Langerhans cell histiocytosis: a review of past, current and future therapies

The goal of therapy in Langerhans cell histiocytosis (LCH) is to decrease the activity and proliferation of histiocytes, lymphocytes and macrophages that cause the disease. Patients with disease that is localized to skin, bone and lymph node (defined as "nonrisk" organs) generally have a good prognosis and require minimal treatment. However, patients with lesions in "risk" organs (liver, spleen, lung, bone marrow) have a worse overall prognosis regarding mortality and morbidity. Likewise, patients with LCH in the central nervous system (CNS), vertebrae, facial bones or bones of the anterior or middle cranial fossa are at higher risk for morbidity and recurrent disease. LCH in the orbit, mastoid or temporal skull regions are classified as "CNS risk" because of an increased frequency of developing diabetes insipidus and other endocrine abnormalities or parenchymal brain lesions. Outcomes of patients with LCH in only one bone in "nonrisk" locations are generally benign, and the disease responds well to several treatment modalities including observation, surgical excision, steroid injection or radiation therapy. The last is generally reserved for a single vertebral lesion or when a risk of pathologic fracture exists in the greater trochanter. The greatest challenge in treatment of LCH is patients with multisystem disease. Patients with persistent or worsening disease in risk organs by the end of the first 6-12 weeks of therapy have significantly decreased overall survival regardless of treatment. Additionally, optimal treatment for patients with late-onset CNS symptoms and adults with LCH remain to be defined. In this article we will review the evolution of multicenter and international treatment studies as well as the current Histiocyte Society research treatment protocol, LCH-III. We also review experiences with a variety of agents that have been used to treat LCH outside of clinical trials. Since LCH is a rare disease in children and adults, these patients should be enrolled on clinical trials whenever possible to advance our knowledge of the optimal therapeutic interventions and long-term outcomes.