The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

Abstract

Thiopurines (e.g., mercaptopurine [MP]) are widely used chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia (ALL) with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with ALL, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely due to toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P = 4.0 × 10−9). Cytosolic TGN and nuclear DNA-TG were positively correlated with each other across genotype groups (P = 6.5 × 10−4), but the ratio of DNA-TG to TGN was significantly higher in NUDT15 deficient patients (P = 3.6 × 10−9), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

“…8,10 Given the widespread use of the thiopurines, these findings may have ramifications beyond the management of IBD in patients of European ancestry. Although NUDT15 variants were first associated with TIM in East Asian patients with IBD, 9 this phenomenon has now been demonstrated in oncology and other immune-mediated diseases 32,33 as well as in other populations. [9][10][11][12][13][14] For population stratification reasons, patients of non-European ancestry were excluded from the genetic analyses of this study.…”

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

“…Complementary clinical laboratory tests are available to measure thiopurine metabolites in erythrocytes: TGNs (for mercaptopurine, azathioprine, and thioguanine) and MeMPNs (or MeTIMP) for those on mercaptopurine or azathioprine (see Supplement for details on associations with TPMT). Erythrocyte TGNs or MeMPNs are not related to NUDT15 genotypes, but there is evidence that intermediate and poor metabolizers for NUDT15 accumulate higher levels of DNA‐TG than normal metabolizers given the same mercaptopurine dosage . Thus, currently available erythrocyte therapeutic drug monitoring tests do not distinguish NUDT15 metabolizer phenotypes.…”

“…17 TPMT and NUDT15 recommendation. Figure 2 [34][35][36] , but there is evidence that intermediate and poor metabolizers for NUDT15 accumulate higher levels of DNA-TG than normal metabolizers given the same mercaptopurine dosage. 20 Thus, currently available erythrocyte therapeutic drug monitoring tests do not distinguish NUDT15 metabolizer phenotypes.…”

Massive parallel variant characterization identifiesNUDT15alleles associated with thiopurine toxicity

“…subjects in previously published datasets 20,21,31,44,45 . The ALL cohort included US Children's 31 .…”

“…The ALL cohort included US Children's 31 . TPMT risk variants (e.g., rs1800462) were also genotyped as previously reported 20,21,31,44,45 , and cases carrying TPMT variants were excluded from further analysis. This study was approved by the respective institutional review boards, and informed consent was obtained from the parents, guardians, and/or patients, as appropriate.…”