Abstract
Introduction
Chimeric antigen receptor (CAR)-T cell therapies have demonstrated remarkable therapeutic efficacy in leukemias and lymphomas that were previously considered incurable. However, concerns persist over potential risks related to toxicities, including those secondary to activation of the patient’s immune system.
Methods
To investigate ocular adverse effects (o-AEs) associated with CAR-T cell therapy, a retrospective cohort study was designed in which data were obtained from the TriNetX aggregated electronic health records database through August 2024, with data analysis performed in August 2024. Billing codes were used to identify patients receiving autologous CAR-T therapy approved by the US Food and Drug Administration (FDA) for the treatment of a hematological malignancy: tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, or axicabtagene ciloleucel.
Results
In a cohort of 684 patients on CAR-T therapy with at least 6 months of follow-up, the most prevalent o-AEs were related to vision changes (1.9%), which included vitreous opacities, visual disturbances, diplopia, and visual discomfort; inflammation (1.8%), which included optic neuritis, conjunctivitis, optic papillitis, chorioretinal inflammation, iridocyclitis, zoster ocular disease; and dry eyes (1.6%), which included dry eye syndrome, keratitis, and ocular manifestations of Vitamin A deficiency.
Conclusion
In the period of 6 months following CAR-T therapy infusion, o-AEs were rare in patients receiving CAR-T cell therapy, indicating that patients without existing eye conditions do not need routine prescreening or directed follow-up after treatment, unless symptomatic. Ongoing monitoring and reporting of ocular adverse events will be important given the durable effects of CAR-T therapy in the treatment of hematologic cancers as well as increasing indications for CAR-T therapy in malignant and nonmalignant disease.
Keywords: Cell therapy, Chimeric antigen receptor T cells, Immunotherapy, Lymphoma, Oncology
Introduction
Chimeric antigen receptor (CAR)-T cells are immune cells engineered to express modular CAR proteins, which enable the specific direction of immune cell activity against a target of interest. CAR-T cell therapy has revolutionized the treatment of hematological malignancies, with demonstrated efficacy in patients with cancers previously considered incurable [1]. Six CAR-T cell products have been approved by the US Food and Drug Administration (FDA) for 12 indications, including large B-cell lymphoma, B-cell acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma, and multiple myeloma. In addition, development and trials of CAR-T cells are ongoing for solid tumors, including glioblastoma, diffuse midline glioma, neuroblastoma, and sarcomas, as well as for nonmalignant diseases, including systemic lupus erythematosus and multiple sclerosis [2–4].
Active investigation is discerning the varied toxicity profiles of CAR-T therapies for different as well as shared clinical indications [5]. As increasing numbers of patients are treated with CAR-T cell therapy, it is imperative to monitor for adverse effects [6, 7]. Given the reported increased risk for ocular adverse effects (o-AEs) with the use of immune checkpoint inhibitors, we hypothesize that immunomodulatory CAR-T cell therapy is similarly associated with o-AEs [8, 9]. Therefore, we aimed to retrospectively evaluate o-AEs associated with new CAR-T cell treatment in a large cohort study population.
Methods
Study Population
A retrospective cohort study was carried out utilizing the TriNetX Health Research network, an electronic health record research network that encompasses several large health organizations in the USA and globally. This network consolidates de-identified electronic health record data, containing diagnoses, procedures, medications, laboratory values, and genomic information, from over 150 million patients across 80 healthcare organizations in four countries (USA, Taiwan, Georgia, and Brazil).
The information for this study was gathered in August 2024, from TriNetX. At the time of data retrieval, the TriNetX database encompassed a total of 153,015,297 patients. Our study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting cohort studies. TriNetX, LLC adheres to the Health Insurance Portability and Accountability Act (HIPAA) rule and holds certification to the ISO 27001:2013 standard. The study was granted an exemption from institutional review board approval.
