ASSOCIATION BETWEEN GENETIC VARIANTS IN TPMT AND NUDT15 AND THIOPURINE TOXICITY IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

Introduction and objectives: Acute lymphoblastic leukemia (ALL) is characterized by accelerated proliferation of blasts in the bone marrow, reducing the production of normal blood cells and leading to accumulation of immature cells. Chemotherapeutic treatment of ALL is crucial for achieving remission and curing these patients. However, some patients might experience toxic effects as a consequence of variations in thiopurine metabolization, including TPMT and NUDT15 enzymes. In Brazil, there is a lack of studies that demonstrate the clinical association between drug toxicity in ALL treatment and genetic variants in genes related to thiopurine metabolism. The main objective of this study was to estimate the toxicity risk regarding polymorphisms of TPMT (rs1142345, rs1800460 e rs1800462) and NUDT15 (rs116855232) in children with ALL. Material and methods: Pediatric patients diagnosed with ALL were included in the study. Recurrent gene fusions were identified by RT-qPCR and the copy number alterations were evaluated with MLPA. Genotyping was performed for TPMT and NUDT15 genes using allele quantification assays with TaqMan probes. Hardy-Weinberg Equilibrium and odds ratio tests were conducted for statistical analysis of clinical and genetic data to assess the association between toxicity and genotype. Results and conclusion: A total of 154 individuals aged 0–18 years with ALL were analyzed, comprising 63 (40.9%) females and 91 (59.1%) males. Most patients (81.2%) had a common B-cell ALL subtype. Genotyping analysis showed heterozygous genotype frequencies of 7.8% for TPMT rs1142345, 2.6% for rs1800460 and 3.3% for rs1800462, while no variant genotype was found for NUDT15 . Patients exhibited various manifestations of treatment toxicity, with febrile neutropenia (51.3%) being the most common. No significant association was found between genetic variants and toxicity symptoms. Considering that only patients with NM phenotype underwent thiopurine dosage adjustments during treatment, our study highlights the lack of clinical adherence to genotyping results for the thiopurine dosage adjustment in patients with the IM phenotype. This may impact their susceptibility to toxicity manifestations that might worsen their clinical condition. This study underscores the importance of pharmacogenetics in personalizing ALL treatment, offering potential to improve clinical outcomes by customizing thiopurine doses according to each patient's genetic profile. Supported by: CNPq, FAPERJ, Ministério da Saúde, Swiss Bridge Fundation.