Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity

Onecha, Esther; Ruiz‐Heredia, Yanira; Martínez‐Cuadrón, David; Barragán, Eva; Martínez Sánchez, María Del Pilar; Linares Gómez, María; Rapado, Inmaculada; Perez‐Oteyza, Jaime; Magro, Elena; Herrera, Pilar; Rojas, José Luis; Gorrochategui, Julián; Villoria, Jesús; Boluda, Blanca; Sargas, Claudia; Ballesteros, Joan; Montesinos, Pau; Martínez López, Joaquín; Ayala Díaz, Rosa María

Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity

Refractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutat...

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Autores:	Onecha, Esther, Ruiz‐Heredia, Yanira, Martínez‐Cuadrón, David, Barragán, Eva, Martínez Sánchez, María Del Pilar, Linares Gómez, María, Rapado, Inmaculada, Perez‐Oteyza, Jaime, Magro, Elena, Herrera, Pilar, Rojas, José Luis, Gorrochategui, Julián, Villoria, Jesús, Boluda, Blanca, Sargas, Claudia, Ballesteros, Joan, Montesinos, Pau, Martínez López, Joaquín, Ayala Díaz, Rosa María
Tipo de recurso:	artículo
Fecha de publicación:	2020
País:	España
Institución:	Universidad Complutense de Madrid (UCM)
Repositorio:	Docta Complutense
Idioma:	inglés
OAI Identifier:	oai:docta.ucm.es:20.500.14352/102749
Acceso en línea:	https://hdl.handle.net/20.500.14352/102749
Access Level:	acceso abierto
Palabra clave:	577.1 577.2 Acute myeloid leukaemia Sequencing Ex vivo sensitivity test Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida

