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. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children’s Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.)

中文翻译：

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撒哈拉以南非洲镰状细胞贫血的羟基脲剂量升高。

背景

羟基脲在撒哈拉以南非洲镰状细胞性贫血儿童中被证明具有安全性，可行性和有效性，研究表明血管闭塞事件的发生率降低，死亡率降低。剂量标准尚未确定，但是逐步增加到最大耐受剂量是否会带来超过治疗相关毒性作用的临床益处尚不清楚。

方法

在一项随机，双盲试验中，我们比较了固定剂量（每天每千克体重约20毫克）和剂量递增（每天每千克约30毫克）的羟基脲。主要结局是24个月后每分升9.0 g或更高的血红蛋白水平或24％或更高的胎儿血红蛋白水平。次要结果包括疟疾，血管闭塞性危机和严重不良事件的发生率。

结果

儿童接受固定剂量的羟基脲（94名儿童；平均[±SD]年龄，4.6±1.0岁）或剂量递增（93名儿童；平均年龄，4.8±0.9岁）；平均剂量分别为每公斤每天19.2±1.8 mg和每公斤每天29.5±3.6 mg。当接受逐步加药的儿童的临床事件数量明显少于接受固定剂量的儿童的临床事件数量时，数据和安全监控委员会终止了试验。在试验结束时，剂量递增组的儿童​​中有86％达到了主要结果阈值，而固定剂量组的儿童中则达到了37％（P <0.001）。剂量增加组中的儿童与镰状细胞相关的不良事件较少（发生率比率为0.43； 95％的置信区间[CI]为0.34至0.54），血管闭塞性疼痛危象（发生率比率为0.43; 95％CI，0.34至0.56），急性胸腔综合征或肺炎病例（发生率，0.27; 95％CI，0.11至0.56），输血（发生率，0.30; 95％CI，0.20至0.43），和住院（发生率，0.21; 95％CI，0.13至0.34）。实验室确认的剂量限制毒性作用在两组中相似，并且没有严重的中性粒细胞减少或血小板减少的病例。

结论

在撒哈拉以南非洲的镰状细胞性贫血儿童中，剂量递增的羟基脲的临床疗效优于固定剂量的羟基脲，且安全性相当。（由Doris Duke慈善基金会和辛辛那提儿童研究基金会资助； NOHARM MTD ClinicalTrials.gov编号，NCT03128515。）