Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition
Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylatio...
Gespeichert in:
Veröffentlicht in: | Hematology 2015-12, Vol.2015 (1), p.565-570 |
---|---|
Hauptverfasser: | , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 570 |
---|---|
container_issue | 1 |
container_start_page | 565 |
container_title | Hematology |
container_volume | 2015 |
creator | Abla, Oussama Weitzman, Sheila |
description | Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies. |
doi_str_mv | 10.1182/asheducation-2015.1.565 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1744659635</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1744659635</sourcerecordid><originalsourceid>FETCH-LOGICAL-c379t-e4e77271d02b50934f6ac6463ad5647845966cf77108975230e14b9acc6396363</originalsourceid><addsrcrecordid>eNpNkE1PwjAYxxujEUS_gu7oZdD3rt6QgBgxGoPnpus6V7MXbLcD394tIPH0PIf_W34A3CE4RSjBMx0Km3VGt66pYwwRm6Ip4-wMjBHDMKYkIeenX6IRuArhG0JECcaXYIQ5J0IIMgbrrbe6rWzdRk0ebXT9ZX2h6xAZW5ZR4ULfYPZtE1x4iHxT2kH2-DFfzV7n7y-RqwuXumHFNbjIdRnszfFOwOdquV2s483b0_NivokNEbKNLbVCYIEyiFMGJaE514ZTTnTGOBUJZZJzkwuBYCIFwwRaRFOpjeFEcsLJBNwfcne--elsaFXlwjBW17bpgkKCUt6HENZLxUFqfBOCt7naeVdpv1cIqgGj-o9RDRgVUj3G3nl7LOnSymYn3x838gueAnAY</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1744659635</pqid></control><display><type>article</type><title>Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition</title><source>MEDLINE</source><source>NCBI_PubMed Central(免费)</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Abla, Oussama ; Weitzman, Sheila</creator><creatorcontrib>Abla, Oussama ; Weitzman, Sheila</creatorcontrib><description>Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.</description><identifier>ISSN: 1520-4391</identifier><identifier>EISSN: 1520-4383</identifier><identifier>DOI: 10.1182/asheducation-2015.1.565</identifier><identifier>PMID: 26637773</identifier><language>eng</language><publisher>United States</publisher><subject>Clinical Trials as Topic ; Erdheim-Chester Disease - genetics ; Histiocytosis, Langerhans-Cell - therapy ; Humans ; Imatinib Mesylate - therapeutic use ; Indoles - therapeutic use ; Inflammation ; MAP Kinase Kinase 1 - genetics ; MAP Kinase Signaling System ; Mutation ; Phosphorylation ; Prospective Studies ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - genetics ; Recurrence ; Risk ; Sulfonamides - therapeutic use</subject><ispartof>Hematology, 2015-12, Vol.2015 (1), p.565-570</ispartof><rights>2015 by The American Society of Hematology. All rights reserved.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-e4e77271d02b50934f6ac6463ad5647845966cf77108975230e14b9acc6396363</citedby><cites>FETCH-LOGICAL-c379t-e4e77271d02b50934f6ac6463ad5647845966cf77108975230e14b9acc6396363</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26637773$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abla, Oussama</creatorcontrib><creatorcontrib>Weitzman, Sheila</creatorcontrib><title>Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition</title><title>Hematology</title><addtitle>Hematology Am Soc Hematol Educ Program</addtitle><description>Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.