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

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.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

“…As previously reported, MM patients present more activating mutations or amplifications in the receptor tyrosine kinase c-KIT, providing a rationale for targeting C-KIT. Imatinib is the most widely investigated c-KIT inhibitor [ 149 ], followed by other approved C-KIT inhibitors such as sunitinib, dasatinib, nilotinib and masitinib, currently under investigation for c-KIT mutated melanoma in several clinical trials [ 150 , 151 , 152 , 153 ]. However, responses to c-KIT inhibitors depend on the type of mutations, as they are longer and higher for the mutations in exon 11 (L576P) and exon 13 (K642E) of the KIT gene [ 154 , 155 ], while KIT amplification is a non-responding genetic alteration (54% vs. 0% partial response, respectively) [ 153 , 156 ].…”

Langerhans Cell Histiocytosis with Good Response to Low-Dose Imatinib: Case Report and Literature Review

“…Imatinib is designed to block the ATP-binding site in the BCR/APL protein, and it is also an inhibitor of PDGF-R and a KIT (CD117) kinase found in some LCH cases [ 13 , 14 ]. Reviewing the literature, we found 4 case reports describing the use of imatinib in 6 LCH patients ( Table 1 ), and one clinical trial evaluated the efficacy of imatinib in LCH; the TETimaX trial conducted by Montella et al [ 15 ] investigated the role of imatinib in the treatment of LCH, administered at a daily dose of 400 mg for 1 year after discontinuation of all previous treatments. Five patients were enrolled in the clinical portion of the study, and all achieved long-lasting disease control [ 16 ] ( Table 2 ).…”

“…Adapted from TETimaX trial done by Montella et al[15] who assessed the role of imatinib in LCH treatment…”