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FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile
FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (FLT3-ITD) and 5–10% a tyrosine kinase domain (TKD) amino acid substitution (FLT3-TKD). The treatment paradigm of...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9869913/ https://www.ncbi.nlm.nih.gov/pubmed/36698434 http://dx.doi.org/10.2147/OTT.S236740 |
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author | Garciaz, Sylvain Hospital, Marie-Anne |
author_facet | Garciaz, Sylvain Hospital, Marie-Anne |
author_sort | Garciaz, Sylvain |
collection | PubMed |
description | FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (FLT3-ITD) and 5–10% a tyrosine kinase domain (TKD) amino acid substitution (FLT3-TKD). The treatment paradigm of AML patients harboring FLT3 mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on FLT3-ITD and TKD, whereas type 2 inhibitors are active only on FLT3-ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients. |
format | Online Article Text |
id | pubmed-9869913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-98699132023-01-24 FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile Garciaz, Sylvain Hospital, Marie-Anne Onco Targets Ther Review FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (FLT3-ITD) and 5–10% a tyrosine kinase domain (TKD) amino acid substitution (FLT3-TKD). The treatment paradigm of AML patients harboring FLT3 mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on FLT3-ITD and TKD, whereas type 2 inhibitors are active only on FLT3-ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients. Dove 2023-01-19 /pmc/articles/PMC9869913/ /pubmed/36698434 http://dx.doi.org/10.2147/OTT.S236740 Text en © 2023 Garciaz and Hospital. https://creativecommons.org/licenses/by-nc/3.0/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/ (https://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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Review Garciaz, Sylvain Hospital, Marie-Anne FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title | FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title_full | FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title_fullStr | FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title_full_unstemmed | FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title_short | FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile |
title_sort | fms-like tyrosine kinase 3 inhibitors in the treatment of acute myeloid leukemia: an update on the emerging evidence and safety profile |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9869913/ https://www.ncbi.nlm.nih.gov/pubmed/36698434 http://dx.doi.org/10.2147/OTT.S236740 |
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