Treatment of nonpulmonary Langerhans cell histiocytosis

INTRODUCTION — 

Langerhans cell histiocytosis (LCH) is a myeloid dendritic cell neoplasm that most commonly affects bones and skin but can also involve bone marrow, liver, spleen, lungs, central nervous system, and other organs. LCH is rare, but it is considerably more common in children (especially younger children) than in adults.

Broadly, histiocytic disorders are categorized as LCH and non-Langerhans histiocytoses. The historical terms for LCH: histiocytosis-X, Letterer-Siwe disease, Hand-Schüller-Christian disease, and diffuse reticuloendotheliosis should be abandoned.

The BRAF V600E mutation is present in more than one-half of LCH cases. Activation of the mitogen-activated protein kinase (MAPK) pathway is present in nearly all patients and is a key driver of this neoplastic disorder.

Management of nonpulmonary LCH in children and adults is presented here.

Related topics include:

●(See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●(See "Pulmonary Langerhans cell histiocytosis".)

PRETREATMENT EVALUATION — 

Pretreatment evaluation of LCH should define the symptoms, involved organ systems, extent of their involvement, and effects on organ function.

Clinical manifestations, diagnosis, and differential diagnosis of LCH are detailed separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Clinical – History and physical examination should define the type and severity of LCH-associated symptoms and signs.

Examples include constitutional symptoms (eg, fever, sweats, fatigue), pulmonary findings (eg, dyspnea, cough, hemoptysis, chest pain), musculoskeletal pain or myalgias, gastrointestinal symptoms (eg, diarrhea, melena, jaundice, abdominal fullness or pain), skin rash or subcutaneous nodules, lymphadenopathy, neurologic findings (eg, headache, ataxia, dysarthria, diplopia, altered hearing, cognitive decline, seizures), and endocrine symptoms (eg, polydipsia, polyuria, cold intolerance, growth delay, decreased libido).

●Laboratory studies

•Complete blood count (CBC), differential count, and reticulocyte count.

•Coagulation – Prothrombin time (PT) and activated partial thromboplastin time (aPTT) for patients with hepatomegaly, jaundice, abnormal liver enzymes, or a low total protein or albumin.

•Serum chemistries:

-Electrolytes, kidney function tests, calcium, liver function tests, total protein, albumin

-Thyroid-stimulating hormone (TSH), free T4

-Prolactin and IGF-1

-Morning serum cortisol, ACTH, and osmolality

-Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) for males or estradiol for females

•Morning urine and serum osmolality.

•Bone marrow examination should be performed in all children ≤2 years and in other patients if the CBC is abnormal or there are concerns for a myeloid neoplasm or hemophagocytic lymphohistiocytosis.

•Pulmonary function tests for patients with respiratory findings or abnormal chest radiograph. (See "Pulmonary Langerhans cell histiocytosis", section on 'Pulmonary function testing'.)

●Pathology – The characteristic microscopic appearance is of Langerhans cells ("coffee bean-shaped nucleus") amidst an inflammatory infiltrate of neutrophils, lymphocytes, macrophages, multinucleated giant cells, and eosinophils. Immunohistochemistry shows expression of CD1a and CD207 (langerin) and is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Pathologic features'.)

We test all patients for MAPK pathway mutations (ie, BRAF, KRAS, NRAS, MAP2K1, PIK3CA) and gene fusions using next-generation sequencing (NGS) assays. A step-wise approach, with testing for the BRAF V600E mutation using immunohistochemistry or polymerase chain reaction (PCR), followed by NGS if negative is also reasonable.

●Imaging

•Whole-body positron emission tomography (PET)/computed tomography (CT), including distal extremities, to determine the initial extent of organ involvement and as a baseline for assessing response to therapy [1,2].

For infants <6 months of age, we favor a whole-body magnetic resonance imaging (MRI) to reduce radiation exposure.

•For selected patients, based on clinical or laboratory evidence of organ involvement, the following may be obtained to stage the disease and monitor response to treatment:

-High-resolution chest CT for patients with respiratory symptoms or abnormalities on chest radiograph/PET-CT, and for all children <6 months.

-MRI of brain, pituitary gland, mastoids for patients with clinical or laboratory findings of arginine vasopressin deficiency (previously called central diabetes insipidus), neurologic abnormalities, or bony involvement of the head or neck.

-CT with contrast of abdomen and pelvis or ultrasound of liver and spleen.

-MRI of the spine for patients with vertebral involvement or symptoms concerning for spinal involvement.

-Pulmonary function tests and exercise capacity testing for patients with respiratory symptoms or those with pulmonary LCH. (See "Pulmonary Langerhans cell histiocytosis".)

-Trans-thoracic echocardiogram (TTE) and right heart catheterization for selected patients with pulmonary LCH. (See "Pulmonary Langerhans cell histiocytosis".)

-Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) for patients with cholestatic liver function tests (elevated alkaline phosphatase and/or bilirubin), or abnormal/dilated bile ducts on CT scan or ultrasound.

•Other clinical testing – For selected patients, colonoscopy or abdominal ultrasound may be useful to monitor disease response when PET or other imaging cannot be used.

•Prior to treatment with a targeted agent:

-Electrocardiogram (EKG) prior to treatment with a BRAF inhibitor.

-Echocardiogram and retina exam prior to treatment with an MEK inhibitor.

OVERVIEW OF MANAGEMENT — 

Management of LCH is guided by the extent and severity of disease, as determined by the pretreatment evaluation. (See 'Pretreatment evaluation' above.)

Each of the following questions should be addressed for management of LCH [3]:

●Central nervous system involvement – Is there involvement of the brain parenchyma, pituitary, or involvement of central nervous system (CNS)-"risk" bones (see below)? (See 'Multiple bone lesions' below.)

Involvement of the CNS requires systemic therapy because it is associated with adverse prognosis and increased risk of neurologic damage. The classic "high risk" organs in patients with LCH are the liver, spleen, and bone marrow, as their involvement confers a higher risk of treatment failure and death [4,5]. Importantly, management of critical/risk organ involvement differs according to the patient's age (ie, ≤20 years versus >20 years). (See 'Children' below and 'Adults' below.)

●Single-system versus multisystem involvement – Is there involvement of only a single organ system (eg, bone or skin) versus involvement of more than one organ system?

•Single system – Single bone lesion LCH can often be managed with local treatment (curettage), while limited skin involvement may be managed with local or systemic therapy. Management of single-system disease is similar for children and adults, except where specifically noted. (See 'Single system (children and adults)' below.)

Note that evaluation and management of isolated pulmonary LCH (ie, involvement of lungs, alone) are discussed separately. (See "Pulmonary Langerhans cell histiocytosis".)

