John A. Moran Eye Center, Salt Lake City, Utah.
Indiana University, Indianapolis.
JAMA Ophthalmol. 2022 Apr 1;140(4):337-344. doi: 10.1001/jamaophthalmol.2022.0030.
Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant.
To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP.
DESIGN, SETTING, AND PARTICIPANTS: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021.
Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection.
Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels.
A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection.
Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.
重要性：玻璃体内注射贝伐单抗可有效治疗严重早产儿视网膜病变（ROP），但它会进入血液，并可能降低血清血管内皮生长因子（VEGF）水平，从而对早产儿发育中的器官产生潜在的不利影响。
目的：评估在预定的、逐渐减少的玻璃体内贝伐单抗剂量给药后 2 周和 4 周，玻璃体内贝伐单抗治疗严重 ROP 的婴儿的血浆贝伐单抗和 VEGF 浓度与玻璃体内贝伐单抗的相关性。
设计、地点和参与者：这是一项在美国 10 家眼科医疗机构进行的 1 期剂量递减病例系列研究，研究时间为 2015 年 5 月 21 日至 2019 年 5 月 7 日。在玻璃体内贝伐单抗注射后 2 周和 4 周采集血样。参与者包括 83 名患有 1 只或 2 只眼 1 型 ROP 且无既往 ROP 治疗史的早产儿。数据分析时间为 2017 年 4 月至 2021 年 8 月。
干预措施：研究眼接受单次玻璃体内注射 0.250mg、0.125mg、0.063mg、0.031mg、0.016mg、0.008mg、0.004mg 或 0.002mg。当对侧眼需要治疗时，给予更高剂量。基线时给予的总剂量定义为 3 天内对每只眼给予的剂量总和。
主要结局和测量指标：注射后 2 周和 4 周时的血浆贝伐单抗浓度以及与预处理水平相比血浆 VEGF 浓度的百分比变化。
结果：共有 83 名婴儿（平均[标准差]年龄 25[2]周；48 名男孩[58%]）纳入本研究。基线时给予较高剂量的贝伐单抗与 2 周（ρ，0.53；95%CI，0.31-0.70）和 4 周（ρ，0.44；95%CI，0.18-0.64）时的血浆贝伐单抗浓度更高相关。66 名婴儿中有 40 名（61%）在 2 周时和 61 名婴儿中有 31 名（51%）在 4 周时，血浆 VEGF 浓度较预处理水平降低 50%或更多，但从基线给予的贝伐单抗总剂量与 2 周（ρ，-0.04；95%CI，-0.28 至 0.20）或 4 周（ρ，-0.17；95%CI，-0.41 至 0.08）后血浆 VEGF 浓度的百分比变化之间无相关性。
结论和相关性：这项 1 期剂量递减病例系列研究的结果表明，玻璃体内给予低至 0.002mg 的贝伐单抗与大多数婴儿在给药后 2 周和 4 周时降低血浆 VEGF 水平相关；然而，与从注射前到 2 周或 4 周时血浆 VEGF 水平的降低相比，给予的总贝伐单抗剂量之间无相关性。需要进一步的研究来评估低剂量贝伐单抗对神经发育和视网膜结构的长期影响。
