Advances in potential targeted therapies for Erdheim-Chester disease

ABSTRACT

Introduction: Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by infiltration of aberrant macrophages into multiple tissues and organs causing rampant inflammation and fibrosis. The clinical severity and the nuances of disease pathogenesis must be considered when pondering different treatment strategies for the individual patient.

Areas covered: Interferon-α has long represented the first-line treatment for ECD, but its preeminence may be reappraised in the future as new effective medications become available. For example, alternative treatment options include cytokine-blocking agents, which dampen local and systemic inflammation.

Of crucial importance, recent evidence indicates that deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD. These advances in the molecular understanding of ECD as an inflammatory myeloid neoplasm translated into the therapeutic use of small-molecule RAF and MEK inhibitors, with unprecedented results in terms of clinical efficacy.

Expert opinion: In the future, the development of ERK inhibitors holds tremendous promise for the treatment of ECD. Combination therapy with small-molecule plus anti-inflammatory agents may prove more beneficial than either treatment alone. New drugs against fibrosis, not amenable to treatment with currently available strategies, remain an unmet clinical need.

KEYWORDS:

• Anakinra
• cobimetinib
• dabrafenib
• Langerhans’ cell histiocytosis
• myeloid neoplasm
• oncogene-induced senescence
• trametinib
• vemurafenib

Article highlights

• Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by infiltration of aberrant macrophages into multiple tissues and organs causing rampant inflammation and fibrosis. Deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD.

• Interferon-α is the first-line treatment for ECD, but a number of new effective medications are becoming available.

• Anti-cytokine treatment may dampen local and systemic inflammation and prove beneficial.

• Therapeutic use of small-molecule RAF and MEK inhibitors resulted in unprecedented clinical responses.

• Future opportunities in the treatment of ECD include the development of novel ERK inhibitors and combination therapy with small-molecule plus anti-inflammatory agents.

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.