•Multisystem – Multisystem LCH typically requires systemic therapy; management of multisystem LCH differs for children and adults, as discussed below. (See 'Multisystem' below.)

●Unifocal versus multifocal involvement – Within a single organ system, is the involvement limited to a single site (unifocal; eg, a single bone lesion), or is it more widespread (multifocal; eg, extensive skin involvement)?

Management of unifocal versus multifocal involvement is discussed within the affected organ system (eg, bone, skin). (See 'Bone' below and 'Skin' below.)

●Symptoms – Does the patient have troublesome symptoms or require treatment to prevent progression or complications of LCH or is the disease asymptomatic?

Our approach to the management of nonpulmonary LCH is consistent with guidelines from an international panel of experts and from the United States National Cancer Center Network [6,7].

We encourage participation of both children and adults in a clinical trial, when possible. The website for the Histiocytosis Association of America and an international directory of affiliated organizations can be found at histio.org, histiocytesociety.org, or clinicaltrials.gov.

SINGLE SYSTEM (CHILDREN AND ADULTS) — 

For both children and adults with single-system LCH, treatment is guided by the involved organ and the extent of disease.

Treatment for single-system LCH is similar for children and adults, except as otherwise noted.

Bone — Management of bone disease is stratified as follows:

●Central nervous system (CNS) risk bones – Involvement of the maxilla, orbit, mastoid, temporal, or sphenoid bones is associated with increased risk for CNS involvement; this association is better documented in children than in adults. Nevertheless, treatment requires systemic therapy because these sites are challenging to treat safely and effectively with surgery and/or radiation therapy (RT). Note that children should not be treated with RT.

Systemic management for CNS risk bones differs for children versus adults, as described below. (See 'Multisystem' below.)

●Non-CNS risk bone lesions

•Single lesion – Management of a single, non-CNS risk bone lesion is the same for children and adults, as described below. (See 'Single bone lesion' below.)

•Multiple bone lesions – Management of other bone disease, including two or more lesions, a single lesion ≥5 cm, and femoral or vertebral involvement requires systemic therapy, as described below. (See 'Multisystem' below.)

Single bone lesion — For a single bone lesion, we generally offer curettage, which provides both a tissue diagnosis and adequate treatment for most patients. RT is a reasonable alternative for selected cases or to enhance symptom control, but it is rarely administered to children. No prospective studies have directly compared curettage versus RT. Spontaneous regression of solitary bone lesions has been reported [8,9].

Note that a single bone lesion ≥5 cm or involvement of a femur, vertebra, or CNS-risk bone (ie, orbit, mastoid, temporal, or sphenoid bone) is managed with systemic therapy, as described below. (See 'Systemic therapy' below.)

Options for the management of a single non-CNS risk bone lesion are:

●Biopsy/curettage – Curettage of a single bone lesion is suitable to establish the diagnosis of LCH, initiate healing, and enable adjacent normal bone to regrow.

Complete excision (ie, "clean margin") of bone lesions is not necessary; complete excision may increase the size of the bony defect, prolong the time for healing, and/or cause permanent skeletal defects. Intra-lesional injection of a glucocorticoid (eg, methylprednisolone 125 mg) may hasten healing and lessen pain at the biopsy site. Clinical judgment should be used to determine if bone grafting is needed.

Curettage is associated with a low recurrence rate (eg, 4 to 10 percent) for small bony lesions [10,11]. Treatment of bone LCH is similar in children and adults, but curettage may be less effective and spontaneous remissions less common in adults. One study compared recurrence rates between skeletally-mature and skeletally-immature patients with solitary LCH [12]. Among 17 skeletally-immature children who underwent biopsy with observation alone or curettage there were no recurrences beyond three years; by contrast, one-quarter of skeletally-mature patients had recurrence following biopsy, curettage, and bone grafting.

●Radiation therapy – RT can be helpful for persistent or recurrent lesions in adults after curettage or systemic therapy. RT should not be used in children.

RT (eg, 6 to 12 gray [Gy] delivered at 2 Gy per fraction) has been used in teenagers and adults with an impending neurologic deficit or if the surgical risk is high (eg, a lesion of the cranial base or odontoid peg) [3,13]. However, we generally favor treatment with single-agent chemotherapy (eg, cytarabine or cladribine), rather than RT for children or adults with osseous sites that are unsafe for RT. (See 'Cytarabine' below and 'Cladribine' below.)

A survey of 30 adults with bone LCH who were treated with various combinations of surgery, radiotherapy, and corticosteroids reported recurrence in one-third, with the lowest rate of recurrence in those who had surgery and RT [14].

●Bisphosphonate therapy – Pamidronate or zoledronic acid may lessen symptoms or improve healing for patients with one or two bone lesions.

Anecdotal reports and small series describe reduced pain, improved function, and/or radiographic response in most patients with osteolytic lesions from LCH when a bisphosphonate was added to surgery or RT in children or adults [15-18]. In one study, responses were seen in 12 of 16 children treated with six courses of pamidronate at four-week intervals, but the role of pamidronate in the healing of bone and other lesions is uncertain [19].

●Denosumab – Denosumab, an antagonist to the receptor activator of NF-kB ligand, can be efficacious for treating bone lesions in adults with LCH.

Treatment with four doses of denosumab 120mg subcutaneously every 8 weeks was associated with 80 percent response rate [20]. No permanent sequelae were reported one year later.

Multiple bone lesions — For patients with two or more bone lesions, a single bone lesion ≥5 cm, femoral or vertebral involvement, or involvement of a CNS risk bone (ie, orbit, mastoid, temporal, or sphenoid bones), treatment involves systemic therapy. Adjunctive surgical techniques (and/or RT for adults) may be added to lessen the risk of complications.

Note that the preferred systemic treatment differs for children versus adults:

Systemic therapy

●Children – For patients ≤20 years with multiple bone lesions, we treat with systemic therapy, as described below. (See 'Children' below.)

●Adults – For adults with multiple bone lesions who do not have CNS or risk organ involvement, we treat with systemic therapy, as described below. (See 'No CNS or risk organ involvement' below.)

Adjunctive treatment — Surgical stabilization, bone grafting, and/or RT may be used to prevent complications with weight-bearing bones. Involvement of the spine or femora can cause bone pain, fracture from weight-bearing, or vertebral collapse/spinal cord compression.

●Surgery – Orthopedic intervention with bracing or bone grafting may be necessary for patients with neurologic symptoms or unstable lesions. For children with lesions of the spine (eg, vertebra plana), bed rest and external immobilization with a rigid orthesis may enable reconstitution of vertebral body height because this does not involve the endochondral ossification centers [21].

