Patel, Sanjay V.

Purpose: The goal of this study was to determine changes in best-corrected visual acuity (BCVA), refractive error, and central corneal thickness (CCT) during the first decade after Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: Outcomes of all consecutive eyes undergoing DSAEK for Fuchs endothelial corneal dystrophy (FECD) were reviewed; eyes with untreatable comorbidities before DSAEK were excluded. DSAEK was performed through a temporal incision and all eyes were pseudophakic postoperatively. Changes in BCVA, manifest spherical equivalent, manifest cylinder (vector analysis), and CCT were assessed by using generalized estimating equation models. Results: BCVA improved between 6 months (0.18 ± 0.12 logarithm of the minimum angle of resolution (logMAR); Snellen equivalent, 20/30) and 5 years (0.10 ± 0.10 logMAR; 20/25; n = 74, P < 0.001) and then remained stable at 10 years (0.09 ± 0.10 logMAR, n = 48, P = 0.22). There was a myopic shift of −0.20 ± 0.51 D between 6 months and 5 years (n = 65, P = 0.002) that remained stable at 10 years (−0.09 ± 0.44 D; 20/25; n = 34, P = 0.33). Manifest cylinder drifted with-the-rule between 6 months and 5 years (n = 65, P < 0.001) and between 5 and 10 years (n = 34, P < 0.001). CCT was stable between 6 months (672 ± 57 μm) and 5 years (677 ± 55 μm, n = 67, P = 0.47), but increased at 10 years (702 ± 60 μm, n = 39, P = 0.001). Conclusions: Excellent BCVA can be achieved during the first decade after DSAEK for FECD, although improvement seems to plateau after 5 years. Changes in manifest refractive error were not clinically significant. The gradual increase in CCT was consistent with longer-term changes found after other types of keratoplasty.

SummaryBelantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

Purpose: The goal of this study was to compare outcomes of Descemet stripping endothelial keratoplasty (DSEK) in eyes with glaucoma and abnormal anatomy to eyes with Fuchs endothelial corneal dystrophy (FECD). Methods: In a retrospective interventional series of all cases of DSEK between April 1, 2006, and November 30, 2015, recipient diagnosis, preoperative glaucoma status, concurrent surgical procedures, and graft outcomes were recorded. Graft survival, risk of rejection, and subsequent glaucoma surgery were estimated by using Kaplan–Meier analysis with risk factors determined by proportional hazard models. Results: Of 703 DSEKs in 666 eyes (509 subjects), the main recipient diagnoses were FECD (n = 496), pseudophakic corneal edema (n = 112), and failed graft (n = 83). Glaucoma was present in 150 cases before DSEK. Overall graft survival was 85%, 75%, and 71% at 5, 10, and 12 years, respectively, and for FECD without glaucoma was 95%, 89%, and 87% at 5, 10, and 12 years, respectively. Independent risk factors for graft failure included recipient diagnoses of pseudophakic corneal edema (HR = 8.3, P < 0.001), failed graft (HR = 6.4, P < 0.001), and preoperative medical glaucoma (HR = 7.1, P < 0.001) or surgical glaucoma (HR = 12.3, P < 0.001). Preoperative glaucoma treated by previous surgery resulted in graft survival of 28% at 10 years. Preoperative glaucoma was associated with an increased risk of graft rejection (HR = 6.8, P < 0.001) and subsequent glaucoma surgery (HR > 17.4, P < 0.001). Conclusions: Preoperative glaucoma increases the risk of graft failure, graft rejection, and needing subsequent glaucoma surgery in the first decade after DSEK. With previous glaucoma surgery, DSEK graft survival was more favorable compared with published reports of Descemet membrane endothelial keratoplasty.

