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

Coenen, Marieke J. H.; van Marrewijk, Corine J.; de Jong, Dirk J.; Derijks, Luc J. J.; Vermeulen, Sita H.; Wong, Dennis R.; Klungel, Olaf H.; te Morsche, Rene H. M.; Verbeek, Andre L. M.; Hooymans, Piet M.; Masclee, A. A. M.; Pierik, M.; Peters, Wilbert H. M.; Mares, W.; Hameeteman, W.; Newman, William G.; Wahab, P. J.; Seinen, H.; Scheffer, Hans; Rijk, M. C. M.; Harkema, I. M.; Guchelaar, Henk-Jan; van Nunen, A. B.; de Bièvre, M.; Franke, Barbara; Oostenbrug, L.; Bakker, C. M.; van Deursen, C.; Aquarius, M.; van Tuyl, S. A. C.; Goedhard, J. G.; Hamacher, M.; Gisbertz, I. A. M.; Brenninkmeijer, B. J.; Tan, A. C. I. T. L.; Aparicio-Pagés, M. N.; Witteman, E. M.; Breumelhof, R.; Stronkhorst, A.; Gilissen, L. P. L.; Schoon, E. J.; Tjhie-Wensing, J. W. M.; Temmerman, A.; van Munster, I. P.; Nicolaï, J. J.; van Bergeijk, J. D.; van Ditzhuijsen, T. J. M.; Bac, D. J.; Witteman, B. J. M.; Mahmmod, N.; Uil, J. J.; Akol, H.; Ouwendijk, R. J. T.; Pennings, M.; van Wijk, H. J.; De Schryver, A. M. P.; Scheffer, R. C. H.; van der Werf, S. D. J.; Römkens, T. E. H.; Schipper, D. L.; Bus, P. J.; Straathof, J. W. A.; van der Linde, K.; Verhulst, M. L.; Boekema, P. J.; Kamphuis, J. T.; Salemans, J. M. J. L.; van Olffen, G. H.; Vermeijden, J. R.; Verburg, R. J.; Spoelstra, P.; de Vree, J. M. L.; Jebbink, H. J. A.; Jansen, M.; Holwerda, H.; van Esch, A. A. J.; van Bentem, N.; Kolkman, J. J.; van Kouwen, M. C. A.; Russel, M. G. V. M.; Kerbert-Dreteler, M. J.; Bargeman, M.; van Vugt, M. W. J.; Götz, J. M.; Schröder, R.; van de Meeberg, P. C.; Jansen, J. M.; van den Hazel, S. J.; Bos, L. P.; Engels, L. G. J. B.; Romberg-Camps, M. J. L.; Keulen, E. T. P.; Drenth, J. P. H.; van den Brande, J. M. H.; Wanten, G. J. A.; Bisseling, T. J.; van Soest, E. J.; Stuifbergen, W. N. H. M.; Grubben, M. J. A. L.; de Wit, U.; Dodemont, G. A. H.; van der Veek, P. P. J.; Eichhorn, R. F.; Naber, A. H. J.; Kingma, P. J.; Talstra, N. C.; Bruin, K. F.; Wolfhagen, F. H. J.; Hommes, D. W.; Hardwick, J. C. A.; Stuyt, R. J.; Fidder, H. H.; Oldenburg, B.; Tan, T. G.

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Publishing House Zaslavsky, Gastroenterology, 4(149), p. 907-917.e7

DOI: 10.1053/j.gastro.2015.06.002

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

Journal article published in 2015 by Marieke J. H. Coenen

, Corine J. van Marrewijk, Dirk J. de Jong, Luc J. J. Derijks, Sita H. Vermeulen, Dennis R. Wong, Olaf H. Klungel, Rene H. M. te Morsche, Andre L. M. Verbeek, Piet M. Hooymans, A. A. M. Masclee, M. Pierik, Wilbert H. M. Peters, W. Mares, W. Hameeteman and other authors.

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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

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

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