title: 6-methylmercaptopurine-induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients.
abstract: OBJECTIVE
  Thiopurines have a favorable benefit-risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6-thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6-methylmercaptopurine (6-MMP). In this case series, we provide a detailed overview of 6-MMP-induced myelotoxicity in inflammatory bowel disease patients.
  
  
  METHODS
  We retrospectively scrutinized pharmacological laboratory databases of five participating centers over a 5-year period. Patients with leukocytopenia at time of elevated 6-MMP levels (>5700 pmol/8 × 108red blood cells) were included for detailed chart review.
  
  
  RESULTS
  In this case series, we describe demographic, clinical, and pharmacological aspects of 24 cases of 6-MMP-induced myelotoxicity on weight-based thiopurine therapy with a median steady-state 6-MMP level of 14 500 pmol/8 × 108red blood cells (range 6600-48 000). All patients developed leukocytopenia (white blood cell count 2.7 ± 0.9 × 109/L) after a median period of 11 weeks after initiation of thiopurine therapy (interquartile range 6-46 weeks). Eighteen patients (75%) developed concurrent anemia (median hemoglobin concentration 6.9 × 109/L), and four patients developed concurrent thrombocytopenia (median platelet count 104 × 109/L). Leukocytopenia resolved in 20 patients (83%) within 4 weeks upon altered thiopurine treatment regimen, and white blood cell count was increasing, but not yet normalized, in the remaining four patients.
  
  
  CONCLUSIONS
  We observed that thiopurine-induced myelotoxicity also occurs because of (extremely) high 6-MMP concentrations in patients with a skewed thiopurine metabolism. Continued treatment with adapted thiopurine therapy was successful in almost all patients.
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Berrie
authors.initials: B
authors.lastname: Meijer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joany E
authors.initials: JE
authors.lastname: Kreijne
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.|Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Sofia A W
authors.initials: SAW
authors.lastname: van Moorsel
authors.affiliation: Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Luc J J
authors.initials: LJJ
authors.lastname: Derijks
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bouma
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris J J
authors.initials: CJJ
authors.lastname: Mulder
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Wong
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: van Bodegraven
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Nanne K H
authors.initials: NKH
authors.lastname: de Boer
mesh_terms: D000328:Adult; D004342:Drug Hypersensitivity / Q000097:blood; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D008875:Middle Aged; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000097:blood; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: C010240:6-methylthiopurine; D015122:Mercaptopurine
keywords: 6-methylmercaptopurine; leukocytopenia; therapeutic drug monitoring; thiopurines