rop – emerging therapies march 2011

Dr Kathryn McCreeryMarch 2011

RVEEH

An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.

Stage 1 ROP with demarcation line

An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.

Stage 2 ROP at the junction between vascularized and avascular retina

ICROP – Staging

Level of abnormal vascular response observed

An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.

Mild to severe stage 3 ROP

Stage 4. Subtotal retinal detachment 4a. Extrafoveal 4b. Retinal detachment involving fovea Stage 5. Total retinal detachment

Funnel: Anterior Posterior Open Open Narrow Narrow Open Narrow Narrow

An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.

Stage 5 retinopathy of prematurity

All infants born in 26 centers Oct 2000 – Sept 2002

BW <1250g Survived 28 days First exam at @ 6 weeks Weekly exams Zone 1 or Zone 2 stage 2

Zone 1, any stage < threshold Zone 2, stage 2, + plus Zone 2 , stage 3, - plus Zone 2, stage 3, + plus < threshold

Data entered to risk programme based on natural history data from Cryo ROP

Stratified into high risk and low risk prethreshold

Risk > 15% - second masked confirming exam Randomized to early or conventional treatment

at threshold (within 48hrs)

401 Randomized

317 Bilateral Cases44 Asymmetric Cases

(Treated)40 Asymmetric Cases

( Controls)

9 month grating (Teller) VA by masked tester Also a 6 and 9 month structural exam Amblyopia /refractive error treated between 6

and 9 month exam

Favorable Normal 3.70

cycles/degree Below normal 1.85 –

3.70 cycles/degree

Unfavorable Poor <1.8 cycles but

measurable Blind (NLP/LP/LV)

Posterior fold involving macula RD involving macula Retrolental tissue Any eye that had vitrectomy or scleral buckle

96% of those who survived Unfavorable outcome reduced form 19.5% to

14.5% with early intervention P < 0.01

Early treatment reduced risk of unfavorable structural outcome

15.9% (conventional) to 9.1%(early) P < 0.001

“Results from 31 infants with bilateral ROP in whom there were discordant outcomes in the 2 eyes provide even stronger evidence of beneficial effect of treatment at high risk prethreshold ( p = .007)”

Overall 37 of 317 (12%) of high risk prethreshold ROP had an unfavourable outcome in both eyes

Mean BW 703 gms Mean GA 25wks Zone 1 eyes accounted for 40% of those

randomized Greatest benefit in Zone 1, stage 3 +/- plus 30.8% vs. 53.8% unfavorable

Youngest infant treated early was 31weeks PMA

Youngest infant treated conventionally was 32 weeks

Average age at treatment 35 weeks prethreshold and 37 weeks at threshold

Only one eye had cryo 11-14% required retreatment

Cryo ROP 6% required treatment ETROP 9% will need treatment

Systemic complications higher in early treatment group (apnea, bradycardia, reintubation)

Ocular complications similar

Zone 1, any stage, + plus Zone 1, stage 3, - plus Zone 2, stage 2 or 3, + plus

An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.

Examples of aggressive posterior retinopathy of prematurity (AP-ROP)

Bevacizumab Eliminates the Angiogenic Threat of ROP

Pathogenesis and Therapy of Retinopathy of Prematurity (ROP).

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

1500 gm and 30 wks PCA March 2008 – August 2010 Stage 3+ ROP Zone 1 or Posterior Zone 2 Retcam photos Confirming evaluation of photos by second

ophthalmologist Both eyes randomized to injection or laser

0.625mg bevacizumab in 0.025ml Indirect laser

Enrollment, Randomization, and Follow-up of the 150 Study Infants.

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

Photos at 1 week, 1 month and 54 weeks Photos sent to BEAT ROP reading centre Photos cropped to remove peripheral retina to

assess structural outcome If at week one there were skip areas in the laser

group they received supplemental laser which were not considered to be recurrences

Significantly less for injection (6%) vs laser (26%) Recurrence significantly higher with laser than

injection in Zone 1 disease 42% vs 6% Only 2 of 70 eyes injected developed RD ( both

unilateral)

Risk Factors and Other Characteristics of Infants with Zone I Retinopathy of Prematurity (ROP) or Zone II Posterior ROP, According to Treatment Group.

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

Ocular Outcomes in the 143 Survivors at 54 Weeks' Postmenstrual Age.

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

Characteristics of Infants Who Died.

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

Fundus Photographs and Fluorescein Angiograms of Retinas in Study Infants with Stage 3+ Retinopathy of Prematurity in Zone I, before and after Treatment.

Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615

Study Overview

• In this trial, one intravitreal injection of bevacizumab was administered to treat retinopathy of prematurity of stage 3+.

• Bevacizumab was more effective than conventional laser therapy in preventing recurrence of neovascularization in infants with zone I but not zone II posterior retinopathy.

Conclusions

• Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease.

• Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina.

• This trial was too small to assess safety.

Avoidance of GA’s Beneficial in Zone 1

eyes Sparing of peripheral

field Normal retinal

vascularization

What happened after failure not clear

Endophthalmitis risk Systemic absorption

and risks Recurrence occurs

later 19 vs 6 wks in zone 1 disease

Visual outcomes?

Monotherapy Initial therapy followed by salvage laser Laser failures Role of repeat injection Biggest concern is systemic safety