Abstract
Background
Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pre-treatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments.
Methods
We performed a multicentre, prospective study of patients with IBD at 5 tertiary medical centres in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2–2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/μL, levels of haemoglobin 10 g/dl, or platelet counts below 100 K/μl.
Results
Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (p = .005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22–0.81; p = 0.009), pre-treatment genotype analysis (HR, 0.37; 95% CI, 0.18–0.77; p = 0.008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19–0.59; p < 0.001) independently decreased risk of myelosuppression. Pre-treatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions.
Conclusion
In a randomised controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leucopoenia significantly reduced the proportion of patients with myelosuppression during treatment.
A Spectrum of Genetic Variants Contributes to Immune Defects and Pathogenesis of Inflammatory Bowel Diseases
