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Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD
Author(s) -
van Gennep Sara,
Konté Kadère,
Meijer Berrie,
Heymans Martijn W.,
D’Haens Geert R.,
Löwenberg Mark,
de Boer Nanne K. H.
Publication year - 2019
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.15403
Subject(s) - leukopenia , thiopurine methyltransferase , medicine , gastroenterology , odds ratio , azathioprine , toxicity , disease
Summary Background Thiopurine‐induced leukopenia, a frequently observed and potentially life‐threatening adverse event, complicates the clinical management of IBD patients. Aim To assess risk factors for thiopurine‐induced leukopenia in IBD. Methods MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine‐induced leukopenia. Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta‐analysis were described qualitatively. Results Seventy articles were included, 34 (11 229 patients) were included in meta‐analyses. A significantly higher thiopurine‐induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5‐6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2‐9.1), G52A (OR 3.2, 95% CI 1.3‐7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8‐11.4). A potential association between high 6‐thioguanine nucleotides (6‐TGN) or 6‐methylmercaptopurine (6‐MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6‐TGN: 204‐308 (Lennard method) and 397 (Dervieux method), 6‐MMP: 4020‐10 450 pmol/8 x 10 8 RBC) compared to controls (6‐TGN: 170‐212 (Lennard method) and 269 (Dervieux method), 6‐MMP: 1025‐4550 pmol/8 x 10 8 RBC). Conclusions TPMT and NUDT15 variants predict thiopurine‐induced leukopenia. High 6‐TGN and 6‐MMP levels might induce leukopenia, although exact cut‐off values remain unclear. Potential preventive measures to reduce the risk of thiopurine‐induced leukopenia include pre‐treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut‐off levels must be validated in advance.