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UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy
Leukemia ( IF 11.4 ) Pub Date : 2020-03-09 , DOI: 10.1038/s41375-020-0784-2
Johana Díaz-Santa , , Rocío Rodríguez-Romanos , Gemma Osca , Marta Pratcorona , Ana Garrido , Rosa Coll , Carla Moret , Lourdes Escoda , Mar Tormo , Inma Heras , Montse Arnan , Susanna Vives , Olga Salamero , Natàlia Lloveras , Joan Bargay , Antònia Sampol , David Cruz , Antoni Garcia , Teresa Quiñones , Jordi Esteve , Jorge Sierra , David Gallardo

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.



中文翻译:

UGT1A1基因型影响以阿糖胞苷为基础的化学疗法治疗的中危急性髓性白血病患者的临床结局

根据细胞遗传学危险因素和分子标志物调整急性髓细胞白血病(AML)的治疗。阿糖胞苷仍然是治疗AML的主要药物,几项研究探讨了阿糖胞苷代谢酶基因型在AML中的预后相关性。葡糖醛酸化作用已被确定与阿糖胞苷清除率有关,但目前尚无关于遗传多态性对AML患者UDP-葡糖醛酸糖基转移酶活性有调节作用的临床影响的数据。在这里,我们报告了UGT1A1 rs8175347基因型与455名接受阿糖胞苷为基础化疗的中危细胞遗传学AML患者的临床结果之间的关联。具有UGT1A1 * 28纯合变体(与较低的UGT1A1活性相关)的患者具有较低的总生存期(OS)(25.8%对45.5%;p:0.004)。多变量分析证实了这种关联(p:0.008; HR:1.79; 95%CI:1.16-2.76)。亚组分析显示,UGT1A1 * 28纯合基因型对女性的OS有负面影响(分别为14.8%和52.7%;p:0.001),而对男性则没有。较低的OS与巩固化疗后更长的中性粒细胞减少症相关,并且与先前未复发的更高死亡率相关,提示低葡萄糖醛酸化活性与致命毒性事件之间存在关联。

更新日期:2020-04-24
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