TPMT、NUDT15基因多态性对成人急性淋巴细胞白血病患者6-巯基嘌呤耐受性的影响

OBJECTIVE: To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462, TPMT*3B rs1800460, TPMT*3C rs1142345, and NUDT15 rs116855232 on the tolerance of 6-mercaptopurine (6-MP) therapy in adult acute lymphoblastic leukemia (ALL). METHODS: A total of 216 adult patients who were diagnosed with ALL and treated with cyclophosphamide, cytarabine, and 6-MP [complementary and alternative medicine (CAM) regimen] from September 2015 to December 2019 were included. Polymorphisms were detected by TaqMan SNP Genotyping Assay. Combined with clinical data, the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed. RESULTS: Among the 216 patients, 185 (85.65％) patients had B-ALL and 31 (14.35％) patients had T-ALL. 216 (100％) patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460. The number of TT and TC genotypes for TPMT*3C rs1142345 was 209 (96.76％) and 7 (3.24％), respectively. The allele frequency was 1.62％ for TPMT*3C rs1142345. The number of CC, CT, and TT genotypes for NUDT15 rs116855232 was 166 (76.85％), 48 (22.22％), and 2 (0.93％), respectively. The allele frequency was 12.04％ for NUDT15 rs116855232. The TPMT*3C rs1142345 mutant group (TC+CC genotype) had less transfusion volume of packed red blood cell than the wild group (CC genotype) (P＝0.036), and the mutant group (TC+CC genotype) had a higher risk to develop hepatotoxicity (increased aspartate aminotransferase) than the wild group (CC genotype) (OR＝9.559, 95％ CI 1.135–80.475, P＝0.038). The durations of white blood cells (WBC)<1×10(9)/L and absolute neutrophil count (ANC)<0.5×10(9)/L in the NUDT15 rs116855232 mutation group (CT+TT genotype) were longer than that in the wild group (CC genotype) (P＝0.005, P＝0.007), and the transfusion volume of apheresis-derived platelets in the mutant group (CT+TT type) was greater than that in the wild group (CC genotype) (P＝0.014). CONCLUSION: Genetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment of adult ALL. Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP, which may help shorten the bone marrow suppression duration and reduce blood transfusion volume.