ITPA:c.94C>A and NUDT15:c.415C>T Polymorphisms and Their Relation to Mercaptopurine-Related Myelotoxicity in Childhood Leukemia in Thailand

Abstract

Background

Mercaptopurine is a key agent in childhood leukemia treatment. Genetic polymorphism in the genes involving thiopurine metabolisms is related to 6-MP related toxicity.

Objective

This study aimed to determine the prevalence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms among Thai children diagnosed with leukemia and their association with mercaptopurine-related myelotoxicity.

Methods

Patients and survivors with a diagnosis of leukemia treated with mercaptopurine-containing chemotherapy regimens were enrolled. Clinical data and laboratory parameters during treatment as well as ITPA:c.94C>A and NUDT15:c.415C>T genotypes were analyzed.

Results

In all, 99 patients with acute leukemia or survivors were enrolled in the study. The prevalences of ITPA:c.94C>A, NUDT15:c.415C>T, and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms were 34, 17, and 4%, respectively. Numbers of absolute neutrophil count (ANC) and platelet count significantly decreased among patients carrying NUDT15:c.415C>T compared with NUDT15 wild type patients with p-values<0.001 and 0.019, respectively. The differences were not observed among patients carrying ITPA:c.94C>A compared with ITPA wild type patients. According to multivariate GEE, NUDT15:c.415C>T and co-occurrence of ITPA:c.94C>A and NUDT15:c.415C>T had a significant negative effect on ANC during treatment (coefficient: −463.81; CI: −778.53, −149.09; p-value=0.004 and coefficient: −527.56; CI: −1045.65, −9.48; p-value=0.046). No significant effect of ITPA:c.94C>A on ANC during treatment was observed.

Conclusion

ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms are common among Thai children with leukemia. A strong association with mercaptopurine-related myelotoxicity was observed among patients carrying either NUDT15:c.415C>T alone or combined with ITPA:c.94C>A.

Keywords:

• NUDT15
• ITPA
• 6-MP
• myelotoxicity
• pediatric oncology

Abbreviations

ALL, acute lymphoblastic leukemia; ANC, absolute neutrophil count; APL, acute promyelocytic leukemia; CBC, complete blood count; CI, confidence interval; CNS, central nervous system; GEE, generalized estimating equation; ITPA, inosine triphosphate pyrophosphohydrolase; MPAL, mixed phenotype acute leukemia; NUDT15, nucleoside diphosphate linked moiety X-type motif 15; PCR-RFLP, PCR-Restriction Fragment Length Polymorphism; PROBE, Preferred Reporting items for OBservational studies in Endodontics; SD, standard deviation; ThaiPOG, Thai Pediatric Oncology Group; TPMT, thiopurine methyltransferase; 6-MP, 6-mercaptopurine.

Data Sharing Statement

The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Acknowledgments

The funding from the Phramongkutklao College of Medicine, Royal Thai Army was used to conduct the study, analyze, and interpret the study results and submit the study for publication. The authors would like to thank the patients and families for participating in the study.

Author Contributions

All authors made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.