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spelling	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivityOnecha, EstherRuiz‐Heredia, YaniraMartínez‐Cuadrón, DavidBarragán, EvaMartínez Sánchez, María Del PilarLinares Gómez, MaríaRapado, InmaculadaPerez‐Oteyza, JaimeMagro, ElenaHerrera, PilarRojas, José LuisGorrochategui, JuliánVilloria, JesúsBoluda, BlancaSargas, ClaudiaBallesteros, JoanMontesinos, PauMartínez López, JoaquínAyala Díaz, Rosa María577.1577.2Acute myeloid leukaemiaSequencingEx vivo sensitivity testCiencias BiomédicasBioquímica (Farmacia)Biología molecular (Farmacia)24 Ciencias de la VidaRefractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutational profiling by next-generation sequencing (NGS, n = 190) and ex vivo PharmaFlow testing (n = 74) for the 10 most widely used drugs for AML induction therapy, in a cohort of adult patients uniformly treated according to Spanish PETHEMA guidelines. We identified an adverse mutational profile (EZH2, KMT2A, U2AF1 and/or TP53 mutations) that carries a greater risk of death [hazard ratio (HR): 3 29, P < 0 0001]. A high correlation was found between the ex vivo PharmaFlow results and clinical induction response (69%). Clinical correlation analysis showed that the pattern of multiresistance revealed by ex vivo PharmaFlow identified patients with a high risk of death (HR: 2 58). Patients with mutation status also ran a high risk (HR 4 19), and the risk was increased further in patients with both adverse profiles (HR 4 82). We have developed a new score based on NGS and ex vivo drug testing for AML patients that improves upon current prognostic risk stratification and allows clinicians to tailor treatments to minimise drug resistance.Universidad Complutense de Madrid20202020-02-1820202020-02-18journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/102749reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PI13%2F02387 Implicaciones clínicas de la detección de mutaciones recurrentes por secuenciación masiva de paneles en Leucemia Mieloide Aguda, y correlación con la sensibilidad a fármacos antileucemiaMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PI16%2F01530 Alteraciones moleculares involucradas en los mecanismos de refractariedad y recaída de la Leucemia Mieloide Aguda: Implicaciones terapéuticasMinisterio de Educación, Cultura y Deporte http://dx.doi.org/10.13039/501100003176 Not available FPU2014%2F01203 FPU2014%2F01203Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available FPDI-2013-16409 FPDI-2013-16409open accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1027492026-06-02T12:44:21Z
dc.title.none.fl_str_mv	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
title	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
spellingShingle	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity Onecha, Esther 577.1 577.2 Acute myeloid leukaemia Sequencing Ex vivo sensitivity test Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
title_short	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
title_full	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
title_fullStr	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
title_full_unstemmed	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
title_sort	Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity
dc.creator.none.fl_str_mv	Onecha, Esther Ruiz‐Heredia, Yanira Martínez‐Cuadrón, David Barragán, Eva Martínez Sánchez, María Del Pilar Linares Gómez, María Rapado, Inmaculada Perez‐Oteyza, Jaime Magro, Elena Herrera, Pilar Rojas, José Luis Gorrochategui, Julián Villoria, Jesús Boluda, Blanca Sargas, Claudia Ballesteros, Joan Montesinos, Pau Martínez López, Joaquín Ayala Díaz, Rosa María
author	Onecha, Esther
author_facet	Onecha, Esther Ruiz‐Heredia, Yanira Martínez‐Cuadrón, David Barragán, Eva Martínez Sánchez, María Del Pilar Linares Gómez, María Rapado, Inmaculada Perez‐Oteyza, Jaime Magro, Elena Herrera, Pilar Rojas, José Luis Gorrochategui, Julián Villoria, Jesús Boluda, Blanca Sargas, Claudia Ballesteros, Joan Montesinos, Pau Martínez López, Joaquín Ayala Díaz, Rosa María
author_role	author
author2	Ruiz‐Heredia, Yanira Martínez‐Cuadrón, David Barragán, Eva Martínez Sánchez, María Del Pilar Linares Gómez, María Rapado, Inmaculada Perez‐Oteyza, Jaime Magro, Elena Herrera, Pilar Rojas, José Luis Gorrochategui, Julián Villoria, Jesús Boluda, Blanca Sargas, Claudia Ballesteros, Joan Montesinos, Pau Martínez López, Joaquín Ayala Díaz, Rosa María
author2_role	author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universidad Complutense de Madrid
dc.subject.none.fl_str_mv	577.1 577.2 Acute myeloid leukaemia Sequencing Ex vivo sensitivity test Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
topic	577.1 577.2 Acute myeloid leukaemia Sequencing Ex vivo sensitivity test Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
description	Refractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutational profiling by next-generation sequencing (NGS, n = 190) and ex vivo PharmaFlow testing (n = 74) for the 10 most widely used drugs for AML induction therapy, in a cohort of adult patients uniformly treated according to Spanish PETHEMA guidelines. We identified an adverse mutational profile (EZH2, KMT2A, U2AF1 and/or TP53 mutations) that carries a greater risk of death [hazard ratio (HR): 3 29, P < 0 0001]. A high correlation was found between the ex vivo PharmaFlow results and clinical induction response (69%). Clinical correlation analysis showed that the pattern of multiresistance revealed by ex vivo PharmaFlow identified patients with a high risk of death (HR: 2 58). Patients with mutation status also ran a high risk (HR 4 19), and the risk was increased further in patients with both adverse profiles (HR 4 82). We have developed a new score based on NGS and ex vivo drug testing for AML patients that improves upon current prognostic risk stratification and allows clinicians to tailor treatments to minimise drug resistance.
publishDate	2020
dc.date.none.fl_str_mv	2020 2020-02-18 2020 2020-02-18
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 AM http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.14352/102749
url	https://hdl.handle.net/20.500.14352/102749
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PI13%2F02387 Implicaciones clínicas de la detección de mutaciones recurrentes por secuenciación masiva de paneles en Leucemia Mieloide Aguda, y correlación con la sensibilidad a fármacos antileucemia Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PI16%2F01530 Alteraciones moleculares involucradas en los mecanismos de refractariedad y recaída de la Leucemia Mieloide Aguda: Implicaciones terapéuticas Ministerio de Educación, Cultura y Deporte http://dx.doi.org/10.13039/501100003176 Not available FPU2014%2F01203 FPU2014%2F01203 Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available FPDI-2013-16409 FPDI-2013-16409
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv	openAccess
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dc.source.none.fl_str_mv	reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM)
instname_str	Universidad Complutense de Madrid (UCM)
reponame_str	Docta Complutense
collection	Docta Complutense
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Improving the prediction of acute myeloid leukaemia outcomes by complementing mutational profiling with ex vivo chemosensitivity

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