Pharmacogenetic study of 6-Mercaptopurine and L-Asparaginase based chemotherapy in pediatric Acute Lymphoblastic Leukemia patients in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia
No Thumbnail Available
Date
2023-09
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Addis Ababa University
Abstract
Background
Acute lymphoblastic leukemia is the most common type of childhood cancer,
necessitating a tailored combination of chemotherapy. However, dose-limiting
hematotoxicity is a significant challenge. Genetic variations, in the thiopurine metabolic
pathway gene, can predict toxicities related to 6-mercaptopurine. While L-asparaginase is
crucial in treating childhood ALL, it can cause hypersensitivity reactions and
hepatotoxicity. Reports have suggested that genetic variants in the CNOT3, GRIA1, and
NFATC2 genes may contribute to hypersensitivity reactions, while PNPLA3 has been
linked to hepatotoxicity.
Objective
The objective of this thesis was to examine the frequency of genetic variants of drug
metabolizing enzyme and transporter polymorphisms and their association with the
occurrence of adverse events during 6-MP and L-ASP based chemotherapy in pediatric
acute lymphoblastic leukemia patients at TASH, Addis Ababa, Ethiopia.
Methods
A Cohort study was used and the clinical profile of the patients was collected for the first
6 months of the maintenance phase treatment. Genotyping of GRIA1 rs4958351, PNPLA3
rs738409, ITPA, and XDH was performed using KASP genotyping assay, while that of
CNOT3 rs73062673, and NFATC2 rs6021191, TPMT, NUDT15, and ABCB1 with
TaqMan® SNP genotyping assays. TPMT activity was measured in whole blood of theparticipant by HPLC.
Results
During the initial six months of the maintenance phase treatment, 52.8% of the patients
experienced grade 4 neutropenia. The risk of developing neutropenia was found to be
higher in children aged six years or less and those with low day 1 maintenance white
blood cell counts. Furthermore, specific genetic variants in ITPA and XDH, were
associated with 6-MP induced neutropenic fever and grade 4 neutropenia, respectively.
Notably, patients with the CC genotype of XDH rs2281547 were found to have a nearly
threefold increased risk of developing grade 4 neutropenia compared to individuals with
the TT genotype (AHR 2.956, 95% CI=1.494-5.849, p = 0.002). Additionally, it was
observed that 12.5% of the patients developed L-ASP hypersensitivity, but there were no
significant differences between the frequency of hypersensitivity reactions and the risk
alleles of the investigated genes.
Conclusion
In ALL patients, the genetic variant XDH rs2281547 was found to be a predictive factor
for hematologic grade 4 toxicities caused by 6-MP. To detect hematotoxicity early, it is
recommended to closely monitor the levels of white blood cells and neutrophils
throughout the maintenance treatment. Furthermore, it is important to consider genetic
variations apart from the TPMT gene that play a role in the metabolic pathway of 6-
mercaptopurine in order to prevent hematological toxicity.
Description
Keywords
Lymphoblastic Leukemia, Patients