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Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases

 Ji Young Chang  ;  Soo Jung Park  ;  Eun Suk Jung  ;  Sung-Ae Jung  ;  Chang Mo Moon  ;  Jaeyoung Chun  ;  Jae Jun Park  ;  Eun Sun Kim  ;  Yehyun Park  ;  Tae-Il Kim  ;  Won Ho Kim  ;  Jae Hee Cheon 
 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, Vol.18(9) : 2010-2018.e2, 2020-08 
Journal Title
Issue Date
Adverse Drug Reaction ; Genetic Risk Factor ; Immune Modulator ; Metabolism
Background & aims: Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments.

Methods: We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers 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 hemoglobin 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 = .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P = .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions.

Conclusions: In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Park, Soo Jung(박수정)
Park, Yehyun(박예현) ORCID logo https://orcid.org/0000-0001-8811-0631
Park, Jae Jun(박재준)
Jung, Eun Suk(정은석)
Chun, Jaeyoung(천재영) ORCID logo https://orcid.org/0000-0002-4212-0380
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
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