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DOP035. Early assessment of thiopurine metabolites predicts the occurrence of leukopenia in inflammatory bowel disease patients

D. Wong1, M. Coenen2, L. Derijks3, C. van Marrewijk2, S. Vermeulen2,4, A. Verbeek4, B. Franke2,5, H.-J. Guchelaar6, D. De Jong7, L. Engels8, P. Hooymans1, 1Orbis Medical Centre, Clinical pharmacy & Toxicology, Sittard-Geleen, Netherlands, 2Radboud University Medical Centre, Human Genetics, Nijmegen, Netherlands, 3Máxima Medical Centre, Clinical Pharmacy, Veldhoven, Netherlands, 4Radboud University Medical Centre, Health Evidence, Nijmegen, Netherlands, 5Radboud University Medical Centre, Psychiatry, Nijmegen, Netherlands, 6University Medical Centre, Clinical Pharmacy and Toxicology, Leiden, Netherlands, 7Radboud University Medical Centre, Gastroenterology, Nijmegen, Netherlands, 8Orbis Medical Centre, Gastroenterology and Hepatology, Sittard-Geleen, Netherlands

Background

Leukopenia is a severe and potential lethal adverse event of azathioprine (AZA) and 6-mercaptopurine (6MP) treatment in inflammatory bowel disease (IBD) patients. Most cases of leukopenia occur during the first months of treatment, which have been mainly attributed to low thiopurine S-methyltransferase (TPMT) activity resulting in myelotoxic 6-thioguanine nucleotides (6TGN) concentrations. The aim was to study the predictive value of 6TGN and/or 6-methylmercaptopurine ribonucleotides (6MMPR) metabolite concentrations, assessed one week after thiopurine therapy initiation, for the development of leukopenia during the first 8 weeks of thiopurine treatment.

Methods

Our study was performed in thiopurine naïve IBD patients starting thiopurine treatment as part of a Dutch randomized multi-centre trial (TOPIC study ClinicalTrials.gov NCT00521950). Blood samples for 6TGN and 6MMPR assessment were collected one week after thiopurine initiation (T1). Development of leukopenia was defined by leukocyte counts of <3.0×109/L during the first 8 weeks after thiopurine initiation. For comparison, patients without leukopenia were selected from the first 272 patients included in the TOPIC study, completing the follow-up period of 8 weeks without any thiopurine dose adjustments.

Results

Thirty-two patients with leukopenia and 162 patients without leukopenia were included. Patients with leukopenia were more frequently treated with 6MP than AZA: Odds Ratio (OR) = 7.3 (95% CI 3.1–17.0; p < 0.00001). Additionally, these patients were more often co-treated with anti-TNF agents: OR 5.1 (95% CI 1.6–16.4; p = 0.009). At T1 threshold values of ∼213 pmol/8×108 red blood cells (RBC) for 6TGN and ∼3525 pmol/8×108 RBC for 6MMPR, patients with elevated T1 6TGN or T1 6MMPR levels were at increased risk of leukopenia between week 1–8: Odds ratios were 6.2 (95% CI: 2.8–13.8; p < 0.001) and 5.9 (95% CI: 2.7–13.3; p < 0.001), respectively. Finally, a logistic regression model was designed including the T1 6TGN and 6MMPR threshold parameters, thiopurine type and concurrent anti-TNF therapy at baseline. The predictive performance measured by Receiver Operating Characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.70 (95% CI: 0.59–0.81; p < 0.001), when either T1 6TGN or 6MMPR threshold values were evaluated. Including all parameters, the AUC was 0.84 (95% CI: 0.76–0.92; p < 0.000001).

Conclusion

Both 6TGN and 6MMPR metabolites were independently associated with the occurrence of leukopenia during the first 8 weeks of thiopurine therapy. Assessment of 6TGN and 6MMPR metabolite concentrations one week after thiopurine initiation helps to identify patients at risk of developing leukopenia.