TY - JOUR
T1 - Tpmt genetic variability and its association with hematotoxicity in indonesian children with acute lymphoblastic leukemia in maintenance therapy
AU - Rosdiana, Dewi Selvina
AU - Setiabudy, Rianto
AU - Andalusia, Rizka
AU - Gatot, Djajadiman
AU - Louisa, Melva
AU - Bardosono, Saptawati
AU - Instiaty, Instiaty
N1 - Funding Information:
This study was supported by Research Grant from the University of Indonesia. W e thank Dr . Pustika Amalia W , dr . Sp.A(K), head of the Hemato-oncology Division of Department of Pediatrics, Cipto Mangunkusumo Hospital, and Haridini Intan, dr . Sp.A(K), head of the Pediatric Oncology Polyclinic, Dharmais National Cancer Hospital, allows us to access patient and medical records. The Authors would like to thank Enago (www .enago.com ) for
Publisher Copyright:
© 2021 Rosdiana et al.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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 LCMS/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.
AB - 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 LCMS/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.
KW - Mercaptopurine
KW - Methylmercaptopurine
KW - Neutropenia
KW - Thioguanine
KW - Thiopurine methyltransferase
UR - http://www.scopus.com/inward/record.url?scp=85101168492&partnerID=8YFLogxK
U2 - 10.2147/PGPM.S288988
DO - 10.2147/PGPM.S288988
M3 - Article
AN - SCOPUS:85101168492
SN - 1178-7066
VL - 14
SP - 199
EP - 210
JO - Pharmacogenomics and Personalized Medicine
JF - Pharmacogenomics and Personalized Medicine
ER -
