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

Background The association betweenNUDT15polymorphisms and thiopurine-induced leucopenia is well known. Aim To investigate the association betweenNUDT15polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship betweenNUDT15polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. Methods This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwentNUDT15andTPMTgenotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship betweenNUDT15polymorphisms 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).NUDT15polymorphism 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 x 10(8)RBC,P = 0.013). The most accurate 6-TGN cut-off level associated with leucopenia was 308.2 pmol/8 x 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 cut-off level was 167.1 pmol/8 x 10(8)RBC (sensitivity 93.3%, specificity 13.6%). Conclusion NUDT15polymorphisms 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 x 10(8)RBC).