Phase I Clinical Trial: Safety of Subconjunctival Cyclosporine Implant for GVHD

移植物vs.宿主病（GVHD）是异基因造血干细胞移植（SCT）的主要并发症，通常影响皮肤、肝脏、胃肠道和眼睛。眼部GVHD最常见的临床表现通常由以下原因引起： 泪腺和结膜受累。泪腺受累可导致水性泪液缺乏，导致严重的干燥性角结膜炎（KCS），可显著增加慢性GVHD患者的发病率。 全身性免疫抑制剂如环孢霉素（CsA）可有效治疗包括泪腺功能障碍的眼部GVHD。然而，对于GVHD的唯一表现是眼部并发症的患者，一般不开具全身免疫抑制剂，因为它可能会否定整体移植物抗-肿瘤效应并降低患者存活率。局部CsA和皮质类固醇通常不能有效治疗水性泪液缺乏症，这可能是由于上皮屏障阻止药物渗透到泪腺。开发了一种缓释结膜下CsA植入物，以绕过这些上皮屏障并显著增加泪腺中的CsA浓度，以治疗与GVHD相关的水性泪液缺乏症。 本随机初步研究的目的是研究CsA植入物在GVHD相关泪腺受累和水状泪液缺乏患者中的安全性和潜在疗效。将根据植入物相关不良事件评价安全性。将通过Schirmer泪液试验（麻醉）的变化评价疗效。次要疗效评价将包括角膜和结膜染色等级的变化、最佳矫正视力（BCVA）、眼表疾病指数（OSDI）、结膜GVHD等级的变化、泪膜破裂时间和睑板腺功能障碍。

Graft-vs.-Host Disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT) commonly affecting the skin, liver, gastrointestinal tract, and eye. The most common clinical manifestations of ocular GVHD generally result from involvement of the lacrimal gland and the conjunctiva. Lacrimal gland involvement can lead to aqueous tear deficiency resulting in severe keratoconjunctivitis sicca (KCS) which can significantly increase the morbidity of patients with chronic GVHD. Systemic immunosuppressants such as cyclosporine (CsA) can be effective for treating ocular GVHD including lacrimal gland dysfunction. However, systemic immunosuppression is not generally prescribed for patients whose sole manifestation of GVHD is ocular complications as it may negate the overall graft-vs.-tumor effect and decrease patient survival. Topical CsA and corticosteroids are generally not effective for treating aqueous tear deficiency possible due to epithelial barriers preventing penetration of the drugs to the lacrimal gland. A sustained-release subconjunctival CsA implant was developed to bypass these epithelial barriers and significantly increase the CsA concentrations in the lacrimal gland to treat aqueous tear deficiency related to GVHD. The objective of this randomized pilot study is to investigate the safety and potential efficacy of a CsA implant in patients with lacrimal gland involvement and aqueous tear deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia). Secondary efficacy evaluation will include changes in corneal and conjunctival staining grades, best-corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI), changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.