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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

Leukemia volume 34, pages 2925–2933 (2020)Cite this article

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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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Authors and Affiliations

  1. Hematology Department, Catalan Institute of Oncology (ICO), Girona. Institut d’Investigació Biomèdica de Girona (IDIBGI), Universitat de Girona, Girona, Spain

    Johana Díaz-Santa, Rocío Rodríguez-Romanos, Gemma Osca, Rosa Coll, Carla Moret, Natàlia Lloveras, David Cruz, Teresa Quiñones & David Gallardo

  2. Hematology Department, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    Marta Pratcorona, Ana Garrido & Jorge Sierra

  3. Hematology Department, Catalan Institute of Oncology (ICO), Hospital Joan XXIII, Tarragona, Spain

    Lourdes Escoda

  4. Hematology Department, Hospital Clínico, Valencia, Spain

    Mar Tormo

  5. Department of Hematology, University Hospital Morales Meseguer, Murcia, Spain

    Inma Heras

  6. Department of Hematology, Catalan Institute of Oncology (ICO), L’Hospitalet, Barcelona, Spain

    Montse Arnan

  7. Hematology Department, Catalan Institute of Oncology (ICO), Badalona, Josep Carreras Leukemia Research Institute (IJC), Badalona, Barcelona, Spain

    Susanna Vives

  8. Hematology Department, Hospital Vall d’Hebró, Barcelona, Spain

    Olga Salamero

  9. Hematology Department, Hospital de Son Llàtzer, Palma de Mallorca, Spain

    Joan Bargay

  10. Hematology Department, Hospital Son Espases, Palma de Mallorca, Spain

    Antònia Sampol

  11. Hematology Department, Hospital Arnau de Vilanova, Lleida, Spain

    Antoni Garcia

  12. Hematology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    Jordi Esteve

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  1. Johana Díaz-Santa
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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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