Screening of the TPMT gene before thiopurine treatment results in a lower leucopenia occurrence in patient with inflammatory bowel disease. M. J. H. Coenen1, C. J. van Marrewijk1, L. J. J. Derijks2, S. H. Vermeulen1,3, O. H. Klungel4, A. L. M. Verbeek3, H. Scheffer1, B. Franke1, H. J. Guchelaar5, D. J. de Jong6, TOPIC study 1) Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2) Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands; 3) Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 4) Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands; 5) Departments of Clinical Pharmacy and Toxicology, University Medical Center, Leiden, The Netherlands; 6) Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

   Thiopurines play an important role in the treatment of inflammatory bowel diseases (IBD). Nowadays, thiopurines are becoming the first treatment of choice to prevent a complicated disease course. Unfortunately, more than 20% of the patients discontinue therapy due to severe adverse drug reactions among which leucopenia is one of the most serious side effects. Thiopurine S-methyltransferase (TPMT) pharmacogenetics has been proven effective for optimizing safety and efficacy of thiopurine treatment. Nonetheless, in clinical practice it is still only used on a limited scale. We aimed to investigate the added value of pre-treatment TPMT genotyping on the occurrence of leucopenia. We performed a prospective randomized clinical trial including 850 IBD patients starting on thiopurine treatment as part of the Dutch multicentre Thiopurine response Optimisation by Pharmacogenetic testing in IBD Clinics (TOPIC) study. Patients were randomly assigned to undergo pre-treatment screening for three common variants in TPMT (TPMT*2, *3A and *3C) or to undergo standard treatment based on the Dutch treatment guidelines. Patients heterozygous for a TPMT variant received 50% of the standard thiopurine dose and patients homozygous for the tested variants received 0-10%. To assess the effect of pre-treatment genotyping we compared patients that were genotyped before treatment with patients that received standard treatment for the occurrence of leucopenia (white blood cell count <3.0*109 /l) in the first 5 months after treatment initiation. Of the patients 62% was diagnosed with Crohns disease and 38% with ulcerative colitis. 64% of the patients were treated with azathioprine and 36% with 6-mercaptopurine. In total 65 patients developed leucopenia. In the pre-treatment genotyped group (n=428) as well as the group receiving standard treatment (n=422) 42 patients (10%) carried at least one genetic variant in the TPMT gene. Analysis of the cases carrying a genetic variant showed a statistically significant reduction of the number of leucopenia cases in the group that underwent pre-treatment genotyping: 2.4% (n=1) versus 21.4% (n=9), p-value 0.003. Using the largest prospective cohort of IBD patients treated with thiopurine we showed that pre-treatment genotyping followed by dose adjustment results in a lower prevalence of leucopenia. This study strongly implies that pharmacogenetic testing for TPMT should be used as standard care to individualize treatment of IBD patients.

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