Recent advances in the understanding of the molecular pathogenesis and targeted therapy options in Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder caused by the clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in the lesion. Advances in genomic sequencing techniques have improved our understanding of the pathophysiology of LCH. Activation of the mitogen-activated protein kinase (MAPK) pathway is a key molecular mechanism involved in the development of LCH. Recurrent BRAF mutations and MAP2K1 mutations are the major molecular alterations involved in the activation of the MAPK pathway. Recent studies have supported the “misguided myeloid differentiation model” of LCH, where the extent of disease is defined by the differentiation stage of the cell in which the activating somatic MAPK mutation occurs, suggesting LCH. Several studies have advocated the efficacy of targeted therapy using BRAF inhibitors with a high response rate, especially in patients with high-risk or refractory LCH. However, the optimal treatment scheme for children remains unclear. This review outlines recent advances in LCH, focusing on understanding the molecular pathophysiology, emerging targeted therapy options, and their clinical implications.

Unique Case of Congenital Langerhans Cell Histiocytosis Presenting as Intrauterine Fetal Demise

“…MAP2K1 mutations, as found in our case, have been identified in approximately 50% of BRAF-WT LCH samples and may have clinical implications as for MEK inhibitor therapy. [28][29][30][31][32] Although we are confident that the MAP2K1 variant was detected, it was seen at a low variant allele fraction, presumably secondary to poor DNA quality. A distinction between germline and de novo somatic variants was not made.…”

“…MAP2K1 mutations, as found in our case, have been identified in approximately 50% of BRAF-WT LCH samples and may have clinical implications as for MEK inhibitor therapy. 28-32…”

Progressive nodular histiocytosis with dramatic response to cobimetinib

“…1 Though difficult to treat, there have been significant developments in describing the pathogenesis and mutational landscape of histiocytic disorders. 2,3 We describe a woman with PNH with a remarkable response to targeted therapy identified by mutational analysis.…”

Dynamic Peripheral Blood Lymphocyte Subsets as Predictive Biomarkers for Langerhans Cell Histiocytosis in Children

“…Advances in genomic sequencing techniques lead to deeper understand of LCH [2] . Previous studies reported that BRAF V600E mutation indicated severer disease and resistance to induction therapy [3,4] .…”