Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens

Peng Chen,Ke-Wei Zhu,Han Liu,Xie-Lan Zhao,Jing Yang,Shu-Ping Chen,Shan Cao,Han Yan,Yan-Ling Liu,Hui Zeng,Xiao-Ping Chen,Dao-Yu Zhang,Gan Zhou

doi:10.1186/s12967-018-1579-3

Abstract

BackgroundsUDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.MethodsUGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.ResultsAfter one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379–0.737, P = 1.7 × 10−4) and better overall survival (HR = 0.787, 95% CI 0.627–0.990, P = 0.040) as compared with homozygotes for both polymorphisms.ConclusionOur results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous hematological malignance derived from the hemopoietic progenitors with highly diverse clinical traits, molecular pathogenesis and clinical outcomes [1]
Our previous studies have reported that polymorphisms in deoxycytidine kinase (DCK), nucleoside diphosphate kinase 2 (NME2), ribonucleotide reductase catalytic subunit M2 (RRM2), and SAM domain and HD domain-containing protein 1 (SAMHD1) are associated with chemosensitivity to Ara-C based therapy and disease prognosis in Chinese AML patients [10, 16]
We investigated the impact of UDP-glucuronosyltransferase family 1 member A1 (UGT1A1)*28 and *6 variants on complete remission (CR) rate after induction chemotherapy, treatment-related mortality (TRM), overall survival (OS) and event-free survival (EFS) in 726 Chinese AML patients treated with Ara-C

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous hematological malignance derived from the hemopoietic progenitors with highly diverse clinical traits, molecular pathogenesis and clinical outcomes [1]. Apart from known prognostic factors including age, white blood cell (WBC) counts, complex karyotype, antecedent hematologic disease and secondary leukemia [2], accumulated evidence has shown that the presence of somatic mutations in genes such as fms-like tyrosine kinase 3 (FLT3), Chen et al J Transl Med (2018) 16:197 mechanisms involved in Ara-C resistance will help optimize regimens for treatment of AML and improve the clinical outcomes as well. Our previous studies have reported that polymorphisms in DCK, nucleoside diphosphate kinase 2 (NME2), ribonucleotide reductase catalytic subunit M2 (RRM2), and SAMHD1 are associated with chemosensitivity to Ara-C based therapy and disease prognosis in Chinese AML patients [10, 16]

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Discussion

Conclusion