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Inosine triphosphate pyrophosphatase, Leukemia, Mercaptopurine, Neutropenia, Transaminitis
Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is an indispensable medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce.
Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed.
Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wildtype ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wildtype ITPA (P = 0.016).
Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wildtype ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.
2. Relling MV, Schwab M. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105:1095-1105. https://doi.org/10.1002/cpt.1304
3. Buaboonnam J, Sripatanatadasakul P, Treesucon A, Glomglao W, Siraprapapat P, Narkbunnam N, et al. Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatr Int. 2019;61:754-758. https://doi.org/10.1111/ped.13905
4. Mao X, Yin R, Sun G, Zhou Y, Yang C, Fang C, et al. Effects of TPMT, NUDT15, and ITPA genetic variants on 6-mercaptopurine toxicity for pediatric patients with acute lymphoblastic leukemia in Yunnan of China. Front Pediatr. 2021;9:719803. https://doi.org/10.3389/fped.2021.719803
5. Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet. 2002;111:360-7. https://doi.org/10.1007/s00439-002-0798-z
6. Citterio-Quentin A, Moulsma M, Gustin M-P, Lachaux A, Boulieu R. ITPA activity in children treated by azathioprine: Relationship to the occurrence of adverse drug reactions and inflammatory response. Basic Clin Pharmacol Toxicol. 2018;122:588-595. https://doi.org/10.1111/bcpt.12958
7. Arenas M, Duley J, Sumi S, Sanderson J, Marinaki A. The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene. Biochim Biophys Acta. 2007;1772:96-102. https://doi.org/10.1016/j.bbadis.2006.10.006
8. Zamzami MA. Inosine triphosphate pyrophosphatase (ITPase): Functions, mutations, polymorphisms and its impact on cancer therapies. Cells. 2022;11:384. https://doi.org/10.3390/cells11030384
9. Yang JJ, Whirl-Carrillo M, Scott SA. Pharmacogene variation consortium gene introduction: NUDT15. Clin Pharmacol Ther. 2019;105:1091-4. https://doi.org/10.1002/cpt.1268
10. Jantararoungtong T, Wiwattanakul S, Tiyasirichokchai R, Prommas S, Sukprasong R, Koomdee N, et al. TPMT*3C as a predictor of 6-mercaptopurine-induced myelotoxicity in Thai children with acute lymphoblastic leukemia. J Pers Med. 2021;11. https://doi.org/10.3390/jpm11080783
11. Moradveisi B, Muwakkit S, Zamani F, Ghaderi E, Mohammadi E, Zgheib NK. ITPA, TPMT, and NUDT15 genetic polymorphisms predict 6-mercaptopurine toxicity in middle eastern children with acute lymphoblastic leukemia. Front Pharmacol. 2019;10. https://doi.org/10.3389/fphar.2019.00916
12. Azimi F, Mortazavi Y, Alavi S, Khalili M, Ramazani A. Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. Leuk Res. 2015;39:1048-1054. https://doi.org/10.1016/j.leukres.2015.06.016
13. Wahlund M, Nilsson A, Kahlin AZ, Broliden K, Myrberg IH, Appell ML, et al. The role of TPMT, ITPA, and NUDT15 variants during mercaptopurine treatment of Swedish pediatric patients with acute lymphoblastic leukemia. J Pediatr. 2020;216:150-7.e1. https://doi.org/10.1016/j.jpeds.2019.09.024
14. Boonyawat B, Monsereenusorn C. ITPA:c.94C>A and NUDT15:c.415C>T polymorphisms and Their relation to mercaptopurine-related myelotoxicity in childhood leukemia in Thailand. Appl Clin Genet. 2021;14:341-51. https://doi.org/10.2147/TACG.S318912
15. Ebbesen MS, Nygaard U, Rosthøj S, Sørensen D, Nersting J, Vettenranta K, et al. Hepatotoxicity during maintenance therapy and prognosis in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2017;39. https://doi.org/10.1097/MPH.0000000000000733
16. Vasta LM, Zanetti RC, Parekh DS, Warwick AB, Lieuw K. A Retrospective review of mercaptopurine metabolism reveals high rate of patients with suboptimal metabolites successfully corrected with allopurinol. J Pediatr Hematol Oncol. 2021;43:e1003-e9. https://doi.org/10.1097/MPH.0000000000001939