PMID- 31342537
OWN - NLM
STAT- MEDLINE
DCOM- 20200526
LR  - 20200526
IS  - 1365-2036 (Electronic)
IS  - 0269-2813 (Linking)
VI  - 50
IP  - 5
DP  - 2019 Sep
TI  - Systematic review with meta-analysis: risk factors for thiopurine-induced 
      leukopenia in IBD.
PG  - 484-506
LID - 10.1111/apt.15403 [doi]
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 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.
CI  - (c) 2019 John Wiley & Sons Ltd.
FAU - van Gennep, Sara
AU  - van Gennep S
AUID- ORCID: 0000-0002-9843-0134
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      The Netherlands.
FAU - Konte, Kadere
AU  - Konte K
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      The Netherlands.
FAU - Meijer, Berrie
AU  - Meijer B
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 
      Amsterdam, The Netherlands.
FAU - Heymans, Martijn W
AU  - Heymans MW
AD  - Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, Vrije 
      Universiteit Amsterdam, Amsterdam, The Netherlands.
FAU - D'Haens, Geert R
AU  - D'Haens GR
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      The Netherlands.
FAU - Lowenberg, Mark
AU  - Lowenberg M
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      The Netherlands.
FAU - de Boer, Nanne K H
AU  - de Boer NKH
AD  - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and 
      Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 
      Amsterdam, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Systematic Review
DEP - 20190725
PL  - England
TA  - Aliment Pharmacol Ther
JT  - Alimentary pharmacology & therapeutics
JID - 8707234
RN  - 0 (Immunosuppressive Agents)
RN  - 6V404DV25O (6-methylthiopurine)
RN  - E7WED276I5 (Mercaptopurine)
RN  - FTK8U1GZNX (Thioguanine)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Azathioprine/*adverse effects/pharmacokinetics/therapeutic use
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Humans
MH  - Immunosuppressive Agents/*adverse effects/pharmacokinetics/therapeutic use
MH  - Inactivation, Metabolic/genetics
MH  - Inflammatory Bowel Diseases/*drug therapy/epidemiology/genetics/metabolism
MH  - Leukopenia/*chemically induced/epidemiology/*etiology/genetics
MH  - Mercaptopurine/*adverse effects/analogs & 
      derivatives/metabolism/pharmacokinetics/therapeutic use
MH  - Risk Factors
MH  - Thioguanine/adverse effects/metabolism
EDAT- 2019/07/26 06:00
MHDA- 2020/05/27 06:00
CRDT- 2019/07/26 06:00
PHST- 2018/12/31 00:00 [received]
PHST- 2019/02/02 00:00 [revised]
PHST- 2019/06/16 00:00 [accepted]
PHST- 2019/07/26 06:00 [pubmed]
PHST- 2020/05/27 06:00 [medline]
PHST- 2019/07/26 06:00 [entrez]
AID - 10.1111/apt.15403 [doi]
PST - ppublish
SO  - Aliment Pharmacol Ther. 2019 Sep;50(5):484-506. doi: 10.1111/apt.15403. Epub 2019 
      Jul 25.