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

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.

[1]  C. Mulder,et al.  Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease , 2015, Therapeutic drug monitoring.

[2]  J. Macdonald,et al.  Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. , 2015, The Cochrane database of systematic reviews.

[3]  Henk-Jan Guchelaar,et al.  Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. , 2015, Gastroenterology.

[4]  L. Lennard.  Implementation of TPMT testing. , 2014, British journal of clinical pharmacology.

[5]  P. Rutgeerts,et al.  Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. , 2014, Gastroenterology.

[6]  J. Bakker,et al.  The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients. , 2014, Journal of Crohn's & colitis.

[7]  J. Mate,et al.  Safety of Thiopurine Therapy in Inflammatory Bowel Disease: Long-term Follow-up Study of 3931 Patients , 2013, Inflammatory bowel diseases.

[8]  A. V. van Kuilenburg,et al.  High TPMT activity as a risk factor for severe myelosuppression during thiopurine therapy. , 2013, Netherlands Journal of Medicine.

[9]  J. Macdonald,et al.  Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. , 2013, The Cochrane database of systematic reviews.

[10]  J. Belaiche,et al.  Does co‐treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab? , 2012, Alimentary pharmacology & therapeutics.

[11]  M. Huang,et al.  The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients , 2012, European journal of gastroenterology & hepatology.

[12]  M. L. Appell,et al.  Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function. , 2012, Journal of Crohn's & colitis.

[13]  M. Barclay,et al.  High TPMT enzyme activity does not explain drug resistance due to preferential 6‐methylmercaptopurine production in patients on thiopurine treatment , 2012, Alimentary pharmacology & therapeutics.

[14]  O. Dewit,et al.  Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. , 2011, Clinical biochemistry.

[15]  H. Guchelaar,et al.  Pharmacogenetics: From Bench to Byte— An Update of Guidelines , 2011, Clinical pharmacology and therapeutics.

[16]  C. Mulder,et al.  Dosing 6-thioguanine in inflammatory bowel disease: expert-based guidelines for daily practice. , 2010, Journal of gastrointestinal and liver diseases : JGLD.

[17]  J. V. van Ginkel,et al.  Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8‐year intercept cohorts , 2010, Inflammatory bowel diseases.

[18]  P. Rutgeerts,et al.  Infliximab, azathioprine, or combination therapy for Crohn's disease. , 2010, The New England journal of medicine.

[19]  J. Sanderson,et al.  Low‐dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease , 2010, Alimentary pharmacology & therapeutics.

[20]  W. Newman,et al.  Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? , 2010, Pharmacogenomics.

[21]  L. Derijks,et al.  Pharmacogenetics of thiopurines in inflammatory bowel disease. , 2010, Current pharmaceutical design.

[22]  A. V. van Bodegraven,et al.  Leukopenia due to Parvovirus B19 in a Crohn's Disease Patient Using Azathioprine , 2009, Digestion.

[23]  M. Cepoiu,et al.  Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. , 2009, The Cochrane database of systematic reviews.

[24]  J. Gisbert,et al.  Thiopurine-Induced Myelotoxicity in Patients With Inflammatory Bowel Disease: A Review , 2008, The American Journal of Gastroenterology.

[25]  C. Mulder,et al.  Dose-Dependent Influence of 5-Aminosalicylates on Thiopurine Metabolism , 2007, The American Journal of Gastroenterology.

[26]  D. Hommes,et al.  Pancytopenia due to high 6-methylmercaptopurine levels in a 6-mercaptopurine treated patient with Crohn's disease. , 2007, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[27]  A. Timmer,et al.  Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. , 2007, The Cochrane database of systematic reviews.

[28]  P. Söderkvist,et al.  Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease , 2006, Gut.

[29]  L. Lennard.  The clinical pharmacology of 6-mercaptopurine , 2005, European Journal of Clinical Pharmacology.

[30]  D. Hommes,et al.  Pharmacokinetics of 6-Mercaptopurine in Patients with Inflammatory Bowel Disease: Implications for Therapy , 2004, Therapeutic drug monitoring.

[31]  V. Armstrong,et al.  Analytic aspects of monitoring therapy with thiopurine medications. , 2004, Therapeutic drug monitoring.

[32]  C. Mulder,et al.  Safety of thiopurines in the treatment of inflammatory bowel disease. , 2003, Scandinavian journal of gastroenterology. Supplement.

[33]  E. Seidman.  Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. , 2003, Reviews in gastroenterological disorders.

[34]  M. Eichelbaum,et al.  Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. , 2002, Pharmacogenetics.

[35]  A. Hall,et al.  The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs. , 2002, Molecular pharmacology.

[36]  C. Peterson,et al.  Differences Between Children and Adults in Thiopurine Methyltransferase Activity and Metabolite Formation During Thiopurine Therapy: Possible Role of Concomitant Methotrexate , 2002, Therapeutic drug monitoring.

[37]  R. Weinshilboum,et al.  Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide , 2001, Gut.

[38]  M. Relling,et al.  Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. , 2001, Cancer research.

[39]  B. Bonaz,et al.  Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. , 2000, Gastroenterology.

[40]  S. Targan,et al.  Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. , 2000, Gastroenterology.

[41]  Y. Théorêt,et al.  6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. , 1996, Gut.

[42]  E. Seidman,et al.  Quantitation of 6-thioguanine in peripheral blood leukocyte DNA in Crohn's disease patients on maintenance 6-mercaptopurine therapy. , 1996, Canadian journal of physiology and pharmacology.

[43]  R. Weinshilboum,et al.  Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia , 1990, The Lancet.

[44]  R. Weinshilboum,et al.  Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. , 1980, American journal of human genetics.