Ocular Graft-versus-host Disease Research Articles

Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

Clinical Manifestations and Prognostic Factors of Chronic Ocular Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:Ocular graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHSCT), typically affecting 40-60% of patients within 3 years after alloHSCT. The most common clinical manifestation is dry eye disease (DED), which may lead to secondary epithelial changes in the cornea such as filamentary keratitis, and contribute to ocular discomfort and further complications. Patients with DED typically require a complete ophthalmologic examination, including a slit lamp exam to look at punctate epithelial erosions (PEEs) and other ocular surface findings. Treatment for chronic ocular GvHD typically ranges from artificial tears and lid hygiene, to anti-inflammatory agents such as corticosteroids or cyclosporine A, and BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) or other scleral lens therapy. Here, we retrospectively describe the clinical manifestations and look at potential prognostic factors of ocular GvHD at our institution.Methods:We identified 113 patients who had undergone alloHSCT by a single hematologist at the Norris Comprehensive Cancer Center from 1/14/2014 to 12/26/2017. Patients were excluded if they had no documented ocular symptoms or no eye exam performed. We created a final cohort of 26 patients whose demographics, transplant-related factors, clinical manifestations, and treatment outcomes were collected. PEE, from the optometrist's perspective, was graded from 0 - 4 with 4 being the most severe, and ocular surface disease index (OSDI), from the patient's perspective, was graded from 0 to 100 with 100 being the most severe. Descriptive statistics were used to characterize the cohort. The T-test was used to describe groups with continuous outcomes and the Fisher's exact test was used to describe groups with categorical outcomes. A p-value of < 0.05 was considered statistically significant.Results:The incidence of ocular symptoms in our study was 30.1%. A total of 26 patients (mean age 43 years old) with 84.6% Hispanic, 11.5% non-Hispanic Whites (NHWs), and 3.8% African American, were included in statistical analysis. The primary disease included 50% acute myeloid leukemia (AML), 30.7% acute lymphoid leukemia (ALL), 7.7% severe aplastic anemia (sAA), chronic myelomonocytic leukemia (CMML), myelofibrosis, and hemophagocytic lymphohistiocytosis (HLH). 50% of the patients underwent alloHSCT with a match related donor (MRD), 34.6% with a match unrelated donor (MUD), and 15.4% of patients with a haploidentical donor (HAPLO). 65.4% of patients had evidence of acute GvHD and 100% of patients had evidence of chronic GvHD in other organs.The most common symptom was DED (73%), followed by light sensitivity (34.6%), gritty sensation (30.8%), eye pain (30.8%), itchy eyes, mucus discharge, foreign body sensation, and tearing. There was a significantly higher PEE score for patients with the A blood type compared to the other blood types (2.0 vs. 0.98; p < 0.0046) and a not statistically significant trend towards higher OSDI scores as well (50.1 vs. 27.3; p = 0.071). There also was a significantly higher OSDI score in patients with donors > 50 years old (65.0 vs. 32.2; p = 0.045) and a significantly higher proportion of filamentary keratitis (66.6% vs. 5%; p = 0.0047), with a statistically insignificant trend towards higher PEE scores (1.92 vs. 1.36; p = 0.2). No prognostic impact was seen with primary disease type, race, age of recipient at transplant, gender of donor or recipient, recipient blood type, type of transplant, CMV status of donor or recipient, recipient CMV reactivation post-transplant, prior acute GvHD or concurrent systemic chronic GvHD.Artificial tears/conservative therapy was recommended in 15.4% of patients, anti-inflammatory eye drops in 42.3% and scleral lens/PROSE therapy in 42.3% of patients. Compliance was poor and only 14 patients had visual acuity data with treatment. There was an improvement in LogMar score of average 0.14 in both eyes (0.08 in right eye and 0.19 in left eye).Conclusions:Ocular GvHD is an important complication in patients undergoing alloHSCT. Patients who had type A blood type had a significantly higher PEE score than those with other blood types. There was also a significantly higher OSDI score in patients who had donors > 50 years of age, as well as a significantly higher proportion of filamentary keratitis, which can lead to severe corneal complications. DisclosuresNo relevant conflicts of interest to declare.

Sjögren's Syndrome, Non-Sjögren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye.

