NUDT15 * 4 (p.R139H) 基因的临床活性及其与西班牙裔种族的关联
Maud Maillard1, Jenny Q Nguyen2, Wenjian Yang1
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clinical pharmacology and therapeutics
|December 17, 2024
概括
努迪克斯化酶15 (NUDT15) 变体*4显著降低了急性淋巴细胞白血病患者的默卡普图林耐受性. 这一发现需要将NUDT15 * 4纳入药理遗传学指导的提奥普林剂量,以获得更安全的治疗.
科学领域:
- 药物遗传学 药物遗传学
- 在瘤学瘤学.
- 临床药理学 临床药理学
背景情况:
- 努迪克斯化酶15 (NUDT15) 缺乏与氨酸诱导的骨髓抑制有关.
- 目前的NUDT15缺陷测试侧重于常见变体 (*2, *3, *9),而西班牙裔/拉丁裔占主导地位的*4变体具有不确定的功能.
- 临床药物遗传学实施联盟将NUDT15 * 4归类为由于有限的数据而具有不确定的临床可行性.
研究的目的:
- 在急性淋巴细胞白血病 (ALL) 患者中评估NUDT15 * 4变体和美卡普图林 (6-MP) 耐受性之间的关联.
- 为了确定NUDT15 *4是否应该纳入药理遗传学引导的硫氨酸剂量算法.
主要方法:
- 对1399名来自不同祖先的ALL患者进行了回顾性队列研究,用于氨酸甲基转移酶 (TPMT) 的野生型.
- 在维持治疗期间评估6MP的耐受剂量,以评估药物毒性.
- 包括通过例行测试确定NUDT15 * 1/ * 4的患者的单独后期验证研究.
主要成果:
- 与NUDT15 *1/*4 (n=16,所有西班牙裔/拉丁裔) 患者相比,NUDT15 *1/*1 (中位数62.2 mg/m2;P <0.001) 患者耐受了明显较低的6-MP剂量 (中位数39.0 mg/m2).
- 没有确定 *4 变种的同卵性患者.
- 验证队列 (n=6) 与NUDT15 *1/*4也显示了降低了6-MP耐受性 (中位数为38.7 mg/m2).
结论:
- 在所有患者中,NUDT15 * 4变体与默卡普图林耐受性显著降低有关.
- 这些发现支持NUDT15 * 4的临床可行性,并需要将其纳入药理遗传学引导的硫氨酸剂量中.
- 将NUDT15 * 4纳入剂量算法可以帮助优化硫氨酸治疗并减轻骨髓抑制风险.
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