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Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease.

Coenen, Marieke J H; de Jong, Dirk J; van Marrewijk, Corine J; Derijks, Luc J J; Vermeulen, Sita H; Wong, Dennis R; Klungel, Olaf H; Verbeek, Andre L M; Hooymans, Piet M; Peters, Wilbert H M; Te Morsche, Rene H M; Newman, William G; Scheffer, Hans; Guchelaar, Henk-Jan; Franke, Barbara

Gastroenterology. 2015;.

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Abstract

BACKGROUND AND AIMS: More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy due to severe adverse drug reactions (ADRs); leucopenia 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 leucopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects outcomes of patients with IBD. METHODS: In a study performed at 30 Dutch hospitals, patients were randomly assigned to groups that received standard treatment (control) or pre-treatment screening (intervention) for 3 common variants of TPMT (TPMT*2, *3A, and *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 those 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 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 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; the groups also had similar mean levels of disease activity (P=0.18 for Crohn's disease and P=0.14 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 those 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 hematological 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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Manchester eScholar ID:
uk-ac-man-scw:267799
Created by:
Newman, William
Created:
2nd July, 2015, 22:28:34
Last modified by:
Newman, William
Last modified:
2nd July, 2015, 22:28:34

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