2nd Department of Paediatrics, Semmelweis University, Faculty of Medicine, Tüzoltó u.7-9, Budapest 1094, Hungary.
Int J Hematol. 2013 Feb;97(2):216-22. doi: 10.1007/s12185-012-1236-1. Epub 2013 Jan 26.
The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.
儿童急性淋巴细胞白血病 (ALL) 的生存率有了显著提高；然而，患者仍遭受各种与药物相关的毒性。个体化治疗方案承诺用毒性最小的治疗方案获得最好的血液学结果。我们的目的是研究糖皮质激素受体 N363S 多态性是否会增加个体糖皮质激素敏感性，从而增加 ALL 治疗期间对类固醇相关毒性的易感性。本研究共纳入 346 例儿科 ALL 患者。通过等位基因特异性 PCR 检测 N363S 载带状态。回顾性分析和比较了糖皮质激素相关毒性的临床和实验室表现、第 8 天泼尼松反应以及 5 年无事件生存情况。346 例患者中有 32 例为杂合子携带者（9.2%）。携带者组的肝毒性（31.3%比 11.2%，p=0.004）和糖代谢异常（18.8%比 3.8%，p=0.001）的发生率明显更高。携带者组和非携带者组高血压和脑病/精神病的发生率无差异。携带者更容易发生多种毒性。所有 N363S 携带者都是良好的泼尼松应答者（100%），5 年无事件生存率明显更高（93.1%比 71.86%，p=0.012），而非携带者中较差的泼尼松应答者更多（8.28%），5 年无事件生存率更差。糖皮质激素受体 N363S 多态性的患者在 ALL 治疗期间更容易发生类固醇相关毒性，应更密切监测。糖皮质激素受体 N363S 多态性的患者可能是个体化治疗设计的合适候选者。