●Radiation – RT should be considered for adult patients with bone lesions of vertebrae or the femoral neck, which are at risk of collapse, but the benefit must be weighed against adverse effects, including potential risk of damage to endochondral ossification centers in children [22,23].

RT for LCH offers symptomatic and radiographic responses in adults; it has only rarely been used in children [24]. LCH-related bone pain generally resolves within four months and provides long-term control for most patients.

Skin — For patients who appear to have skin-only LCH, it is important to exclude involvement of other organs, as many children who present with cutaneous involvement also have multisystem LCH [25]. Clinical evaluation, laboratory studies, and positron emission tomography (PET)/CT to evaluate systemic disease are discussed above. (See 'Pretreatment evaluation' above.)

Patients with skin-only disease may have spontaneous regression of cutaneous LCH (ie, "self-healing cutaneous LCH"), or they may progress to multisystem involvement; up to 40 percent of infants have been reported to progress to multisystem involvement [26-28]. Pediatric patients with circulating BRAF-mutated cells are more likely to have multisystem involvement or to relapse, but the natural history only becomes apparent with clinical investigation and follow-up.

Management of skin disease is informed by the presence of symptoms and the extent of involvement (eg, unifocal versus multifocal or extensive disease):

●Asymptomatic – Observation alone is acceptable for asymptomatic patients with limited (eg, small surface area) LCH, if that is acceptable to the patient and/or caregivers. Some patients may favor treatment as described for symptomatic disease.

●Symptomatic and/or extensive skin disease – We treat symptomatic and/or extensive skin involvement with topical therapy or an oral agent. The choice of treatment varies with the severity and extent of disease and patient preference.

•Topical triamcinolone

•Hydroxyurea – Hydroxyurea 10 mg/kg twice daily, as a single agent or in combination with either [29-31]:

-Prednisolone 20 to 40 mg/m² twice daily

-6-mercaptopurine 50 mg/m² daily

•Lenalidomide 25 mg on days 1 to 21 in 28-day cycles [32]. Thromboprophylaxis should be considered when administering lenalidomide or thalidomide. (See "Multiple myeloma: Prevention of venous thromboembolism", section on 'Choice of VTE prophylaxis'.)

•Thalidomide 100 mg daily, by mouth [33].

Small retrospective studies and case reports have described responses to topical steroids, topical and oral methotrexate, hydroxyurea, lenalidomide, and thalidomide [29,31-35], but there are no prospective comparisons of these agents for cutaneous LCH. The combination of methotrexate plus hydroxyurea has been particularly successful for women with genital lesions [31].

Other noncritical organs — Lymph nodes, thyroid, and thymus are considered noncritical organs, but they require systemic chemotherapy, as described for multisystem involvement. (See 'Multisystem' below.)

Lymph nodes that drain another LCH lesion are not considered lymph node involvement unless they are enlarged and asymmetrically PET-avid. In addition, it is important to rule out reactive infiltration of a lymph node by non-neoplastic Langerhans cells [36].

Spontaneous regression of lymph node involvement has been reported. Extensive surgery (eg, neck dissection) should not be performed to avoid the adverse surgical effects.

Management of specific sites such as oral cavity and gingiva may include hydroxyurea or oral methotrexate.

For a single polyp in the gastrointestinal tract, observation or endoscopic excision are acceptable [37]. For more extensive gastrointestinal involvement, systemic therapy should be offered.

Evaluation, diagnosis, and management of lung involvement (isolated pulmonary LCH) are discussed separately. (See "Pulmonary Langerhans cell histiocytosis".)

MULTISYSTEM — 

Management of multisystem LCH is risk-adjusted and informed by the patient's age.

We encourage participation in a clinical trial, when possible. (See 'Clinical trials' below.)

The level of risk is determined by whether there is involvement of the central nervous system (CNS) and/or one of the critical ("risk") organs (ie, bone marrow, liver, or spleen).

●High risk – High-risk multisystem LCH includes involvement of CNS and/or a risk organ.

•Children – Management of high-risk multisystem LCH in children (<20 years old) is described below. (See 'Vinblastine-prednisone induction therapy' below.)

•Adults – Management of high-risk multisystem LCH in adults is described below. (See 'CNS or risk organ involvement' below.)

●Low risk – Low-risk multisystem LCH may involve skin, bone, lymph nodes, thymus, hypophysis, and gastrointestinal tract, but not the CNS or a risk organ.

•Children – Management of low-risk multisystem LCH in children (<20 years old) is described below. (See 'Vinblastine-prednisone induction therapy' below.)

•Adults – Management of low-risk multisystem LCH in adults is described below. (See 'No CNS or risk organ involvement' below.)

Children — For initial treatment of children with multisystem LCH, we suggest induction therapy with vinblastine plus prednisone (V-P), rather than other chemotherapy regimens or a targeted agent. This suggestion is based on high rates of response and tolerable toxicity with V-P; by contrast, there is limited experience with targeted agents for initial treatment in children.

V-P induction therapy is associated with an objective response in approximately 90 percent of children, including nearly two-thirds of children with critical organ involvement; V-P is generally well-tolerated in children, but half of patients relapse or progress [5,38]. Details of V-P therapy in children are presented in Outcomes (below).

Vinblastine-prednisone induction therapy — V-P is efficacious and well tolerated in children and is considered the standard systemic treatment for patients ≤20 years old [5]. Subsequent management is guided by the response to induction therapy. (See 'Continuation phase' below.)

●Administration – We treat both high-risk (CNS and/or risk organ involvement) and low-risk patients with the following induction therapy:

•Vinblastine (6 mg/m² intravenous bolus weekly) for six weeks

•Prednisone (40 mg/m² daily by mouth for four weeks, then tapering over two weeks)

Response should be assessed within two weeks of completing induction therapy, as described below. (See 'Response assessment' below.)

Subsequent treatment is guided by the response to induction therapy and whether there was CNS or risk-organ involvement at the time of induction initiation, as described below. (See 'Continuation phase' below.)

●Adverse effects (AEs) – The most common side effects of vinblastine are constipation, mild cytopenias, and, rarely, alopecia. Peripheral neuropathy is more common in teenagers than in younger children. Over the course of 12 months therapy, prednisone causes excessive appetite and weight gain and mood changes in many; it may be associated with hypertension, glucose intolerance, osteopenia, and myalgias. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Other vinca alkaloids'.)

●Outcomes – V-P is effective and well-tolerated in children, but it has limited efficacy and is poorly tolerated in patients >20 years. (See 'Adults' below.)

In the LCH-III study, >500 children (<18 years) were stratified for treatment as high risk (CNS or risk-organ involvement) versus low risk (no CNS or risk-organ involvement) [5].

