The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial
Ayala, Rosa (Centro de Investigación Biomédica en Red de Cáncer)
Rapado, Inmaculada (Centro de Investigación Biomédica en Red de Cáncer)
Onecha, Esther (Hematological Malignancies Clinical Research Unit (Madrid))
Martínez-Cuadrón, David (Hospital Universitari i Politècnic La Fe (València))
Carreño-Tarragona, Gonzalo (Hematological Malignancies Clinical Research Unit (Madrid))
Bergua Burgues, Juan Miguel (Hospital San Pedro de Alcántara)
Vives Polo, Susana (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Algarra Algarra, Jesus Lorenzo (Complejo Hospitalario Universitario de Albacete)
Tormo, Mar (Hospital Clínic Universitari (València))
Martinez, Pilar (Hospital Universitario 12 de Octubre (Madrid))
Serrano, Josefina (Hospital Universitario Reina Sofía (Còrdova, Espanya))
Herrera, Pilar (Hospital Universitario Ramon y Cajal (Madrid))
Ramos, Fernando (Hospital Universitario de León)
Salamero, Olga (Hospital Universitari Vall d'Hebron)
Lavilla, Esperanza (Hospital Universitario Xeral de Lugo)
Gil, Cristina (Hospital General Universitario de Alicante (Alacant, País Valencià))
López Lorenzo, Jose Luis (Hematology Department, Fundación Jiménez Díaz (Madrid))
Vidriales, María Belén (Instituto de Investigación Biomédica de Salamanca)
Labrador, Jorge (Hospital Universitario de Burgos)
Falantes, José Francisco (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Sayas, María José (Hospital Universitari Doctor Peset (València))
Paiva, Bruno (Clínica Universidad de Navarra)
Barragán, Eva (Hospital Universitari i Politècnic La Fe (València))
Prosper, Felipe (Clínica Universidad de Navarra)
Sanz, Miguel A.. (Hospital Universitari i Politècnic La Fe (València))
Martínez-López, Joaquín (Centro de Investigación Biomédica en Red de Cáncer)
Montesinos, Pau (Hospital Universitari i Politècnic La Fe (València))
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	Mutational profiling using a custom 43-gene next-generation sequencing panel revealed that patients with mutated DNMT3A or EZH2, or an increase in TET2 VAF and lower TP53 VAF showed a higher overall response. NRAS and TP53 variants were associated with shorter overall survival (OS), whereas only mutated BCOR was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk and mutated NRAS benefited from azacytidine therapy and patients with mutated TP53 showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1. 014; p = 0. 030) and lower TP53 VAF (OR, 0. 981; p = 0. 003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1. 9, p = 0. 005) and TP53 (HR, 2. 6, p = 9. 8 × 10 −7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3. 6, p = 0. 0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk (HR, 1. 51, p = 0. 045) and mutated NRAS (HR, 3. 66, p = 0. 047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4. 71, p = 0. 009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials. gov as NCT02319135.
Grants:	Ministerio de Economía y Competitividad CB16/12/00369 Ministerio de Economía y Competitividad PI16/01530 Ministerio de Economía y Competitividad PI16/01661 Instituto de Salud Carlos III PI19/01518 Instituto de Salud Carlos III PI19/00730
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Clinical trials and observations ; Myeloid neoplasia ; NGS ; Variants ; Leukemia ; Myelocytic ; Acute ; Leukemic cells ; Older adults ; Genetic risk ; Complete remission ; Cytarabine ; Azacytidine ; Prognostic factors
Published in:	Cancers, Vol. 13 (may 2021) , ISSN 2072-6694

DOI: 10.3390/cancers13102458
PMID: 34070172

14 p, 6.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles