TPMT Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic Leukemia in Maintenance Therapy

Dewi Selvina Rosdiana; Rianto Setiabudy; Rizka Andalusia; Djajadiman Gatot; Melva Louisa; Saptawati Bardosono; Instiaty Instiaty

doi:10.2147/PGPM.S288988

TPMT Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic Leukemia in Maintenance Therapy

Pharmgenomics Pers Med. 2021 Feb 3:14:199-210. doi: 10.2147/PGPM.S288988. eCollection 2021.

Authors

Dewi Selvina Rosdiana¹, Rianto Setiabudy¹, Rizka Andalusia^{2

3}, Djajadiman Gatot⁴, Melva Louisa¹, Saptawati Bardosono⁵, Instiaty Instiaty¹

Affiliations

¹ Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
² Dharmais National Cancer Hospital, Jakarta, Indonesia.
³ Drug Registration Directorate, National Agency for Drug and Food Control, Jakarta, Indonesia.
⁴ Division of Hematology-Oncology, Department of Pediatrics, Faculty of Medicine, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
⁵ Department of Nutrition, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.

Abstract

Purpose: Hematotoxicity monitoring in children with acute lymphoblastic leukemia (ALL) is critical to preventing life-threatening infections and drug discontinuation. The primary drug that causes hematotoxicity in ALL children is 6-mercaptopurine (6-MP). Genetic variability of the drug-metabolizing enzymes of 6-MP, thiopurine S-methyltransferase (TPMT), is one factor that might increase the susceptibility of children to hematotoxicity. The present study aimed to determine the variability in TPMT genotypes and phenotypes and its association with the occurrence of hematotoxicity in ALL children in maintenance therapy.

Patients and methods: A cross-sectional study was conducted at Cipto Mangunkusumo and Dharmais National Cancer Hospital, Jakarta, Indonesia, from June 2017 to October 2018. We included ALL patients, 1-18 years, who were receiving at least one month of 6-MP during maintenance therapy according to the Indonesian protocol for ALL 2013. Direct sequencing was used to determine TPMT*3A, *3B, and *3C genotypes, and LC-MS/MS analysis was performed to measure the plasma concentrations of 6-MP and its metabolites. Association analysis between the TPMT genotype and hematotoxicity was evaluated using the unpaired t-test or Mann-Whitney's test.

Results: The prevalence of neutropenia, anemia, and thrombocytopenia in ALL children during maintenance therapy was 51.9%, 44.3%, and 6.6%, respectively. We found a low frequency of TPMT*3C, which is 0.95%. No association was found between hematotoxicity and TPMT genotypes or age, nutritional status, serum albumin levels, risk stratification, the daily dose of 6-MP, and cotrimoxazole co-administration. However, hematotoxicity was associated with 6-methylmercaptopurine (6-MeMP) plasma concentrations and the ratio 6-MeMP/6-thioguanine (6-TGN). We also found no association between TPMT genotypes and TPMT phenotypes.

Conclusion: The 6-MeMP/6-TGN ratio is associated with hematotoxicity in ALL children during maintenance therapy but is not strong enough to predict hematotoxicity.

Keywords: mercaptopurine; methylmercaptopurine; neutropenia; thioguanine; thiopurine methyltransferase.