•High-risk patients were randomly assigned to induction with V-P versus V-P plus methotrexate, followed by 12 months of continuation therapy (using the induction regimen plus mercaptopurine). Addition of methotrexate did not increase the response rate, accelerate disease resolution, or increase survival, but it was associated with increased toxicity. Outcomes included 71 percent response, 84 percent five-year overall survival (OS), and 27 percent relapse/progression. Grade ≥3 toxicity (eg, infections, cytopenias, hepatotoxicity) was more common in the patients treated with methotrexate (30 versus 7 percent).

•Low-risk patients received V-P induction and responders were randomly assigned to 6 versus 12 months of continuation therapy. Responses occurred in 86 percent, but longer continuation therapy was associated with lower reactivation rates at three years (34 versus 44 percent, respectively) and at five years (37 versus 54 percent). Toxicity was mild in both arms.

Results in LCH-III were superior to outcomes from earlier studies [38]. LCH-II used the same induction regimen but included only six months of continuation therapy [39], while LCH-I compared induction with a glucocorticoid plus vinblastine versus a glucocorticoid plus etoposide [40]. In LCH-III, five-year OS in high-risk patients (84 percent) was superior to that in LCH-II (69 percent) and LCH-I (62 percent); five-year reactivation was also lower in LCH-III compared with LCH-II and LCH-I (27 versus 44 and 55 percent, respectively). Other modifications of the V-P regimen (eg, increased prednisone dose, adding cytarabine) and lengthening continuation therapy did not substantially increase the response rate or improve event-free survival (EFS) among 82 children [41].

Ongoing studies are testing if addition of mercaptopurine to V-P is beneficial for high-risk patients (LCH-IV) and comparing V-P versus single-agent cytarabine (NCT02670707).

Continuation phase — Relapse can be expected if no continuation therapy is given after achieving a response with V-P induction therapy [40]. Continuation therapy is stratified according to involvement of critical organs at initiation of induction therapy and the extent of response:

●Complete response (CR) after six-week induction treatment

•Low risk – Continuation therapy comprises vinblastine (6 mg/m² intravenously once every three weeks) plus prednisone (40 mg/m² daily in three doses orally on days 1 to 5 every three weeks) for a total therapy time of 12 months.

•High risk – For children who presented with CNS or risk-organ involvement, continuation therapy adds mercaptopurine (50 mg/m² daily orally) to prednisone (40 mg/m² daily in three doses orally on days 1 to 5) and vinblastine (6 mg/m² intravenously per day once every three weeks) for 12 months.

●Partial response (PR) – Repeat V-P induction therapy. (See 'Vinblastine-prednisone induction therapy' above.)

●Stable disease or progressive disease – Treat with a second-line chemotherapy regimen. (See 'Relapsed or refractory LCH' below.)

After completing a year of treatment, we reassess patients clinically every three months for two years, every six months for two years, and then yearly. Repeat imaging is done at 3, 6, and 12 months and then stopped, unless clinical symptoms or signs indicate the need for repeat imaging.

Adults — Treatment for multisystem LCH in adults is stratified according to whether there is involvement of the CNS and/or one of the "risk" organs (ie, bone marrow, liver, spleen).

No CNS or risk organ involvement — For adults with multisystem LCH that does not involve the CNS or a risk organ, we suggest single-agent cytarabine or cladribine, rather than combination chemotherapy or a targeted agent.

Single-agent cytarabine or cladribine was associated with superior efficacy and less toxicity compared with V-P in a study that included 58 adults with bone or multisystem LCH [42]. Cytarabine and cladribine have not been directly compared with a targeted agent.

Some patients with multisystem LCH may warrant treatment with a BRAF inhibitor or an MEK inhibitor rather than chemotherapy; advantages and disadvantages of these approaches are discussed below. (See 'BRAF V600E LCH' below and 'Non-BRAF V600E LCH' below.)

Cytarabine and cladribine have not been compared in prospective studies, and the preferred agent varies between institutions. While six or more cycles of cladribine therapy can be associated with prolonged thrombocytopenia and lymphopenia, two to four monthly cycles are effective and unlikely to cause severe cytopenias and/or infections [43]. Some experts favor cytarabine for patients with multifocal bone disease and favor cladribine for brain involvement [42,44,45]. Single-agent chemotherapy options are discussed below. (See 'Cytarabine' below and 'Cladribine' below.)

Cytarabine — Low-dose cytarabine can be effective for patients with multisystem LCH, including multiple bone lesions, but it is generally not administered for patients who have extensive skin lesions.

●Administration – Cytarabine 100 mg/m² over 30 minutes daily for five days, repeated monthly for 12 months.

●Toxicity – Most toxicity is hematologic; grade ≥3 adverse events (AE) were reported in 20 percent of adults in one report [42]. Some patients develop high fevers and/or hypotension with cytarabine.

●Outcomes – A retrospective study reported that cytarabine achieved and sustained a response for one year in 79 percent of 24 adults; most patients had bone involvement, while 43 percent had other sites of disease [42]. In this study, cytarabine was more effective and less toxic than V-P. Cytarabine was also more efficacious than cladribine (79 versus 41 percent responses) and less toxic (grade ≥3 AEs 20 percent versus 37 percent).

Cladribine — Treatment with single-agent cladribine (2-chlorodeoxyadenosine [2-CdA]) is well-tolerated and efficacious for adults and children with LCH.

●Administration – Cladribine is administered as 5 mg/m² (or 0.14 mg/kg) intravenous daily for five days, repeated monthly. We generally treat with two cycles of cladribine, followed by disease restaging. If there is no response, we discontinue cladribine and switch to alternative treatment (targeted therapy or cytarabine). If there is at least a PR to two cycles, we administer two more cycles. We typically use four cycles, but no more than six cycles. Some patients with a PR continue to respond without further therapy [43]. Prophylaxis is generally given for Pneumocystis jirovecii pneumonia, varicella-zoster, and herpes simplex virus, as these patients may become profoundly lymphopenic.

●Toxicity – Cladribine is generally well tolerated but is associated with lymphopenia and/or thrombocytopenia and rarely with febrile neutropenia. Cytopenias can be prolonged, especially after >4 cycles of therapy.

●Outcomes

•Adults – Single-agent cladribine was associated with 79 percent response rate (including 26 percent CR) in a retrospective study that included 38 adults (median 45 years) with multifocal LCH (82 percent with multisystem LCH) [44]. Cladribine was the front-line treatment for three-quarters of the patients and responses were reported in bone, lymph node, skin, lung, and pituitary; a median of four cycles of cladribine was administered. Grade ≥3 AEs included two patients with leukopenia that required treatment delay and one patient with febrile neutropenia; one patient died from sclerosing cholangitis, which is a rare complication of LCH. Five-year progression-free survival (PFS) and OS were 58 percent and 75 percent, respectively.