I have reviewed available literature on dry eye related to Sjögren's syndrome (SS), non-Sjögren's syndrome (non-SS), and graft-versus-host disease (GVHD) to examine aqueous tear deficient dry eye as a subtype of dry eye. This section will focus on clinical studies regarding those subtypes of dry eye. I searched the PubMed database from 1990-2017 for discussion of clinical features, diagnostic criteria, and risk factors of SS, non-SS, and GVHD-related dry eye. In addition, therapeutic options for each subtype of dry eye are described. Although the clinical presentations of SS and chronic graft-versus-host disease (cGVHD) are similar, ocular surface fibrotic changes are characteristic of ocular GVHD but not SS- or non-SS-related dry eye. Recently, diagnostic criteria for each disease have been proposed and include the American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) for SS and the International Chronic Ocular GVHD consensus criteria. Although there has been gradual progress, there are currently no specific therapies and few approved treatment options for these intractable diseases, including SS and GVHD. As judged by the findings, these subtypes of dry eye are different clinical entities from simple dry eye. Therefore, novel therapies, specific to these subtypes of dry eye, may be required in the future.

Single-Center Retrospective Study on Meibomian Gland Loss in Patients With Ocular Chronic Graft-Versus-Host Disease.

This study aimed to analyze the influencing factors of meibomian gland loss in patients with ocular chronic graft-versus-host disease (GVHD) and its correlation with other clinical ocular surface assessment indexes. The clinical data of patients with ocular chronic GVHD from the ocular surface and corneal outpatient clinic of the First Affiliated Hospital of Soochow University were reviewed from June 2012 to June 2016. The relationship between the percentage of meibomian gland acinar area and the influencing factors, such as patient's sex, age, transplantation method, human leukocyte antigen (HLA) matching, the time when eye discomfort appeared after transplantation (month), and the severity of ocular chronic GVHD, was investigated. Moreover, the correlation between the percentage of meibomian gland acinar area and other ocular surface assessment indexes, such as subjective ocular symptom score, eyelid margin score, tear film break-up time, corneal and conjunctival staining score, and the Schirmer test, was analyzed. A linear relationship was found between the percentage of meibomian gland acinar area and the severity of ocular chronic GVHD, but no linear relationship existed between the percentage of meibomian gland acinar area and the factors such as sex, age, transplantation method, HLA matching, and the time when eye discomfort appeared after transplantation. A negative correlation was observed between the percentage of meibomian gland acinar area and eyelid margin score. The percentage of meibomian gland acinar area can reflect the severity of ocular chronic GVHD. The clinical significance of the percentage of meibomian gland acinar area needs further investigation.

Eyelid metrics assessment in patients with chronic ocular graft versus-host disease

PurposeTo assess eyelid metrics in the setting of chronic ocular graft versus-host disease (oGVHD), and to further correlate them with hematological and ocular characteristics. MethodsProspective case-control study conducted at a single tertiary-referred Center. The following eyelid tests were performed in oGVHD patients and control subjects: vertical lid pull; anterior/lower distraction; lateral/medial distraction; distance between lateral canthal angle and orbital rim; margin reflex distances (MRD) 1 and 2; duration of tarsus exposure; snap back. Correlations of eyelid metrics with hematological and ocular parameters in the oGVHD group were performed. ResultsTwenty-seven patients with oGVHD and 27 healthy matched subjects were finally included. Significantly higher values of vertical lid pull, anterior/lower distraction, lateral/medial distraction, and distance between lateral canthal angle and orbital rim were found in the oGVHD group compared to controls (always p < 0.02). Conversely, MRD1 was lower in oGVHD patients compared to controls (p < 0.001). Duration of tarsus exposure and snap back test were pathological in a higher percentage in oGVHD group compared to controls (respectively 66.7 and 59.3% vs 33.3 and 25.9%; p < 0.005). Vertical lid pull test was significantly higher in oGVHD patients with superior limbic keratoconjunctivitis (13.8 ± 2.4 vs 10.9 ± 2.4, p = 0.010). Ocular GVHD patients with subtarsal fibrosis had a higher percentage of pathological values for duration of tarsus exposure test (77.3 vs 20.0%; p = 0.014). ConclusionsThe present study highlighted for the first time higher eyelid laxity in oGVHD patients. This intriguing association may add a further piece to the puzzle of clinical features occurring in the setting of oGVHD.

SYK inhibitor entospletinib prevents ocular and skin GVHD in mice.

