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OP006. Personalized thiopurine dosing based on TPMT genotyping reduces leucopenia occurrence and results in cost-savings in IBD patients. Results from a randomized trial in the Netherlands

M. Coenen1, C. van Marrewijk1, L. Derijks2, S. Vermeulen1,3, D. Wong4, O. Klungel5, A. Verbeek3, P. Hooymans4, H. Scheffer1, H.-J. Guchelaar6, B. Franke1,7, D. de Jong8, 1Radboud university medical center, Human Genetics, Nijmegen, Netherlands, 2Máxima Medical Centre, Clinical Pharmacy, Veldhoven, Netherlands, 3Radboud university medical center, Health Evidence, Nijmegen, Netherlands, 4Orbis Medical Centre, Clinical Pharmacy and Toxicology, Nijmegen, Netherlands, 5Utrecht Institute of Pharmaceutical Sciences, Pharmacoepidemiology and Pharmacotherapy, Utrecht, Netherlands, 6University Medical Center, Clinical Pharmacy and Toxicology, Leiden, Netherlands, 7Radboud university medical center, Psychiatry, Nijmegen, Netherlands, 8Radboud university medical center, Gastroenterology, Nijmegen, Netherlands

Background

More than 20% of inflammatory bowel diseases (IBD) patients discontinue thiopurine therapy due to severe adverse drug reactions among which leucopenia is one of the most serious. Thiopurine S-methyltransferase (TPMT) pharmacogenetics has been proven effective for optimizing azathioprine/mercaptopurine safety. Nevertheless, TPMT screening is used in clinical practice on a very limited scale. The aim of our study was to assess whether pre-treatment TPMT genotype-based dosing reduces the occurrence of leucopenia and whether this strategy is cost-effective.

Methods

We performed a randomized trial in thiopurine naïve IBD patients starting on thiopurine treatment [the Dutch “Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics” (TOPIC) study (ClinicalTrials.gov: NCT00521950)]. Patients were randomly assigned to pre-treatment screening for three common variants in TPMT (TPMT*2, *3A and *3C) or standard thiopurine treatment. Patients heterozygous for a TPMT variant received 50% of the standard thiopurine dose, patients homozygous for the tested variants 0–10%. We compared pre-treatment genotyped patients with patients receiving standard dose for the occurrence of leucopenia (leucocyte count <3.0×109/l) in the first 20 weeks after treatment initiation. For the cost-effectiveness analysis we only included complete cases (patients with outcome (EQ-5D) and self-reported costs data).

Results

Seven hundred sixty-nine patients met the inclusion criteria. Of them 74 patients (9.6%) carried a TPMT variant, and 58 (7.5%) developed leucopenia. Overall, the occurrence of leucopenia did not differ between the intervention and control group (7.2% vs. 7.8%). However, among carriers of a genetic variant the occurrence of leucopenia was significantly reduced in those receiving a TPMT guided dose compared to the control group (2.6% versus 22.9%, OR 0.09, 95% CI=0.01–0.75). Treatment efficacy appeared to be similar across both study arms (delta EQ-5D (mean ± standard deviation) 0.014±0.080 versus 0.016±0.071). The average costs (direct medical costs and indirect costs) were lower for patients who received a genotype-guided dose advise (n = 238) than for those that received standard dose (n = 216): €4433 versus €6150, p = 0.023.

Conclusion

Ten percent of IBD patients have an increased risk of thiopurine-induced leucopenia due to low TPMT activity. Prior-to-treat TPMT screening of IBD patients reduces the risk of leucopenia and produces substantial cost-savings over the initial 20 weeks. This study strongly implies that personalized treatment by pharmacogenetic testing for TPMT should be advocated as standard care for IBD patients.