Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment
Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN, and RAS mutati...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2021-02-01
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Series: | Frontiers in Pediatrics |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2020.614521/full |
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English |
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author |
Nerea Vega-García Nerea Vega-García Sara Perez-Jaume Elena Esperanza-Cebollada Elena Esperanza-Cebollada Clara Vicente-Garcés Clara Vicente-Garcés Montserrat Torrebadell Montserrat Torrebadell Montserrat Torrebadell Antonio Jiménez-Velasco Margarita Ortega Marta Llop Marta Llop Lorea Abad José Manuel Vagace Alfredo Minguela Marta Pratcorona Joaquín Sánchez-Garcia Clara B. García-Calderón María Teresa Gómez-Casares Estela Martín-Clavero Adela Escudero Marta Riñón Martinez-Gallo Luz Muñoz María Rosario Velasco Marina García-Morin Albert Català Albert Català Albert Català Antonia Pascual Pablo Velasco José Mª. Fernández Alvaro Lassaletta José Luis Fuster Isabel Badell Águeda Molinos-Quintana Antonio Molinés Pilar Guerra-García Pilar Guerra-García Antonio Pérez-Martínez Antonio Pérez-Martínez Miriam García-Abós Reyes Robles Ortiz Sandra Pisa Rosa Adán Cristina Díaz de Heredia José Luis Dapena José Luis Dapena Susana Rives Susana Rives Susana Rives Manuel Ramírez-Orellana Mireia Camós Mireia Camós Mireia Camós |
spellingShingle |
Nerea Vega-García Nerea Vega-García Sara Perez-Jaume Elena Esperanza-Cebollada Elena Esperanza-Cebollada Clara Vicente-Garcés Clara Vicente-Garcés Montserrat Torrebadell Montserrat Torrebadell Montserrat Torrebadell Antonio Jiménez-Velasco Margarita Ortega Marta Llop Marta Llop Lorea Abad José Manuel Vagace Alfredo Minguela Marta Pratcorona Joaquín Sánchez-Garcia Clara B. García-Calderón María Teresa Gómez-Casares Estela Martín-Clavero Adela Escudero Marta Riñón Martinez-Gallo Luz Muñoz María Rosario Velasco Marina García-Morin Albert Català Albert Català Albert Català Antonia Pascual Pablo Velasco José Mª. Fernández Alvaro Lassaletta José Luis Fuster Isabel Badell Águeda Molinos-Quintana Antonio Molinés Pilar Guerra-García Pilar Guerra-García Antonio Pérez-Martínez Antonio Pérez-Martínez Miriam García-Abós Reyes Robles Ortiz Sandra Pisa Rosa Adán Cristina Díaz de Heredia José Luis Dapena José Luis Dapena Susana Rives Susana Rives Susana Rives Manuel Ramírez-Orellana Mireia Camós Mireia Camós Mireia Camós Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment Frontiers in Pediatrics measurable (minimal) residual disease T-cell acute lymphoblastic leukemia oncogenetics NOTCH1 flow cytometry pediatrics |
author_facet |
Nerea Vega-García Nerea Vega-García Sara Perez-Jaume Elena Esperanza-Cebollada Elena Esperanza-Cebollada Clara Vicente-Garcés Clara Vicente-Garcés Montserrat Torrebadell Montserrat Torrebadell Montserrat Torrebadell Antonio Jiménez-Velasco Margarita Ortega Marta Llop Marta Llop Lorea Abad José Manuel Vagace Alfredo Minguela Marta Pratcorona Joaquín Sánchez-Garcia Clara B. García-Calderón María Teresa Gómez-Casares Estela Martín-Clavero Adela Escudero Marta Riñón Martinez-Gallo Luz Muñoz María Rosario Velasco Marina García-Morin Albert Català Albert Català Albert Català Antonia Pascual Pablo Velasco José Mª. Fernández Alvaro Lassaletta José Luis Fuster Isabel Badell Águeda Molinos-Quintana Antonio Molinés Pilar Guerra-García Pilar Guerra-García Antonio Pérez-Martínez Antonio Pérez-Martínez Miriam García-Abós Reyes Robles Ortiz Sandra Pisa Rosa Adán Cristina Díaz de Heredia José Luis Dapena José Luis Dapena Susana Rives Susana Rives Susana Rives Manuel Ramírez-Orellana Mireia Camós Mireia Camós Mireia Camós |
author_sort |
Nerea Vega-García |
title |
Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment |
title_short |
Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment |
title_full |
Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment |
title_fullStr |
Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment |
title_full_unstemmed |
Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment |
title_sort |
measurable residual disease assessed by flow-cytometry is a stable prognostic factor for pediatric t-cell acute lymphoblastic leukemia in consecutive sehop protocols whereas the impact of oncogenetics depends on treatment |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pediatrics |
issn |
2296-2360 |
publishDate |
2021-02-01 |
description |
Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN, and RAS mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: NOTCH1 mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of CDKN2A/B had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients. |
topic |
measurable (minimal) residual disease T-cell acute lymphoblastic leukemia oncogenetics NOTCH1 flow cytometry pediatrics |
url |
https://www.frontiersin.org/articles/10.3389/fped.2020.614521/full |
