Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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
_version_ 1785113437802594304
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
work_keys_str_mv AT othmanjad flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT potternicola flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT mokretarkatya flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT taussigdavid flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT khananjum flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT krishnamurthypramila flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT latifannelouise flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT cahalinpaul flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT ariesjames flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT amermariam flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT belshamedward flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT conneallyeibhlin flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT craddockcharles flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT culligandominic flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT dennismike flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT duncancaroline flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT freemansylvied flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT furnesscaroline flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT gilkesamanda flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT gkrekaparaskevi flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT hodgsonkatherine flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT ingramwendy flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT jainmanish flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT kingandrew flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT knappersteven flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT kottaridispanagiotis flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT mcmullinmaryfrances flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT mohiteunmesh flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT nguloretta flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT onionsjenny flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT patrickkatharine flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT ridertom flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT robertswing flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT severinsenmariannetang flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT storrarneill flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT taylortom flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT russellnigelh flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml
AT dillonrichard flt3inhibitorsasmrdguidedsalvagetreatmentformolecularfailureinflt3mutatedaml