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P343. TPMT genotyping before thiopurine treatment results in lower leucopenia occurrence in a prospective randomized strategy study in 850 patients with inflammatory bowel disease

M.J. Coenen1, C.J. van Marrewijk1, L. Derijks2, S.H. Vermeulen3, H. Scheffer1, B. Franke1, H.-J. Guchelaar4, D.J. de Jong5, 1Radboud University Nijmegen Medical Centre, Genetics, Nijmegen, Netherlands, 2Maxima Medical Centre, Clinical Pharmacy, Veldhoven, Netherlands, 3Radboud University Nijmegen Medical Centre, Epidemiology, Biostatistics and Health Technology, Nijmegen, Netherlands, 4Leiden University Medical Centre, Clinical Pharmacy and Toxicology, Leiden, Netherlands, 5Radboud University Nijmegen Medical Centre, Gastroenterology; Topic study group, Nijmegen, Netherlands

Background

Thiopurines play an important role in the treatment of IBD. However, over 20% of the patients discontinue therapy due to adverse drug reactions. Leucopenia is a serious side effect, which is associated with thiopurine S-methyltransferase (TPMT) genotype in retrospective studies. Yet, TPMT pharmacogenetics in order to improve safety and efficacy of thiopurine treatment is only used on a limited scale. Our aim was to investigate the value of pre-treatment TPMT genotyping and thiopurine dose adjustments based on genotype on the occurrence of leucopenia.

Methods

We performed a prospective randomized trial in thiopurine naïve IBD patients starting thiopurine treatment as part of the Dutch TOPIC study (ClinicalTrials.gov NCT00521950). Patients were randomly assigned to undergo pre-treatment genotyping for three common variants in TPMT (TPMT*2, *3A and *3C) or to undergo standard treatment with azathioprine or 6-mercaptopurine (6-MP). The standard initial dose was 2.0 to 2.5 mg/kg bodyweight for azathioprine and 1.0 to 1.5 mg/kg for 6-MP. In the genotype group, patients that carried one of the TPMT variants were recommended a dose reduction of 50% and for patients with a variant on both alleles a maximum of 10% of the standard dose was recommended. The primary endpoint to assess the effect of pre-treatment genotyping was the rate of leucopenia <3.0×109/l in the first 5 months after treatment initiation between both arms.

Results

850 patients were randomized (62% with Crohn's disease; 38% with ulcerative colitis) and 64% of these patients were treated with azathioprine and 36% with 6-MP. In both the genotype guided group (n = 428) and the standard treatment group (n = 422) 42 patients (10%) carried at least one genetic variant in the TPMT gene. Finally 832 patients started with a thiopurine and 65 of these patients (8%) developed leucopenia <3.0×109/l. Overall, the rate of leucopenia was not significant different between both groups (7.2% versus 8.1%). However, in the group of intermediate metabolizers, we found a statistically significant reduction of the number of leucopenia cases in the group that underwent pre-treatment genotyping versus standard treatment (2.4% (n = 1) versus 21.4% (n = 9), p-value 0.003).

Conclusion

In this prospective pharmacogenetic study in thiopurine naïve IBD patients, we demonstrated that pre-treatment TPMT genotyping results in a significant lower occurrence of leucopenia in patients with at least one variant in the TPMT gene, which is the case in 10% of the population.