Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD

Sara van Gennep, Kadère Konté, Berrie Meijer, Martijn W. Heymans, Geert R. D’Haens, Mark Löwenberg, Nanne K. H. de Boer

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

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 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 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.
Original languageEnglish
Pages (from-to)484-506
JournalAlimentary Pharmacology and Therapeutics
Volume50
Issue number5
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

@article{5c5c1c6ea5804b118fa7fc57badbb4c8,
title = "Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD",
abstract = "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 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 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.",
author = "{van Gennep}, Sara and Kad{\`e}re Kont{\'e} and Berrie Meijer and Heymans, {Martijn W.} and D’Haens, {Geert R.} and Mark L{\"o}wenberg and {de Boer}, {Nanne K. H.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/apt.15403",
language = "English",
volume = "50",
pages = "484--506",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
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}

Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD. / van Gennep, Sara; Konté, Kadère; Meijer, Berrie; Heymans, Martijn W.; D’Haens, Geert R.; Löwenberg, Mark; de Boer, Nanne K. H.

In: Alimentary Pharmacology and Therapeutics, Vol. 50, No. 5, 01.01.2019, p. 484-506.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD

AU - van Gennep, Sara

AU - Konté, Kadère

AU - Meijer, Berrie

AU - Heymans, Martijn W.

AU - D’Haens, Geert R.

AU - Löwenberg, Mark

AU - de Boer, Nanne K. H.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 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.

AB - 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 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31342537

U2 - 10.1111/apt.15403

DO - 10.1111/apt.15403

M3 - Review article

VL - 50

SP - 484

EP - 506

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 5

ER -