1. World Cornea Congress VII Loteprednol Etabonate 0.5% Versus Cyclosporine 0.05% for Dry-Eye Syndrome After Bone Marrow Transplantation: A Prospective Randomized Trial Grace E. Boynton, B.A. Duna Raoof, M.D. Leslie M. Niziol, M.S. Munira Hussain, M.S. Shahzad I. Mian, M.D. Financial Disclosure: This investigator initiated protocol was funded by Bausch & Lomb, Rochester, NY.

2. Background Ocular involvement occurs in 45-60% of patients with graft versus host disease (GVHD). 1,2 – Dry eye syndrome (DES) is the most common primary manifestation of ocular GVHD. 3 Ocular surface inflammation following hematopoetic stem cell transplantation (HSCT) is thought to be primarily mediated by T lymphocytes. 4,5 Few immunosuppressive therapies are available to address the underlying ocular surface inflammation in patients who have undergone HSCT. 1 (Franklin RM, Kenyon KR, Tutschka PJ et al., 1983) 2 (Hirst LW, Jabs DA, Tutschka PJ, et al., 1983) 3 (Tabbara KF, Al-Ghamdi A, Al-Mohareb F, et al., 2009) 4 (Saito T, Shinagawa K, Takenaka K, et al., 2002) 5 (Ogawa Y, Yamazaki K, Kuwana M, et al., 2001)

3. Purpose The purpose of this study was to prospectively evaluate the safety and efficacy of topical loteprednol etabonate 0.5% versus topical cyclosporine-A 0.05% for the prophylaxis and treatment of dry eye syndrome in patients undergoing HSCT.

4. Methods Study Population – Inclusion criteria: age ≥ 18 years old, scheduled for HSCT within 6 weeks – Exclusion criteria: allergy to topical LE 0.5% or topical CsA 0.05%, active eye infection, pregnant or nursing, severe dry eye Treatment Arms – Patients were randomized to topical LE 0.5% BID OU or topical CsA 0.05% BID OU starting one month before transplantation. Follow Up – Patients were examined at baseline and followed at 3, 6, 9, and 12 months after transplantation.

5. Methods Exam Parameters – best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp biomicroscopy with staining, Schirmer score, tear film osmolarity, tear breakup time (TBUT), and Ocular Surface Disease Index (OSDI) score Dry eye severity was graded based on exam and symptom report (Table 1). Table 1: Dry Eye-Grading Schema* No Dry EyeMild Dry EyeModerate Dry EyeSevere Dry Eye Schirmer score (mm)≥ 116 - 103 – 5≤ 2 TBUT (sec)**≥ 10< 10 Staining Score***< 11- 3> 3 and < 4≥ 4 Osmolarity (mOsm/L)≤ 308309 - 324325 – 334≥ 335 OSDI0 - 1213 - 2223 – 3233 - 100 *To qualify for a given level of severity, a patient had to meet at least two of five criteria. If a patient met criteria for multiple levels of dry eye, they were categorized into the highest level of dry eye severity in which they met as least two criteria. **A maximum of 1 point was assigned for tear break-up time, if the tear break-up time was less than 10 seconds. ***Staining score denotes the highest staining score of the three regions of the ocular surface evaluated (the temporal conjunctiva, cornea, and nasal conjunctiva).

6. Results: Patient Demographics ParameterCyclosporine-A 0.05%Loteprednol Etabonate 0.5%p-value* Number of patients (number of eyes)37 (74)38 (76) Mean Age at Enrollment, years (SD)51.21 (14.44)54.06 (13.68)0.40 Sex, n (%)0.91 Male19 (51.35)20 (52.63) Female18 (48.65)18 (47.37) Type of Transplant, n (%)0.60 Unrelated donor23 (62.16)21 (55.26) Related donor12 (32.43)16 (42.11) Transplant did not occur2 (5.41)1 (2.63) History of Chemotherapy (n, %)35 (94.59)38 (100.00)0.24 History of Radiation (n, %)3 (8.11)2 (5.26)0.49 *A Mann-Whitney U test was used to compare mean age at enrollment between the two study groups. Gender distribution was compared between the two groups with a chi-square test. Fischer’s exact tests were performed to compare type of transplant, history of chemotherapy, and history of radiation. 150 eyes (of 75 patients) were enrolled. 38 patients were randomized to topical LE 0.5% BID and 37 patients were randomized to topical CsA 0.05% BID.

7. Results: Dry Eye Signs and Symptoms at Baseline At baseline, there were no significant differences in OSDI, tear osmolarity, Schirmer score, corneal staining score, TBUT, BCVA, or IOP between the two study arms. Patients in both groups had slightly elevated tear osmolarity at baseline. Additionally, the majority of patients had tear break-up time < 10 seconds, suggesting tear film instability at baseline. Cyclosporine-A 0.05%Loteprednol Etabonate 0.5% ParameterBaseline Mean (SD) P-value* Screening Visit OSDI7.5 (10.7)4.5 (6.3)0.15 Tear Osmolarity (mOsm/L)299.1 (11.9)302.6 (16.7)0.15 Schirmer (mm)12.8 (8.4)13.6 (8.9)0.57 Corneal and Conjunctival Staining**0.4 (0.8)0.6 (1.1)0.19 BCVA (logMAR)0.1 (0.3)0.0 (0.2)0.50 IOP (mmHg)13.4 (3.3)14.0 (3.1)0.25 <10 seconds TBUT, number of eyes (%) 62 (86.1)68 (89.5)0.53 *Comparisons were performed using independent samples t-tests (assuming all eyes are independent) for continuous variables and Chi-Square tests for categorical variables. **Corneal and conjunctival staining score denotes the sum of the nasal conjunctiva, cornea, and temporal conjunctiva staining scores.

