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.
Highlights
Acute lymphoblastic leukemia (ALL) is responsible for almost a third of all childhood cancers and can be cured with combination chemotherapy alone [1,2,3]. 6mercaptopurine (6-MP) is one of the most commonly prescribed chemotherapeutic agents to treat ALL [4,5,6]
A complete blood count was performed at a 4-week interval. 6-MP was either increased or decreased by 50% of the previous dose or even discontinued to maintain a white blood cell (WBC) count of 2.0–3.0 × 109/L and/or avoid occurrence of infections and hepatotoxicity. 6-MP dose intensity was defined as the ratio between clinician prescribed 6-MP dose and protocol dose (%) and was captured on a monthly basis for the 6-month duration of the study [14]
Genotype frequencies In the present study, six single nucleotide polymorphisms (SNPs) in three genes were analyzed in 105 children with ALL
Summary
Acute lymphoblastic leukemia (ALL) is responsible for almost a third of all childhood cancers and can be cured with combination chemotherapy alone [1,2,3]. 6mercaptopurine (6-MP) is one of the most commonly prescribed chemotherapeutic agents to treat ALL [4,5,6]. Zhou et al BMC Cancer (2018) 18:516 presents wide inter-individual variability, partly arising from genetic polymorphisms. TPMT genotyping is a successful example of pharmacogenetic implementation in clinical practice. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released evidence based guidelines for upfront TPMT genotyping to individualize thiopurine therapy [12]. Loss of function of TPMT is a robust predictor of thiopurine-induced leukopenia, quite a few patients who are wild type for TPMT still develop toxicity that requires 6-MP dose reduction or treatment interruption [14]. East Asian patients are more sensitive to full dose of 6-MP [18], suggesting that additional variables, including other genetic variants, may contribute to the inter-patient variability in 6-MP-induced leukopenia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