In adults with bone-predominant disease, treatment with six cycles of cladribine (26 adults) was less efficacious and more toxic (37 versus 20 percent grade ≥3 cytopenias) than cytarabine (24 patients) [42].

Combination chemotherapy in adults — Combination chemotherapy is generally not administered to adults (ie, >20 years) because it is more toxic and less efficacious than single-agent cytarabine or cladribine, as discussed above. (See 'No CNS or risk organ involvement' above.)

●Vinblastine plus prednisone – Treatment of 19 adults with V-P (the standard combination chemotherapy for children) was associated with grade ≥3 neuropathy in 75 percent but achieved and sustained a response for one year in only 16 percent of patients [42]. Neuropathy caused by V-P can be irreversible for some patients [46]. A retrospective multicenter study that included 35 adults (80 percent with multisystem LCH) reported 70 percent response to V-P, no grade ≥3 peripheral neuropathy, but 40 percent of patients experienced LCH reactivation [47].

Other combination chemotherapy regimens that have been evaluated for LCH in adults include:

•Vindesine plus prednisone – A retrospective single-center study reported that vindesine plus prednisone was associated with 64 percent response, which was comparable to the 70 percent response with more intensive CEVP (cyclophosphamide, etoposide, vindesine, prednisone) [48]. However, vindesine-prednisone in adults was associated with more disease recurrence and deaths compared with pediatric patients [49].

•Methotrexate plus cytarabine – Treatment of adults with cytarabine plus methotrexate (MTX) was associated with high rates of response but substantial toxicity. Six cycles of MTX (1 g/m² body surface area [BSA] intravenously) on day 1 and cytarabine (0.1 g/m² BSA intravenously) on days 1 to 5 of every 28-day cycle was associated with 100 percent response (17 percent CR), 97 percent OS, and 49 month estimated EFS, with median follow-up of 44 months [50]. However, grade ≥3 neutropenia and thrombocytopenia were reported in 78 and 61 percent, respectively. Another study reported 88 percent response rate, but grade ≥3 cytopenias in 94 percent and 48 percent febrile neutropenia [51].

•MACOP-B – A retrospective report of seven patients treated with MACOP-B (cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomycin, and prednisone) reported five CR and two PR; three patients relapsed from 5 to 62 months after treatment [52]. No patient required discontinuation of treatment for toxicity and only two patients had a treatment delay due to grade 3 neutropenia.

CNS or risk organ involvement — Involvement of the CNS or a critical/risk organ (ie, bone marrow, liver, or spleen) is associated with inferior outcomes.

BRAF V600E LCH — For BRAF V600E-mutated LCH in adults who are systemically ill with involvement of the CNS or a critical/risk organ, we suggest a BRAF inhibitor (eg, vemurafenib, dabrafenib) rather than systemic chemotherapy. BRAF inhibitors act quickly to prevent progression in nearly all patients and are associated with acceptable toxicity, but they require prolonged therapy. BRAF inhibitors have not been compared with chemotherapy in a prospective trial.

Management of ascending cholangitis or neurodegenerative LCH with BRAF V600E is discussed below. (See 'Special considerations' below.)

There is no evidence that either BRAF inhibitor is more effective or better tolerated. Patients with an intolerance for one BRAF inhibitor may be able to switch to an alternate BRAF inhibitor without the same AEs. Follow-up with BRAF inhibitors has been limited and they can cause cutaneous AEs (including cancers), are expensive, have limited availability, and may require life-long treatment. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'BRAF V600 mutant disease'.)

Some patients or clinicians may favor chemotherapy, instead of a targeted agent. Advantages and disadvantages of chemotherapy versus a targeted agent include:

●Single-agent chemotherapy – Treatment with chemotherapy requires frequent medical visits for intravenous administration and is associated with hematologic and other AEs. However, chemotherapy is only administered for a limited period (eg, six months) and it may achieve long-term disease control and potential cure. Many patients favor chemotherapy to avoid the life-long treatment that may be needed for a targeted agent.

●BRAF inhibitors – Targeted agents are administered orally, but they require prolonged therapy; some targeted agents are associated with development of secondary cancers, while discontinuation of BRAF inhibitors may lead to recurrence of disease. Agents that target mutant BRAF (BRAF is mutated in more than half of LCH cases) are associated with prompt, robust, and potentially long-lasting responses. In practice, patients who have achieved a good response can be maintained in remission with chronic low-level dosing, with planned treatment breaks and close monitoring.

Vemurafenib has demonstrated efficacy in LCH with BRAF V600E [53]. The VE-BASKET trial reported that vemurafenib was associated with a complete metabolic response by positron emission tomography (PET) in all four patients with LCH [54]. In another study, treatment of six adults with vemurafenib or dabrafenib was associated with a response in 83 percent (33 percent CR, 50 percent PR), four to six months median time to response, and three patients with CNS disease attained a sustained remission >12 months [55]. Cutaneous AEs were common, including squamous cell carcinomas (SCC) and keratoacanthomas; one patient developed sclerosing cholangitis while on vemurafenib resulting in death.

Non-BRAF V600E LCH — For adults with CNS or risk-organ involvement whose tumor does not harbor BRAF V600E, we suggest single-agent cytarabine, cladribine, or a MEK inhibitor rather than combination chemotherapy. Single-agent chemotherapy is more efficacious and less toxic than combination chemotherapy in adults.

No studies have directly compared these treatments in this setting.

●Cytarabine – Administration, toxicity, and outcomes with cytarabine are presented above. (See 'Cytarabine' above.)

●Cladribine – Administration, toxicity, and outcomes with cladribine are presented above. (See 'Cladribine' above.)

●MEK inhibitors – MEK inhibitors can be considered for initial therapy, especially if a rapid response is warranted in patients with non-BRAF-V600E MAPK pathway mutations (BRAF indels, KRAS, MEK1 [MAP2K1], MEK2 [MAP2K2], ARAF) or without a detectable mutation, or where mutation testing is unfeasible.

For rare cases with mutations outside of the MAPK-ERK pathway (eg, CSF1R mutations, RET, or ALK gene fusions, where MEK inhibitors are not expected to yield a response), specific inhibitors for those abnormalities can be considered.

•Administration – We generally begin with cobimetinib 40 mg orally daily for the first 21 days of each 28-day cycle. The dose can be titrated according to response and tolerability, and the treatment continues until disease progression or unacceptable toxicity.

