Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

Abstract

Background6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients.MethodsA total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated.ResultsThe minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377–9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764–33.514, P = 3.75 × 10− 4). No differences were found between 6-MP dose intensity and ITPA polymorphisms.ConclusionNUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.

Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia

“…In concurrence with this, TPMT polymorphism in the present Thai pediatric ALL patients was low. The observed allele frequency of NUDT15c.415C>T was consistent with the 11–15% frequency reported in Asian subjects, and is generally reported to be lower in Hispanic, European, and African than in Asian subjects …”

“…had one Thai patient with TT who required a 6‐MP dose at 36 mg/m 2 . Similarly, another study of Chinese patients noted a dose intensity of 60.27% in two TT patients . Ethnicity or other genetic determinants may play a particular role in the discrepancies in 6‐MP dose reduction in Thai children.…”

Characterization of pharmacogenetic markers related to Acute Lymphoblastic Leukemia toxicity in Amazonian native Americans population

“…This drug is the only anti-leukemia medication used in the treatment of ALL for which the FDA (Food and Drug Administration) recommends the prior determination of the patient's genetic profile prior to the administration of the drug, to allow for the adjustment of the treatment. A number of studies have shown an association between the rs1142345 and rs1800460 markers of the TPMT gene and an increased susceptibility to grave toxicity during the treatment of ALL with 6-MP [20][21][22] .…”

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

“…16 Allele frequency of TPMT Ã 3C in this study was comparable with those previous reports in Thais 20,21 and African-Americans. 22 Compared with other Asian ALL populations, 13,[23][24][25][26][27] the frequency of TPMT Ã 3C in this Thai pediatric ALL population was somewhat higher but did not reach statistical significance except with the Korean population. 28,29 In addition, the allele frequency TPMT Ã 3C in our study population was extremely higher than those reported in European ALL patients 30 (►Table 2).…”