Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach.
Key points
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Nearly every patient with Langerhans cell histiocytosis and Erdheim-Chester disease has ERK activation owing to activating mutations in ARAF, BRAF, MEK1/2, or N/KRAS, or kinase fusions.
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BRAF inhibition results in dramatic and durable responses in patients with BRAF V600E mutant histiocytosis.
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MEK inhibitors may be efficacious for treating BRAF -wild-type histiocytosis.
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The safety and therapeutic usefulness of targeted therapy versus conventional therapy for children with Langerhans cell histiocytosis remains to be determined.
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Further genomic analyses are needed to define fusions in patients without point mutations in kinases and those alterations that cooperate with kinase mutations in histiocytoses.