8. Results: Signs and Symptoms at Months 3 and 6 Cyclosporine-A 0.05%Loteprednol Etabonate 0.5% ParameterN Mean Change from Baseline (SD) N P-value* 3 Month OSDI42-0.4 (8.1)485.8 (12.5)0.06 Tear Osmolarity (mOsm/L)32-2.3 (15.7)381.4 (19.1)0.39 Schirmer (mm)380.1 (8.4)480.5 (9.6)0.84 Corneal and Conjunctival Staining**421.0 (1.8)500.0 (1.3)0.004 BCVA (logMAR)380.0 (0.1)470.0 (0.1)0.51 IOP (mmHg)42-1.1 (3.5)52-1.0 (3.9)0.92 6 Month OSDI3810.3 (23.3)365.1 (11.5)0.41 Tear Osmolarity251.4 (15.1)33-2.9 (20.0)0.37 Schirmer (mm)320.5 (11.1)38-2.6 (7.2)0.18 Corneal and Conjunctival Staining**381.2 (2.8)380.9 (1.5)0.48 BCVA (logMAR)380.0 (0.3)360.0 (0.1)0.78 IOP (mmHg)340.0 (3.1)38-0.6 (3.4)0.45 *Comparisons were performed using independent samples t-tests (assuming all eyes are independent) **Corneal and Conjunctival Staining score denotes the sum of the nasal conjunctiva, cornea, and temporal conjunctiva staining scores. The CsA 0.05% group had a greater increase in staining from baseline compared to the LE 0.5% group at 3 months (p= 0.004). However, this difference was not observed at subsequent examinations.

9. Results: Signs and Symptoms at Months 9 and 12 On average, both groups had increased OSDI scores, decreased Schirmer scores, reduced tear break-up times, and increased corneal staining at 12 months compared to baseline. No patient had an IOP elevation of 10 mmHg or greater from baseline at any study visit. In both groups, BCVA remained relatively stable through the duration of the study. Cyclosporine-A 0.05%Loteprednol Etabonate 0.5% ParameterN Mean Change from Baseline (SD) N P-value* 9 Month OSDI288.8 (16.2)2210.2 (16.3)0.84 Tear Osmolarity (mOsm/L)204.0 (12.7)174.4 (26.8)0.95 Schirmer (mm)243.5 (10.2)21-6.3 (14.4)0.01 Corneal and Conjunctival Staining**282.5 (2.8)211.9 (2.3)0.39 BCVA (logMAR)280.1 (0.3)210.1 (0.7)0.61 IOP (mmHg)280.5 (3.6)21-0.9 (4.1)0.22 12 Month OSDI3016.0 (23.7)3820.5 (26.0)0.61 Tear Osmolarity (mOsm/L)18-1.3 (11.4)2410.6 (29.3)0.08 Schirmer (mm)28-3.3 (10.3)32-6.8 (9.5)0.18 Corneal and Conjunctival Staining**302.3 (3.1)402.6 (3.3)0.75 BCVA (logMAR)280.0 (0.2)370.0 (0.2)0.45 IOP (mmHg)290.4 (4.6)370.0 (3.4)0.70 *Comparisons were performed using independent samples t-tests (assuming all eyes are independent) **Corneal and Conjunctival Staining score denotes the sum of the nasal conjunctiva, cornea, and temporal conjunctiva staining scores.

10. Results: Disease Incidence 33% of eyes (49 eyes) had no DES at enrollment. There was no significant difference between CsA 0.05% and LE 0.5% treated eyes regarding the probability of developing DES during the course of the study (p = 0.22). By 12 months, 90% of the CsA- treated eyes and 79% of the LE-treated eyes with no DES at baseline had developed dry eye syndrome.

11. Results: Disease Progression 66% of eyes (n=99 eyes) enrolled in this study had dry eye syndrome at enrollment. There was no significant difference between CsA 0.05% and LE 0.5% treated eyes regarding probability of DES progression over time (p=0.41). By 12 months, 38% of CsA- treated eyes and 26% of LE- treated eyes demonstrated disease progression.

12. Conclusions There were no significant differences between LE 0.5% and CsA 0.05% in limiting incident dry eye syndrome and controlling the progression of pre-existing disease among patients undergoing HSCT. Both treatments were well-tolerated by patients. In each study arm, a single patient experienced ocular sensitivity and discomfort with their assigned treatment, and subsequently discontinued the medication. In both treatment groups, the incidence and severity of dry eye syndrome increased over the course of the study, despite prophylactic treatment. There remains a continued need for the investigation of therapeutic and palliative treatments for patients undergoing HSCT.