Cobimetinib can be taken with or without food and should not be taken with strong or moderate CYP3A inhibitors.

Patients should be monitored for retinopathy and reduced left ventricular ejection fraction.

Cobimetinib is approved by the US Food and Drug Administration as a single agent for adults with histiocytic neoplasms.

•Toxicity – Grade ≥3 rash, fatigue, and/or thrombocytopenia are reported in approximately one-third of patients. The rash associated is mostly acneiform and can be treated with topical acne medications (benzoyl peroxide, tretinoin) for mild cases or oral doxycycline and minocycline for more severe cases.

Less common AEs include cutaneous malignancies, hemorrhage, cardiomyopathy, cutaneous reactions, retinopathy, retinal vein occlusion, hepatotoxicity, rhabdomyolysis, and photosensitivity.

•Outcomes

-Cobimetinib was associated with 89 percent overall response rate (ORR) in 18 patients with histiocytic neoplasms (including two cases with LCH and two with mixed histiocytosis) [56].

-A retrospective study in 23 adults with LCH, published in abstract form, reported 78 percent ORR to an MEK inhibitor (either cobimetinib or trametinib); 4 patients received the MEK inhibitor as frontline therapy [57]. Grade ≥3 rash, fatigue, and/or thrombocytopenia were reported in one-third of patients.

Cobimetinib and trametinib appear to have comparable efficacy; some AEs can be alleviated by switching from one drug to another.

Special considerations — The following conditions require special considerations:

●CNS mass lesions – Chemotherapy is generally given after resection and/or radiation therapy (RT) for CNS mass lesions.

CNS mass lesions, including the hypothalamus and pituitary, have been effectively treated with clofarabine, cladribine, or V-P [45,46,58]. We generally favor cladribine, based on tolerability. If cytarabine is given, we treat with a higher dose (eg, 150mg/m²) and/or in combination with methotrexate.

Among 212 patients with diabetes insipidus in a registry study of 1741 patients, treatment of the pituitary damaged by LCH did not reverse arginine vasopressin deficiency, but some patients required lower doses of desmopressin (DDAVP) after receiving chemotherapy [59].

Rarely, a solitary brain mass or enlarged pituitary has been treated with surgical resection or RT alone (ie, without chemotherapy), usually in a patient with known LCH. Low-dose RT has achieved remission, according to a case series [60].

●Neurodegenerative LCH – We treat neurodegenerative LCH with a BRAF or MEK inhibitor, but there is only limited experience in this setting [6].

Treatment with vemurafenib or dabrafenib was associated with clinical and MRI improvements in three of four patients [61].

Cytarabine, with or without vincristine, was associated with improved clinical (six of eight patients) and MRI findings (five of eight patients); all but two of seven patients had stable neurologic and radiographic findings for >10 years after stopping therapy [62]. Some experts have used higher-dose cytarabine (eg, 175 mg/m²) in this setting.

●Ascending cholangitis – We generally treat this grave complication with a targeted agent because it is often poorly responsive to chemotherapy. The choice of a targeted agent is guided by the patient's mutation.

It is important to biopsy the liver for histopathologic assessment and molecular testing, even if the biopsy may not reveal LCH-type morphology. Patients with progressive worsening of liver function but no active LCH should be considered for liver transplantation.

●Mixed LCH/Erdheim-Chester disease (ECD) – LCH can occur concomitantly with or before ECD in adults.

Mixed LCH/ECD is associated with BRAF V600E mutations in 80 percent of patients, and multiple organs are generally involved [63-65]. There is a high prevalence of secondary or concomitant myeloid neoplasms (eg, myelodysplastic syndromes/neoplasms, chronic myelomonocytic leukemia, and myelofibrosis).

Treatment is usually with a targeted agent, as with the management of ECD. (See "Erdheim-Chester disease".)

RESPONSE ASSESSMENT — 

We assess the response to treatment for LCH using positron emission tomography (PET). PET is sensitive to the detection of most LCH and typically demonstrates a response before it is apparent with other modalities, such as bone scan or plain radiography [2].

For settings where PET is not useful (eg, brain lesions), when there are no imaging abnormalities (eg, gastrointestinal [GI] tract), or if PET is not available or contraindicated (eg, infants), we use clinical evaluation (including endoscopy for GI lesions), computed tomography (CT), and/or magnetic resonance imaging (MRI) to assess response. Circulating BRAF-mutated cells can be monitored in the peripheral blood by a sensitive polymerase chain reaction (PCR) test, if available [63].

Timing of response assessment depends on the sites of disease:

●Single-system disease – We generally review symptoms, examine involved sites, and repeat PET/CT two months after curettage of a bone lesion or treatment of skin disease.

●Multisystem disease

•Children – PET/CT imaging should be repeated after completion of induction therapy.

•Adults – Response is guided by the treatment. We assess response after two cycles of chemotherapy after three to six months of a targeted agent, or as clinically indicated.

Responses are defined as:

●Complete response (CR)

•PET – Normalization of lesions with FDG uptake equal to surrounding background tissue.

•CT or MRI – Complete anatomic resolution of lesions or abnormal features (eg, enhancement, diffusion restriction).

●Partial response (PR)

•PET – Reduction from baseline standardized uptake value (SUV) of lesions, but persistent uptake greater than surrounding background tissue.

•CT or MRI – Reduction, but not complete resolution of lesions or abnormal imaging features.

●Progressive disease (PD)

•PET – Appearance of new FDG-avid lesions or increased SUV value of previously detected lesions.

•CT or MRI – Appearance of new lesions or worsening of abnormal features or growth of existing lesions.

●Stable disease (SD) – Does not meet any of the criteria described above.

The level of circulating tumor (ct) BRAF V600E deoxyribonucleic acid (DNA) has been reported to correlate with high-risk clinical characteristics, higher risk of relapse, and more extensive disease in children [64-69]. We await further validation before using this clinically because apparent responses may reflect low levels of circulating cells.

RELAPSED OR REFRACTORY LCH — 

Management of relapsed or refractory (r/r) LCH should be individualized according to the timing of relapse, sites of disease, performance status, and previous treatment. Only case reports and small case series are available to guide the care of these patients; we encourage enrollment in a clinical trial, when available.

Single-system r/r disease — Management of r/r single-system disease is guided by the disease site.

Systemic therapy can be used for multiply relapsed disease, as discussed below. (See 'Multisystem r/r disease' below.)

●Bone-only – For bone disease that recurs after curettage, treatments may include radiation therapy, chemotherapy (cytarabine or cladribine), and/or a bisphosphonate. (See 'Bone' above.)

●Skin-only – For skin recurrence after topical therapy, treatment with an oral agent (eg, hydroxyurea, methotrexate, lenalidomide, or thalidomide) can provide disease control and symptomatic relief [30-33]. (See 'Skin' above.)