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.

Topical cyclosporine-A in pediatric ocular graft versus host disease

Ocular involvement has been reported with a range between 3-90% in graft versus host disease (GVHD) and dry eye syndrome is most frequent finding of ocular involvement.Topical cyclosporine-A might be an effective and safe treatment option in dry eye related to chronic GVHD in combination with topical steroids, autologous serum, lubricant eye drops and ointments. In this study we evaluated the efficacy of topical cyclosporine-A in pediatric ocular GVHD patients.

Retrobulbar Optic Neuritis Associated with Tacrolimus Decrease after Allogeneic hematopoietic Stem Cell Transplantation for Acute Myeloblastic Leukemia Patient

Neurological complications are common after allogeneic hematopoietic stem cell transplantation (HSCT) but it is often difficult to define the cause among infections, Graft- versus-Host Disease (GvHD), adverse effects from medications or nervous system disease (for instance autoimmune disease). We describe a rare case of ocular GvHD associated with the reduction of tacrolimus in a female patient, three months after allogeneic HSCT for acute myeloblastic leukemia in second remission. The multidisciplinary investigations led to the diagnosis of retrobulbar optic neuritis associated with the expression of auto (allo)immune markers. Quickly after rising dosage of tacrolimus to therapeutic level, the ocular symptoms disappeared without relapse thereafter.

Ocular chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in an Italian referral center

PurposeThis study aimed to assess the prevalence and clinical manifestations of ocular graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods269 patients who received allo-HSCT for hematologic malignancies were evaluated between December 2013 and April 2017 in this prospective observational study. Subjects underwent ophthalmologic examination at 6, 12 and 24 months after allo-HSCT. We evaluated the ophthalmologic and hematological data using the NIH consensus criteria definition and the International Chronic Ocular GVHD Consensus Group scoring systems. ResultsAccording to NIH consensus criteria definition, ocular GVHD developed in 46.1%, 51.9% and 54.7% of patients at the follow-up visits. According to the International Chronic Ocular GVHD Consensus Group, ocular GVHD developed in 41.3%, 47.7% and 51.9% of patients at the follow-up visits. We found a strong association between the presence of systemic GVHD and the development of chronic ocular GVHD throughout the entire follow-up period. Weaker associations were found between the presence of a female donor, matched related donor, conjunctival hyperemia and conjunctival fibrosis. ConclusionsMore than 50% of subjects develop chronic ocular GVHD after allo-HSCT. The presence of active systemic GVHD, female donor and matched related donor are associated with ocular GVHD development.

Reduced Efficacy of Low-dose Topical Steroids in Dry Eye Disease Associated With Graft-versus-Host Disease

To compare the response of dry eye disease (DED) to treatment with topical steroid in patients with and without graft-vs-host disease (GVHD). Post hoc analysis of a double-masked, randomized clinical trial. This single-center study included 42 patients with moderate-to-severe DED associated with (n= 21) or without (n= 21) chronic GVHD. In each group, patients received either loteprednol etabonate 0.5% ophthalmic suspension or artificial tears twice daily for 4weeks. Clinical data, including Ocular Surface Disease Index (OSDI) questionnaire, corneal fluorescein staining (CFS), conjunctival lissamine green staining, tear break-up time (TBUT), and Schirmer test, were evaluated before and after treatment. There were no significant differences in signs and symptoms of DED between the groups at baseline. In non-GVHD patients receiving loteprednol treatment, the average OSDI score decreased by 34% from 49.5 ± 5.9 to 32.6 ± 4.8 (mean ± standard error of the mean, P= .001) and the average CFS score decreased by 41% from 5.6 ± 0.6 to 3.3 ± 0.9 (P= .02). On the other hand, loteprednol treatment in GVHD patients resulted in minimal change in OSDI (59.2 ± 6.7 to 61.1 ± 7.1, 3% increase, P= .66) and CFS (5.5 ± 0.5 to 5.3 ± 1.1, 4% decrease, P= .85) scores. Treatment with artificial tears resulted in 22% decrease of OSDI (P= .10) and 32% decrease of CFS (P= .02) scores in non-GVHD patients, and had minimal effect in patients with GVHD. DED patients with ocular GVHD have a less favorable response to a low-dose topical steroid regimen compared with those without ocular GVHD even with similar baseline disease severity.

