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

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 × 10 8 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 × 10 8 red blood cells (range 6600-48 000). All patients developed leukocytopenia (white blood cell count 2.7 AE 0.9 × 10

Real‐life study of safety of thiopurine‐allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment

“…Remarkably, we also observed benefit of LDTA prescribed for thiopurine therapy associated myelotoxicity in 87% of these patients. Indeed, it has been described that myelotoxicity can be induced by the presence of substantially elevated 6‐MMPR levels . Allopurinol is an inhibitor of xantine oxidase and has an indirect inhibiting function on TPMT enzyme activity and therefore induces a shift in metabolites favouring 6‐TGN and lowering 6‐MMPR production .…”

“…Indeed, it has been described that myelotoxicity can be induced by the presence of substantially elevated 6-MMPR levels. 9 Allopurinol is an inhibitor of xantine oxidase and has an indirect inhibiting function on TPMT enzyme activity and therefore induces a shift in metabolites favouring 6-TGN and lowering 6-MMPR production. 31,33 In addition, allopurinol seems to have an enhancing effect on hypoxanthine-guanine phosphoribosyltransferase (HGPRT), contributing to higher 6-TGN formation as well.…”

“…The active 6‐TGN metabolites are responsible for the immunosuppressive effect and related clinical response, but high 6‐TGN levels are associated with myelotoxicity. The 6‐MMPR metabolites are associated with adverse events such as hepatotoxicity and also myelotoxicity . Therapeutic response and toxicity are highly variable between patients, partly explained by differences in formation of these metabolites, due to genetic variants in the genes encoding for crucial enzymes in the thiopurine metabolism …”

“…The 6-MMPR metabolites are associated with adverse events such as hepatotoxicity and also myelotoxicity. 9,10 Therapeutic response and toxicity are highly variable between patients, partly explained by differences in formation of these metabolites, due to genetic variants in the genes encoding for crucial enzymes in the thiopurine metabolism. 11 Therapeutic drug monitoring through assessment of pharmacogenetics and thiopurine metabolite levels, allows for identification of drug metabolism variations, thiopurine under-dosing/ over-dosing and noncompliance.…”

Editorial: can we get more clinical benefit from thiopurine metabolite testing? Authors’ reply

“…This explains, at least in part, why only up to a quarter of these cases can be related to TPMT deficiency . A recent case series seems to corroborate this myelotoxic effect of high 6‐MMPR concentrations during thiopurine therapy …”