Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measur...

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Authors: González-Gil, C., Morgades, M., Lopes, T., Fuster-Tormo, F., García-Chica, J., Zhao, R., Montesinos, P., Torrent, A., Diaz-Beya, M., Coll, R., Hermosín, L., Mercadal, S., González-Campos, J., Zamora, L., Artola, T., Vall-Llovera, F., Tormo, M., Gil-Cortés, C., Barba, P., Novo Domínguez, Alejandro, Ribera, J., Bernal, T., de Ugarriza, P.L., Queipo, M.-P., Martínez-Sánchez, P., Giménez, A., González Martínez, María Teresa, Cladera, A., Cervera, J., Fernández-Martín, R., Ardaiz, M.Á., Vidal, M.J., Baena, Á., López-Bigas, N., Bigas, A., Maciejewski, J., Orfao, A., Ribera, J.M., Genescà, E.
Format: article
Publication Date:2023
Country:España
Institution:Servizo Galego de Saúde (SERGAS)
Repository:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/21539
Online Access:https://portalcientifico.sergas.gal//documentos/643af6e21656ab66db7e0f6f
http://hdl.handle.net/20.500.11940/21539
Access Level:Open access
Keyword:Humans
Adult
Aged
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease-Free Survival
Prognosis
Neoplasm, Residual
Genomics
T-Lymphocytes
AS Santiago
CHUS
FPGMX
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oai_identifier_str oai:runa.sergas.gal:20.500.11940/21539
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spelling Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trialsGonzález-Gil, C.Morgades, M.Lopes, T.Fuster-Tormo, F.García-Chica, J.Zhao, R.Montesinos, P.Torrent, A.Diaz-Beya, M.Coll, R.Hermosín, L.Mercadal, S.González-Campos, J.Zamora, L.Artola, T.Vall-Llovera, F.Tormo, M.Gil-Cortés, C.Barba, P.Novo Domínguez, AlejandroRibera, J.Bernal, T.de Ugarriza, P.L.Queipo, M.-P.Martínez-Sánchez, P.Giménez, A.González Martínez, María TeresaCladera, A.Cervera, J.Fernández-Martín, R.Ardaiz, M.Á.Vidal, M.J.Baena, Á.López-Bigas, N.Bigas, A.Maciejewski, J.Orfao, A.Ribera, J.M.Genescà, E.HumansAdultAgedPrecursor T-Cell Lymphoblastic Leukemia-LymphomaPrecursor Cell Lymphoblastic Leukemia-LymphomaDisease-Free SurvivalPrognosisNeoplasm, ResidualGenomicsT-LymphocytesAS SantiagoCHUSFPGMXGenetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.This project was supported by the AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, A way to make Europe/Investing in your future, CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/La Caixa. C Gon-zalez-Gil was supported by AGAUR grant (ref: 2020 FI_B2 00210).2023info:eu-repo/semantics/articlehttps://portalcientifico.sergas.gal//documentos/643af6e21656ab66db7e0f6fhttp://hdl.handle.net/20.500.11940/21539reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/215392026-06-12T08:40:47Z
dc.title.none.fl_str_mv Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
title Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
spellingShingle Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
González-Gil, C.
Humans
Adult
Aged
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease-Free Survival
Prognosis
Neoplasm, Residual
Genomics
T-Lymphocytes
AS Santiago
CHUS
FPGMX
title_short Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
title_full Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
title_fullStr Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
title_full_unstemmed Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
title_sort Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials
dc.creator.none.fl_str_mv González-Gil, C.
Morgades, M.
Lopes, T.
Fuster-Tormo, F.
García-Chica, J.
Zhao, R.
Montesinos, P.
Torrent, A.
Diaz-Beya, M.
Coll, R.
Hermosín, L.
Mercadal, S.
González-Campos, J.
Zamora, L.
Artola, T.
Vall-Llovera, F.
Tormo, M.
Gil-Cortés, C.
Barba, P.
Novo Domínguez, Alejandro
Ribera, J.
Bernal, T.
de Ugarriza, P.L.
Queipo, M.-P.
Martínez-Sánchez, P.
Giménez, A.
González Martínez, María Teresa
Cladera, A.
Cervera, J.
Fernández-Martín, R.
Ardaiz, M.Á.
Vidal, M.J.
Baena, Á.
López-Bigas, N.
Bigas, A.
Maciejewski, J.
Orfao, A.
Ribera, J.M.
Genescà, E.
author González-Gil, C.
author_facet González-Gil, C.
Morgades, M.
Lopes, T.
Fuster-Tormo, F.
García-Chica, J.
Zhao, R.
Montesinos, P.
Torrent, A.
Diaz-Beya, M.
Coll, R.
Hermosín, L.
Mercadal, S.
González-Campos, J.
Zamora, L.
Artola, T.
Vall-Llovera, F.
Tormo, M.
Gil-Cortés, C.
Barba, P.
Novo Domínguez, Alejandro
Ribera, J.
Bernal, T.
de Ugarriza, P.L.
Queipo, M.-P.
Martínez-Sánchez, P.
Giménez, A.
González Martínez, María Teresa
Cladera, A.
Cervera, J.
Fernández-Martín, R.
Ardaiz, M.Á.
Vidal, M.J.
Baena, Á.
López-Bigas, N.
Bigas, A.
Maciejewski, J.
Orfao, A.
Ribera, J.M.
Genescà, E.
author_role author
author2 Morgades, M.
Lopes, T.
Fuster-Tormo, F.
García-Chica, J.
Zhao, R.
Montesinos, P.
Torrent, A.
Diaz-Beya, M.
Coll, R.
Hermosín, L.
Mercadal, S.
González-Campos, J.
Zamora, L.
Artola, T.
Vall-Llovera, F.
Tormo, M.
Gil-Cortés, C.
Barba, P.
Novo Domínguez, Alejandro
Ribera, J.
Bernal, T.
de Ugarriza, P.L.
Queipo, M.-P.
Martínez-Sánchez, P.
Giménez, A.
González Martínez, María Teresa
Cladera, A.
Cervera, J.
Fernández-Martín, R.
Ardaiz, M.Á.
Vidal, M.J.
Baena, Á.
López-Bigas, N.
Bigas, A.
Maciejewski, J.
Orfao, A.
Ribera, J.M.
Genescà, E.
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
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Humans
Adult
Aged
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease-Free Survival
Prognosis
Neoplasm, Residual
Genomics
T-Lymphocytes
AS Santiago
CHUS
FPGMX
topic Humans
Adult
Aged
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease-Free Survival
Prognosis
Neoplasm, Residual
Genomics
T-Lymphocytes
AS Santiago
CHUS
FPGMX
description Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://portalcientifico.sergas.gal//documentos/643af6e21656ab66db7e0f6f
http://hdl.handle.net/20.500.11940/21539
url https://portalcientifico.sergas.gal//documentos/643af6e21656ab66db7e0f6f
http://hdl.handle.net/20.500.11940/21539
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas
instname:Servizo Galego de Saúde (SERGAS)
instname_str Servizo Galego de Saúde (SERGAS)
reponame_str RUNA. Repositorio da Consellería de Sanidade e Sergas
collection RUNA. Repositorio da Consellería de Sanidade e Sergas
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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