Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Celia González-Gil, Mireia Morgades, Thaysa Lopes, Francisco Fuster-Tormo, Jesús García-Chica, Ran Zhao, Pau Montesinos, Anna Torrent Catarineu, Marina Díaz-Beyá, Rosa Coll, Lourdes Hermosín, Santiago Mercadal, José González-Campos, Lurdes Zamora, Teresa Artola, Ferran Vall-Llovera, Mar Tormo, Cristina Gil-Cortés, Pere Barba, Andrés NovoJordi Ribera Salas, Teresa Bernal, Paula López de Ugarriza, María-Paz Queipo, Pilar Martínez-Sánchez, Alicia Giménez, Teresa González-Martínez, Antonia Cladera, José Cervera, Rosa Fernández-Martín, María Ángeles Ardaiz, María Jesús Vidal, Ángela Baena, Nuria López-Bigas, Anna Bigas Salvans, Jaroslaw Maciejewski, Alberto Orfao, Jose-Maria Ribera, Eulàlia Genescà

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Resum

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.
Idioma originalEnglish
Pàgines (de-a)0969-980
Nombre de pàgines12
RevistaHaematologica
Volum108
DOIs
Estat de la publicacióPublicada - 2022

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