Multisystem r/r disease — For r/r multisystem LCH, we generally offer systemic treatment that differs from the initial therapy.

●Children – For children who relapse >12 months after completing vinblastine plus prednisone (V-P), retreatment with V-P alone or combined with oral methotrexate or mercaptopurine can be effective; approximately 85 percent of patients achieved a second remission using this approach [70].

For other cases of r/r LCH in children, we generally treat with single-agent cytarabine or cladribine. A BRAF inhibitor may be effective for BRAF-mutated disease.

Outcomes with treatment of r/r LCH in children include:

•Cladribine monotherapy

-In the prospective study of r/r LCH (LCH-S-98), response to cladribine was related to whether critical organs were involved. The response rate was 62 percent in 37 children with no risk-organ involvement compared with 22 percent in 46 children with risk-organ involvement [71]

-Treatment of 44 children (median age four years; none with risk-organ involvement) with cladribine (median six cycles) was associated with 57 percent objective response, 14 percent stable disease, and 30 percent progressive disease [72]. Five-year overall survival (OS) was 98 percent, and disease progression or reactivation occurred in 34 percent. Lymphopenia <500/microL was reported in 72 percent; grade ≥3 adverse effects were uncommon, and there was no neuropathy or second malignancies.

-Response to cladribine was reported in 4 of 10 patients with refractory high-risk disease in a retrospective study [73].

•Cladribine combination therapy

-Cladribine plus high-dose cytarabine – Higher-dose cladribine 9 mg/m²/d for five days plus high-dose cytarabine 1 g/m²/d for five days has been used for children with r/r high-risk LCH [74-76]. Treatment of 27 patients with refractory, risk-organ-involved LCH reported 92 percent response rate and 85 percent five-year OS [76]. Long periods of pancytopenia may occur after each course.

-Reduced-dose cladribine plus cytarabine – Reduced-dose cladribine 5 mg/m²/d for five days plus cytarabine 100 mg/m²/d for four days together with other agents (eg, vincristine, mercaptopurine, and others) was active for children with relapsed LCH, including four of nine patients who maintained a complete response (CR) for >6 years and three patients with a CR for 1 to 2.4 years [77].

•Cytarabine – Single-agent cytarabine for recurrent LCH was associated with 41 percent three-year progression-free survival (PFS) [78].

•Clofarabine – In children with refractory LCH, clofarabine was well tolerated and efficacious, including 100 percent PFS in patients treated for ≥12 months [79-81]

•Targeted agents

-BRAF inhibitors can achieve a response in patients with neurodegenerative LCH, but PFS was only 33 percent [69]. A study of 54 children reported 100 responses after two months of therapy, but PFS was approximately 5 percent [67]. BRAF inhibitors may be particularly effective in children with bone marrow and liver LCH that were refractory to standard therapy. Treatment with BRAF inhibitors is discussed above. (See 'BRAF V600E LCH' above.)

-Dabrafenib combined with trametinib (MEK inhibitor) achieved a rapid and sustained response in a patient with BRAF V600E-mutant LCH [66].

●Adults – For adults who relapse after treatment with cytarabine or cladribine, we generally treat with a targeted agent or an alternative chemotherapy agent. The choice of therapy should be individualized based on patient and disease-specific factors.

•Chemotherapy – There is limited experience with switching from one chemotherapy regimen to another in relapsed LCH. For patients who relapse after V-P, single-agent cytarabine or cladribine is a good choice. Switching treatments from cladribine to cytarabine (and vice versa) can be considered if the relapse occurs >1 year after initial treatment.

•Targeted agents – Treatment with a kinase inhibitor for r/r LCH after chemotherapy is discussed above. (See 'BRAF V600E LCH' above.)

•Allogeneic hematopoietic cell transplantation (HCT) – Allogeneic HCT is rarely used for LCH, is associated with substantial toxicity, and is not well studied for multiply relapsed disease.

A report of 87 patients (mostly children) with high-risk LCH who underwent HCT reported 73 percent OS for those transplanted since 2000 [82]. Estimated survival at three years was similar following myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) (77 versus 71 percent, respectively), but relapses were more common after RIC (28 versus 8 percent).

Case reports and small case series suggest that HCT may be effective in preventing relapse among patients in complete remission at the time of HCT [82-87].

POST-TREATMENT SURVEILLANCE

Monitoring — Patients should be monitored periodically for relapse and treatment-related toxicity after completion of therapy.

We generally see patients every two to three months until a complete response is achieved and individualize the schedule of visits based on clinical judgment and comfort of the patient and clinician. Positron-emission tomography (PET)/CT can be performed every two to three months until the best response, and the interval extended to six months or longer. However, the frequency and extent of follow-up visits should be individualized according to disease activity, treatment, and comfort of the clinician and patient.

The need for long-term follow-up for disease relapse was shown by a retrospective study of 335 pediatric patients with multisystem LCH who achieved a complete response; nearly one-half had disease reactivation within two years, but most again responded to therapy [70]. Similarly, in a study of 219 adults with LCH, five-year progression-free survival was 58 percent, and deaths unrelated to relapsed LCH started rising after that time point [88].

Patients with arginine vasopressin deficiency (AVP-D) and/or skull lesions in the orbit, mastoid, or temporal bone are at high risk of central nervous system (CNS) involvement at the time of initial diagnosis and at the time of relapse. These patients should have an MRI without gadolinium contrast every 1 to 2 years for 10 years after treatment [89]. Although radiologic changes may be present, treatment for progression in the CNS is usually reserved for those with worsening radiologic findings or evidence of clinical neurodegeneration.

Guidelines following the treatment of childhood cancer or in those who have received chemotherapy have been published by the Children's Oncology Group [90].

Late effects — Long-term survivors can have residual abnormalities and late effects of the disease and its treatment.

The incidence of late effects is largely dependent on the extent of disease at diagnosis and the treatment received. Children with low-risk disease usually complete treatment with no long-term sequelae beyond mild obesity associated with prednisone therapy. Among 182 patients in a multi-institution study, 24 percent of patients with single-system LCH had permanent consequences, compared with 71 percent who presented with multisystem disease [91]. Among 71 children at a single institution, late sequelae were present in nearly two-thirds of patients who had >3-year follow-up, including dental problems, endocrine disorders, hearing loss, and CNS dysfunction [92]. It should be noted that patients in these two studies were often treated for only six months, which is shorter than the current standard of care.

It is presently unclear if the standard one year of continuation therapy will result in more or different late effects than previous treatments.

