Association of Multiple Gene Polymorphisms Including Homozygous NUDT15 R139C With Thiopurine Intolerance During the Treatment of Acute Lymphoblastic Leukemia

Abstract

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.

Azathioprine-induced toxoplasma gondii infection in a patient with Crohn's disease with NUDT15 variation

“…It also revealed that the risk of developing thiopurine-induced early leukopenia among individuals with 1 copy of the NUDT15 risk allele was significantly increased by 88fold compared to non-carriers. In recent years, severe adverse reactions have been reported in patients with mutations in the NUDT15 gene and wild TPMP gene after treatment with AZA, with leukopenia and alopecia being the most common, [23,[29][30][31][32][33][34][35] indicating the necessity of determining NUDT15 activity status prior to treatment with AZA. In addition, NUDT15_rs116855232 might have a higher diagnostic accuracy than NUDT15_rs554405994 and NUDT15_rs186364861.…”