CURRENT THERAPIES PRIMARY LANGERHANS CELL HYSTIOCYTOSIS

Langerhans cell histiocytosis (LCH) is a neoplastic histiocytic disorder that most commonly affects bones and skin, but it can also involve the bone marrow, liver, spleen, lungs, pituitary gland/central nervous system, and other organs. LCH is rare, but it is considerably more common in children (especially younger children) than in adults LCH is so-named because the neoplastic cells resemble dendritic Langerhans cells in the skin and mucosa; however, the CD1a+, CD207+ neoplastic cells of LCH are derived from myeloid dendritic cells, rather than from epidermal Langerhans cells. The BRAF V600E mutation is present in more than half of cases, and activation of the mitogen-activated protein kinase (MAPK) pathway is a key driver of this neoplastic disorder. According the Histiocytic Society classification, histiocytic disorders divide into five categories, based on clinical, histologic, immunophenotypic, and molecular features. • Langerhans (L) group: The L group includes LCH, Erdheim-Chester disease (ECD), mixed LCH/ECD, indeterminate cell histiocytosis, and extracutaneous juvenile xanthogranuloma. • Cutaneous and mucocutaneous (C) group • Rosai-Dorfman disease (R) group • Malignant histiocytosis (M) group • Hemophagocytic lymphohistiocytosis (H) group Symptoms, affected organ systems, and disease tempo of LCH vary between patients. Affected individuals range from neonates to adults, although it is more common in young children than adults. The diagnosis may not be made for years after the first clinical manifestations because of its variable presentation. LCH can present as a single site or multiple sites of disease in one organ (eg, in bone or skin) or it can present in multiple organ systems simultaneously or sequentially. This distinction is important for determining prognosis and disease management ➢ Single-system LCH – Patients who present with single-system LCH can be of any age; they typically do not have systemic symptoms of weight loss or fever. The following organs are most often affected and can exhibit unifocal or multifocal involvement: • Bone • Skin • Lungs • Pituitary • Central nervous system (CNS) • Lymph nodes (excluding draining lymph node of another LCH lesion) and other rare locations (eg, thyroid, thymus) ➢ Multisystem LCH – Two or more organs/systems are involved. Among patients with multisystem disease, it is important to identify those with involvement of critical organs (CNS and lung) and "risk" organs (bone marrow, liver, spleen). ➢ Children – Among children, LCH is limited to one organ system in approximately 55 percent of cases; the remainder present with multisystem disease . Acute disseminated multisystem disease is most often seen in children <3 years, while involvement of a single organ is more common in older children and adults. A report involving 1741 children with LCH registered in prospective trials reported the following areas of involvement at the time of diagnosis - Bone – 77 % - Skin – 39 % - Lymph nodes – 19% - Liver – 16% - Spleen – 13% - Oral mucosa – 13% - Lung – 10% - CNS – 6% Adults most commonly present with skin rash, skull or jaw tumor, dyspnea or tachypnea, polydipsia/polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems Management – Management of LCH is guided by the extent and severity of disease, as determined by the pretreatment evaluation. • Single-system versus multisystem disease • Involvement of 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) Single-system disease • Bone-only –Single bone – Curettage provides tissue diagnosis and treatment. Radiation therapy (RT) may be used for selected adults, but not children. - Multiple bones – For ≥2 bone lesions, lesion ≥5 cm, femoral or vertebral involvement, or CNS-risk bone (ie, orbit, mastoid, temporal, sphenoid), treatment involves systemic therapy. Surgery or RT may be added in selected cases. • Skin-only – Topical steroids or mustard, or oral hydroxyurea, methotrexate, thalidomide, or lenalidomide can be effective. • 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). Treatment response guides further management; continuation therapy is 12 months for response to V-P. - 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). 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). • 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). • Long-term surveillance – Patients are at risk for treatment-related toxicity, second cancers, and endocrine complications.