Subtarsal Fibrosis Is Associated With Ocular Surface Epitheliopathy in Graft-Versus-Host Disease

To evaluate occurrence of subtarsal fibrosis in patients with graft-vs-host disease (GVHD) and to determine its association with ocular surface epitheliopathy. Cross-sectional study. We enrolled 40 patients with moderate or severe dry eye disease, including 20 patients with chronic ocular GVHD and 20 patients without (as the control group). All patients had a comprehensive ophthalmic assessment including evaluation for subtarsal fibrosis, corneal and conjunctival staining, tear break-up time (TBUT), and Schirmer test. Furthermore, meibomian gland drop-out area and densities of epithelial and stromal immune cells were measured using meibography and invivo confocal microscopy, respectively. Subtarsal fibrosis was not seen in any eye of the non-GVHD group. However, 16 eyes (40%) of 10 patients (50%) in the GVHD group had subtarsal fibrosis (P < .001) with an average involvement of 28.9% ± 13.7% of the tarsal area. Fibrosis was more frequent in the upper lids (35%) than in the lower lids (5%). Regression analyses showed that corneal fluorescein staining was significantly associated with the extent of fibrosis (P < .001, β= 0.14) and TBUT (P < .001, β=-0.53) but not with other clinical or imaging parameters. Conjunctival lissamine green staining also had a statistically significant association with the extent of fibrosis (P= .04, β= 0.12) but not other clinical or imaging parameters. Eyes with subtarsal fibrosis had a more severe ocular surface epitheliopathy compared with eyes without fibrosis. Subtarsal fibrosis is present in a significant percentage of patients with chronic ocular GVHD, likely contributing to the ocular surface damage in these patients.

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease.

Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.

Scleral Lenses Therapy for Ocular Graft-Versus-Host Disease

Over the past several decades, hematopoietic stem cell transplantation (HCT) has become the routine treatment for a number of hematological disorders (e.g., leukemia, lymphoma), as well as treatment for some autoimmune diseases and inherited metabolic disorders. One possible complication after stem cell transplantation is graftversus- host disease (GVHD), an inflammatory condition that can affect many different organs, including the eyes. Ocular manifestations of GVHD are common and can significantly decrease quality of life. Without a basic understanding of ocular GVHD, the condition can be challenging to diagnose and adequately treat. This report summarizes the basics of HCT and ocular GVHD, and gives an example case of ocular GVHD treated with scleral lenses.

Graft versus host disease: what should the oculoplastic surgeon know?

To provide a concise review of the oculoplastic manifestations of ocular graft versus host disease (GVHD), and to discuss their management. Ocular GVHD occurs as a common immune-mediated complication of hematopoietic stem cell transplantation that presents as a Stevens-Johnson-like syndrome in the acute phase or a Sjögren-like syndrome in the chronic phase. Cicatricial conjunctivitis may be underreported in ocular GVHD. The spectrum of oculoplastic manifestations includes GVHD of the skin, cicatricial entropion, nasolacrimal duct obstruction, and lacrimal gland dysfunction. Surgical treatment is indicated for patients with significant corneal complications from entropion. Surgical approach to repair of nasolacrimal duct obstruction is presented in this review, including modified approaches for treating patients at risk for keratitis sicca. Management of the ocular graft versus host patient may require a multidisciplinary approach involving collaboration from the oculoplastic surgeon, the corneal specialist, and the stem cell transplant physician. Oculoplastic manifestations of ocular GVHD typically present as cicatricial changes in the eyelid and lacrimal system. Careful oculoplastic and corneal evaluation are necessary when considering surgical management for the ocular GVHD patient.

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Ocular surface analysis in hematological patients before and after allogeneic hematopoietic stem cell transplantation: implication for daily clinical practice

