mercaptopurine, 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).

See local specialist protocol for dosing guidelines.

Primary options

vinblastine

and

prednisone

1st line – chemotherapy or targeted therapy

Back
ACUTE
|
multisystem disease
|
adults
1st line – 

chemotherapy or targeted therapy

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., central nervous system, 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.

See local specialist protocol for dosing guidelines.

Primary options

cladribine injection

OR

cytarabine

OR

vemurafenib

OR

dabrafenib

ONGOING

relapsed/refractory disease

1st line – chemotherapy or targeted therapy

Back
ONGOING
|
relapsed/refractory disease
1st line – 

chemotherapy or targeted therapy

There are no standard salvage regimens for patients with relapsed/reactivated or refractory disease. Selection of regimens depends on whether the patient has single-system or multisystem disease, and which organs are involved.

For children with high-risk refractory disease, the most successful published salvage regimen is a combination of higher doses of cladribine plus high-dose 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]

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 mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway mutations (KRAS, MEK, etc.), targeted agents like BRAF inhibitors may be utilized following reports of efficacy.[54][76][77][101][102]

2nd line – allogeneic hematopoietic stem cell transplant

Back
ONGOING
|
relapsed/refractory disease
2nd line – 

allogeneic hematopoietic stem cell transplant

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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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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