Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Acute myeloid leukemia

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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


  1. 1.

    Boissel N, Cayuela JM, Preudhomme C, Thomas X, Grardel N, Fund X, et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia. 2002;16:1699–704.

    CAS  Article  Google Scholar 

  2. 2.

    Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66.

    CAS  Article  Google Scholar 

  3. 3.

    Hyo Kim L, Sub Cheong H, Koh Y, Ahn KS, Lee C, Kim HL, et al. Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML. J Hum Genet. 2015;60:749–54.

    CAS  Article  Google Scholar 

  4. 4.

    Yee SW, Mefford JA, Singh N, Percival ME, Stecula A, Yang K, et al. Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. J Hum Genet. 2013;58:353–61.

    CAS  Article  Google Scholar 

  5. 5.

    Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 2014;511:90–3.

    CAS  Article  Google Scholar 

  6. 6.

    Zahreddine HA, Borden KL. Molecular pathways: GLI1-induced drug glucuronidation in resistant cancer cells. Clin Cancer Res. 2015;21:2207–10.

    CAS  Article  Google Scholar 

  7. 7.

    Zahreddine HA, Culjkovic-Kraljacic B, Gasiorek J, Duchaine J, Borden KLB. GLI1-Inducible glucuronidation targets a broad spectrum of drugs. ACS Chem Biol. 2019;14:348–55.

    CAS  Article  Google Scholar 

  8. 8.

    Guillemette C, Lévesque É, Rouleau M. Pharmacogenomics of human uridine diphospho-glucuronosyltransferases and clinical implications. Clin Pharm Ther. 2014;96:324–39.

    CAS  Article  Google Scholar 

  9. 9.

    Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA. 1998;95:8170–4.

    CAS  Article  Google Scholar 

  10. 10.

    Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    CAS  Article  Google Scholar 

  11. 11.

    Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.

    CAS  Article  Google Scholar 

  12. 12.

    Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005;106:3618–20.

    CAS  Article  Google Scholar 

  13. 13.

    Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22:624–33.

    Article  Google Scholar 

  14. 14.

    Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 2000;60:6921–6.

    CAS  PubMed  Google Scholar 

  15. 15.

    Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382–8.

    CAS  Article  Google Scholar 

  16. 16.

    de Jong FA, Kehrer DF, Mathijssen RH, Creemers GJ, de Bruijn P, van Schaik RH, et al. Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. Oncologist. 2006;11:944–54.

    Article  Google Scholar 

  17. 17.

    Fleming RA, Capizzi RL, Rosner GL, Oliver LK, Smith SJ, Schiffer CA, et al. Clinical pharmacology of cytarabine in patients with acute myeloid leukemia: a cancer and leukemia group B study. Cancer Chemother Pharm. 1995;36:425–30.

    CAS  Article  Google Scholar 

  18. 18.

    Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333:1171–5.

    CAS  Article  Google Scholar 

  19. 19.

    Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42:107–21.

    CAS  Article  Google Scholar 

  20. 20.

    Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 2008;38:62–75.

    CAS  Article  Google Scholar 

  21. 21.

    Chen P, Zhu KW, Zhang DY, Yan H, Liu H, Liu YL, et al. Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens. J Transl Med. 2018;16:197.

    CAS  Article  Google Scholar 

Download references


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


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.

Author information




Corresponding author

Correspondence to David Gallardo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the CETLAM Group are listed below Acknowledgements

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading


Quick links