PurposeTo evaluate ocular surface parameters before and after hematopoietic stem cell transplantation (HSCT) and to correlate them with clinical and transplant variables.MethodsThis is a retrospective analysis of data from 93 patients affected by hematological malignancies undergoing HSCT. Values from Ocular Surface Disease Index, Schirmer test, Break-up Time, ocular surface staining, and Meibomian Gland Dysfunction score obtained before HSCT and 3-6 months after were retrieved from charts. Diagnosis and staging of dry eye (DE) disease was performed according to Dry Eye WorkShop criteria. Graft-versus-host-disease (GVHD) was classified according to the NIH criteria. Odds ratios for DE onset after HSCT were estimated for demographic, ocular, hematological and transplant variables.ResultsDE was diagnosed before HSCT in 50 (53%) of the patients, mostly of hyperevaporative profile. After HSCT, all ocular parameters significantly worsened with no change in DE profile. A 51% incident cases (22 of the 43 non-DE subjects) were reported. Increasing recipient age and female sex, higher CD34+ cells infused, donor-recipient sex mismatch (males receiving from females), related donors, and peripheral blood cells as stem cell source were associated with a significant higher incidence of DE after HSCT. Systemic chronic GVHD was diagnosed in 42% while ocular GVHD in 35.5% of the patients, which decreased to 12% when taking into account only incident cases.ConclusionsHigh DE prevalence was shown already before HSCT. A pre-HSCT ocular surface assessment is recommended for early DE diagnosis and treatment. This new protocol also influences the prevalence of ocular GVHD.

A Review of Ocular Graft-Versus-Host Disease.

: Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic hematopoietic stem cell transplantation, which is a potential curative therapy used in a variety of malignant or benign hematological diseases. Graft-versus-host disease primarily occurs in many organs, but most notably in the skin, lungs, gastrointestinal tract, liver, eyes, mucosa, and musculoskeletal system. Ocular manifestations of GVHD may precede other systemic GVHD findings, and it may be a poor prognosis for mortality. While all parts of the eye may be affected, ocular GVHD occurs primarily in the ocular surface. Dry eye disease or keratoconjunctivitis sicca is the most common presenting manifestation of chronic ocular GVHD. Dry eye disease in ocular GVHD is a multifactorial process, which involves destruction and fibrosis of lacrimal glands and conjunctiva, leading to tear film deficiency and instability. Depending on the severity of ocular involvement and response to treatment, ocular GVHD may cause decreased quality of life. Management of GVHD begins with prevention by understanding risk factors and by implementing prophylactic treatment after allogeneic hematopoietic stem cell transplantation. A multidisciplinary approach to the prevention and treatment of GVHD is important, and there are currently no preventive therapies available for ocular GVHD. Once diagnosed, ocular GVHD treatment strategies target ocular surface lubrication and support, tear film stabilization, inflammation reduction, and surgical intervention. The goal of this review is to define ocular GVHD and its categorical manifestations, as well as to describe the importance of comprehensive assessment, diagnosis, and ophthalmologic treatment and management of ocular GVHD with a multidisciplinary approach.

Réaction oculaire du greffon contre l’hôte : une étiologie de syndrome sec à ne pas méconnaître

To report a case of severe ocular graft-versus-host disease (GVHD) after cataract surgery. Observational case report. We describe the case of a 59-year-old man with postoperative corneal ulcer on his only functional eye. His past history reported allogenic bone marrow transplant. His visual acuity (VA) was limited tohand motions. Slit lamp examination revealed diffuse conjunctival hyperemia, severe blepharitis, Meibomian dysfunction, total corneal opacification with epithelial and stromal keratitis and neovascular invasion. Because of the severe dry eye symptoms and history of allogenic hematological stem cell transplantation, ocular GVHD was diagnosed. Functional and anatomical improvement occurred rapidly with topical cyclosporine 2%, with improved VA after treatment. With any severe dry eye syndrome in the context of allogenic bone marrow transplant, ocular GVHD must be considered. For planned ocular surgery, we recommend adding cyclosporine 0.1% treatment before and after surgery to prevent severe ocular GVHD.

Ocular Graft-Versus Host Disease Prevention with Topical Cyclosporine in Non-Myeloablative Allogeneic Stem Cell Transplant

