Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease
Background & Aims More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic ac...
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Published in | Gastroenterology (New York, N.Y. 1943) Vol. 149; no. 4; pp. 907 - 917.e7 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
01.10.2015
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Subjects | |
Online Access | Get full text |
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Summary: | Background & Aims More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD. Methods In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT ( TPMT *2, TPMT *3A, and TPMT *3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%–10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*109 /L or reduced platelet count < 100*109 /L) and disease activity (based on the Harvey–Bradshaw Index for Crohn’s disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]). Results Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57–1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity ( P = .18 for Crohn’s disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01–0.85). Conclusions Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950. |
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ISSN: | 0016-5085 1528-0012 |
DOI: | 10.1053/j.gastro.2015.06.002 |