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P305 No increased risk for infections with thiopurine-induced leukopenia in inflammatory bowel disease patients without a variant in thiopurine S-methyltransferase

M. Broekman*1, M. Coenen2, C. van Marrewijk2, G. Wanten1, L. Derijks3, S. Vermeulen2, 4, D. Wong5, O. Klungel6, A. Verbeek4, P. Hooymans5, H. Scheffer2, H.-J. Guchelaar7, D. de Jong1

1Radboud University Medical Centre, Department of Gastroenterology, Nijmegen, Netherlands, 2Radboud University Medical Centre, Department of Human Genetics, Nijmegen, Netherlands, 3Maxima Medical Centre Loc. Veldhoven, Department of Gastroenterology and Hepatology, Veldhoven, Netherlands, 4Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands, 5Zuyderland Medical Centre, Department of Clinical Pharmacy, Pharmacology and Toxicology, Sittard, Netherlands, 6Utrecht University, Departement of Pharmacoepidemiology and Clinical Pharmacotherapy, Utrecht, Netherlands, 7Leiden University Medical Centre, Department of Clinical Pharmacy and Toxicology, Leiden, Netherlands

Background

Leukopenia during thiopurine treatment is a frequent reason for dose reduction or treatment discontinuation in patients with inflammatory bowel disease (IBD). Genetic variants in the thiopurine S-methyltransferase (TPMT) gene explain up to 25% of leukopenia during thiopurine treatment. Therefore, leukopenia is frequently observed in patients without a genetic variant in TPMT (approximately 90% of the population). We focused on these latter patients to explore factors that predispose to leukopenia and to investigate whether these patients have an increased risk for infectious complications.

Methods

We performed a post-hoc analysis of data from the TOPIC trial (‘Thiopurine response Optimization by Pharmacogenetic testing in IBD Clinics’), where 796 thiopurine-naïve IBD patients were randomised for thiopurine dosing based on TPMT genotype (*2, *3A, and *3C were tested) vs standard thiopurine dose (patients were genotyped afterwards for TPMT variants). Patients were followed for 20 weeks, and white blood cell counts (WBC) were obtained at week 0, 1, 2, 4, 6, 8, and 20. Moderate leukopenia was defined as WBC < 3.0x10(9)/L and severe leukopenia as WBC < 2.0x10(9)/L. Patients with a TPMT variant (n = 73) were excluded from this analysis. Infections were classified according to the Common Terminology Criteria for Adverse Events. Characteristics of patients with and without leukopenia and with and without infections, were compared, and multivariate analysis with a Cox proportional hazard model was performed to identify factors associated with leukopenia or infections.

Results

In the TOPIC trial, 767 patients started with a thiopurine; 695 patients (90%) had no genetic variants in the TPMT gene. Leukopenia was reported in 45 patients (6.5%), being moderate in 41 patients and severe in 4 patients. Median time to leukopenia was 56 days (IQR 28–110 days). Higher baseline WBC protected against leukopenia (hazard ratio [HR] 0.80 [95%CI, 0.71–0.89]) and the use of 6-mercaptopurine (compared with azathioprine) was identified as risk factor (HR 2.61 [95%CI, 1.39–4.88]). This is probably related to a relatively higher thiopurine dose (mg/kg) in patients treated with 6-mercaptopurine. Further, 5 patients (11%) developed an infection whilst being leukopenia, compared with 54 patients without leukopenia (8%), p = 0.41. Risk factors for infectious complications comprised concomitant use of biologics (HR 2.15 [95% CI, 1.14–4.07]) and higher age (per 10 year; HR 2.07 [95% CI, 1.18–3.63]), but not leukopenia.

Conclusion

Our results suggest that moderate leukopenia during thiopurine treatment in IBD patients with a normal TPMT genotype is not associated with an increased risk for infections.