IntroductionOcular Graft versus host disease (oGVHD) is a common complication in receptors of allogeneic or haploidentical stem cell transplants (allo, haplo-SCT); incidence has been reported between 37-55%. Manifestations can range from mild (dry eye) to very severe (corneal perforation). Topical (eye drops) cyclosporine (CsA) has been reported to be an effective treatment of oGVHD once the disease has been established, but long before clinical manifestations are evident, lymphocyte infiltration and damage to the lacrimal gland have taken place. In this study, we evaluate if topical CsA administered from the day of graft success and over one year is effective for prevention of oGVHDMethodsWe conducted a prospective, single arm, phase 2 study. We included patients that received an allo-SCT or haplo-SCT for malignant and non-malignant hematologic diseases who previously didn´t have dry eye syndrome (primary or secondary to other diseases) or corneal surgeries. All patients received systemic CsA for one year aiming serum at levels of 250-350 ng/mL and metothrexate 10 mg/m2 at days+3,+5 and +7 post-transplant (PT). Patients with haplo-SCT also received PT cyclophosphamide 50 mg/kg at days +3 and +4 and mofetil mycophenolate 1 gram/day for one month. We administered CsA in eye drops immediately at the day of graft success (demonstrated with > than 500 X 109 /L neutrophils and >20,000 109 /L platelets for two days unsupported with transfusions) and for one year PT. Systemic steroids 2nd line rituximab and 3rd line bortezomib were allowed in case of systemic GVHD. All patients were evaluated by an ophtalmologist before entering the trial for adequate tear quality with Schirmer test, integrity of corneal surface, eye pressure, and tear breakup time. After grafting, all patients were evaluated monthly with Schirmer test and a complete opftalmologic evaluation was made in months 3,6,9 and 12 post-transplant. Patients were evaluated and diagnosed with oGVHD according NIH criteria. We compared our results with an historical cohort of patients allografted in our center. This study was registered in Clinical Trials.gov NCT02144025ResultsWe included 21 patients (15 HLA identical (71.4%) and 6 haploidentical (28.6%) transplants). Median age was 42(17-62) years, the causes of transplants were hematologic malignancies in 19 patients and aplastic anemia in 2; median CD34 cell dose was 5.8 X 106/Kg (0.70-18.76 X 106/Kg). Median follow up of the whole cohort was 254 days (76-583). Systemic CsA target levels were met in 17 patients at all measurements, in the other 4 median levels were of 164 ng/mL (159-179 ng/mL). Seven patients (33.3%) received CsA+prednisone (PDN), 6 CsA+PDN+rituximab and 1 CsA+PDN+rituximab+bortezomib for systemic GVHD. OS at 365 days was 58% and EFS was 38%. Systemic acute GVHD (aGVHD) incidence grade II-IV was 57% (n=12) and grade III-IV 9.5%(n=2). Chronic systemic GVHD (cGVHD) incidence was 57% (n=12) and extensive (EcGVHD) 14.3% (n=3). We documented 1 case of definite oGVHD at last follow-up of the cohort. Systemic aGVHD grade II-IV (P=0.57), grade III-IV (P=0.48), cGVHD (P=0.52) or EcGVHD (P=0.13) did not have association with oGVHD development. Median of first Schrimer measurement (at study entry) of all cohort was 7.5 mm and 11.3 mm (P=0.005) at last follow-up. Comparing incidence of oGVHD of our study group (n=1, 5%) with an historical cohort of 26 patients allografted in our center (n=6, 23%) (P=0.087) difference is not statistically significant.ConclusionAllografted patients that received topical CsA augmented the quantity and quality of the tear. Although not statistical significant, there is a clear tendency of less oGVHD incidence in the stydy cohort Tear quality improved, which might be a sign of preservation of lacrimal gland function. A randomized, blinded and placebo-controled trial is needed to clearly determine if topical CsA is effective for oGVHD prevention. DisclosuresGomez-Almaguer:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model

Ocular complications occur after transplantation in 60% to 90% of chronic graft-versus-host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease are the most common manifestations of ocular GVHD. Ocular GVHD can be viewed as an excellent preclinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ocular complications after hematopoietic stem cell transplantation (HSCT) and have focused on the acute GVHD process. To address this issue, we used a preclinical animal model developed by our group where ocular involvement was preceded by systemic GVHD to gain insight regarding the contributing immune mechanisms. Employing this “matched unrelated donor” model enabled the development of clinical scoring criteria, which readily identified different degrees of ocular pathology at both the ocular surface and adnexa, dependent on the level of conditioning before HSCT. As far as we are aware, we report for the first time that these clinical and immune responses occur not only on the ocular surface, but they also heavily involve the lid margin region. In total, the present study reports a preclinical scoring model that can be applied to animal models as investigators look to further explore GVHD's immunologic effects at the level of the ocular surface and eyelid adnexa compartments. We speculate that future studies will use this clinical scoring index in combination with what is recognized histologically and correlated with serum biomarkers identified in chronic/ocular GVHD.