Risk factors of ocular graft-versus-host disease after allogeneic haematopoietic stem cell transplantation in Denmark

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) is used to cure both malignant and non-malignant haematological diseases. HSCT can be either myeloablative (MA) or non-myeloablative (NMA) depending on the conditioning regimen given to the patient before transplantation. Despite HSCT having been available for more than 50 years, chronic graft-versus-host disease (cGVHD) remains a difficult immunologically mediated challenge, which increases morbidity and mortality after transplantation. When cGVHD targets the eyes, it causes reduced tears and inflammation, which lead to red, irritated eyes, corneal damage and blindness in worst cases. Furthermore, ocular cGVHD significantly reduces the quality of life after HSCT. More knowledge of who develops the disease and why is needed to predict the disease and optimize treatment in this patient group.

The overall aim of this PhD project (Jeppesen 2025) was to investigate the incidence and risk factors for developing ocular cGVHD in both adults and children. Furthermore, the aim was to investigate possible associations between ocular cGVHD and cGVHD in other organs and mortality after HSCT.

The studies were based on data from ophthalmological and haematological medical records from a large group of consecutive patients receiving HSCT at Copenhagen University Hospital, Rigshospitalet, during 1980–2016, N = 1936 (1452 adults and 484 children). According to the hospital guidelines, the patients had a baseline ophthalmological examination performed before HSCT, annually up to 5 years after HSCT, and more frequently if ocular symptoms occurred.

Our studies showed that in adults, the 5-year cumulative incidence of ocular cGVHD was 18% after MA and 35% after NMA regimen (Jeppesen et al., 2021). Several factors were associated with a higher risk of ocular cGVHD after both conditioning regimens. In the MA group, malignant disease, Schirmer's test ≤10 mm/5 min before HSCT, the use of a matched unrelated donor or female donor, peripheral blood as stem cell source and acute GVHD (grades III–IV) increased the risk of ocular cGVHD. In the NMA group, Schirmer's test ≤10 mm/5 min before transplantation and higher recipient age increased the risk of ocular cGVHD (Jeppesen et al., 2021).

In children, the incidence of ocular cGVHD was 6%, and therefore less common than in adults (Jeppesen, Kielsen, et al., 2022). Ocular cGVHD was more frequent in patients with extensive cGVHD and when other ectodermal-derived organs were involved (skin, mouth, genitals and nails). (Jeppesen, Gjærde, et al., 2022) The frequency of ocular cGVHD was especially high in patients with skin sclerosis as a manifestation of cGVHD (70%) (Jeppesen, Gjærde, et al., 2022). Our studies suggest that target antigens in ectodermal-derived organs might be involved in the complex pathophysiology of ocular cGVHD, but more studies are needed to explore this. Ocular cGVHD was furthermore found to be associated with a higher non-relapse mortality. (Jeppesen, Gjærde, et al., 2022).

In conclusion, several risk factors for developing ocular cGVHD exist. This knowledge may be applied to guide clinical trials (i.e. power calculations), to inform patients of their risk of developing ocular cGVHD and to guide clinicians in scheduling patient follow-up. Because of many patients with signs of dry eyes before HSCT (which increase the risk of ocular cGVHD), we recommend performing a baseline ophthalmological examination before HSCT.

More studies are needed to elucidate the pathophysiology of ocular graft-versus-host disease and finding biomarkers. In the future, this could lead to more accurate diagnostics, better treatment options and potentially prevention of the disease.