Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Liliana Montella,Mario Giuliano,Giovannella Palmieri,Fernanda Picozzi,Luigi Insabato,Vittorio Riccio,Margaret Ottaviano,Gaetano Facchini

doi:10.3390/biomedicines9121759

Abstract

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

Highlights

Langerhans cell histiocytosis (LCH) is a rare disease (4.6 cases per 1 million among children under 15 years of age; 1–2 cases per million among adults) and its origin was long a matter of debate
LCH is characterized by the infiltration of tissue, such as skin, bone, brain, lung, and liver tissue, by the hallmark CD1a+ CD207+ cells, such as Langerhans cells (LCs), eosinophils, neutrophils, macrophages, and lymphocytes
LCs belong to the family of dendritic cells that derive from hematopoietic medullary precursors

Summary

Introduction

Langerhans cell histiocytosis (LCH) is a rare disease (4.6 cases per 1 million among children under 15 years of age; 1–2 cases per million among adults) and its origin was long a matter of debate. LCH is characterized by the infiltration of tissue, such as skin, bone, brain, lung, and liver tissue, by the hallmark CD1a+ CD207+ cells, such as Langerhans cells (LCs), eosinophils, neutrophils, macrophages, and lymphocytes. The hallmark cells are present in variable percentages in LCH lesions, ranging from 1% to 70% [1]. The clonally expanded LCs suggest the presence of pathogenetic mechanisms such as those involved in hematological and cancerous disease. The detection of clonal mutations in genes of the mitogen-activated protein kinase (MAPK) pathway placed LCH near to Biomedicines 2021, 9, 1759.

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