AUTHOR=Gándara-Mireles Jesús Alonso , Lares-Asseff Ismael , Reyes Espinoza Elio Aarón , Loera Castañeda Verónica , Córdova Hurtado Lourdes Patricia , Reyes Gutiérrez Flor de María , Sandoval-Cabrera Antonio , Villanueva Fierro Ignacio , Grijalva Ávila Julio Cesar , Castro Arreola Claudia , Patrón-Romero Leslie , Almanza Reyes Horacio 

TITLE=Impact of single-nucleotide variants and individual characteristics on adverse events of L-asparaginase in children with acute lymphoblastic leukemia

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1423049

DOI=10.3389/fphar.2024.1423049

ISSN=1663-9812

ABSTRACT=<sec><title>Introduction</title><p>L-Asparaginase (L-Asp) is a key drug in the treatment of acute lymphoblastic leukemia (ALL); however, it is commonly associated with the occurrence of adverse events (AE). Risk factors such as age, sex, nutritional status, and some single nucleotide variants (SNVs) in specific genes could be related to hypersensitivity reactions to L-Asp. The objective of this study was to identify the influence of individual characteristics and three SNVs in the <italic>GRIA1</italic> and <italic>NFATC2</italic> genes on the occurrence of the most significant adverse events caused by the use of L-Asp in Mexican children with ALL.</p></sec><sec><title>Methods</title><p>Eighty-five children from ages 0–17 years old diagnosed with ALL were included. The patients were treated at two hospital centers in Mexico. The SNV genotypes of the <italic>GRI1A</italic> and <italic>NFATC2</italic> genes studied were examined using real-time qPCR. The evaluation of AE was carried out according to the Common Terminology Criteria for adverse events, and the determination of anti-L-Asp antibodies was conducted using Western blot immunoassay.</p></sec><sec><title>Results</title><p>Homozygosity (AA) of the <italic>GRIA1</italic> rs4958351 SNV was significantly associated with the occurrence of AE with the use of L-Asp (OR = 4.05; 95% CI = 1.06 to 15.40, <italic>p</italic> = 0.04) and was strongly associated with the development of anti-L-Asp antibodies (OR = 3.4375, 95% CI = 1.04 to 11.25, <italic>p</italic> = 0.04). With this, we found a significant risk association for the SNV rs4958351 of the <italic>GRIA1</italic> gene. On the other hand, we did not find significant risk associations for the <italic>GRIA1</italic> rs6889909 and <italic>NFATC2</italic> rs6021191 SNVs, although other populations have shown a significant risk.</p></sec><sec><title>Discussion</title><p>Our study has some limitations, such as the small sample size, the heterogeneity in adverse events due to the patients’ different regions of origin, and the limited ability to conduct a more detailed follow-up on pancreatitis. Additionally, since no significant associations were found between the <italic>NFATC2</italic> rs6021191 and <italic>GRIA1</italic> rs6889909 SNVs and the development of adverse events or the presence of antibodies due to the use of L-Asp, it is necessary to investigate new specific SNVs that may improve the efficacy and safety of treatment in Mexican children with ALL.</p></sec>