Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity

Abstract

IMPORTANCEIntravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants.OBJECTIVE To find the lowest dose of intravitreous bevacizumab effective for severe ROP.DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONSBevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. MAIN OUTCOMES AND MEASURESSuccess was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.RESULTS 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.CONCLUSIONS AND RELEVANCE These data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.

Longitudinal Development of Refractive Error in Children Treated With Intravitreal Bevacizumab or Laser for Retinopathy of Prematurity

“… 36 (3) Our study evaluated only the standard dosage of 0.625mg IVB even though lower dosages of IVB may also be efficacious. 37 , 38 (4) Our study evaluated only refractive error. Other biometric measures would be very helpful in understanding the pathophysiology of myopia associated with ROP (Lenis et al 30 ); however, taking these measurements in young infants is difficult and was beyond the scope of this study.…”

Stellungnahme der Deutschen Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbands der Augenärzte Deutschlands zur Anti-VEGF-Therapie der Frühgeborenenretinopathie

“…Für die Behandlung der ROP ist bisher nur Ranibizumab in einer Dosierung von 0,2 mg (40 % der Erwachsenendosis) zugelassen. Die kleinsten bisher in prospektiven Studien bei ROP erprobten und als wirksam beschriebenen Dosierungen liegen für Bevacizumab bei 0,004 mg (0,3 % der Erwachsenendosis) [24] und für Ranibizumab bei 0,1 mg (20 % der Erwachsenendosis) [23]. Für Aflibercept liegen bisher nur begrenzte Daten zur Wirksamkeit bei ROP vor.…”

“…B. der BEAT-ROP-Studie in einer Dosierung von 0,625 mg in 0,025 ml (50 % der Erwachsenendosis) eingesetzt [16]. In einer Dosis-Deeskalationsstudie zur Bevacizumab-Therapie bei ROP zeigte sich selbst für eine Dosierung von 0,004 mg (0,3 % der Erwachsenendosis) noch ein initiales Therapieansprechen bei 90 % der damit behandelten Augen [24]. Langzeitverläufe für diese Dosierung liegen bislang noch nicht vor.…”

Playing With Fire

“…We appreciate the collaborative effort and initiative of Wallace et al 1,2 to investigate the lowest effective dose of intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) for the treatment of type 1 retinopathy of prematurity (ROP). Given the biological plausibility of systemic effects from IVB, dose de-escalation studies are important to establish the safety and efficacy of its use in the treatment of ROP.…”

“…The 2020 de-escalation study did not disclose the anatomical description of the failures despite six out of 23 failing in the 0.002 mg group. 1 It also only reports results in a 4-week period. This short period was likely chosen to investigate whether the lowest dose was safe and efficacious.…”