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TPMT Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic
Dewi Selvina Rosdiana1, Rianto Setiabudy1, Rizka Andalusia2,3
1Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
Insights
Hematotoxicity in children with acute lymphoblastic leukemia (ALL) receiving 6-mercaptopurine (6-MP) is common. The 6-MeMP/6-TGN ratio, not TPMT genotype, is linked to this toxicity.
Area of Science:
- Pharmacogenomics
- Pediatric Oncology
- Clinical Pharmacology
Background:
- Hematotoxicity is a significant concern in children with acute lymphoblastic leukemia (ALL) undergoing maintenance therapy with 6-mercaptopurine (6-MP).
- Genetic variations in thiopurine S-methyltransferase (TPMT), an enzyme crucial for 6-MP metabolism, are implicated in increased susceptibility to hematotoxicity.
- Effective monitoring is vital to prevent severe infections and treatment interruptions.
Purpose of the Study:
- To investigate the variability of TPMT genotypes and phenotypes in pediatric ALL patients.
- To determine the association between TPMT variability and the occurrence of hematotoxicity during 6-MP maintenance therapy.
- To explore potential predictors of hematotoxicity in this patient population.
Main Methods:
- A cross-sectional study involving pediatric ALL patients (1-18 years) on 6-MP maintenance therapy in Jakarta, Indonesia.
- TPMT*3A, *3B, and *3C genotypes were determined using direct sequencing.
- Plasma concentrations of 6-MP and its metabolites were measured using LC-MS/MS analysis.
- Association analyses were performed using appropriate statistical tests.
Main Results:
- The prevalence of neutropenia, anemia, and thrombocytopenia was 51.9%, 44.3%, and 6.6%, respectively.
- A low frequency of the TPMT*3C genotype (0.95%) was observed.
- No significant association was found between TPMT genotypes and hematotoxicity, age, nutritional status, or other clinical factors.
- Hematotoxicity was associated with 6-methylmercaptopurine (6-MeMP) plasma concentrations and the 6-MeMP/6-thioguanine (6-TGN) ratio.
- No correlation was found between TPMT genotypes and phenotypes.
Conclusions:
- The 6-MeMP/6-TGN ratio is associated with hematotoxicity in pediatric ALL patients receiving 6-MP maintenance therapy.
- This ratio, however, is not sufficiently predictive to be used as a standalone indicator for hematotoxicity.
- Further research may be needed to identify more robust predictors of 6-MP-induced hematotoxicity.
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.
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