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

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

Dewi Selvina Rosdiana  1 , Rianto Setiabudy  1 , Rizka Andalusia  2   3 , Djajadiman Gatot  4 , Melva Louisa  1 , Saptawati Bardosono  5 , Instiaty Instiaty  1
Affiliations

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

Dewi Selvina Rosdiana et al. Pharmgenomics Pers Med. .

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.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Box plots of 6-TGN levels in patients with and without hematotoxicity. The 6-TGN levels were not significantly different in both groups (p=0.938).
Figure 2
Figure 2
Box plots of 6-MeMP levels in patients with and without hematotoxicity. The 6-MeMP levels were higher in patients with hematotoxicity (**p<0.01).
Figure 3
Figure 3
Box plots of 6-MeMP/6-TGN ratio in patients with and without hematotoxicity. The 6-MeMP/6-TGN ratio was higher in patients with hematotoxicity (*p<0.05).
Figure 4
Figure 4
Box plots of 6-MeMP/6-TGN ratio in patients with and without grade 3–4 neutropenia. The 6-MeMP/6-TGN ratio was higher in patients with grade 3–4 neutropenia (*p<0.05).
Figure 5
Figure 5
Erythrocyte 6-TGN and 6-MeMP concentrations (pmol/8x108 RBC) by TPMT genotype (wild type, n=104; mutant, n=2).
See this image and copyright information in PMC

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