Study Design
The primary analysis assessed the rate of o-AEs of interest in patients treated with at least one CAR-T cell infusion. Subjects treated with CAR-T cell therapy were identified by a Prescription for Electronic Drug Information Exchange (RxNorm) record of treatment with tisagenlecleucel (Novartis, 1986438), brexucabtagene autoleucel (Kite Pharmaceuticals, 387277), lisocabtagene maraleucel (Juno Therapeutics, 2479136), ciltacabtagene autoleucel (Janssen Biotech, 2594775), idecabtagene vicleucel (Celgene Corporation, 2536430), or axicabtagene ciloleucel (Kite Pharmaceuticals, 1987398). CAR-T cell-associated ocular toxicity was defined as o-AEs diagnosed within 6 months after CAR-T cell treatment; patients who developed o-AEs and had at least one follow-up visit 6 months after initiating CAR-T therapy were included in the study. o-AEs of interest were grouped into the following categories based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes – dry eye: dry eye syndrome (H04.12), keratitis (H16), and ocular manifestations of vitamin A deficiency (E50.0-7); pupillary abnormalities: pupillary abnormalities (H21.56), mydriasis (H57.04), anisocoria (H57.02), unspecified anomaly of pupillary function (H57.00); papilledema (H47.1); vision changes: diplopia (H53.2), visual discomfort (H53.14), other visual disturbances (H53.8), other subjective visual disturbances (H53.19), and other vitreous opacities (H43.3); inflammatory and infectious: optic neuritis (H46), acute atopic conjunctivitis (H10.1), optic papillitis (H46.0), chorioretinal inflammation (H30), iridocyclitis (H20), and zoster ocular disease (B02.3). To reduce the risk of misclassification due to preexisting conditions, patients who had any of the o-AEs’ ICD-10 codes within 1 month prior to CAR-T administration were excluded. Baseline demographics such as age, sex, race, ethnicity, and cancer type were recorded. Race, ethnicity, and sex were determined based on the presence of these designations within the electronic medical record.
Results
A cohort of 684 patients receiving CAR-T cell therapy with a minimum of 6-month follow-up was identified (shown in Table 1). The average age of patients receiving CAR-T cell therapy was 58.1 ± 18.5. The majority was male (58.3%) and identified as White (79%). Patients were treated for malignancy of the lymph nodes or hematopoietic and reticuloendothelial system, particularly diffuse large B-cell lymphoma (15%) and plasma cell myeloma (8%). The most prevalent o-AEs were related to vision changes (1.9%), which included vitreous opacities, visual disturbances, diplopia, and visual discomfort; inflammation (1.8%), which included optic neuritis, conjunctivitis, optic papillitis, chorioretinal inflammation, iridocyclitis, zoster ocular disease; dry eyes (1.6%), which included dry eye syndrome, keratitis, and ocular manifestations of Vitamin A deficiency (shown in Table 2).
Table 1.
Baseline demographics in the CAR-T cell therapy cohort
| 6-month follow-up (N = 684) | |
|---|---|
| Age at Index ± SD, years | 58.1±18.5 |
| Sex, n (%) | |
| Female | 263 (38)1 |
| Male | 399 (58)1 |
| Race, n (%) | |
| White | 542 (79)1 |
| Black or African American | 68 (10)1 |
| Asian | 15 (2)1 |
| Cancer type, n (%) | |
| Lymph nodes | 117 (17)1 |
| Hematopoietic and reticuloendothelial systems | 73 (11)1 |
1Percentages do not add to 100%, as sex, ethnicity, and cancer type were not reported for all patients.
Table 2.
o-AEs associated with CAR-T cell therapy
| 6-month follow-up (N = 684) | |
|---|---|
| Dry eye, n (%) | 11 (1.6) |
| Dry eye syndrome | |
| Keratitis | |
| Other ocular manifestations of vitamin A deficiency | |
| Vitamin A deficiency with night blindness | |
| Vitamin A deficiency with corneal xerosis | |
| Vitamin A deficiency with conjunctival xerosis | |
| Vitamin A deficiency with Bitot’s spot and conjunctival xerosis | |
| Vitamin A deficiency with corneal ulceration and xerosis | |
| Vitamin A deficiency with xerophthalmic scars of cornea | |
| Pupillary abnormalities, n (%) | ≤10 (≤1.5)1 |
| Anomalies of pupillary function | |
| Pupillary abnormalities | |
| Papilledema, n (%) | 0 (0) |
| Vision changes, n (%) | 13 (1.9) |
| Diplopia | |
| Visual discomfort | |
| Other visual disturbances | |
| Other subjective visual disturbances | |
| Other vitreous opacities | |
| Inflammatory and infectious, n (%) | 12 (1.8) |
| Optic neuritis | |
| Conjunctivitis | |
| Optic papillitis | |
| Chorioretinal inflammation | |
| Iridocyclitis | |
| Zoster ocular disease |
1TriNetX denotes outcomes affecting 1–10 patients identically to preserve patient anonymity in circumstances of low occurrence.
