Key factors associated with 6-thioguanine and 6-methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease.

Abstract

Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8× 108 RBC for 6TGN and 6MMPN. Children (n= 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7years in IBD (P <.0001). ALL received 6-mercaptopurine (mean dose 1.7mg/kg/d with methotrexate), IBD received AZA (1.9mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8× 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.