The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

Rosa Ayala; Inmaculada Rapado; Esther Onecha; David Martínez-Cuadrón; Gonzalo Carreño-Tarragona; Juan Miguel Bergua; Susana Vives; Jesus Lorenzo Algarra; Mar Tormo; Pilar Martinez; Josefina Serrano; Pilar Herrera; Fernando Ramos; Olga Salamero; Esperanza Lavilla; Cristina Gil; Jose Luis López Lorenzo; María Belén Vidriales; Jorge Labrador; José Francisco Falantes; María José Sayas; Bruno Paiva; Eva Barragán; Felipe Prosper; Miguel Ángel Sanz; Joaquín Martínez-López; Pau Montesinos; On Behalf Of The Programa Para El Estudio de la Terapeutica En Hemopatias Malignas Pethema Cooperative Study Group

doi:10.3390/cancers13102458

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

Cancers (Basel). 2021 May 18;13(10):2458. doi: 10.3390/cancers13102458.

Authors

Rosa Ayala^{1

2

3

4}, Inmaculada Rapado^{1

2

4}, Esther Onecha^{1

2}, David Martínez-Cuadrón⁵, Gonzalo Carreño-Tarragona^{1

2}, Juan Miguel Bergua⁶, Susana Vives⁷, Jesus Lorenzo Algarra⁸, Mar Tormo⁹, Pilar Martinez¹⁰, Josefina Serrano¹¹, Pilar Herrera¹², Fernando Ramos¹³, Olga Salamero¹⁴, Esperanza Lavilla¹⁵, Cristina Gil¹⁶, Jose Luis López Lorenzo¹⁷, María Belén Vidriales¹⁸, Jorge Labrador¹⁹, José Francisco Falantes²⁰, María José Sayas²¹, Bruno Paiva^{4

22}, Eva Barragán^{4

5}, Felipe Prosper^{4

22}, Miguel Ángel Sanz^{4

5}, Joaquín Martínez-López^{1

2

3

4}, Pau Montesinos^{4

5}, On Behalf Of The Programa Para El Estudio de la Terapeutica En Hemopatias Malignas Pethema Cooperative Study Group

Affiliations

¹ Hematology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Imas12, 28041 Madrid, Spain.
² Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, Spain.
³ Departament of Medicine, Complutense University, 28040 Madrid, Spain.
⁴ Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 28029 Madrid, Spain.
⁵ Hematology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
⁶ Hematology Department, Hospital San Pedro Acantara, 10003 Cáceres, Spain.
⁷ Department of Hematology, ICO Badalona-Hospital Germans Trias i Pujol. Josep Carreras Leukemia Research Institute. Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
⁸ Hematology Department, Hospital General de Albacete, 02006 Albacete, Spain.
⁹ Hematology Department, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain.
¹⁰ Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain.
¹¹ Hematology Department, Hospital Universitario Reina Sofía, 14004 Cordoba, Spain.
¹² Hematology Department, Hospital Ramon y Cajal, 28034 Madrid, Spain.
¹³ Hematology Department, Hospital Universitario de León, 24008 León, Spain.
¹⁴ Hematology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.
¹⁵ Hematology Department, Hospital Universitario Xeral de Lugo, 27003 Lugo, Spain.
¹⁶ Hematology Department, Hospital General de Alicante, 03010 Alicante, Spain.
¹⁷ Hematology Department, Fundación Jiménez Díaz, 28040 Madrid, Spain.
¹⁸ Hematology Department, Hospital Universitario de Salamanca, IBSAL, 37007 Salamanca, Spain.
¹⁹ Hematology Department, Hospital Universitario de Burgos, 09001 Burgos, Spain.
²⁰ Hematology Department, Hospital Universitario Vírgen del Rocío, Instituto de BioMedicina de Sevilla, 41013 Sevilla, Spain.
²¹ Hematology Department, Hospital Doctor Peset, 46017 Valencia, Spain.
²² Hematology Department, Clínica Universitaria de Navarra, 31008 Navarra, Spain.

Abstract

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.

Keywords: NGS; acute; azacytidine; clinical trials and observations; complete remission; cytarabine; genetic risk; leukemia; leukemic cells; myelocytic; myeloid neoplasia; older adults; prognostic factors; variants.

Associated data

ClinicalTrials.gov/NCT02319135

Abstract

Associated data

Grants and funding