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Acute myeloid leukemia

UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy

Abstract

The treatment of acute myeloid leukemia (AML) is adjusted according to cytogenetic risk factors and molecular markers. Cytarabine remains the main drug to treat AML, and several studies have explored the prognostic relevance of the genotype of cytarabine metabolizing enzymes in AML. Glucuronidation has been identified to be relevant in the cytarabine clearance, but there are still few data concerning the clinical impact of genetic polymorphisms known to condition the activity of UDP-glucuronosyl transferases in AML patients. Here we report the association between the UGT1A1 rs8175347 genotype and the clinical outcome of 455 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients with the UGT1A1*28 homozygous variant (associated to a lower UGT1A1 activity) had a lower overall survival (OS) (25.8% vs. 45.5%; p: 0.004). Multivariate analysis confirmed this association (p: 0.008; HR: 1.79; 95% CI: 1.16–2.76). Subgroup analysis showed the negative effect of the UGT1A1*28 homozygous genotype on OS in women (14.8% vs. 52.7%; p: 0.001) but not in men. This lower OS was associated with longer neutropenia after consolidation chemotherapy and with higher mortality without previous relapse, suggesting an association between a low glucuronidation activity and mortal toxic events.

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Fig. 1: Overall survival.
Fig. 2: Subgroup analysis.
Fig. 3: Subgroup overall survival.
Fig. 4: Specific effect of patientʼs gender.

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Acknowledgements

This study has been financed in part by grant Oncotrail (Oncolliga Girona) and by grant Llavaneres contra el Càncer.

CETLAM Group

Jorge Sierra, Jordi Esteve, Josep M. Ribera, David Gallardo, Joan Bargay, Olga Salamero, Mar Tormo, Montserrat Arnán, Antònia Sampol, Rosa Coll, Johana Díaz-Santa, Natàlia Lloveras, David Cruz, Carla Moret, Teresa Quiñones, Marina Díaz-Beya, Àlex Bataller, Dolors Costa, María Rozman, Neus Villamor, Francisca Guijarro, Marta Pratcorona, Ana Garrido, Montserrat Hoyos Colell, Marisa Calabuig, Mª Salut Brunet Mauri, Josep F. Nomdedeu, Josep M. Martí-Tutusaus, Ferran Vall.llovera, Marta Canet, Carme Pedro, Leonor Arenillas, Xavier Calvo, Carlos Palacio, Bárbara Tazón, Ester Alonso, Helena Pomares, Susanna Vives, Blanca Xicoy, Lurdes Zamora, Isabel Granada, Marta Cabezón, Francesc Solé, Marcus Buschbeck, Lourdes Escoda, M. Carme Talarn, Marta Cervera, Vicent Castelló, M. Teresa Giménez, Granada Perea, Elena Rámila, M. Luz Muñoz, Marta Gómez, Antoni García-Guiñón, M. Eugènia Rivero, Eva Villamón, Inma Heras, Antonia Cladera, Jordi Martínez, Xavier Ortín, Cristina Motlló.

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Correspondence to David Gallardo.

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Díaz-Santa, J., Rodríguez-Romanos, R., Osca, G. et al. UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy. Leukemia 34, 2925–2933 (2020). https://doi.org/10.1038/s41375-020-0784-2

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