Pharmacogenetic study of 6-Mercaptopurine and L-Asparaginase based chemotherapy in pediatric Acute Lymphoblastic Leukemia patients in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia
| dc.contributor.advisor | Abula,Tefera(Prof.) | |
| dc.contributor.advisor | Howe,Raweligh(Dr.) | |
| dc.contributor.advisor | Adam,Haileyesus(Dr.) | |
| dc.contributor.advisor | Coenen,Marieke(Dr.) | |
| dc.contributor.author | Ali,Awol Mekonnen(PhD) | |
| dc.date.accessioned | 2025-08-13T08:16:09Z | |
| dc.date.available | 2025-08-13T08:16:09Z | |
| dc.date.issued | 2023-09 | |
| dc.description.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. | |
| dc.identifier.uri | https://etd.aau.edu.et/handle/123456789/6745 | |
| dc.language.iso | en_US | |
| dc.publisher | Addis Ababa University | |
| dc.subject | Lymphoblastic Leukemia | |
| dc.subject | Patients | |
| dc.title | Pharmacogenetic study of 6-Mercaptopurine and L-Asparaginase based chemotherapy in pediatric Acute Lymphoblastic Leukemia patients in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia | |
| dc.type | Thesis |