Dr Marieke Coenen, Prof. Hans Scheffer, Prof. Barbara Franke, Dept. of Human Genetics, Dr Sita Vermeulen, Dept. for Health Evidence and colleagues published the results of the TOPIC trial in Gastroenterology. This trial for the first time proved that thiopurine dosing based on the TPMT genotype results in a lower occurrence of hematological ADRs.
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. It is known that variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leucopenia. Despite this knowledge a genetic test prior to treatment is hardly used to optimize IBD treatment. In this randomized trial in 30 Dutch hospitals patients were randomly assigned to groups that received standard treatment (control group) or pre-treatment screening for 3 common variants of TPMT followed by a personalized dose (intervention group). Similar proportions of patients in the intervention and control groups developed a hematologic ADR. 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.
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