Current treatment of Langerhans cell histiocytosis

ABSTRACT

Introduction: Langerhans Cell Histiocytosis (LCH) is caused by clonal expansion of CD1a+/CD207+ cells and is characterized by a spectrum of organ involvement and dysfunction. The pathogenic cells are defined by activation of the MAPK signaling pathway. Treatment of LCH is risk-adapted; patients with single lesions may respond well to local treatment, whereas patients with multi-system disease require systemic therapy. The combination of steroids and vinblastine given for a total duration of a year is the standard of care. While survival for patients without organ dysfunction is excellent, mortality rates for patients with organ dysfunction may reach 20%. Despite progress made in the treatment of LCH, disease reactivation rates remain above 30%, and standard second-line treatment is yet to be established. Treatment with BRAF inhibitors is a very promising alternative to current therapies, although prospective validation is required.

Areas covered: This article describes the biology, disease characteristics, treatment modalities, and new directions in the treatment of LCH.

Expert opinion: The pathogenesis of LCH has been redefined by the universal activation of the RAF/MEK/ERK signaling pathway. Therapies designed to target this pathway are promising. New technology for detection of cell free DNA may be used for monitoring response and early detection of recurrence.

KEYWORDS:

• BRAF
• chemotherapy
• disease reactivation
• Langerhans cell histiocytosis

Article highlights

• LCH is a neoplasm of myeloid origin characterized by a clonal proliferation of CD1a+/CD207+ cells. In two-thirds of the cases, a BRAF^V600E mutation is identified, and mutations of other members of the MAPK/ERK pathway such as MAP2K1, MAP3K1, or ARAF are present in the remainder of cases.

• Patients with involvement of only one organ system can often be treated with surgery alone and have excellent outcomes. Patients with multisystem disease, especially with risk organ involvement, need multimodality treatment. Standard front-line treatment includes vinblastine and prednisone.

• Approximately 30-50% of patients experience a disease reactivation. Longer treatments appear to result in lower risk of reactivation.

• Best second-line regimens include nucleoside analogues, alone or in combination. This class of agents is also commonly used in the upfront management of adult patients.

• Treatment with BRAF inhibitors have shown to induce responses in LCH, and the role of BRAF and MEK inhibitors is currently being investigated.

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Declaration of interest

C Rodriguez-Galindo has a consulting/advisory relationship with Novimmune as a member of the Data Safety and Monitoring Board for NC501 study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work has been supported in part by a grant from the St. Baldrick’s Foundation.