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

Dennis R Wong; Marieke J H Coenen; Sita H Vermeulen; Luc J J Derijks; Corine J van Marrewijk; Olaf H Klungel; Hans Scheffer; Barbara Franke; Henk-Jan Guchelaar; Dirk J de Jong; Leopold G J B Engels; André L M Verbeek; Piet M Hooymans; TOPIC Recruitment Team

doi:10.1093/ecco-jcc/jjw130

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

Dennis R Wong
, Marieke J H Coenen
, Sita H Vermeulen
, Luc J J Derijks
, Corine J van Marrewijk
, Olaf H Klungel
, Hans Scheffer
, Barbara Franke
, Henk-Jan Guchelaar
, Dirk J de Jong
, Leopold G J B Engels
, André L M Verbeek
, Piet M Hooymans
, TOPIC Recruitment Team

Research output: Contribution to journal › Article › Academic › peer-review

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 × 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 × 108 erythrocytes and 3525 pmol/8 × 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.

Original language	English
Pages (from-to)	175-184
Number of pages	10
Journal	Journal of Crohn's & Colitis
Volume	11
Issue number	2
DOIs	https://doi.org/10.1093/ecco-jcc/jjw130
Publication status	Published - Feb 2017
Externally published	Yes

Keywords

Adult
Aged
Azathioprine/administration & dosage
Drug Hypersensitivity/diagnosis
Drug Interactions
Female
Guanine Nucleotides/analysis
Humans
Immunosuppressive Agents/administration & dosage
Inflammatory Bowel Diseases/drug therapy
Leukocyte Count/methods
Leukopenia/chemically induced
Male
Mercaptopurine/administration & dosage
Middle Aged
Netherlands
Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis
Reproducibility of Results
Risk Assessment/methods
Thioinosine/analogs & derivatives
Thionucleotides/analysis
Tumor Necrosis Factor-alpha/antagonists & inhibitors

Access to Document

10.1093/ecco-jcc/jjw130

https://dspace.library.uu.nl/handle/1874/336980Licence: Other

Cite this

Wong, D. R., Coenen, M. J. H., Vermeulen, S. H., Derijks, L. J. J., van Marrewijk, C. J., Klungel, O. H., Scheffer, H., Franke, B., Guchelaar, H.-J., de Jong, D. J., Engels, L. G. J. B., Verbeek, A. L. M., Hooymans, P. M., & TOPIC Recruitment Team (2017). Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease. Journal of Crohn's & Colitis, 11(2), 175-184. https://doi.org/10.1093/ecco-jcc/jjw130

@article{f8a14dd473b8432fa6873f10b0151a10,

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

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 × 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 × 108 erythrocytes and 3525 pmol/8 × 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 \textasciitilde{}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.",

keywords = "Adult, Aged, Azathioprine/administration \& dosage, Drug Hypersensitivity/diagnosis, Drug Interactions, Female, Guanine Nucleotides/analysis, Humans, Immunosuppressive Agents/administration \& dosage, Inflammatory Bowel Diseases/drug therapy, Leukocyte Count/methods, Leukopenia/chemically induced, Male, Mercaptopurine/administration \& dosage, Middle Aged, Netherlands, Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis, Reproducibility of Results, Risk Assessment/methods, Thioinosine/analogs \& derivatives, Thionucleotides/analysis, Tumor Necrosis Factor-alpha/antagonists \& inhibitors",

author = "Wong, \{Dennis R\} and Coenen, \{Marieke J H\} and Vermeulen, \{Sita H\} and Derijks, \{Luc J J\} and \{van Marrewijk\}, \{Corine J\} and Klungel, \{Olaf H\} and Hans Scheffer and Barbara Franke and Henk-Jan Guchelaar and \{de Jong\}, \{Dirk J\} and Engels, \{Leopold G J B\} and Verbeek, \{Andr{\'e} L M\} and Hooymans, \{Piet M\} and \{TOPIC Recruitment Team\}",

note = "Copyright {\textcopyright} 2016 European Crohn{\textquoteright}s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].",

year = "2017",

month = feb,

doi = "10.1093/ecco-jcc/jjw130",

language = "English",

volume = "11",

pages = "175--184",

journal = "Journal of Crohn's \& Colitis",

issn = "1873-9946",

publisher = "Oxford University Press",

number = "2",

}

Wong, DR, Coenen, MJH, Vermeulen, SH, Derijks, LJJ, van Marrewijk, CJ, Klungel, OH, Scheffer, H, Franke, B, Guchelaar, H-J, de Jong, DJ, Engels, LGJB, Verbeek, ALM, Hooymans, PM & TOPIC Recruitment Team 2017, 'Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease', Journal of Crohn's & Colitis, vol. 11, no. 2, pp. 175-184. https://doi.org/10.1093/ecco-jcc/jjw130

TY - JOUR

T1 - Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease

AU - Wong, Dennis R

AU - Coenen, Marieke J H

AU - Vermeulen, Sita H

AU - Derijks, Luc J J

AU - van Marrewijk, Corine J

AU - Klungel, Olaf H

AU - Scheffer, Hans

AU - Franke, Barbara

AU - Guchelaar, Henk-Jan

AU - de Jong, Dirk J

AU - Engels, Leopold G J B

AU - Verbeek, André L M

AU - Hooymans, Piet M

AU - TOPIC Recruitment Team

PY - 2017/2

Y1 - 2017/2

N2 - 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 × 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 × 108 erythrocytes and 3525 pmol/8 × 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.

AB - 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 × 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 × 108 erythrocytes and 3525 pmol/8 × 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.

KW - Adult

KW - Aged

KW - Azathioprine/administration & dosage

KW - Drug Hypersensitivity/diagnosis

KW - Drug Interactions

KW - Female

KW - Guanine Nucleotides/analysis

KW - Humans

KW - Immunosuppressive Agents/administration & dosage

KW - Inflammatory Bowel Diseases/drug therapy

KW - Leukocyte Count/methods

KW - Leukopenia/chemically induced

KW - Male

KW - Mercaptopurine/administration & dosage

KW - Middle Aged

KW - Netherlands

KW - Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis

KW - Reproducibility of Results

KW - Risk Assessment/methods

KW - Thioinosine/analogs & derivatives

KW - Thionucleotides/analysis

KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors

U2 - 10.1093/ecco-jcc/jjw130

DO - 10.1093/ecco-jcc/jjw130

M3 - Article

C2 - 27402913

SN - 1873-9946

VL - 11

SP - 175

EP - 184

JO - Journal of Crohn's & Colitis

JF - Journal of Crohn's & Colitis

IS - 2

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this