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doaj-76d44086f8a049c3816cf6758487be242021-02-05T05:38:00ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602021-02-01810.3389/fped.2020.614521614521Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on TreatmentNerea Vega-García0Nerea Vega-García1Sara Perez-Jaume2Elena Esperanza-Cebollada3Elena Esperanza-Cebollada4Clara Vicente-Garcés5Clara Vicente-Garcés6Montserrat Torrebadell7Montserrat Torrebadell8Montserrat Torrebadell9Antonio Jiménez-Velasco10Margarita Ortega11Marta Llop12Marta Llop13Lorea Abad14José Manuel Vagace15Alfredo Minguela16Marta Pratcorona17Joaquín Sánchez-Garcia18Clara B. García-Calderón19María Teresa Gómez-Casares20Estela Martín-Clavero21Adela Escudero22Marta Riñón Martinez-Gallo23Luz Muñoz24María Rosario Velasco25Marina García-Morin26Albert Català27Albert Català28Albert Català29Antonia Pascual30Pablo Velasco31José Mª. Fernández32Alvaro Lassaletta33José Luis Fuster34Isabel Badell35Águeda Molinos-Quintana36Antonio Molinés37Pilar Guerra-García38Pilar Guerra-García39Antonio Pérez-Martínez40Antonio Pérez-Martínez41Miriam García-Abós42Reyes Robles Ortiz43Sandra Pisa44Rosa Adán45Cristina Díaz de Heredia46José Luis Dapena47José Luis Dapena48Susana Rives49Susana Rives50Susana Rives51Manuel Ramírez-Orellana52Mireia Camós53Mireia Camós54Mireia Camós55Haematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainDevelopmental Tumour Biology Laboratory, Institut de Recerca Hospital Sant Joan de Déu Barcelona, Barcelona, SpainHaematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainHaematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainHaematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainHaematology and Hemotherapy Laboratory, Hospital Carlos Haya, Málaga, SpainCytogenetics Unit, Hematology Department, Hospital Vall d'Hebron, Barcelona, SpainMolecular Biology Unit, Clinical Analysis Service, La Fe University and Polytechnic Hospital, Valencia, SpainCentro de Investigación Biomédica en Red - Cáncer (CIBERONC CB16/12/00284), Madrid, SpainPaediatric Hemato-Oncology Laboratory, Hospital Niño Jesús, Madrid, Spain0Haematology Laboratory, Hospital Materno Infantil, Badajoz, Spain1Immunology Service, Clinic University Hospital Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain2Haematology Laboratory, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain3Hematology Department, Hospital Reina Sofía, IMIBIC, UCO, Córdoba, Spain4Instituto de Biomedicina de Sevilla (IBIS/Consejo Superior de Investigaciones Científicas (CSIC)/Centro de Investigación Biomédica en Red - Cáncer (CIBERONC)), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain5Biology and Molecular Haematology and Hemotherapy Service, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canarias, Spain6Haematology-Cytology Department, Hospital Universitario 12 de Octubre, Madrid, Spain7Translational Research in Pediatric Oncology Hematopoietic Transplantation and Cell Therapy, Institute of Medical and Molecular Genetics (INGEMM), Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain8Immunology Laboratory, Hospital de Cruces, Bilbao, Spain9Haematology Laboratory, Hospital Parc Taulí, Sabadell, Spain0Haematology Department, Hospital Virgen de la Salud, Toledo, Spain1Paediatric Hematology Unit, Hospital General Universitario Gregorio Marañón, Madrid, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain2Paediatric Hematology and Oncology Departments, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain3Haematology Department, Hospital Carlos Haya, Málaga, Spain4Pediatric Hematology and Oncology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain5Haematology and Oncology Department, Hospital de La Fe, Valencia, Spain6Haematology and Oncology Department, Hospital Niño Jesús, Madrid, Spain7Paediatric Oncohematology Department, Clinic University Hospital Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain8Paediatric Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain4Instituto de Biomedicina de Sevilla (IBIS/Consejo Superior de Investigaciones Científicas (CSIC)/Centro de Investigación Biomédica en Red - Cáncer (CIBERONC)), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain9Unit of Hematology and Hemotherapy, H.U. Materno Infantil de Canarias, Canarias, Spain0Paediatric Hemato-Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain1Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain7Translational Research in Pediatric Oncology Hematopoietic Transplantation and Cell Therapy, Institute of Medical and Molecular Genetics (INGEMM), Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain1Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain2Pediatric Onco-Hematology Department, Hospital Universitario Donostia, Donostia, Spain3Pediatric Onco-Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain4Paediatric Hematology Department, Hospital Parc Taulí, Sabadell, Spain5Haematology and Oncology Department, Hospital de Cruces, Bilbao, Spain4Pediatric Hematology and Oncology Department, Hospital Universitari Vall d'Hebron, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, Spain2Paediatric Hematology and Oncology Departments, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain2Paediatric Hematology and Oncology Departments, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainPaediatric Hemato-Oncology Laboratory, Hospital Niño Jesús, Madrid, SpainHaematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, SpainDevelopmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainRobust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN, and RAS mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: NOTCH1 mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of CDKN2A/B had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients.https://www.frontiersin.org/articles/10.3389/fped.2020.614521/fullmeasurable (minimal) residual diseaseT-cell acute lymphoblastic leukemiaoncogeneticsNOTCH1flow cytometrypediatrics |