Published online Oct 14, 2019. doi: 10.3748/wjg.v25.i38.5850
Peer-review started: July 24, 2019
First decision: August 17, 2019
Revised: September 5, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 14, 2019
Thiopurine-induced leukopenia (TIL) is life-threatening and occurs with a high frequency in Asia. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants improve the predictive sensitivity of TIL, more than 50% of TIL cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL is controversial.
Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?
To obtain a better model with combination of 6TGN levels and NUDT15 R139C genotypes to predict thiopurine-induced TIL and improve the safety for the thiopurine treatment.
A total of 411 patients diagnosed with Crohn’s disease at the Sixth Affiliated Hospital of the Sun Yat-sen University were included in this study. Peripheral blood from patients was collected to detect the NUDT15 R139C/TPMT*3C genotypes and 6TGN concentrations at School of Pharmaceutical Sciences, Sun Yat-sen University. The X2 method or Fisher’s exact test was used to check the association of TIL with NUDT15 R139C/TPMT*3C diplotypes. A receiver operating characteristic (ROC) curve was used to obtain 6TGN cut-off levels to predict the development of TIL.
TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). After comparing the 6TGN levels based on NUDT15 R139C, for CC (n = 342) and CT (n = 65), the median 6TGN level in patients with TIL was significantly higher than that in patients without (P = 9.4 × 10-5, 474.8 pmol/8 × 108 RBC vs 306.0 pmol/8 × 108 RBC and P = 0.039, 291.7 pmol/8 × 108 RBC vs 217.6 pmol/8 × 108 RBC, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. The area under the ROC curve for the obtained predicted probabilities based on NUDT15 R139C and the 6TGN level was 0.79 (95%CI: 0.76-0.92).
The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping patients according to NUDT15 R139C genotypes.
Applying these specific 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 R139C is strongly recommended during the thiopurine treatment.