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  • Title: Pharmacogenetics of 6-mercaptopurine in a black Zimbabwean cohort treated for acute lymphoblastic leukaemia.
    Author: Chikondowa P, Munkombwe D, Chikwambi Z, Kuona P, Masimirembwa C.
    Journal: Pharmacogenomics; 2023 Jun; 24(8):449-457. PubMed ID: 37248698.
    Abstract:
    Background: 6-mercaptopurine usage is associated with myelotoxicity and increased risk in patients carrying metabolism-related genetic variations. This study aimed to determine the frequency of candidate gene polymorphisms and their association with 6-mercaptopurine intolerance. Methods: A total of 41 patients on acute lymphoblastic leukaemia treatment were genotyped for TPMT and NUDT15 (rs116855232) alleles, and their association with dose intensity was analyzed. Results: The defective TPMT*3C allele frequency was 9.8%. The median maintenance dose intensity for TPMT*1/*3C participants was considerably lower (47%) when compared with the TPMT*1/*1 wild-type (77%), although not statistically significant. Conclusion: This is the first pharmacogenetics study carried out in a black Zimbabwean leukemia patient cohort. The high defective TPMT*3C (9.8%) allele frequency points to the potential utility of pharmacogenetics testing for safe usage of 6-mercaptopurine in this population. Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children in Zimbabwe and 6-mercaptopurine is frequently used as part of its treatment. However, 6-mercaptopurine is associated with side-effects such as severe neutropenia (a condition where you have a low number of white blood cells called neutrophils in your blood), with increased risk observed in patients carrying variants in genes involved in the metabolism of 6-mercaptopurine. Therefore, this study aimed to determine the frequency of polymorphisms in specific genes as well as their association with drug intolerance. A total of 41 patients on ALL treatment were studied. Review of treatment records was done to determine the cumulative 6-mercaptopurine dose and calculate dose intensity. Genotyping (to determine the versions of a gene a patient carries) for TPMT and NUDT15 (rs116855232) was performed and results correlated with drug dose intensity. The most frequent genotype was TPMT*1/*1, occurring in 80% of the participants. The remaining 20% were carriers with two different copies of TPMT (*1/*3C). The defective TPMT*3C variation occurred at 9.8% and none had TPMT*2, *3A, *3B or NUDT15 rs116855232 variants. Comparison analysis with dose intensity was done for 23 participants (56%) who had maintenance records available. The median dose intensity of 47% for TPMT*1/*3C participants was considerably low when compared to that of a normal TPMT*1/*1 patient, which was 77%. However, no statistically significant difference was observed between TPMT genotype and dose intensity. This is the first study in a group of leukemic Zimbabweans to investigate the frequency of TPMT and NUDT15 variants. With a high variation frequency of 9.8% for the defective TPMT*3C, pharmacogenetics testing for TPMT before treatment with 6-MP is recommended in the Zimbabwean population.
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