The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia

Abstract

Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.

Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China

“…In this study, we focused on TPMT * 3C, the most frequent TPMT genotype in China (19)(20)(21). In 149 pediatric ALL, only four TPMT * 3C heterozygotes were found with allele frequency of 1.34%, a little lower than that in Chinese children with ALL (2.9%) reported by Zhou et al (12), but higher than in Korean (0.6%) (22) and Indonesian pediatric ALL (0.95%) patients (23). Meanwhile, no significant association between TPMT * 3C and 6-MP toxicities was found in our study, which was consistent with previous reports (23-25) but not compatible with another report from Chinese pediatric ALL by Zhou et al (12).…”

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

“…We assessed potential effects of gene polymorphism on the dose adjustment of 6-MP in ALL. Two articles with 1,109 patients qualified for a meta-analysis about the association between NUDT15 c.415C>T gene polymorphism and dose intensity of 6-MP in ALL, 21 , 47 and one provided two groups of data (1 represents AALL03N1 cohort, another 1 represents St Jude cohorts). 21 The dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than wild-type patients (CC) (MD: 19.43%, 95% CI: -25.36 to -13.51; P <0.00001) ( Figure 7A ).…”

Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine

“…Diminished activity of nucleoside diphosphate metabolizing enzymes (NUDT15) and inosine triphosphate pyrophosphatase (ITPA) significantly impacts the clinical presentation of adverse effects. 21 , 22 NUDT15 plays a pivotal role in the conversion of toxic thioguanine triphosphate (TGTP) metabolites into less harmful thioguanine monophosphate, and a reduction in its enzymatic activity results in elevated toxicity and cell apoptosis due to the failure to reduce TGTP concentrations in patients treated with 6-MP. 23 To date, 26 molecular variants associated with reduced or loss of function in NUDT15 have been documented.…”