Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease

Abstract

Introduction: Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15C415T is a promising predictor in Asia. Aims:To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. Methods:Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 10 9 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36. Results:The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up.Conclusions: Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies.Clinical trial number: NCT02929706.

Personalized medicine to implementation science: Thiopurines set for the leap

“…In a multicenter Korean randomized trial, myelosuppression was less frequently noted in patients with polymorphism testing as compared with those who did not (16.7% vs 35.9%) 19 . In a Chinese study, where NUDT15 testing was compared with the control group, leukopenia occurred less frequently in the testing arm (23.7% vs 32.4%) 20 . Therefore, the evidence through RCTs suggests that the pretherapy genotype assessment reduces the myelotoxicity associated with thiopurine use (Table 2).…”

“… 20 Therefore, the evidence through RCTs suggests that the pretherapy genotype assessment reduces the myelotoxicity associated with thiopurine use (Table 2 ). 18 , 19 , 20 …”

“…19 In a Chinese study, where NUDT15 testing was compared with the control group, leukopenia occurred less frequently in the testing arm (23.7% vs 32.4%). 20 Therefore, the evidence through RCTs suggests that the pretherapy genotype assessment reduces the myelotoxicity associated with thiopurine use (Table 2). [18][19][20] Dosing strategies.…”

“…20 Therefore, the evidence through RCTs suggests that the pretherapy genotype assessment reduces the myelotoxicity associated with thiopurine use (Table 2). [18][19][20] Dosing strategies. Because of clear evidence, we usually test for common polymorphisms of TPMT and NUDT15 before initiating thiopurines and modify the dose based on genotype testing.…”

“…Randomized control trials which have compared genotype-based dosing for thiopurines in the setting of inflammatory bowel disease (IBD)[18][19][20] …”