Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response

Abstract

The thiopurine S-methyltransferase (TPMT) gene encodes for the TPMT enzyme that plays a crucial role in the metabolism of thiopurine drugs. Genetic polymorphisms in this gene can affect the activity of the TPMT enzyme and have been correlated with variability in response to treatment with thiopurines. Advances in the pharmacogenetics of TPMT allowed the development of dosing recommendations and treatment strategies to optimize and individualize prescribing thiopurine in an attempt to enhance treatment efficacy while minimizing toxicity. The influence of genetic polymorphisms in the TPMT gene on clinical outcome has been well-documented and replicated in many studies. In this review, we provide an overview of the evolution, results, conclusions and recommendations of selected studies that investigated the influence of TPMT pharmacogenetics on thiopurine treatment in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders. We focus mainly on prospective studies that explored the impact of individualized TPMT-based dosing of thiopurines on clinical response. Together, these studies demonstrate the importance of preemptive TPMT genetic screening and subsequent dose adjustment in mitigating the toxicity associated with thiopurine treatment while maintaining treatment efficacy and favorable long-term outcomes. In addition, we briefly address the cost-effectiveness of this pharmacogenetics approach and its impact on clinical practice as well as the importance of recent breakthrough advances in sequencing and genotyping techniques in refining the TPMT genetic screening process.

Keywords: 6-mercaptopurine; ADRs; TPMT; azathioprine; pharmacogenetics; thiopurine.

Figure 1

Metabolic pathways involved in the mechanism of action of thiopurines. Notes: This figure illustrated the pathways involved in the metabolism of Azathioprin, 6-mercaptopurine and thioguanine highlighting the genes/enzymes that can potentially affect the metabolism of these drugs. Abbreviations: 6-MP, 6-mercaptopurine; 6-Me-MP, 6-methyl-mercaptopurine; 6-Me-TG, 6-methyl-thioguanine; 6-Me-tIMP, 6-methyl-thioinosine-monophosphate; 6-Me-tITP, 6-methyl-thioinosine-triphosphate; 6-TG, thioguanine; 6-TGN, 6-thioguanine nucleotides; 6-tIDP, 6-thio-inosine diphosphate; 6-tIMP, 6-thio-inosine monophosphate; 6-tITP, 6-thio-inosine triphosphate; AZA, azathioprine; GMPS, guanosine monophosphatase synthetase; HGPRT, hypoxanthine guanine phosphoribosyl transferase; IMPDH, inosine monophosphate dehydrogenase; ITPA, inosine triphosphate pyrophosphatase; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine; TPMT, thiopurine S-methyltransferase; XO, xanthine oxidase.