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FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML
Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a win...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10539160/ https://www.ncbi.nlm.nih.gov/pubmed/37558736 http://dx.doi.org/10.1038/s41375-023-01994-x |
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author | Othman, Jad Potter, Nicola Mokretar, Katya Taussig, David Khan, Anjum Krishnamurthy, Pramila Latif, Anne-Louise Cahalin, Paul Aries, James Amer, Mariam Belsham, Edward Conneally, Eibhlin Craddock, Charles Culligan, Dominic Dennis, Mike Duncan, Caroline Freeman, Sylvie D. Furness, Caroline Gilkes, Amanda Gkreka, Paraskevi Hodgson, Katherine Ingram, Wendy Jain, Manish King, Andrew Knapper, Steven Kottaridis, Panagiotis McMullin, Mary Frances Mohite, Unmesh Ngu, Loretta O’Nions, Jenny Patrick, Katharine Rider, Tom Roberts, Wing Severinsen, Marianne Tang Storrar, Neill Taylor, Tom Russell, Nigel H. Dillon, Richard |
author_facet | Othman, Jad Potter, Nicola Mokretar, Katya Taussig, David Khan, Anjum Krishnamurthy, Pramila Latif, Anne-Louise Cahalin, Paul Aries, James Amer, Mariam Belsham, Edward Conneally, Eibhlin Craddock, Charles Culligan, Dominic Dennis, Mike Duncan, Caroline Freeman, Sylvie D. Furness, Caroline Gilkes, Amanda Gkreka, Paraskevi Hodgson, Katherine Ingram, Wendy Jain, Manish King, Andrew Knapper, Steven Kottaridis, Panagiotis McMullin, Mary Frances Mohite, Unmesh Ngu, Loretta O’Nions, Jenny Patrick, Katharine Rider, Tom Roberts, Wing Severinsen, Marianne Tang Storrar, Neill Taylor, Tom Russell, Nigel H. Dillon, Richard |
author_sort | Othman, Jad |
collection | PubMed |
description | Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies. |
format | Online Article Text |
id | pubmed-10539160 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-105391602023-09-30 FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML Othman, Jad Potter, Nicola Mokretar, Katya Taussig, David Khan, Anjum Krishnamurthy, Pramila Latif, Anne-Louise Cahalin, Paul Aries, James Amer, Mariam Belsham, Edward Conneally, Eibhlin Craddock, Charles Culligan, Dominic Dennis, Mike Duncan, Caroline Freeman, Sylvie D. Furness, Caroline Gilkes, Amanda Gkreka, Paraskevi Hodgson, Katherine Ingram, Wendy Jain, Manish King, Andrew Knapper, Steven Kottaridis, Panagiotis McMullin, Mary Frances Mohite, Unmesh Ngu, Loretta O’Nions, Jenny Patrick, Katharine Rider, Tom Roberts, Wing Severinsen, Marianne Tang Storrar, Neill Taylor, Tom Russell, Nigel H. Dillon, Richard Leukemia Article Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies. Nature Publishing Group UK 2023-08-09 2023 /pmc/articles/PMC10539160/ /pubmed/37558736 http://dx.doi.org/10.1038/s41375-023-01994-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Othman, Jad Potter, Nicola Mokretar, Katya Taussig, David Khan, Anjum Krishnamurthy, Pramila Latif, Anne-Louise Cahalin, Paul Aries, James Amer, Mariam Belsham, Edward Conneally, Eibhlin Craddock, Charles Culligan, Dominic Dennis, Mike Duncan, Caroline Freeman, Sylvie D. Furness, Caroline Gilkes, Amanda Gkreka, Paraskevi Hodgson, Katherine Ingram, Wendy Jain, Manish King, Andrew Knapper, Steven Kottaridis, Panagiotis McMullin, Mary Frances Mohite, Unmesh Ngu, Loretta O’Nions, Jenny Patrick, Katharine Rider, Tom Roberts, Wing Severinsen, Marianne Tang Storrar, Neill Taylor, Tom Russell, Nigel H. Dillon, Richard FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title | FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title_full | FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title_fullStr | FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title_full_unstemmed | FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title_short | FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML |
title_sort | flt3 inhibitors as mrd-guided salvage treatment for molecular failure in flt3 mutated aml |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10539160/ https://www.ncbi.nlm.nih.gov/pubmed/37558736 http://dx.doi.org/10.1038/s41375-023-01994-x |
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