Cargando…

Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies

More than a century after its first description, Langerhans cell histiocytosis (LCH) still remains an intriguing disease. Considerable progress in understanding its biology has been achieved recently. Description of the V600E BRAF mutation in samples of LCH tissue in 2010 was followed by description...

Descripción completa

Detalles Bibliográficos
Autores principales: Hutter, Caroline, Minkov, Milen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066850/
https://www.ncbi.nlm.nih.gov/pubmed/27785447
http://dx.doi.org/10.2147/ITT.S91058
_version_ 1782460551737114624
author Hutter, Caroline
Minkov, Milen
author_facet Hutter, Caroline
Minkov, Milen
author_sort Hutter, Caroline
collection PubMed
description More than a century after its first description, Langerhans cell histiocytosis (LCH) still remains an intriguing disease. Considerable progress in understanding its biology has been achieved recently. Description of the V600E BRAF mutation in samples of LCH tissue in 2010 was followed by description of additional mutations, all leading to constitutive ERK activation. Current experimental data suggest that LCH is a myeloid neoplasia with inflammatory properties, yet the exact pathophysiology remains poorly understood. Disease management paradigms have changed over time, closely reflecting the evolving view of the nature of the disease. The international Histiocyte Society have conducted three prospective clinical studies on multisystem LCH since the early 1990s. The standard frontline therapy for patients with multisystem LCH based on the cumulative knowledge of those trials consists of 6–12 weeks of initial therapy (daily oral steroids and weekly vinblastine injections), followed by pulses of prednisolone/vinblastine every 3 weeks, for a total treatment duration of 12 months. A currently ongoing study (LCH-IV) with a complex design (five interventional and two observational strata) targets further reduction of mortality and morbidity by tailoring treatment intensity depending on expected risk, as well as by exploring treatment regimens for special locations. Current knowledge on LCH pathobiology opens opportunities for improvement in the patient outcome. The activating BRAF and MAP2K1 mutations collectively accounting for about 75% of the LCH population as well as the resulting constitutive activation of downstream ERK offer an opportunity for targeted treatment. Related issues (eg, finding most effective and less toxic drugs or combinations, appropriate dosage, and optimal treatment duration) must be addressed in controlled prospective trials. Additional mechanisms, such as the interactions of the mutated dendritic cell clone with other inflammatory cells and key cytokines and chemokines, still remain attractive targets for therapeutic intervention, particularly in patients with localized, less aggressive disease.
format Online
Article
Text
id pubmed-5066850
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-50668502016-10-26 Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies Hutter, Caroline Minkov, Milen Immunotargets Ther Review More than a century after its first description, Langerhans cell histiocytosis (LCH) still remains an intriguing disease. Considerable progress in understanding its biology has been achieved recently. Description of the V600E BRAF mutation in samples of LCH tissue in 2010 was followed by description of additional mutations, all leading to constitutive ERK activation. Current experimental data suggest that LCH is a myeloid neoplasia with inflammatory properties, yet the exact pathophysiology remains poorly understood. Disease management paradigms have changed over time, closely reflecting the evolving view of the nature of the disease. The international Histiocyte Society have conducted three prospective clinical studies on multisystem LCH since the early 1990s. The standard frontline therapy for patients with multisystem LCH based on the cumulative knowledge of those trials consists of 6–12 weeks of initial therapy (daily oral steroids and weekly vinblastine injections), followed by pulses of prednisolone/vinblastine every 3 weeks, for a total treatment duration of 12 months. A currently ongoing study (LCH-IV) with a complex design (five interventional and two observational strata) targets further reduction of mortality and morbidity by tailoring treatment intensity depending on expected risk, as well as by exploring treatment regimens for special locations. Current knowledge on LCH pathobiology opens opportunities for improvement in the patient outcome. The activating BRAF and MAP2K1 mutations collectively accounting for about 75% of the LCH population as well as the resulting constitutive activation of downstream ERK offer an opportunity for targeted treatment. Related issues (eg, finding most effective and less toxic drugs or combinations, appropriate dosage, and optimal treatment duration) must be addressed in controlled prospective trials. Additional mechanisms, such as the interactions of the mutated dendritic cell clone with other inflammatory cells and key cytokines and chemokines, still remain attractive targets for therapeutic intervention, particularly in patients with localized, less aggressive disease. Dove Medical Press 2016-10-12 /pmc/articles/PMC5066850/ /pubmed/27785447 http://dx.doi.org/10.2147/ITT.S91058 Text en © 2016 Hutter and Minkov. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Review
Hutter, Caroline
Minkov, Milen
Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title_full Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title_fullStr Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title_full_unstemmed Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title_short Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies
title_sort insights into the pathogenesis of langerhans cell histiocytosis: the development of targeted therapies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066850/
https://www.ncbi.nlm.nih.gov/pubmed/27785447
http://dx.doi.org/10.2147/ITT.S91058
work_keys_str_mv AT huttercaroline insightsintothepathogenesisoflangerhanscellhistiocytosisthedevelopmentoftargetedtherapies
AT minkovmilen insightsintothepathogenesisoflangerhanscellhistiocytosisthedevelopmentoftargetedtherapies