Recurrence following Intravitreal Bevacizumab (IVB) Monotherapy for ROP Stage 3+

Helen Mintz-Hittner, MD University of Texas Health Science Center-Houston Medical School, Houston, TX

Memorial Hermann Children’s Hospital, Houston, TX

Introduction: With the knowledge that vascular endothelial growth factor (VEGF) is one of the key factors in the pathogenesis of ROP,1 use of Anti-VEGF substances, primarily intravitreal bevacizumab (IVB), has begun for the treatment of acute ROP. Case reports and case series have been published using IVB for ROP Stages 3, 4, and 5, both as monotherapy and in combination with laser therapy and vitrectomy.2 To maximize clinical outcomes and avoid the complications of laser surgery, the use of IVB monotherapy for ROP Stage 3+ has been reported in a case series3 and is being compared to laser therapy for ROP Stage 3+ in a prospective, randomized, controlled, multi-center clinical trial (BEAT-ROP).4 More than 65 years after ROP was initially described, it has been established that screening should begin at 31 weeks post menstrual age (PMA) or at 4 weeks post natal age, whichever occurs first. The end of screening if no treatment is indicated has been established to be before 45 weeks PMA if active disease is not present and vascularization is complete. Some small infants never complete vascularization to the ora serrata,5 but they do vascularize anterior to the equator by the suggested end of screening for ROP. Following the CRYO-ROP and ET-ROP clinical trials, it is apparent that acute ROP recurrences following peripheral retinal ablation generally occur before 55 weeks PMA. However, with IVB monotherapy for ROP Stage 3+, similar recurrences have not been reported. Thus, standards for follow-up (duration and intervals) and the end of repeated screening for acute ROP recurrences following IVB monotherapy for ROP Stage 3+ have not been established. We present 5 eyes of 3 patients with recurrences from mild to extremely severe that received IVB monotherapy. We suggest that recurrence can be considerably delayed and extremely severe if patients are not followed frequently and re-treated promptly.

Methods: RetCam photography (Clarity Medical Systems, Pleasanton, CA) was used to document ROP prior to the initial injection of IVB [0.625 mg (0.025 mL)] as monotherapy for ROP Stage 3+. RetCam photography also was employed to document regression of ROP and continued peripheral retinal vascularization. It also was utilized to establish the development of active ROP recurrence in eyes that initially had been treated successfully by IVB monotherapy for ROP Stage 3+.

Conclusions: IVB as monotherapy for ROP Stage 3+ is not uniformly successful in preventing recurrence. Recurrence of ROP following IVB as monotherapy occurs from both the original ridge/extraretinal fibrovascular proliferative (EFP) complex and the advancing edge of new vessels. There are too few cases in this series to suggest when close follow-up can be suspended; however, the same criteria as for untreated or peripheral retinal ablation apply: absence of active disease and completion of vascularization. The duration and interval of follow-up to identify recurrence prior to structural damage is unknown; therefore, close follow-up to allow re-injection of IVB and/or late peripheral retinal laser therapy are both considerations for infants receiving IVB . Whether this duration is established to be before 60, 70, or 80 weeks PMA may be dependent on type of ROP, severity of initial disease, number and type of risk factors, dose of bevacizumab, or other factors not yet established.

Mild Recurrence (Stage 3b)Case 1: Patient 23 weeks GA and 660g at birth was injected at 34.0 weeks PMA for ROP Zone II (Posterior) Stage 3b+. Mild recurrence with plus disease was identified in both eyes at 47.7 weeks PMA. A second injection of the same dose of IVB in each eye resulted in decreased plus disease, regression of the neovascularization, and continued growth of vessels into the peripheral retina.

Case Reports:

Temporal fundus photographs at 47.7 weeks PMA with early recurrence (Stage 3b without excessive tractional elements) can be seen by the presence of plus disease and the formation of neovascular tissue both from the original ridge/EFP complex ( ) and the advancing edge of new vessels ( ).

Moderate Recurrence (Stages 3c to 4a)Case 2: Patient 22 weeks GA and 550g at birth was injected at 32.6 weeks PMA for ROP Zone I Stage 3b+. Considerable myofibroblast formation temporally, which advanced slowly, was identified in the right eye at 61.9 weeks PMA (Figure 2). A second injection of the same dose of IVB in the right eye stopped the progressive formation of myofibroblasts and decreased the tractional elements volumetrically, but did not result in complete resolution of the membranes causing traction. (The left eye did not develop recurrence.)

Right Eye-Montage-at 61.9 weeks PMA with moderate recurrence (Stage 4a with macular dragging) as seen by the macular dragging and the formation neovascular tissue both from the original ridge/EFP complex ( ) and especially in the advancing edge of new vessels ( ) in the temporal retina.

Severe Recurrence (Stages 4b to 5)Case 3: Patient 24 weeks GA and 590g at birth was injected at 35.4 weeks PMA for ROP Zone II (Posterior) Stage 3b+. He returned late for follow-up at age 54.3 weeks PMA with severe recurrences in both eyes. The right eye was considered inoperable (Figure 3); the left eye required laser and vitrectomy surgery (Figure 4).

Figure 1A Figure 1B

Figure 2

References:1. Smith LEH. Through the eyes of a child: Understanding retinopathy through ROP. The Friedenwald Lecture. Invest Ophthalmol Vis Sci 2008;49(12):5177-82.

2. Mintz-Hittner HA, Best LM. Anti-vascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatrics 2009;21(2):182-7.

3. Mintz-Hittner H, Kuffel R. Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina 2008;28(6):831-838.

4. Mintz-Hittner H. Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP). ClinicalTrials.gov 2008-2009. NCT 00622726.5. Mintz-Hittner HA, Kretzer FL. Postnatal retinal vascularization in former preterm infants with retinopathy of prematurity. Ophthalmology 1994;101(3):548-58.

Acknowledgements:NEI Core Grant EY10608 (Bethesda, MD), Research to Prevent Blindness, Inc. (New York, NY), UT-HSC CCTS/CRU CTSA Grant UL1 RR024148, Alfred W. Lasher III Research Funds, and Hermann Eye Fund (Houston, TX), and special thanks for making the montages to Leslie MacKeen, BSc, CRA of Clarity Medical Systems, Inc. (Pleasanton, CA)

Left Eye-Montage-at 54.3 weeks PMA w/ moderately severe recurrence (Stage 4b w/ macular dragging and detachment) accompanied by dense neovascular tissue emanating from both the original ridge/ EFP complex ( ) and the advancing edge of new vessels ( ).

Right Eye-Montage-at 54.3 weeks PMA w/ extremely severe recurrence (Stage 5 w/ complete retinal detachment) accompanied by dense neovascular tissue emanating from both the original ridge/EFP complex ( ) and the advancing edge of new vessels ( ).

Figure 3 Figure 4