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A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia

Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indic...

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Autores principales: Enjeti, Anoop K., D’Crus, Angel, Melville, Kathleen, Verrills, Nicole M., Rowlings, Philip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881728/
https://www.ncbi.nlm.nih.gov/pubmed/26967515
http://dx.doi.org/10.1097/CAD.0000000000000358
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author Enjeti, Anoop K.
D’Crus, Angel
Melville, Kathleen
Verrills, Nicole M.
Rowlings, Philip
author_facet Enjeti, Anoop K.
D’Crus, Angel
Melville, Kathleen
Verrills, Nicole M.
Rowlings, Philip
author_sort Enjeti, Anoop K.
collection PubMed
description Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indications. The initial positive results of PP2A activators in vitro and mouse models of AML are promising; however, its safety for use in AML has not been assessed. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A literature review was carried out to assess safety before the commencement of Phase I trials of the PP2A activator Fingolimod in AML. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A systematic review of published literature in Medline, EMBASE and the Cochrane Library of critical reviews was carried out. International standards for the design and reporting of search strategies were followed. Search terms and medical subject headings used in trials involving PP2A activators as well as a specific search were performed for ‘adverse events’, ‘serious adverse events’, ‘delays in treatment’, ‘ side effects’ and ‘toxicity’ for primary objectives. Database searches were limited to papers published in the last 12 years and available in English. The search yielded 677 articles. A total of 69 journal articles were identified as relevant and included 30 clinical trials, 24 review articles and 15 case reports. The most frequently reported adverse events were nausea, diarrhoea, fatigue, back pain, influenza viral infections, nasopharyngitis and bronchitis. Specific safety concerns include monitoring of the heart rate and conduction at commencement of treatment as cardiotoxicity has been reported. There is little evidence to suggest specific bone marrow toxicity. Lymophopenia is a desired effect in the management of multiple sclerosis, but may have implications in patients with acute leukaemia as it may potentially increase susceptibility to viral infections such as influenza. Fingolimod is a potential treatment option for AML with an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and the relatively low rate of serious side effects. As most patients with AML are elderly, specific monitoring for cardiac toxicity as well as infection would be required.
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spelling pubmed-48817282016-06-15 A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia Enjeti, Anoop K. D’Crus, Angel Melville, Kathleen Verrills, Nicole M. Rowlings, Philip Anticancer Drugs Clinical Report Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indications. The initial positive results of PP2A activators in vitro and mouse models of AML are promising; however, its safety for use in AML has not been assessed. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A literature review was carried out to assess safety before the commencement of Phase I trials of the PP2A activator Fingolimod in AML. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A systematic review of published literature in Medline, EMBASE and the Cochrane Library of critical reviews was carried out. International standards for the design and reporting of search strategies were followed. Search terms and medical subject headings used in trials involving PP2A activators as well as a specific search were performed for ‘adverse events’, ‘serious adverse events’, ‘delays in treatment’, ‘ side effects’ and ‘toxicity’ for primary objectives. Database searches were limited to papers published in the last 12 years and available in English. The search yielded 677 articles. A total of 69 journal articles were identified as relevant and included 30 clinical trials, 24 review articles and 15 case reports. The most frequently reported adverse events were nausea, diarrhoea, fatigue, back pain, influenza viral infections, nasopharyngitis and bronchitis. Specific safety concerns include monitoring of the heart rate and conduction at commencement of treatment as cardiotoxicity has been reported. There is little evidence to suggest specific bone marrow toxicity. Lymophopenia is a desired effect in the management of multiple sclerosis, but may have implications in patients with acute leukaemia as it may potentially increase susceptibility to viral infections such as influenza. Fingolimod is a potential treatment option for AML with an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and the relatively low rate of serious side effects. As most patients with AML are elderly, specific monitoring for cardiac toxicity as well as infection would be required. Lippincott Williams & Wilkins 2016-07 2016-05-23 /pmc/articles/PMC4881728/ /pubmed/26967515 http://dx.doi.org/10.1097/CAD.0000000000000358 Text en Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Clinical Report
Enjeti, Anoop K.
D’Crus, Angel
Melville, Kathleen
Verrills, Nicole M.
Rowlings, Philip
A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title_full A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title_fullStr A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title_full_unstemmed A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title_short A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
title_sort systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia
topic Clinical Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881728/
https://www.ncbi.nlm.nih.gov/pubmed/26967515
http://dx.doi.org/10.1097/CAD.0000000000000358
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