Lowest dose bevacizumab effective for Retinopathy of Prematurity: JAMA
It has become common practice in many neonatal intensive care nurseries to treat severe retinopathy of prematurity (ROP) by intravitreous injection of drugs blocking the bioactivity of vascular endothelial growth factor (VEGF). Bevacizumab is often used for this purpose, typically at doses of 0.25 mg to 0.625 mg, the latter being the dose that demonstrated efficacy in the Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) trial. After intravitreous injection, bevacizumab is found in the systemic circulation and plasma VEGF levels decrease, so there are concerns about possible adverse effects. Vascular endothelial growth factor is necessary for normal development of tissues such as the brain, lungs, bones, kidneys, and retina, so blocking its action is potentially harmful to neonates. There is particular concern that anti-VEGF drugs could increase the risk of neurodevelopmental disability. To determine the lowest dose of bevacizumab that may be effective in severe ROP that warranted treatment (type 1), David K. Wallace and team conducted a masked, multicenter, dose de-escalation phase 1 study.
Between April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-μL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019.Success was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.
Fifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.
Future studies with masked outcome assessment are needed to determine if low-dose bevacizumab is associated with long-term improvement, to assess its effect on plasma VEGF levels and peripheral retinal vascularization compared with higher doses, and to compare the effect of a low dose on retinal and neurodevelopment outcomes vs treatment with laser photocoagulation.
Authors found that a dose as low as 0.004 mg (0.6% of the BEAT-ROP1 dose) met criteria for successful outcome at 4 weeks in 9 of 10 study eyes (1 per infant). However, at the lower dose of 0.002 mg, a short-term successful outcome was achieved in only 74% of 23 eyes, suggesting that 0.004 mg may be the lower limit of bevacizumab dose effectiveness for ROP.
Source: David K. Wallace, MD, MPH; Raymond T. Kraker, MSPH; Sharon F. Freedman; JAMA Ophthalmol. 2020;138(6):698-701.
doi:10.1001/jamaophthalmol.2020.0334
