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

María Teresa Gómez-Casares¹  Margarita Ortega²  Susana Rives³  Albert Català³  José Luis Dapena⁴  Sara Perez-Jaume⁵  Antonia Pascual⁶  María Rosario Velasco⁷  José Manuel Vagace⁸  Luz Muñoz⁹  Elena Esperanza-Cebollada^1,10  Nerea Vega-García^1,10  Clara Vicente-Garcés^1,10  Mireia Camós^1,11  Montserrat Torrebadell^1,11  Marta Pratcorona^1,12  Antonio Jiménez-Velasco^1,13  Alvaro Lassaletta^1,14  Rosa Adán^1,15  José Mª. Fernández^1,16  Estela Martín-Clavero^1,17  Joaquín Sánchez-Garcia^1,18  Marta Riñón Martinez-Gallo^1,19  Alfredo Minguela^2,20  Águeda Molinos-Quintana^2,21  Clara B. García-Calderón^2,21  Marta Llop^2,22  Pilar Guerra-García^2,23  Lorea Abad^2,24  Manuel Ramírez-Orellana^2,24  Sandra Pisa^2,25  Isabel Badell^2,26  Marina García-Morin^2,27  José Luis Fuster^2,28  Pablo Velasco^2,29  Cristina Díaz de Heredia^2,29  Reyes Robles Ortiz^3,30  Miriam García-Abós^3,31  Adela Escudero^3,32  Antonio Pérez-Martínez^3,33  Antonio Molinés^3,34 

[1] Biology and Molecular Haematology and Hemotherapy Service, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canarias, Spain;Cytogenetics Unit, Hematology Department, Hospital Vall d'Hebron, Barcelona, Spain;Developmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;Paediatric Hematology and Oncology Departments, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Developmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, Spain;Paediatric Hematology and Oncology Departments, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Developmental Tumour Biology Laboratory, Institut de Recerca Hospital Sant Joan de Déu Barcelona, Barcelona, Spain;Haematology Department, Hospital Carlos Haya, Málaga, Spain;Haematology Department, Hospital Virgen de la Salud, Toledo, Spain;Haematology Laboratory, Hospital Materno Infantil, Badajoz, Spain;Haematology Laboratory, Hospital Parc Taulí, Sabadell, Spain;Haematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Developmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, Spain;Haematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Developmental Tumor Biology Group, Leukemia and Other Pediatric Hemopathies, Institut de Recerca Sant Joan de Déu, Barcelona, Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;Haematology Laboratory, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;Haematology and Hemotherapy Laboratory, Hospital Carlos Haya, Málaga, Spain;Haematology and Oncology Department, Hospital Niño Jesús, Madrid, Spain;Haematology and Oncology Department, Hospital de Cruces, Bilbao, Spain;Haematology and Oncology Department, Hospital de La Fe, Valencia, Spain;Haematology-Cytology Department, Hospital Universitario 12 de Octubre, Madrid, Spain;Hematology Department, Hospital Reina Sofía, IMIBIC, UCO, Córdoba, Spain;Immunology Laboratory, Hospital de Cruces, Bilbao, Spain;Immunology Service, Clinic University Hospital Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain;Instituto 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, Spain;Molecular Biology Unit, Clinical Analysis Service, La Fe University and Polytechnic Hospital, Valencia, Spain;Centro de Investigación Biomédica en Red - Cáncer (CIBERONC CB16/12/00284), Madrid, Spain;Paediatric Hemato-Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain;Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain;Paediatric Hemato-Oncology Laboratory, Hospital Niño Jesús, Madrid, Spain;Paediatric Hematology Department, Hospital Parc Taulí, Sabadell, Spain;Paediatric Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;Paediatric Hematology Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain;Paediatric Oncohematology Department, Clinic University Hospital Virgen de la Arrixaca (HCUVA) and Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain;Pediatric Hematology and Oncology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain;Pediatric Onco-Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain;Pediatric Onco-Hematology Department, Hospital Universitario Donostia, Donostia, Spain;Translational 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, Spain;Translational 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, Spain;Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain;Unit of Hematology and Hemotherapy, H.U. Materno Infantil de Canarias, Canarias, Spain;

关键词: measurable (minimal) residual disease;    T-cell acute lymphoblastic leukemia;    oncogenetics;    NOTCH1;    flow cytometry;    pediatrics;    risk-factors;   

DOI  :  10.3389/fped.2020.614521

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

CC BY