Abstract INTRODUCTION: Belantamab mafodotin (BLMF) is a first-in-class, antibody-drug conjugate targeting B-cell maturation antigen on myeloma cells. BLMF was approved for use in patients (pts) with advanced multiple myeloma (MM). Due to the risk of ocular toxicity, it is made available through a restricted program under a Risk Evaluation and Mitigation Strategy. It is speculated that monomethyl auristatin F (MMAF), the cytotoxic payload of BLMF may be internalised by the corneal epithelium via an off-target mechanism, leading to epithelial changes. In the pivotal DREAMM-2 trial, only 1% of pts permanently discontinued treatment due to keratopathy. Data regarding BLMF-induced ocular toxicity following its commercial availability since August 2020, are sparse, and in this context, we evaluated our clinical experience with BLMF to determine the impact of its ocular toxicity on outcomes when utilized outside of stringent clinical trial settings. METHODS: We reviewed records of pts with advanced MM who were evaluated at Mayo Clinic between 09/01/2020-07/01/2021 and initiated on BLMF monotherapy following a baseline ophthalmic examination that was also performed prior to each dose, and as needed for worsening ocular symptoms. Data pertaining to ocular symptoms, best corrected visual acuity (BCVA) and corneal examinations were collected and analyzed with respect to patient outcomes. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0. RESULTS: Thirty-four pts, with median age of 67 (range:49-90) years who received BLMF at the approved 2.5 mg/kg dose as their first infusion and completed at least one cycle were included. All patients were instructed to use preservative-free lubricant eye drops at least 4 times a day, starting with the initial infusion and continuing until the end of therapy, and avoid contact lenses. The median number of prior lines of therapy was 8 (range: 2-15). The median time to BLMF initiation from the diagnosis of MM was 7.5 (range: 1.3-19.7) years. The median follow-up from initiation of BLMF was 7 [95% confidence interval (CI): 5.7-8.6] months, and the median number of BLMF doses administered was 2 (range: 1-6). Twenty-seven (79%) pts experienced ocular toxicity, comprising keratopathy [n=25 (74%)] and/or decreased visual acuity [n=21 (62%)]. Table 1 outlines the keratopathy-related details. Thirteen pts (38%) developed symptomatic xerophthalmia. A clinically significant decrease in BCVA of equal or worse than 20/40 in the better-seeing eye was observed in 12 (35%) pts at a median of 1.7 (95%CI: 1.4-2.2) months of commencing BLMF. In 7 (58%) pts, it improved to better than 20/40 within a median of 3 (range: 0.7-4) months from the time of documentation of impaired BCVA following withholding treatment (n=5), with or without subsequent dose reduction or its permanent discontinuation (n=2). Treatment was permanently discontinued in 5 (15%) pts after a median of 3 doses due to grade ≥2 keratopathy. It was withheld in 9 (26%) due to grade ≥2 keratopathy. Four (12%) pts required dose reduction due to keratopathy (Table 1). Of 14 pts in whom BLMF was held or permanently discontinued due to keratopathy, 10 (77%) had disease progression within a median of 1 month (range 0.4-2.5) following BLMF interruption. Among 11 pts (32%) responded to BLMF, 45% developed grade 2 or higher keratopathy after the first dose compared to 13% of pts who were refractory to BLMF (n=23). The median duration of response was 4 (95%CI: 0.7-NR) months. Among responders, 2 pts (18%) had to permanently discontinue BLMF due to keratopathy, with subsequent progression from partial remission at 1.4 and 4.6 months following its discontinuation. Additionally, 73% of responders required dose withholding due to keratopathy and of those, 50% had evidence of disease progression within a median of 1.2 month (range: 0.7-1.7) following BLMF interruption. DISCUSSION & CONCLUSIONS : Despite efficacy in pts with advanced MM, in routine practice, ocular toxicity of BLMF is a major challenge and a deterrent to its continuous use. While frequent ocular toxicity-related interruptions were observed at expected rates, permanent treatment discontinuation due to keratopathy was observed in a higher proportion of pts than that encountered in the DREAMM-2 trial. Larger prospective studies are warranted to accurately discern the effects of ocular toxicities on outcomes of pts treated with BLMF. Figure 1 Figure 1. Disclosures Patel: Emmecell: Consultancy; GlaxoSmithKline: Consultancy; Senju Pharmaceuticals: Consultancy; Santen, Inc.: Consultancy. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: AbbVie: Consultancy; Xencor: Research Funding; Medimmune: Research Funding; Genentech: Consultancy; Ascentage: Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Karyopharm: Consultancy; Beigene: Consultancy. Bergsagel: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Karyopharm: Consultancy; AbbVie: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding.

Purpose: To investigate the key factors associated with eyes with an endothelial cell density (ECD) of ≥2000 cells/mm2 at 5 years after corneal transplantation. Methods: This retrospective cohort study included 174 eyes that underwent penetrating keratoplasty by 1 corneal specialist surgeon at the Baptist Eye Institute, Kyoto, Japan, from 1998 through 2011 and that were carefully followed for over 5 years postoperative. In all operated eyes, corneal ECD was measured at 1, 2, 3, 4, and 5 years postoperative. Multivariate analysis with adjustment for preoperative donor ECD was performed between eyes with an ECD of ≥2000 cells/mm2 and those with an ECD of <2000 cells/mm2 at 5 years postoperative. Results: Of the 174 eligible eyes, 16 eyes (9.2%) had an ECD of ≥2000 cells/mm2 at 5 years postoperative, and the annual rate of endothelial cell loss (mean ± SD) was 2.3% ± 3.7%. Multivariate analysis findings revealed that the donor-associated and surgery-related factors were not significant factors. Only the recipient diagnosis of bullous keratopathy was significantly associated with an ECD of <2000 cells/mm2 at 5 years postoperative. Of those 16 eyes, 6 (37.5%) had a recipient diagnosis of bullous keratopathy. Conclusions: None of the donor- and surgery-related factors, previously recognized as associated with a lower endothelial cell loss after penetrating keratoplasty, were found to be significant in this study, thus suggesting that there are still unknown factors associated with maintaining a higher ECD over the long-term postoperative period.

