Venetoclax-based therapy versus hypomethylating agents alone in unfit patients with newly diagnosed acute myeloid leukemia: a real-world study from the PETHEMA registry

Real-world comparisons of venetoclax (VEN)-based versus hypomethylating agent (HMA) monotherapy in unfit, newly diagnosed AML remain limited by short follow-up, low genomic testing, and inadequate statistical power. We conducted the largest comparative analysis to date from the PETHEMA registry, including 2610 patients (929 VEN-based, 1681 HMA). Composite complete remission was higher with VEN-based therapy (64.4% vs 20.0%; P < 0.001), and both 30-day (4.8% vs 7.5%; P = 0.011) and 60-day mortality (9.7% vs 15.7%; P < 0.001) were significantly lower. Median overall survival was 11.4 versus 8.2 months (HR, 0.66; 95% CI, 0.60–0.73; P < 0.001), consistent with that of VIALE-A (HR, 0.66) despite a broader cohort (ECOG 3–4, 4.7%; secondary AML, 42.5%; adverse-risk cytogenetics, 36.5%). The benefit was confirmed by propensity score matching (HR, 0.66), era-restricted analysis (HR, 0.71), and multivariable Cox regression. A molecular gradient of benefit emerged—greatest in IDH2 (HR, 0.43), NPM1 (0.46), FLT3 -ITD (0.48), IDH1 (0.55), and favorable-risk cytogenetics (0.25). In TP53 -mutated AML, OS improved significantly (HR, 0.70) but remained dismal (7.0 vs 3.7 months); no benefit was observed in AML arising from antecedent MDS or MPN. These findings confirm and extend VIALE-A, refining patient selection for VEN-based therapy in routine practice.

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Journal
Leukemia
Published
2026-10-06
DOI
https://doi.org/10.1038/s41375-026-03154-3
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Venetoclax-based therapy versus hypomethylating agents alone in unfit patients with newly diagnosed acute myeloid leukemia: a real-world study from the PETHEMA registry

Gaspar Aspas Requena, María Marta Rivas, Silvina Palmer, Pau Montesinos et al.
Leukemia
Acute Myeloid Leukemia Research
article

Venetoclax-based therapy versus hypomethylating agents alone in unfit patients with newly diagnosed acute myeloid leukemia: a real-world study from the PETHEMA registry

Gaspar Aspas Requena, María Marta Rivas, Silvina Palmer, Pau Montesinos, Daniel García Belmonte, Olga Salamero, Marta Valero Núñez, Mar Tormo, María Ángeles Foncillas, José Mariz, María José Mela Osorio, María Dolores Madrigal, Jorge Labrador, Sandra Casal Marini, Ana Lisa Basquiera, Diana Cuervo, Raimundo García Boyero, Ana Alfonso Piérola, Cristina Gil, María Lourdes Amador Barciela, Eliana Vale Aguiar, Alicia Roldán, Alberto Giménez‐Conca, Maria Carmen García Garay, Francisco Ibáñez Alís, Eduardo Rodríguez‐Arbolí, Lara M. Gómez García, Marcela Espinoza, Juan Bergua, María‐Belén Vídriales, María‐Luz Amigo, Olga Arce Fernández, Teresa Bernal, Rosa María Ayala, Susana Vives, María Solé Rodriguez, Ágata Almela, Josefina Serrano López, Bernardo Javier González González, Isabel Recio, Carlos Rodríguez‐Medina, Kenny Galvez, Manuel Pérez‐Encinas, Miguel López, Carlos Varon, Joana Brioso, Pilar Lloret Madrid, Claudia Lucía Sossa Melo, José Luis López Lorenzo, Aitor Abuín
article en

Abstract

Real-world comparisons of venetoclax (VEN)-based versus hypomethylating agent (HMA) monotherapy in unfit, newly diagnosed AML remain limited by short follow-up, low genomic testing, and inadequate statistical power. We conducted the largest comparative analysis to date from the PETHEMA registry, including 2610 patients (929 VEN-based, 1681 HMA). Composite complete remission was higher with VEN-based therapy (64.4% vs 20.0%; P < 0.001), and both 30-day (4.8% vs 7.5%; P = 0.011) and 60-day mortality (9.7% vs 15.7%; P < 0.001) were significantly lower. Median overall survival was 11.4 versus 8.2 months (HR, 0.66; 95% CI, 0.60–0.73; P < 0.001), consistent with that of VIALE-A (HR, 0.66) despite a broader cohort (ECOG 3–4, 4.7%; secondary AML, 42.5%; adverse-risk cytogenetics, 36.5%). The benefit was confirmed by propensity score matching (HR, 0.66), era-restricted analysis (HR, 0.71), and multivariable Cox regression. A molecular gradient of benefit emerged—greatest in IDH2 (HR, 0.43), NPM1 (0.46), FLT3 -ITD (0.48), IDH1 (0.55), and favorable-risk cytogenetics (0.25). In TP53 -mutated AML, OS improved significantly (HR, 0.70) but remained dismal (7.0 vs 3.7 months); no benefit was observed in AML arising from antecedent MDS or MPN. These findings confirm and extend VIALE-A, refining patient selection for VEN-based therapy in routine practice.

Leukemia
Universitat de València (ES), Pontificia Universidad Católica de Chile (CL), Université de Montpellier (FR), Hospital Universitario de Canarias (ES), Clínica Alemana (CL), Hospitais da Universidade de Coimbra (PT), Hospital Italiano de Buenos Aires (AR), Hospital de São João (PT), Hospital Universitari i Politècnic La Fe (ES), Josep Carreras Leukaemia Research Institute (ES), Hospital Universitario Virgen Macarena (ES), Hospital General Universitario Morales Meseguer (ES), Hospital de Basurto (ES), Hospital La Luz (ES), Centre Hospitalier Universitaire de Montpellier (FR), Hospital Clínico Universitario de Valencia (ES), Complejo Hospitalario Universitario de Santiago (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Complejo Hospitalario de Salamanca (ES), Hospital Universitario Austral (AR), Hospital Universitario 12 De Octubre (ES), Escola Superior de Tecnologia da Saúde de Coimbra (PT), IPO Porto (PT), Hospital San Pedro de Alcántara (ES), Hospital Pablo Tobon Uribe (CO), Centro Hospitalar Lisboa Norte (PT), Hospital Universitario de Burgos (ES), Hospital Arnau de Vilanova (ES), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), Hospital Juan Ramón Jiménez (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Fundación Universitaria de Ciencias de la Salud (CO), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Central de Asturias (ES), Clinica Universidad de Navarra (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Hospital Universitario Lucus Augusti (ES), Hospital Británico de Buenos Aires (AR), Instituto Português de Oncologia de Coimbra Francisco Gentil (PT), Hospital de Santa Maria (PT), Hospital Universitario Virgen de la Arrixaca (ES), Foscal Hospital (CO), Hospital Privado (AR), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), Clínica Dávila (CL), Hospital Clínico Universitario de Valladolid (ES), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Complejo Hospitalario de Pontevedra (ES), Hospital Universitario de León (ES), Hospital Universitario Infanta Sofía (ES), Hospital Universitario Infanta Leonor (ES)
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