Race, Genotype, and Azathioprine Discontinuation : A Cohort Study.
Race, Genotype, and Azathioprine Discontinuation : A Cohort Study.
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DOI：
10.7326/m21-4675
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发表时间：
2022-08
影响因子：
39.2
通讯作者：
Chung, Cecilia P.
中科院分区：
文献类型：
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作者：
Dickson, Alyson L.;Daniel, Laura L.;Jackson, Elise;Zanussi, Jacy;Yang, Wenjian;Plummer, W. Dale;Dupont, William D.;Wei, Wei-Qi;Nepal, Puran;Hung, Adriana M.;Cox, Nancy J.;Van Driest, Sara L.;Feng, QiPing;Yang, Jun J.;Stein, C. Michael;Mosley, Jonathan D.;Chung, Cecilia P.
硫嘌呤类药物是一类重要的免疫抑制剂，尽管它们具有造血毒性和治疗指数狭窄的风险。与ACKR1变异(rs2814778-CC)相关的良性中性粒细胞减少症在非洲血统的个体中很常见。我们测试了rs2814778-CC是否与硫唑嘌呤停用有关，该停用归因于造血毒性和较低的硫代嘌呤剂量。回顾性队列研究。两个三级护理中心。有白人或黑人血统的硫唑嘌呤使用者。硫唑嘌呤停用归因于造血毒性。次要结果包括体重调整的末次剂量、白细胞(WBC)和增量WBC计数。在CC基因携带者(n=101)和非CC基因携带者(n=1,365)中，因造血毒性而导致的硫唑嘌呤停用率分别为3.92/100人年和1.34/100人年[风险比(HR)=2.92，95%CI：1.57~5.41，竞争风险模型]。根据种族因素调整后，风险仍然显著(HR=2.61，1.01-6.71)。通过调整基因分型(HR=1.13，0.48-2.69)，消除了单独与种族相关的风险(HR=2.13，1.21-3.75)。在没有因造血毒性而停止治疗的患者中，较低的剂量和其他次要结果(除了增量白细胞计数)是显著的。较低剂量在94名非洲血统儿童的外部队列中得到验证，这些儿童在急性淋巴细胞白血病(ALL)中服用硫嘌呤6-巯基嘌呤(6-MP)。与目标日剂量-75 mg/m2相比，CC基因型与较低的6-MP强度剂量独立相关(CC：中位数0.83四分位数范围[0.70-0.94]对TT或TC：0.94[0.73-1.13]，P=0.013)。无法测量的混乱。数据仅限于三级中心。CC基因型的患者因造血毒性和剂量较低而面临更高的停药风险。即使对种族因素进行了调整，基因型也与这些风险有关。美国国立卫生研究院
Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among individuals of African ancestries. We tested whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. Retrospective cohort study. Two tertiary care centers. Thiopurines users with White or Black race. Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted last dose, white blood cell (WBC) and delta WBC counts. The discontinuation rate of azathioprine attributed to hematopoietic toxicity was 3.92/100 person-years among patients with the CC genotype (n=101) and 1.34/100 person-years among patients without the CC genotype (n=1,365) [hazard ratio (HR)=2.92, 95%CI: 1.57–5.41, competing hazards model]. The risk remained significant when adjusted by race (HR=2.61, 1.01–6.71). The risk associated with race alone (HR=2.13, 1.21–3.75) was abrogated by adjustment for genotype (HR=1.13, 0.48–2.69). Lower dosing and other secondary outcomes, except delta WBC count, were significant among patients who did not discontinue for hematopoietic toxicity. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia (ALL). The CC genotype was independently associated with lower 6-MP intensity dosages relative to the target daily dose—75 mg/m2 (CC: median 0.83 interquartile range [0.70–0.94] vs TT or TC: 0.94 [0.73–1.13], P=0.013). Unmeasured confounding. Data limited to tertiary centers. Patients with the CC genotype faced higher risk for discontinuation for attributed hematopoietic toxicity and lower doses. Genotype, even adjusted for race, is associated with those risks. National Institutes of Health