Berrie Meijer1, Joany E Kreijne2, Sofia A W van Moorsel3,4, Luc J J Derijks5, Gerd Bouma1, Chris J J Mulder1, Dennis R Wong3, C Janneke van der Woude2, Adriaan A van Bodegraven1,6, Nanne K H de Boer1. 1. Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. 2. Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. 3. Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands. 4. Department of Clinical Pharmacy, Maastricht University Medical Center, Maastricht, The Netherlands. 5. Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands. 6. Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.
Abstract
BACKGROUND AND AIM: 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 × 108 red 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 × 108 red 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. CONCLUSION: 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.
BACKGROUND AND AIM: 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 diseasepatients. 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 × 108 red 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 × 108 red 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. CONCLUSION: 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: Berrie Meijer; Abraham J Wilhelm; Chris J J Mulder; Gerd Bouma; Adriaan A van Bodegraven; Nanne K H de Boer Journal: Ther Drug Monit Date: 2017-08 Impact factor: 3.681
Authors: M M T J Broekman; M J H Coenen; G J Wanten; C J van Marrewijk; O H Klungel; A L M Verbeek; P M Hooymans; H-J Guchelaar; H Scheffer; L J J Derijks; D R Wong; D J de Jong Journal: Aliment Pharmacol Ther Date: 2017-09-15 Impact factor: 8.171
Authors: Berrie Meijer; Margien L Seinen; Remco van Egmond; Gerd Bouma; Chris J J Mulder; Adriaan A van Bodegraven; Nanne K H de Boer Journal: Inflamm Bowel Dis Date: 2017-11 Impact factor: 5.325