6-methylmercaptopurine-induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients.

Abstract

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. 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 (>5700pmol/8×108 red blood cells) were included for detailed chart review. 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 14500pmol/8×108 red blood cells (range 6600-48000). All patients developed leukocytopenia (white blood cell count 2.7±0.9×109 /L) after a median period of 11weeks after initiation of thiopurine therapy (interquartile range 6-46weeks). 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 4weeks upon altered thiopurine treatment regimen, and white blood cell count was increasing, but not yet normalized, in the remaining four patients. 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.