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Abstract：
BACKGROUND: Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years.
METHODS: In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sβ zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing.
RESULTS: We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 109 cells per L to 3·6 [2·2] × 109 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths.
CONCLUSIONS: Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa.
BACKGROUND: US National Heart, Lung, and Blood Institute and Cincinnati Children\'s Research Foundation.
METHODS: In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sβ zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing.
RESULTS: We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 109 cells per L to 3·6 [2·2] × 109 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths.
CONCLUSIONS: Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa.
BACKGROUND: US National Heart, Lung, and Blood Institute and Cincinnati Children\'s Research Foundation.
摘要：
背景：使用羟基脲（REACH）实现跨大洲的有效性是一项针对撒哈拉以南非洲地区镰状细胞贫血儿童的羟基脲（羟基脲）的开放标签非随机试验。REACH对安全性的短期结果，可行性,和羟基脲的有效性以前发表过。在本文中，我们报告了REACH队列中延长羟基脲治疗长达8年的结果。
方法：在此开放标签中，非随机化，1/2期试验,参与者从基利菲的四个临床地点招募，肯尼亚；姆贝尔，乌干达；罗安达，安哥拉；和金沙萨，刚果民主共和国。符合条件的儿童为1-10岁，有记录的血红蛋白SS或血红蛋白Sβ零地中海贫血，体重至少10公斤。参与者接受固定剂量的羟基脲，每天17.5（±2.5）mg/kg，持续6个月（固定剂量阶段），随后6个月的剂量递增（每8周增加2·5-5·0mg/kg）作为耐受，每天20-35mg/kg（最大耐受剂量；MTD），定义为轻度骨髓抑制。达到MTD后，根据体重和实验室值随时间的变化（具有优化阶段的MTD），为每个参与者优化了羟基脲给药。完成前12个月后，毒性特征可接受且反应良好的儿童有机会继续使用羟基脲,直至18岁.3年后的安全性和可行性结果已有报道。这里,血液学反应，临床事件，和毒性率在给药阶段(固定剂量羟基脲vsMTD,优化阶段)作为方案指定的结局进行比较.REACH已在ClinicalTrials.gov（NCT01966731）上注册，并且正在进行中。
结果：我们在2014年7月4日至2016年11月11日之间招募了635名儿童。606名儿童接受了羟基脲治疗，522名（86％；266[51％]男孩和256[49％]女孩）接受了中位93个月的治疗（IQR84-97），4340患者-年的治疗。当前（2023年10月5日）平均剂量为每天28·2（SD5·2）mg/kg，平均血红蛋白浓度增加（基线时7·3[SD1·1]g/dL至8·5[1·5]g/dL）和平均胎儿血红蛋白水平（10·9％[SD6·8]至23·3％[9·5]/L细胞×8·109/L细胞计数0·109MTD与固定剂量羟基脲的发生率比（IRR）表明血管闭塞发作减少（0·60；95％CI0·52-0·70；p<0·0001），急性胸部综合征事件（0·21；0·13-0·33；p<0·0001），复发性卒中事件（0·27；0·07-1·06；p=0·061），疟疾感染（0·58；0·46-0·72；p<0·0001），非疟疾感染（0·52；0·46-0·58；p<0·0001），严重不良事件（0·42；0·27-0·67；p<0·0001），和死亡（0·70；0·25-1·97；p=0·50）。固定剂量（每100例患者年24·1）和MTD阶段（每100例患者年23·2；0·97；0·70-1·35；p=0·86）之间的剂量限制性毒性率相似。3级和4级不良事件很少发生（每100名患者年18·5），包括疟疾感染，非疟疾感染，血管闭塞性疼痛,和急性胸部综合症。严重不良事件并不常见（3·6/100患者-年），包括疟疾感染，细小病毒相关性贫血,脓毒症,和中风，没有治疗相关的死亡。
结论：在剂量优化的情况下，羟基脲剂量递增至MTD显著改善了临床反应和治疗结果，在撒哈拉以南非洲，不会增加镰状细胞贫血儿童的毒性。
背景：美国国家心脏，肺，血液研究所和辛辛那提儿童研究基金会。
方法：在此开放标签中，非随机化，1/2期试验,参与者从基利菲的四个临床地点招募，肯尼亚；姆贝尔，乌干达；罗安达，安哥拉；和金沙萨，刚果民主共和国。符合条件的儿童为1-10岁，有记录的血红蛋白SS或血红蛋白Sβ零地中海贫血，体重至少10公斤。参与者接受固定剂量的羟基脲，每天17.5（±2.5）mg/kg，持续6个月（固定剂量阶段），随后6个月的剂量递增（每8周增加2·5-5·0mg/kg）作为耐受，每天20-35mg/kg（最大耐受剂量；MTD），定义为轻度骨髓抑制。达到MTD后，根据体重和实验室值随时间的变化（具有优化阶段的MTD），为每个参与者优化了羟基脲给药。完成前12个月后，毒性特征可接受且反应良好的儿童有机会继续使用羟基脲,直至18岁.3年后的安全性和可行性结果已有报道。这里,血液学反应，临床事件，和毒性率在给药阶段(固定剂量羟基脲vsMTD,优化阶段)作为方案指定的结局进行比较.REACH已在ClinicalTrials.gov（NCT01966731）上注册，并且正在进行中。
结果：我们在2014年7月4日至2016年11月11日之间招募了635名儿童。606名儿童接受了羟基脲治疗，522名（86％；266[51％]男孩和256[49％]女孩）接受了中位93个月的治疗（IQR84-97），4340患者-年的治疗。当前（2023年10月5日）平均剂量为每天28·2（SD5·2）mg/kg，平均血红蛋白浓度增加（基线时7·3[SD1·1]g/dL至8·5[1·5]g/dL）和平均胎儿血红蛋白水平（10·9％[SD6·8]至23·3％[9·5]/L细胞×8·109/L细胞计数0·109MTD与固定剂量羟基脲的发生率比（IRR）表明血管闭塞发作减少（0·60；95％CI0·52-0·70；p<0·0001），急性胸部综合征事件（0·21；0·13-0·33；p<0·0001），复发性卒中事件（0·27；0·07-1·06；p=0·061），疟疾感染（0·58；0·46-0·72；p<0·0001），非疟疾感染（0·52；0·46-0·58；p<0·0001），严重不良事件（0·42；0·27-0·67；p<0·0001），和死亡（0·70；0·25-1·97；p=0·50）。固定剂量（每100例患者年24·1）和MTD阶段（每100例患者年23·2；0·97；0·70-1·35；p=0·86）之间的剂量限制性毒性率相似。3级和4级不良事件很少发生（每100名患者年18·5），包括疟疾感染，非疟疾感染，血管闭塞性疼痛,和急性胸部综合症。严重不良事件并不常见（3·6/100患者-年），包括疟疾感染，细小病毒相关性贫血,脓毒症,和中风，没有治疗相关的死亡。
结论：在剂量优化的情况下，羟基脲剂量递增至MTD显著改善了临床反应和治疗结果，在撒哈拉以南非洲，不会增加镰状细胞贫血儿童的毒性。
背景：美国国家心脏，肺，血液研究所和辛辛那提儿童研究基金会。
