美国辛辛那提儿童医院医疗中心Russell E. Ware团队分析了羟基脲剂量递增治疗撒哈拉以南非洲镰状细胞贫血儿童的疗效。该成果于2020年6月25日发表在《新英格兰医学杂志》上。

羟基脲在撒哈拉以南非洲治疗镰状细胞贫血儿童已证明具有安全性、可行性和有效性，研究表明血管闭塞事件的发生率和死亡率有所降低。但给药标准尚未确定，提高到最大耐受剂量带来的毒副作用是否会超过其临床益处尚不清楚。

在一项随机、双盲试验中，研究组招募镰状细胞贫血儿童，将其随机分组，其中94名（平均年龄4.6岁）接受固定剂量羟基脲治疗，93名（平均年龄4.8岁）接受剂量递增的羟基脲治疗，两组平均剂量分别为每天每公斤体重19.2 mg和29.5 mg。当剂量递增组的临床事件数量明显低于固定剂量组时，试验终止。主要结果为24个月后血红蛋白水平超过9.0g/dL，或胎儿血红蛋白水平超过20%。

当试验结束时，剂量递增组中有86％的儿童达到主要结果，显著高于固定剂量组（37％）。剂量递增组的儿童镰状细胞相关不良事件发生较少，比率为0.43； 血管闭塞性疼痛为0.43； 急性胸腔综合征或肺炎为0.27；输血为0.30；住院为0.21。两组间实验室确认的剂量限制毒性作用相差不大，且没有严重的中性粒细胞减少或血小板减少的病例。

总之，在撒哈拉以南非洲的镰状细胞贫血儿童中，采用剂量递增的羟基脲进行治疗，临床疗效优于固定剂量的羟基脲，且未增加安全风险。

附：英文原文

Title: Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa

Author: Chandy C. John, M.D.,, Robert O. Opoka, M.Med.,, Teresa S. Latham, M.A.,, Heather A. Hume, M.D.,, Catherine Nabaggala, M.B., B.S.,, Phillip Kasirye, M.Med.,, Christopher M. Ndugwa, M.Med.,, Adam Lane, Ph.D.,, and Russell E. Ware, M.D., Ph.D.

Issue&Volume: 2020-06-24

Abstract: BACKGROUND

Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.

METHODS

In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.

RESULTS

Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell–related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia.

CONCLUSIONS

Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety.

DOI: 10.1056/NEJMoa2000146

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2000146