Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 6‐Mercaptopurine (6‐MP) and azathioprine (AZA) are both inactive prodrugs that require intracellular activation into the active 6‐thioguanine nucleotides (6‐TGNs). • This metabolic process undergoes three different competitive pathways that are catalysed by three different enzymes; xanthine oxidase (XO), thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA), all of which exhibit genetic polymorphisms. • Although the impact of genetic variation in theTPMTgene on treatment outcome and toxicity has been demonstrated, the role of other polymorphisms remains less well known. WHAT THIS STUDY ADDS • New information on the allelic variation of these three enzymes (XO, TPMT and ITPA) and their influence on 6‐MP/AZA metabolism and toxicity. • Confirmation of the association ofTPMTpolymorphism with haematological toxicity. • Identified potential genetic characteristics that may contribute to higher risk of adverse events (such asITPA IVS2+21A→Cmutation). AIMS To examine the allelic variation of three enzymes involved in 6‐mercaptopurine/azathioprine (6‐MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6‐MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase,inosine triphosphatase(C94→AandIVS2+21A→C) andthiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS Thiopurine methyltransferasevariant alleles were associated with a preferential metabolism away from 6‐methylmercaptopurine nucleotides (P = 0.008 in ALL patients,P = 0.038 in IBD patients) favouring 6‐thioguanine nucleotides (6‐TGNs) (P = 0.021 in ALL patients). Interestingly, carriers ofinosine triphosphatase IVS2+21A→Cvariants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6‐TGNs (P = 0.008 in ALL patients,P = 0.047 in IBD patients). The study confirmed the association ofthiopurine methyltransferaseheterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association betweeninosine triphosphatase IVS2+21A→Cvariants with thrombocytopenia (P = 0.012). CONCLUSIONS Pharmacogenetic polymorphisms in the 6‐MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.