Adjustment of azathioprine dose should be based on a lower 6‐TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers

Abstract

Background: The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known. Aim: To investigate the association between NUDT15 polymorphisms and time-toleucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. Methods: This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed. Results: Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolizers respectively (P < 0.001). NUDT15 polymorphism was significantly associated with time-to-leucopenia (HR = 5.26, 95% CI = 2.74-10.09, P < 0.001). There was a positive association between 6-TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolizers (median 361.3 vs 263.8 pmol/8 × 10 8 RBC, P = 0.013). The most accurate 6-TGN cutoff level associated with leucopenia was 308.2 pmol/8 × 10 8 RBC (AUC = 0.742, 95% CI = 0.569-0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6-TGN cutoff level was 167.1 pmol/8 × 10 8 RBC (sensitivity 93.3%, specificity 13.6%). Conclusions: NUDT15 polymorphisms were associated with time-to-leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine-induced leucopenia (<15%) in NUDT15 intermediate metabolizers, adjustment of azathioprine doses should be based on a lower 6-TGN target level (<167.1 pmol/8 × 10 8 RBC).

Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study

“…Frontiers in Pharmacology | www.frontiersin.org mostly limited to a certain disease or a type [such as inflammatory bowel disease (Al-Judaibi et al, 2016;Wang et al, 2018;Walker et al, 2019;Kang et al, 2020), autoimmune disease (Fei et al, 2018;Fan et al, 2019), and acute lymphoblastic leukemia (Yang et al, 2015;Zhu et al, 2018)], and have generally included a small number of study subjects, with a focus on only one or two genes.…”

“…The retrospective case analysis was performed on a large number of relative cases involving various diseases. Current reports are mostly limited to a certain disease or a type [such as inflammatory bowel disease ( Al-Judaibi et al, 2016 ; Wang et al, 2018 ; Walker et al, 2019 ; Kang et al, 2020 ), autoimmune disease ( Fei et al, 2018 ; Fan et al, 2019 ), and acute lymphoblastic leukemia ( Yang et al, 2015 ; Zhu et al, 2018 )], and have generally included a small number of study subjects, with a focus on only one or two genes. In this study, 40 diseases were included, which covered all of the indications for AZA, and the correlation between genetic polymorphisms of AZA-metabolizing enzymes and AZA-induced myelosuppression were compared under different pathological states.…”

“…However, Asians have a low tolerance to AZA and a high incidence of leukopenia, which makes it necessary to explore predictive genes suitable for the Asian population specifically. In recent years, some studies have shown that NUDT15 might be highly correlated with AZA-induced myelosuppression in Asians ( Chao et al, 2017 ; Wang et al, 2018 ; Banerjee et al, 2020 ; Kang et al, 2020 ), and the CPIP guideline also recommends that the NUDT15 genotype should be determined prior to the administration of AZA (2018) ( Relling et al, 2019 ).…”

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

“…But, interestingly, 6‐TG levels differed significantly in patients with or without leucopenia in NUDT15 intermediate/TPMT normal metabolizer group. Hence they recommended lower cut off levels for NUDT15 intermediate metabolizers 33 …”

Editorial: balancing safety and efficacy—6‐TGN thresholds in NUDT15 intermediate metabolisers treated with thiopurines

“…We read with interest the current paper by Kang et al 9 who performed a retrospective analysis of 167 Korean paediatric patients with IBD treated with thiopurines. Patients were dosed according to TPMT status and weight, and the relationship between leukopenia and TGNs, stratified by NUDT15 variant status, was subsequently investigated.…”