Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring

Abstract

Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

A national-wide survey on clinical implementation of pharmacogenetic testing into precision therapeutics for Chinese children: A long way before standard clinical practice

“…Clinical PGx testing in children is strongly supported by evidence in some areas, such as TPMT testing in association with thiopurine therapy for childhood leukemia [21][22][23][24][25] , CYP3A5 testing in association with tacrolimus therapy for childhood refractory nephrotic syndrome [12,26] . However, research results showed that there was still room for expansion and development in the variety of PGx testing conducted in China (Figure 7).…”

Impact of Pharmacogenomics in Clinical Practice

“…Thiopurine drugs, azathioprine, 6-mercaptopurine, and 6-thioguanine, are widely used to treat cancer, onco-hematological diseases, and autoimmune diseases and to prevent transplant rejection [63]. TPMT, together with nudix hydrolase, is the most im-portant enzyme for thiopurine metabolism [64], and TPMT activity is inversely correlated with the levels of the active metabolites, as observed in children with leukemia [65] and in patients with inflammatory bowel diseases [66]. Patients with high TPMT activity are at risk of poor treatment efficacy due to a low production of active metabolites.…”

Editorial: Genetics and ontogeny in precision therapeutics for children

“…Similarly, genetic variants in ITPA were associated with neutropenic fever in the same population and XDH rs2281547 was identified as a genetic risk factor for then grade 4 hematologic toxicities. Arguably, when using 6-MP, it is important to take into account genetic polymorphisms in enzymes other than TPMT and NUDT15 that are involved in its pathway ( Guo et al, 2022 ). This consideration might help prevent the occurrence of hematological toxicities.…”