Marieke J H Coenen1, Dirk J de Jong2, Corine J van Marrewijk3, Luc J J Derijks4, Sita H Vermeulen5, Dennis R Wong6, Olaf H Klungel7, Andre L M Verbeek8, Piet M Hooymans6, Wilbert H M Peters2, Rene H M te Morsche2, William G Newman9, Hans Scheffer10, Henk-Jan Guchelaar11, Barbara Franke12. 1. Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: marieke.coenen@radboudumc.nl. 2. Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands. 3. Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands. 4. Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands. 5. Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands. 6. Department of Clinical Pharmacy and Toxicology, Orbis Medical Center, Sittard-Geleen, The Netherlands. 7. Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 8. Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands. 9. Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. 10. Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands. 11. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. 12. Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands.
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.
RCT Entities:
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.
Authors: M M T J Broekman; D R Wong; G J A Wanten; H M Roelofs; C J van Marrewijk; O H Klungel; A L M Verbeek; P M Hooymans; H-J Guchelaar; H Scheffer; L J J Derijks; M J H Coenen; D J de Jong Journal: Pharmacogenomics J Date: 2017-01-03 Impact factor: 3.550
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