Co-mutation signatures are age-dependent and impact the prognosis in <i>NPM1</i>-mutated acute myeloid leukemia: a PETHEMA multicenter study

NPM1-mutated acute myeloid leukemia is genetically heterogeneous, and risk assessment remains focused exclusively on FLT3-ITD despite the potential role of other co-mutations. We retrospectively analyzed 1,360 adults from a multicenter cohort to map age-resolved co-mutation architecture and prognostic impact. Co-mutations were present in 97% of patients (median = 3 mutations) with DNMT3A (45%), FLT3-ITD (42%), TET2 (27%), and IDH2 (20%) predominating. RTK/RAS partners were enriched in younger adults, whereas myelodysplasia-related genes (MR-genes), epigenetic lesions and higher mutation burden accumulated in the elderly. Pairwise co-mutations mapped to distinct clinical phenotypes with NPM1+FLT3-ITD showing a hyperproliferative profile, and NPM1+SRSF2/TET2 associated to older patients with cytopenic disease. In the 688 patients receiving upfront intensive therapy, NPM1 type Non-ABD exhibited a tendency toward poorer OS compared with type A. In competing-risk models, SRSF2 and DNMT3A were associated with a higher cumulative incidence of relapse (CIR). Consistently, multivariable analyses showed that increasing age and SRSF2 independently conferred adverse risk across OS, RFS, and EFS; KRAS adversely impacted OS, whereas FLT3-OTHER was associated with improved OS; and DNMT3A with inferior RFS and EFS but not OS. These findings show that co-mutation signatures in NPM1-mutated AML are age-structured and clinically meaningful, refining risk beyond FLT3-ITD.

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Journal
Haematologica
Published
2026-07-16
DOI
https://doi.org/10.3324/haematol.2026.301025
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Co-mutation signatures are age-dependent and impact the prognosis in NPM1-mutated acute myeloid leukemia: a PETHEMA multicenter study

Victor Noriega, R. Colmenares, Ayala Rp, Elena Soria et al.
Haematologica
Acute Myeloid Leukemia Research
article

Co-mutation signatures are age-dependent and impact the prognosis in NPM1-mutated acute myeloid leukemia: a PETHEMA multicenter study

Victor Noriega, R. Colmenares, Ayala Rp, Elena Soria, María Dolores Madrigal, Claudia Sargas, M GONZALEZ COLORADO, Lorenzo Algarra, María José García-Pérez, Carmen Couto, Isabel Cano‐Ferri, Norma C. Gutiérrez, Carmen Martínez‐Chamorro, Raimundo García‐Boyero, María Lourdes Hermosín, Cristina Bilbao, Teresa Bernal, María Teresa Gómez‐Casares, Maria del Carmen Mateos, Mayte Olave, María García‐Fortes, Josè Antonio Pérez-Simón, Ágata Almela, María Luz Amigo, Esther Pérez‐Santaolalla, Eduardo Rodríguez-Arbolí, Francisco Ibañez, Juan Bergua, Joaquín Sánchez-García, Antonio Solana-Altabella, Irene Navarro, Maria Sole, Esther Prados-de La Torre, María del Carmen García-Garay, Carlos Rodríguez-Medina, Eva Barragán, María José Calasanz, Pau Montesinos, Beatriz Martín-Herreros, Mar Tormo, Ana Yurena Oliva, Joaquín Martínez-López, Juan Manuel Alonso-Domínguez, María del Carmen Chillón, María José Larrayoz, José Vicente Gil, Josefina Serrano, Cristina Gil
article en

Abstract

NPM1-mutated acute myeloid leukemia is genetically heterogeneous, and risk assessment remains focused exclusively on FLT3-ITD despite the potential role of other co-mutations. We retrospectively analyzed 1,360 adults from a multicenter cohort to map age-resolved co-mutation architecture and prognostic impact. Co-mutations were present in 97% of patients (median = 3 mutations) with DNMT3A (45%), FLT3-ITD (42%), TET2 (27%), and IDH2 (20%) predominating. RTK/RAS partners were enriched in younger adults, whereas myelodysplasia-related genes (MR-genes), epigenetic lesions and higher mutation burden accumulated in the elderly. Pairwise co-mutations mapped to distinct clinical phenotypes with NPM1+FLT3-ITD showing a hyperproliferative profile, and NPM1+SRSF2/TET2 associated to older patients with cytopenic disease. In the 688 patients receiving upfront intensive therapy, NPM1 type Non-ABD exhibited a tendency toward poorer OS compared with type A. In competing-risk models, SRSF2 and DNMT3A were associated with a higher cumulative incidence of relapse (CIR). Consistently, multivariable analyses showed that increasing age and SRSF2 independently conferred adverse risk across OS, RFS, and EFS; KRAS adversely impacted OS, whereas FLT3-OTHER was associated with improved OS; and DNMT3A with inferior RFS and EFS but not OS. These findings show that co-mutation signatures in NPM1-mutated AML are age-structured and clinically meaningful, refining risk beyond FLT3-ITD.

Haematologica
Hospital Universitario Nuestra Señora de Candelaria (ES), Hospital Universitario Virgen Macarena (ES), Hospital General Universitario Morales Meseguer (ES), Instituto Maimónides de Investigación Biomédica de Córdoba (ES), Hospital Clínico Universitario de Valencia (ES), Complejo Hospitalario de Navarra (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Hospital Universitario Quirónsalud Madrid (ES), Hospital San Pedro de Alcántara (ES), Navarre Institute of Health Research (ES), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Hospital General Universitario De Valencia (ES), Hospital Juan Ramón Jiménez (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Instituto de Biomedicina de Sevilla (ES), Clinica Universidad de Navarra (ES), Hospital Clínico Universitario Lozano Blesa (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Centro de Investigación del Cáncer (ES), Donostiako Unibertsitate Ospitalea (ES), Complexo Hospitalario Universitario A Coruña (ES), Hospital General Universitario de Albacete (ES), Hospital Universitario de Valme (ES), Hospital Universitario Virgen de la Arrixaca (ES), Complejo Hospitalario Torrecárdenas (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Jerez Puerta del Sur (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), Hospital Universitario de León (ES), Instituto de Investigación Sanitaria La Fe (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES)
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