Examples include:

●Growth and development – Growth and development problems are common (20 percent) in children who present at a young age; long-term prednisone therapy can be very toxic for very young children. Significant cognitive defects may develop in some long-term survivors [93], and hearing loss was found in 13 percent of survivors [91].

●Endocrine abnormalities – Patients with AVP-D are at risk for panhypopituitarism and should be monitored carefully for adequate growth and development. (See "Clinical manifestations of hypopituitarism" and "Diagnostic testing for hypopituitarism".)

•In a retrospective review of 141 patients with LCH and AVP-D, the 5- and 10-year risks of growth hormone (GH) deficiency were 35 and 54 percent, respectively [94]. There was no increased reactivation of LCH in patients who received growth hormone compared with those who did not.

•A study of 144 patients with multisystem LCH who were followed in a late effects clinic reported that 35 percent had an endocrinopathy, including 49 of 50 with AVP-D [95]. Fifteen patients had received cranial irradiation for treatment of LCH causing AVP-D. GH deficiency occurred to 12 years (median 3.5 years) after diagnosis in 21 patients, 7 of whom had other anterior pituitary deficiencies; GH replacement was beneficial in some patients.

●Infertility – Fertility preservation should be discussed, as there is a risk of infertility with cytotoxic chemotherapy. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

●Second cancers – Patients with LCH can have second cancers before, coincident with, or after the diagnosis of LCH [88]. It is uncertain if and how much treatment increases the risk for second cancers [96,97]. Acute myeloid leukemia and lymphoblastic lymphoma are reported [98,99]. Solid tumors reported to be associated with LCH include retinoblastoma, lung cancer, brain tumors, hepatocellular carcinoma, Askin tumor, and Ewing sarcoma.

●Neurodegenerative LCH – Neurodegenerative LCH is a potentially catastrophic complication of brain involvement caused by infiltration of myeloid dendritic cells [61]. It can present with ataxia, behavioral dysfunction, and cognitive dysfunction more than a decade after the initial diagnosis of LCH and is potentially irreversible. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Central nervous system'.)

Management of neurodegenerative LCH is discussed above. (See 'Non-BRAF V600E LCH' above.)

●Other late effects – Neurologic problems, either secondary to vertebral compression or CNS-LCH (11 percent), and orthopedic defects from lesions of the femur, tibia, or humerus (20 percent) may be seen.

Liver disease may lead to ascending cholangitis, which is not amenable to any treatment other than liver transplant [100]. Patients with LCH-associated ascending cholangitis should be referred promptly for consideration of liver transplantation.

●Chronic pain and fatigue – Patients with LCH often experience chronic pain and debilitating fatigue. The cause is uncertain and symptoms do not necessarily correlate with disease burden.

Many of these patients meet the criteria for myalgic encephalomyelitis/chronic fatigue syndrome; these symptoms may be compounded by concomitant depression and anxiety. Acknowledging these symptoms is important and referral to appropriate specialties (eg, supportive care, fatigue clinic, psychiatry, psychology) may improve the quality of life. In some cases, use of oral stimulants like methylphenidate may be helpful and is considered safe for long-term use. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)

CLINICAL TRIALS — 

An international directory of affiliated organizations dealing with the histiocytic disorders as well as the website for the Histiocytosis Association of America can be found at histio.org. The optimal therapy for all patients with LCH is to be enrolled on clinical trials. Information can be found at histiocytesociety.org or clinicaltrials.gov.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Histiocytic and dendritic cell neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Management – Management of Langerhans cell histiocytosis (LCH) is guided by (see 'Overview of management' above):

•Single-system versus multisystem disease.

•Involvement of the central nervous system (CNS) or a critical ("risk") organ (bone marrow, liver, or spleen).

•Unifocal versus multifocal/extensive disease.

•Symptoms.

•Age – Preferred systemic treatment for children (≤20 years) (see 'Children' above) differs from adults. (See 'Adults' above.)

●Single-system disease

•Bone-only – Classification is described above. (See 'Bone' above.)

-Single bone – Curettage provides tissue diagnosis and treatment. Radiation therapy (RT) may be used for selected adults, but not children. (See 'Single bone lesion' above.)

-Multiple bones – For ≥2 bone lesions, lesions ≥5 cm, femoral or vertebral involvement, or CNS-risk bone (ie, orbit, mastoid, temporal, sphenoid), treatment involves systemic therapy. (See 'Systemic therapy' above.)

Surgery or RT may be added in selected cases. (See 'Adjunctive treatment' above.)

•Skin-only – Topical steroids, oral hydroxyurea, methotrexate, thalidomide, or lenalidomide can be effective. (See 'Skin' above.)

•Primary pulmonary LCH is discussed separately. (See "Pulmonary Langerhans cell histiocytosis".)

●Multisystem – Multisystem disease requires systemic therapy.

•Children – For initial systemic treatment of children with LCH, we suggest induction therapy with vinblastine plus prednisone (V-P), rather than other chemotherapy regimens or a targeted agent (Grade 2C). (See 'Vinblastine-prednisone induction therapy' above.)

Treatment response guides further management; continuation therapy is 12 months for response to V-P. (See 'Continuation phase' above.)

•Adults – Stratify treatment for adults according to the involvement of CNS or risk organ (ie, liver, spleen, bone marrow):

-No CNS or risk organ involvement – For multisystem LCH in adults with no CNS or risk organ involvement, we suggest single-agent cytarabine or cladribine, rather than combination chemotherapy or a targeted agent (Grade 2C). (See 'No CNS or risk organ involvement' above.)

-CNS or risk organ involvement – For adults with BRAF V600E-mutated LCH and involvement of CNS or a risk organ, we suggest a BRAF inhibitor (eg, vemurafenib, dabrafenib), rather than systemic chemotherapy (Grade 2C). (See 'BRAF V600E LCH' above.)

For adults with BRAF wildtype LCH with CNS or risk organ involvement, we suggest cytarabine or cladribine, rather than combination chemotherapy or a targeted agent (Grade 2C). (See 'Non-BRAF V600E LCH' above.)

●Response assessment – Positron emission tomography (PET) is preferred for response assessment, but computed tomography (CT), magnetic resonance imaging (MRI), or clinical assessment is used when PET is not available or appropriate (eg, brain lesions).

●Relapsed/refractory (r/r) disease – Treatment of r/r LCH is individualized according to the timing of relapse, sites of disease, performance status, and previous treatment. We generally treat with a different therapy from that used initially. (See 'Relapsed or refractory LCH' above.)

●Long-term surveillance – Patients are at risk for treatment-related toxicity, second cancers, and endocrine complications. (See 'Late effects' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Laurence A Boxer, MD, who contributed to earlier versions of this topic review.