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

M.J. Coenen, D.J. de Jong, C.J. van Marrewijk, L.J. Derijks, S.H. Vermeulen, D.R. Wong, O.H. Klungel, A.L. Verbeek, P.M. Hooymans, W. H. Peters, R.H. te Morsche, W.G. Newman, H. Scheffer, H.J. Guchelaar, A. TOPIC Recruitment Team (incl. Masclee), M. TOPIC Recruitment Team (incl. Pierik), B. Franke

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Abstract

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*10(9)/L or reduced platelet count < 100*10(9)/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.
Original languageEnglish
Pages (from-to)907-917 e907
JournalGastroenterology
Volume149
Issue number4
DOIs
Publication statusPublished - 1 Jan 2015

Cite this

Coenen, M. J., de Jong, D. J., van Marrewijk, C. J., Derijks, L. J., Vermeulen, S. H., Wong, D. R., Klungel, O. H., Verbeek, A. L., Hooymans, P. M., Peters, W. H., te Morsche, R. H., Newman, W. G., Scheffer, H., Guchelaar, H. J., TOPIC Recruitment Team (incl. Masclee), A., TOPIC Recruitment Team (incl. Pierik), M., & Franke, B. (2015). Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology, 149(4), 907-917 e907. https://doi.org/10.1053/j.gastro.2015.06.002