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P080 Thioguanine nucleotide cut-off levels to predict leucopoenia should be considered differently based on NUDT15 R139C genotypes in Chinese Crohn’s disease

X. Zhu1, K. Chao2, H. Zheng1, P. Hu2, M. Huang1, X. Gao*2, X. Wang1

1Sun Yat-sen University, Guangzhou, China, 2The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Background

To date, excessive level of thioguanine nucleotide (6-TGN) poses an increased risk for leucopoenia, which has been identified in Caucasian patients. However, basing on 6-TGN levels alone would overlook NUDT15-deficient patients who are prone to thiopurine-induced leucopoenia in East Asian. In our study, we investigated the relationship between 6-TGN levels and leucopoenia in different NUDT15 R139C genotypes to obtain the cut-off level in each subgroup.

Methods

Patients with Crohn’s diease (CD) in the sixth affiliated hospital, Sun Yat-sen university form July 2014 to December 2017 were retrospectively studied. The CD patients with stable dosage of thioprine were recuited. Clinical and epidemiological characteristics were reviewed from medical records. NUDT15 R139C was genotyped. 6-TGN/6-MMPR concentrations were measured with high-performance liquid chromatography (HPLC).

Results

A total of 434 CD patients with at least one 6TGN measurement were included in this study. Leucopoenia was observed in 78 individuals (18.0%) with median 6-TGN level of 332.3 pmol/8 × 108 RBC, which was marginally different from the median level of 291.9 pmol/8 × 108 RBC in the patients without leucopoenia (p = 0.040). Then we compared 6TGN levels of the whole patients after dividing them into three groups according to the genotype of NUDT15 R139C. For CC genotypes (n = 361), the median 6-TGN concentrations in patients who developed leucopoenia was significantly higher than that in patients who did not (p < 0.0001, 474.8 (174.2–1179.5) vs. 305.7 (62.2–1822.9) pmol/8 × 108 RBC). For CT carriers (n = 69), the 6-TGN levels were also higher in patients developing leucopoenia (p = 0.027, 292.8 (80.7–701.5) vs. 216.2 (62.9–631.0) pmol/8 × 108 RBC). ALL of the TT (n = 4) developed leukopoenia with the median 6-TGN concentration of 135.8 (90.0~291.3) pmol/8 × 108 RBC. The cut-off 6-TGN levels of 319.2 pmol/8 × 108 RBC in CT subgroup was 96.9% specific to leucopoenia, with a sensitivity of 43.2% and area under curve (AUC) of 0.66 (p = 0.027). Meanwhile, the cut-off 6-TGN levels in CC subgroup was 409.6 pmol/8 × 108 RBC with the 73.5% specificity and 59.5% sensitivity to leucopoenia (p < 0.0001, AUC = 0.71). 6-MMPR was not correlated with leucopoenia (p >0.05).

Conclusion

In Chinese CD patients, it is strongly recommended to consider different 6TGN cut-off levels to predict thiopurine-induced leucopoenia based on NUDT15 R139C genotypes.