背景:硫嘌呤诱导的白细胞减少严重阻碍了硫嘌呤的广泛应用。nudix水解酶15(NUDT15)指导的剂量优化显著降低了早期白细胞减少率,但尚无明确的晚期白细胞减少风险预测的生物标志物。
目的:确定在NUDT15指导的硫嘌呤给药策略下,早期监测DNA-硫鸟嘌呤(DNATG)或6-硫鸟嘌呤核苷酸(6TGN)对晚期白细胞减少症的预测价值克罗恩病(CD)。
方法:在硫嘌呤开始后两个月内采集血样,用于检测代谢物浓度。晚期白细胞减少症定义为两个月内白细胞计数<3.5×109/L。
结果:在研究的148名患者中,在15.6%(17/109)的NUDT15/硫嘌呤甲基转移酶(TPMT)正常人和64.1%(25/39)的中间代谢者中观察到晚期白细胞减少。晚期白细胞减少症患者,早期DNATG水平显著高于未发生晚期白细胞减少症的患者(P=4.9×10-13).DNATG阈值319.43fmol/μgDNA可以预测整个样品中的晚期白细胞减少症,曲线下面积(AUC)为0.855(灵敏度为83%,特异性81%),在NUDT15/TPMT正常代谢产物中,阈值为315.72fmol/μgDNA的预测性能更为显著,AUC为0.902(灵敏度88%,特异性85%)。无论是在整个样本中(P=0.021)还是在NUDT15/TPMT正常或中间代谢者中(分别为P=0.018,P=0.55),6TGN与晚期白细胞减少症的相关性都相对较差。
结论:DNATG的积极治疗药物监测可能是预防患有CD的NUDT15/TPMT正常和中间代谢者晚期白细胞减少症的有效策略,尤其是前者。
BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction.
OBJECTIVE: To determine the predictive value of early monitoring of DNA-
thioguanine (DNATG) or 6-
thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn\'s disease (CD).
METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months.
RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively).
CONCLUSIONS: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.