The surgical treatment of Fuchs endothelial corneal dystrophy (FECD) has advanced dramatically over the last two decades. Penetrating keratoplasty has been superseded by various iterations of endothelial keratoplasty, and currently, surgical removal of host Descemet membrane without keratoplasty is being investigated. These surgical advances have been accompanied by significant improvement of our understanding of the underlying disease mechanisms, not least the discovery that FECD in western populations is predominantly an intronic trinucleotide repeat expansion disorder in the transcription factor 4 gene that results in RNA toxicity and mis-splicing. Understanding the disease mechanisms augurs well for developing targeted molecular medical therapies, which will require careful clinical investigation through trials to prove their efficacy and safety. As the field advances towards clinical trials, investigators should carefully define the disease state being treated and consider the options for outcome measures relevant to the type of intervention. FECD, and the outcomes of interventions to treat the disease, can be measured in terms of corneal morphology, corneal function and clinical impact. Standardising the approach for defining FECD and careful thought about the outcomes of intervention that are reported will help make the results of future trials for FECD applicable in clinical practice.

Purpose: To evaluate agreement between eye banks (EBs) and a reading center on endothelial cell density (ECD) determinations in the Cornea Preservation Time Study. Methods: The Cornea Image Analysis Reading Center (CIARC) performed variable frame image analysis on EB-obtained–preoperative central endothelial images (after lamellar dissection for Descemet stripping automated endothelial keratoplasty by the EBs or before shipping, if surgeon prepared) to determine ECD. The EBs performed their usual method of ECD determination. The CIARC and EBs also provided ECD determinations from screening central endothelial images taken by the EBs during donor evaluation. Two independent masked CIARC readers determined ECD with measurements averaged. Results: The mean preoperative ECD was 15 cells/mm2 greater by the EBs than by CIARC (N = 1286, P < 0.001) with 95% limits of agreement of (−644, 675 cells/mm2). The limits of agreement in preoperative ECD were wider in the After-Lamellar-Dissection Group (−687, 683 cells/mm2) than in the Before Shipping Group [(−505, 633 cells/mm2); P = 0.03]. The EBs-determined preoperative ECD was within 10% of the CIARC-determined ECD for 886 (69%) image sets, with 236 (18%) higher by >10% and 164 (13%) lower by >10%. Excellent agreement appeared between the EBs and CIARC when 100–300 cells could be analyzed in contrast to <100 cells (SD = 308 cells/mm2 vs. SD = 603 cells/mm2; P < 0.001). Conclusions: The mean ECD by the EBs and CIARC were similar, but there was considerable variability between determinations for individual corneas. Agreement improved between the 2 measurements when more than 100 cells were able to be analyzed.

Purpose: To determine the long-term changes in epithelial, stromal, and corneal thickness after LASIK and photorefractive keratectomy (PRK). Methods: In two prospective observational case series, 11 patients (16 eyes) received LASIK and 12 patients (18 eyes) received PRK to correct myopia or myopic astigmatism. None of the corneas had retreatment procedures. Corneas were examined using confocal microscopy before and at 1 month, and at 1, 2, 3, 5, and 7 years after surgery. Central thicknesses were measured from reflected light intensity profiles recorded by confocal microscopy. Postoperative epithelial thickness was compared to preoperative, and postoperative stromal and corneal thicknesses were compared to thickness at 1 month after surgery. Results: In LASIK, epithelial thickness at 1 month (51±4 µ m, n=11) was greater than before surgery (41±4 µ m, n=16; P <.001) and remained thicker through 7 years (52±6 µ m, n=13; P <.001). Stromal and corneal thickness did not change between 1 month and 7 years after LASIK. After PRK, corneal thickness at 1 year (464±44 µ m, n=17) was greater than at 1 month (442±39 µ m, n=15; P =.001) and remained thicker at 7 years after PRK (471±45 µ m, n=17; P <.001). Conclusions: The early increase in central epithelial thickness after myopic LASIK persists for at least 7 years and is probably the result of epithelial hyperplasia. Central corneal thickness increases during the first year after PRK and remains stable thereafter up to 7 years. [ J Refract Surg . 2007;23:385–392.]