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Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy

Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate d...

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Autores principales: Nassereddine, Samah, Lap, Coen J, Tabbara, Imad A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314316/
https://www.ncbi.nlm.nih.gov/pubmed/30643428
http://dx.doi.org/10.2147/OTT.S182443
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author Nassereddine, Samah
Lap, Coen J
Tabbara, Imad A
author_facet Nassereddine, Samah
Lap, Coen J
Tabbara, Imad A
author_sort Nassereddine, Samah
collection PubMed
description Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the onco-metabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years.
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spelling pubmed-63143162019-01-14 Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy Nassereddine, Samah Lap, Coen J Tabbara, Imad A Onco Targets Ther Review Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the onco-metabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years. Dove Medical Press 2018-12-28 /pmc/articles/PMC6314316/ /pubmed/30643428 http://dx.doi.org/10.2147/OTT.S182443 Text en © 2019 Nassereddine et al. 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
Nassereddine, Samah
Lap, Coen J
Tabbara, Imad A
Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title_full Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title_fullStr Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title_full_unstemmed Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title_short Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy
title_sort evaluating ivosidenib for the treatment of relapsed/refractory aml: design, development, and place in therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314316/
https://www.ncbi.nlm.nih.gov/pubmed/30643428
http://dx.doi.org/10.2147/OTT.S182443
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