Discussion
CAR-T cell therapy for the treatment of hematological malignancies, including lymphoma, leukemia, and multiple myeloma, is associated with low rates of vision changes, ophthalmic inflammation, and dry eye conditions after 6 months. CAR-T cells have demonstrated fledgling success in neurological malignancies and autoimmune conditions. As CAR-T cell therapy extends beyond hematological malignancies to other tumor types and diseases, particularly of the nervous system, it will be important to evaluate for neuroophthalmological adverse effects [10]. Moreover, as neurotoxicity of CAR-T cell therapy, such as immune effector cell-associated neurotoxicity syndrome, continues to occur and be managed, including by glucocorticoids, anti-IL6, and anti-IL1, the o-AEs secondary to these treatments should be monitored. Given CAR-T cells are approved both in pediatric and adult malignancies and are also being explored for chronic autoimmune conditions, it will be important to consider the long-term impacts and ocular effects.
Strengths and Limitations
Strengths of this study include a large, diverse, and up-to-date population to discern side effect profiles in near real-time as well as strict inclusion and exclusion criteria. Limitations of the study include the possibility of inaccurate ICD-10 coding and inability to evaluate any potential CAR-T dose-related impact on o-AEs. In addition, the impact of different CAR-T cell therapies as well as different lymphodepletion regimens, which typically occur days before infusion, were not assessed and call for further study. Finally, we chose relatively short posttreatment time frames to assess for ocular toxicity noting the acute time course of other systemic AEs, so longer term follow-up of these patients is warranted.
Conclusion
Treatment with CAR-T cell therapy significantly improves the prognosis of increasing types of hematological malignancies, with demonstrated efficacy in solid tumors and nonmalignant disease. While prior case studies documented o-AEs in patients treated with CAR-T cells with small sample sizes, our research successfully identified the most common o-AEs in a uniquely large cohort of patients [11–13]. Based on a short-term follow-up period, patients without existing eye conditions do not need routine ophthalmic pre-screening or directed follow-up after treatment, unless acutely symptomatic. However, with demonstration of durable long-term effects of CAR-T cells, patients and care providers should be aware of the uncommon risk of side effects, prompting evaluation [14, 15]. This insight underscores the importance of multidisciplinary care among oncology and ophthalmology providers in recognizing, managing, and reporting o-AEs of CAR-T cell therapies.
Statement of Ethics
This retrospective study is exempt from informed consent. The data reviewed is a secondary analysis of existing data, does not involve intervention or interaction with human subjects, and is de-identified per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data is de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. This study was granted an exemption from Institutional Review Board approval by Stanford University, Approval No. 78274, date November 21, 2024.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was funded by the National Eye Institute Award P30-026877, awarded to Jeffrey Goldberg MD, Byers Eye Institute at Stanford University, Research to Prevent Blindness, Byers Eye Institute at Stanford University, and The Alan and Irene Adler Fund for Innovation in Ocular Oncology, awarded to Prithvi Mruthyunjaya, MD, MHS, Byers Eye Institute at Stanford University. The funders had no role in the design, data collection, data analysis, and reporting of this study.
Author Contributions
T.M.: conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing – original draft, and writing – review and editing. K.M.W: data curation, formal analysis, investigation, methodology, and writing – review and editing. E.R.: methodology and writing – review and editing. P.M.: funding acquisition, methodology, and writing – review and editing.
Funding Statement
This study was funded by the National Eye Institute Award P30-026877, awarded to Jeffrey Goldberg MD, Byers Eye Institute at Stanford University, Research to Prevent Blindness, Byers Eye Institute at Stanford University, and The Alan and Irene Adler Fund for Innovation in Ocular Oncology, awarded to Prithvi Mruthyunjaya, MD, MHS, Byers Eye Institute at Stanford University. The funders had no role in the design, data collection, data analysis, and reporting of this study.
Data Availability Statement
The data used in this study was collected in September 2024 from the TriNetX Live Network, which provided access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) from approximately 140 million patients from 128 healthcare organizations. The data in this study are available through TriNetX at https://live.trinetx.com/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study was collected in September 2024 from the TriNetX Live Network, which provided access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) from approximately 140 million patients from 128 healthcare organizations. The data in this study are available through TriNetX at https://live.trinetx.com/.