</description><subject>Clinical Trials as Topic</subject><subject>Erdheim-Chester Disease - genetics</subject><subject>Histiocytosis, Langerhans-Cell - therapy</subject><subject>Humans</subject><subject>Imatinib Mesylate - therapeutic use</subject><subject>Indoles - therapeutic use</subject><subject>Inflammation</subject><subject>MAP Kinase Kinase 1 - genetics</subject><subject>MAP Kinase Signaling System</subject><subject>Mutation</subject><subject>Phosphorylation</subject><subject>Prospective Studies</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Recurrence</subject><subject>Risk</subject><subject>Sulfonamides - therapeutic use</subject><issn>1520-4391</issn><issn>1520-4383</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkE1PwjAYxxujEUS_gu7oZdD3rt6QgBgxGoPnpus6V7MXbLcD394tIPH0PIf_W34A3CE4RSjBMx0Km3VGt66pYwwRm6Ip4-wMjBHDMKYkIeenX6IRuArhG0JECcaXYIQ5J0IIMgbrrbe6rWzdRk0ebXT9ZX2h6xAZW5ZR4ULfYPZtE1x4iHxT2kH2-DFfzV7n7y-RqwuXumHFNbjIdRnszfFOwOdquV2s483b0_NivokNEbKNLbVCYIEyiFMGJaE514ZTTnTGOBUJZZJzkwuBYCIFwwRaRFOpjeFEcsLJBNwfcne--elsaFXlwjBW17bpgkKCUt6HENZLxUFqfBOCt7naeVdpv1cIqgGj-o9RDRgVUj3G3nl7LOnSymYn3x838gueAnAY</recordid><startdate>20151205</startdate><enddate>20151205</enddate><creator>Abla, Oussama</creator><creator>Weitzman, Sheila</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20151205</creationdate><title>Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition</title><author>Abla, Oussama ; Weitzman, Sheila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-e4e77271d02b50934f6ac6463ad5647845966cf77108975230e14b9acc6396363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Clinical Trials as Topic</topic><topic>Erdheim-Chester Disease - genetics</topic><topic>Histiocytosis, Langerhans-Cell - therapy</topic><topic>Humans</topic><topic>Imatinib Mesylate - therapeutic use</topic><topic>Indoles - therapeutic use</topic><topic>Inflammation</topic><topic>MAP Kinase Kinase 1 - genetics</topic><topic>MAP Kinase Signaling System</topic><topic>Mutation</topic><topic>Phosphorylation</topic><topic>Prospective Studies</topic><topic>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Recurrence</topic><topic>Risk</topic><topic>Sulfonamides - therapeutic use</topic><toplevel>online_resources</toplevel><creatorcontrib>Abla, Oussama</creatorcontrib><creatorcontrib>Weitzman, Sheila</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Hematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abla, Oussama</au><au>Weitzman, Sheila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition</atitle><jtitle>Hematology</jtitle><addtitle>Hematology Am Soc Hematol Educ Program</addtitle><date>2015-12-05</date><risdate>2015</risdate><volume>2015</volume><issue>1</issue><spage>565</spage><epage>570</epage><pages>565-570</pages><issn>1520-4391</issn><eissn>1520-4383</eissn><abstract>Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.</abstract><cop>United States</cop><pmid>26637773</pmid><doi>10.1182/asheducation-2015.1.565</doi><tpages>6</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1520-4391 |
ispartof | Hematology, 2015-12, Vol.2015 (1), p.565-570 |
issn | 1520-4391 1520-4383 |
language | eng |
recordid | cdi_proquest_miscellaneous_1744659635 |
source | MEDLINE; NCBI_PubMed Central(免费); EZB-FREE-00999 freely available EZB journals |
subjects | Clinical Trials as Topic Erdheim-Chester Disease - genetics Histiocytosis, Langerhans-Cell - therapy Humans Imatinib Mesylate - therapeutic use Indoles - therapeutic use Inflammation MAP Kinase Kinase 1 - genetics MAP Kinase Signaling System Mutation Phosphorylation Prospective Studies Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics Recurrence Risk Sulfonamides - therapeutic use |
title | Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T09%3A14%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Treatment%20of%20Langerhans%20cell%20histiocytosis:%20role%20of%20BRAF/MAPK%20inhibition&rft.jtitle=Hematology&rft.au=Abla,%20Oussama&rft.date=2015-12-05&rft.volume=2015&rft.issue=1&rft.spage=565&rft.epage=570&rft.pages=565-570&rft.issn=1520-4391&rft.eissn=1520-4383&rft_id=info:doi/10.1182/asheducation-2015.1.565&rft_dat=%3Cproquest_cross%3E1744659635%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1744659635&rft_id=info:pmid/26637773&rfr_iscdi=true |