As prodrugs, the TPs MP (major treatment component in lymphoid malignancies) and thioguanine (TG; treatment component in myeloid malignancies) are metabolized by numerous enzymes, either to activate TPs to thioguanine nucleotides (TGNs) or to inactivate TPs via methylation or dephosphorylation of TGNs. Although there is genetic polymorphism in enzymes involved in TP activation (e.g., hypoxanthine phosphoribosyltransferase 1 [HPRT1]), there is little evidence that genetic polymorphisms in these enzymes play an important role in controlling the pharmacologic effects of TPs, with the exception of patients who inherit HPRT1 deficiency, an X-linked disease that occurs in approximately 1 in 350,000 males of European ancestry (Lesch–Nyhan syndrome), because these patients cannot activate TPs. In contrast, genetic polymorphisms in two enzymes involved in the inactivation of TPs increase the accumulation of their active TGNs, thereby increasing the risk of hematopoietic toxicity; TPMT and NUDT15 (nucleoside diphosphate linked moiety X-type motif 15 or nucleotide triphosphate diphosphatase). Inherited variants in TPMT were first discovered in the 1990s, with two major inactive variant alleles accounting for the majority of inherited TPMT deficiency in major world populations studied to date (TPMT*3C is the most common variant allele in persons of Asian and African ancestry, and TPMT*3A in persons of European ancestry). TPMT*3A, TPMT*3C, and a third variant TPMT*2 account for more than 95% of the clinically actionable TPMT variants. Variant TPMT alleles encode unstable proteins, and each named star (*) allele is defined by a certain genotype (haplotype) at one (e.g., TPMT*2 [rs1800462] and TPMT*3C [rs1800460]) or more (e.g., TPMT*3A [rs1142345 and rs1800469]) specific loci and is associated with a lower level of enzyme activity (the star [*] nomenclature system provides a “common language” to name a growing number of variants being discovered; however, attempts are being made to implement the conventional “rs” designation). The TPMT*1 allele encodes the wild-type normal function allele, and individuals who carry TPMT*1/*1 alleles are named “normal metabolizers” (for details see the website of the Clinical Pharmacogenetics Implementation Consortium [CPIC])[1]. Patients who are heterozygous (e.g., TPMT*1/*2, *1/*3A, or *1/*3C alleles, so-called intermediate metabolizers, 5% to 10% of Europeans or Africans) are approximately 5 times more likely to develop hematologic toxicity, whereas patients who inherit two variant alleles (e.g., the alleles TPMT*3A/*3A, *2/*3A, *3A/*3C, or *2/*3C, so-called poor metabolizers, 1 in 300 persons of European or African ancestry) will all develop hematologic toxicity if treated with conventional doses of TPs.[1]

It has been recognized for many years that patients of Asian ancestry develop more hematologic toxicity than patients of European or African ancestry, yet the frequency of nonfunctional TPMT alleles is lower in Asians. Important new insights were initially provided in 2014 by the identification of a missense variant in NUDT15 (nsSNP rs116855232, c.415 C>T causing p.R139C) in South Korean patients with inflammatory bowel disease who developed hematologic toxicity while receiving azathioprine therapy.[2] NUDT15 encodes a nucleoside diphosphatase which catalyzes the conversion of cytotoxic thioguanine triphosphate (TGTP) metabolites to the less toxic thioguanine monophosphates (TGMP). In vitro studies showed that the p.R139C change leads to nearly complete loss of NUDT15 enzymatic activity due largely to protein instability.[3] Loss of-function variants in NUDT15 result in higher levels of cytotoxic TGTPs, which are incorporated into DNA (i.e., DNA-TGs), leading to apoptosis, resulting in antileukemic and myelotoxic effects. Like for TPMT, other rare variants have been discovered and function ally characterized in NUDT15.[4] However, the p.R139C variant is the most common and clinically actionable and can be observed either alone (NUDT15*3 allele) or together with the p.V18_V19dup (rs869320766; c.50_55dup) variant as a distinctive haplotype (NUDT15*2 allele).[1] In a GWAS of children with ALL from diverse ethnic backgrounds receiving MP maintenance therapy, both TPMT (20%) and NUDT15 (22%) were estimated to account for 42% of interpatient variability in MP tolerance; 80% of patients with severe myelosuppression during MP therapy had risk alleles of either one of these genes.[5] Together, these studies show that genetic polymorphisms in both of these genes influence TP tolerance and that TPMT variants are more common in patients of European and African ancestry, whereas NUDT15 variants are much more common in East Asians and Hispanics with high levels of Native American ancestry.[5] The CPIC guidelines for dosing TPs now incorporate both TPMT and NUDT15 (see box on MP Dosage Adjustment and Table 1).[1]

Table1. CPIC Recommendations on Medications Whose Adverse Effects Have Been Associated with Variability in Candidate Genes and Manifest Predominantly as Hematologic Abnormalities

In addition, it was recently discovered that acquired somatic mutations in NT5C2 (encoding 5′-nucleotidase, cytosolic II) and in PRPS1 (encoding ribose-phosphate pyrophosphokinase 1) are relatively common in ALL cells at the time of disease relapse, conferring resistance to TP.[6,7] The mechanisms by which each of these genetic polymorphisms or somatic variants influence the pharmacologic effects of TP medications in children with ALL and the appropriate dosage adjustments for such patients are discussed in greater detail in the box on MP Dosage Adjustment and in the following section.

References

-----------------

[1] Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105(5):1095–1105.

 [2] Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leucopenia. Nat Genet. 2014;46(9):1017–1020.

[3] Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48(4):367–373.

[4] Suiter CC, Moriyama T, Matreyek KA, et al. Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity. Proc Natl Acad Sci U S A. 2020;117(10):5394–5401.

[5] Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235–1242.

[6] Tzoneva G, Perez-Garcia A, Carpenter Z, et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med. 2013;19(3):368–371.

 [7] Li B, Li H, Bai Y, et al. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL. Nat Med. 2015;21(6):563–571.

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