Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease

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Title:	Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease
Author(s):	Wong, D.R.; Coenen, M.J.H. ; Vermeulen, S.H. ; Derijks, L.J.; Marrewijk, C.J. van ; Klungel, O.H.; Scheffer, H. ; Franke, B. ; Guchelaar (LUMC), H.J.; Jong, D.J. de ; Engels, L.G.; Verbeek, A.L.M. ; Hooymans, P.M.
Publication year:	2017
Source:	Journal of Crohn'S and Colitis, vol. 11, iss. 2, (2017), pp. 175-184
ISSN:	1873-9946
DOI:	https://doi.org/10.1093/ecco-jcc/jjw130
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/169964
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Subject:	Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences Radboudumc 17: Women's cancers RIHS: Radboud Institute for Health Sciences Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience
Organization:	Radboudumc Extern Human Genetics Health Evidence Haematology Psychiatry Gastroenterology
Journal title:	Journal of Crohn'S and Colitis
Volume:	vol. 11
Issue:	iss. 2
Page start:	p. 175
Page end:	p. 184
Abstract:	BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 x 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 x 108 erythrocytes and 3525 pmol/8 x 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.