Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are...

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Authors: Hernández-Sánchez, Alberto, González, Teresa, Sobas, Marta, Sträng, Eric, Castellani, Gastone, Abáigar, María, Valk, Peter J. M., Villaverde-Ramiro, Ángela, Benner, Axel, Metzeler, Klaus H., Azibeiro, Raúl, Tettero, Jesse M., Martínez-López, Joaquín, Pratcorona, Marta, Martínez Elicegui, Javier, Mills, Ken I., Thiede, Christian, Sanz, Guillermo, Döhner, Konstanze, Heuser, Michael, Haferlach, Torsten, Turki, Amin T., Reinhardt, Dirk, Schulze-Rath, Renate, Barbus, Martje, Hernández, Jesús M., Huntly, Brian J. P., Ossenkoppele, Gert, Döhner, Hartmut, Bullinger, Lars
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/381914
Online Access:http://hdl.handle.net/10261/381914
Access Level:Open access
Keyword:Acute myeloid leukaemia
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spelling Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY studyHernández-Sánchez, AlbertoGonzález, TeresaSobas, MartaSträng, EricCastellani, GastoneAbáigar, MaríaValk, Peter J. M.Villaverde-Ramiro, ÁngelaBenner, AxelMetzeler, Klaus H.Azibeiro, RaúlTettero, Jesse M.Martínez-López, JoaquínPratcorona, MartaMartínez Elicegui, JavierMills, Ken I.Thiede, ChristianSanz, GuillermoDöhner, KonstanzeHeuser, MichaelHaferlach, TorstenTurki, Amin T.Reinhardt, DirkSchulze-Rath, RenateBarbus, MartjeHernández, Jesús M.Huntly, Brian J. P.Ossenkoppele, GertDöhner, HartmutBullinger, LarsAcute myeloid leukaemiaBalanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.Funding is received from the IMI 2 Joint Undertaking and is listed under grant agreement for HARMONY No. 116026 and grant agreement for HARMONY PLUS No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Program and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This study presents results from the AML workgroup in HARMONY. AHS is supported by Contrato Río Hortega CM23/00101 (ISCIII). ATT received additional support by the Deutsche Forschungsgemeinschaft (DFG) grant FU 356/12-1 (ATT). Open Access funding enabled and organized by Projekt DEAL.Peer reviewedSpringer NatureEuropean CommissionInstituto de Salud Carlos IIIGerman Research FoundationProjekt DEALConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/381914reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/116026info:eu-repo/grantAgreement/EC/H2020/945406The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41375-024-02333-4https://doi.org/10.1038/s41375-024-02333-4Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3819142026-05-22T06:33:51Z
dc.title.none.fl_str_mv Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
title Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
spellingShingle Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
Hernández-Sánchez, Alberto
Acute myeloid leukaemia
title_short Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
title_full Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
title_fullStr Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
title_full_unstemmed Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
title_sort Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
dc.creator.none.fl_str_mv Hernández-Sánchez, Alberto
González, Teresa
Sobas, Marta
Sträng, Eric
Castellani, Gastone
Abáigar, María
Valk, Peter J. M.
Villaverde-Ramiro, Ángela
Benner, Axel
Metzeler, Klaus H.
Azibeiro, Raúl
Tettero, Jesse M.
Martínez-López, Joaquín
Pratcorona, Marta
Martínez Elicegui, Javier
Mills, Ken I.
Thiede, Christian
Sanz, Guillermo
Döhner, Konstanze
Heuser, Michael
Haferlach, Torsten
Turki, Amin T.
Reinhardt, Dirk
Schulze-Rath, Renate
Barbus, Martje
Hernández, Jesús M.
Huntly, Brian J. P.
Ossenkoppele, Gert
Döhner, Hartmut
Bullinger, Lars
author Hernández-Sánchez, Alberto
author_facet Hernández-Sánchez, Alberto
González, Teresa
Sobas, Marta
Sträng, Eric
Castellani, Gastone
Abáigar, María
Valk, Peter J. M.
Villaverde-Ramiro, Ángela
Benner, Axel
Metzeler, Klaus H.
Azibeiro, Raúl
Tettero, Jesse M.
Martínez-López, Joaquín
Pratcorona, Marta
Martínez Elicegui, Javier
Mills, Ken I.
Thiede, Christian
Sanz, Guillermo
Döhner, Konstanze
Heuser, Michael
Haferlach, Torsten
Turki, Amin T.
Reinhardt, Dirk
Schulze-Rath, Renate
Barbus, Martje
Hernández, Jesús M.
Huntly, Brian J. P.
Ossenkoppele, Gert
Döhner, Hartmut
Bullinger, Lars
author_role author
author2 González, Teresa
Sobas, Marta
Sträng, Eric
Castellani, Gastone
Abáigar, María
Valk, Peter J. M.
Villaverde-Ramiro, Ángela
Benner, Axel
Metzeler, Klaus H.
Azibeiro, Raúl
Tettero, Jesse M.
Martínez-López, Joaquín
Pratcorona, Marta
Martínez Elicegui, Javier
Mills, Ken I.
Thiede, Christian
Sanz, Guillermo
Döhner, Konstanze
Heuser, Michael
Haferlach, Torsten
Turki, Amin T.
Reinhardt, Dirk
Schulze-Rath, Renate
Barbus, Martje
Hernández, Jesús M.
Huntly, Brian J. P.
Ossenkoppele, Gert
Döhner, Hartmut
Bullinger, Lars
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Instituto de Salud Carlos III
German Research Foundation
Projekt DEAL
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Acute myeloid leukaemia
topic Acute myeloid leukaemia
description Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/381914
url http://hdl.handle.net/10261/381914
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/116026
info:eu-repo/grantAgreement/EC/H2020/945406
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41375-024-02333-4
https://doi.org/10.1038/s41375-024-02333-4
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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