Reversible corneal stromal thinning, acute-onset white cataract and angle-closure glaucoma due to erdafitinib, a fibroblast growth factor receptor inhibitor: Report of three cases

Toxicité oculaire de l’Erdafitinib, inhibiteur du récepteur au facteur de croissance des fibroblastes: amincissement stromal cornéen, cataracte blanche aiguë et glaucome aigu: report de 3 cas G. Bautersa, M. Paquesa,b, V. Borderiea,b, N. Bouheraouaa,b,∗

Summary

Purpose. — To report corneal and lens toxicity in patients undergoing chemotherapy with erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor.
Methods. — This retrospective case series contains three patients from a cohort of 41 patients receiving erdafitinib, a selective pan-FGFR inhibitor, for chemotherapy. These three patients underwent complete ophthalmic examination: one was followed by corneal topography and the other two were followed by anterior segment optical coherence tomography.
Results. — All three patients had severe dry eye syndrome. One patient had bilateral corneal thinning. One patient had bilateral neurosensory retinal detachment, unilateral corneal thinning and white cataracts in both eyes. The third patient had bilateral corneal thinning, a corneal ulcer of the left eye and acute-onset white cataracts in both eyes, causing angle-closure glaucoma in the left eye. Following the cessation of erdafitinib treatment or a decrease in the dose used, corneal thinning resolved in all three cases within four months. Acute-onset cataracts were treated urgently by surgery, with no complications. In one patient, although the corneal ulcer healed, corneal transparency was lost, and the patient never fully recovered his initial vision.
Conclusion. — Bilateral neurosensory retinal detachment associated with FGFR inhibitor use has already been reported. However, we provide herein the first report of reversible corneal thinning and acute-onset white cataracts causing angle-closure glaucoma associated with FGFR inhibitor use. Early recognition and management of these adverse ocular reactions are required to prevent vision loss due to acute glaucoma and/or corneal ulcer.

KEYWORDS
Cornea;
Erdafitinib;
FGF;
FGFR inhibitor;
Cataract;
Glaucoma; Optical coherence tomography

Introduction

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a wide range of biological functions, from developmental processes during embryogenesis to diverse physiological functions crucial for homeostatic regulation of the body [1], including tissue regeneration and repair [2]. There is growing evidence to suggest that the FGF pathway plays a crucial role in oncogenesis, through its potent mitogenic effects. Multiple FGFR inhibitors with various degrees of selectivity are currently being tested for cancer treatment, with promising results. The toxicities of conventional chemotherapy agents are well known, but the toxicity of targeted agents, such as monoclonal antibodies or kinase inhibitors, remains poorly documented [3]. Ocular toxicities are among the most common adverse events associated with targeted agents [4]. In most cases, these events consist of conjunctivitis and dry-eye syndrome, and sight-threatening events remain relatively rare [5]. Cases of subfoveal neurosensory retinal detachment associated with FGFR inhibitor use have already been reported [6]. In this case series, we focus on three patients who received erdafitinib, a selective pan-FGFR inhibitor, for chemotherapy. These three patients suffered sight-threatening adverse events, with corneal thinning, one case of chronic corneal ulcer, and acute-onset white cataracts causing angle-closure glaucoma in one patient.

Case Series

This retrospective case series consists of three patients from a cohort of 41 patients given erdafitinib, a selective panFGFR inhibitor, for chemotherapy. These 41 patients were initially screened by retinal optical coherence tomography (OCT) (Spectralis, Heidelberg Engineering, Heidelberg, Germany) to monitor the occurrence of subfoveal neurosensory retinal detachment. The three cases studied here underwent complete ophthalmic examination at the Quinze-Vingts National Ophthalmological Hospital. One patient was followed by corneal topography (Orbscan II, Bausch and Lomb Surgical, Rochester, NY) and the other two patients were followed by corneal OCT (RTVue; Optovue, Inc, Fremont, CA). The characteristics of the patients are summarized in Table 1.

Case 1

A 69-year-old man was treated for metastatic urothelial cancer. He initially received a daily dose of 9 mg erdafitinib for three months. He had no history of prior ocular disease and had undergone cataract surgery on both eyes before the start of the trial. At the first examination, this patient complained of vision loss, photophobia and dry eyes. His visual acuity was 20/40 for the right eye (RE) and 20/50 for the left eye (LE). Intraocular pressure (IOP) was normal. Slitlamp biomicroscopy revealed superficial punctate keratitis and stromal thinning in both eyes. Central pachymetry measurements were performed by OCT at 447 m for the RE and 461 m for the LE. The patient was treated with sodium hyaluronate lubricating eye drops. The decision taken to stop erdafitinib treatment for three weeks. Erdafitinib was then reintroduced at a daily dose of 6 mg.
After two months of intensive lubrication, the patient recovered 20/20 vision in both eyes. Examination revealed the resolution of dry eye symptoms, and no superficial punctate keratitis. Corneal pachymetry measurements had improved significantly, to 469 m for the RE and 493 m for the LE.
Eight months after the start of follow-up (erdafitinib at a daily dose of 6 mg), the patient had a visual acuity of 20/20 in both eyes, his intra-ocular pressure was normal and clinical examination of the corneas revealed no signs of dry eye syndrome. Pachymetry measurements gradually increased, eventually stabilizing at 500 m for the RE and 504 m for the LE (Fig. 1 ).

Case 2

A 36-year-old man was treated for metastatic urothelial cancer. He initially received a daily dose of 9 mg erdafitinib for three months. He had no history of prior ocular disease.
Three months after the start of treatment, the patient complained of dry eyes and vision loss. On examination, visual acuity was initially 20/25 for the RE and 20/25 for the LE. Slit-lamp examination revealed superficial punctate keratitis in both eyes. The patient had no cataracts at this point.
IOP was normal in both eyes, at 13 mmHg for the RE and 14 mmHg for the LE. The patient was treated with sodium hyaluronate lubricating eye drops. The daily dose of erdafitinib was decreased to 8 mg.
Three months later, the patient complained of further vision loss. On examination, visual acuity was 20/25 for the RE and 20/40 for the LE. Slit-lamp examination revealed bilateral corneal thinning and a central sterile corneal ulcer in the LE. Central pachymetry by OCT was 443 m for the RE but was not performed for the LE because of the artifacts caused by the ulcer. The patient was treated with sodium hyaluronate lubricating eye drops (both eyes) and with two drops per week of a regenerating matrix therapy agent (Cacicol©, Thea Pharmaceuticals, Clermont-Ferrand, France) for two weeks, plus autologous serum (left eye only). Erdafitinib treatment was stopped.
Two months after the cessation of erdafitinib, central pachymetry measurements improved to 482 m for the RE. The ulceration healed, leaving a corneal scar, in the LE.
Ten months after the start of treatment, central pachymetry measurements stabilized at 490 for the RE and 478 m for the LE (Fig. 2).
Two months after stopping erdafitinib treatment, the patient came to the emergency room with vision loss and pain in the LE. His visual acuity was 20/20 for the RE and hand motion for the LE. On examination, the RE was normal, with no cataract and an IOP of 11 mmHg. The LE presented a white cataract causing angle-closure glaucoma, with an IOP of 35 mmHg. The patient was treated with acetazolamide per os and with drops of acetazolamide, timolol and latanoprost. Laser iridotomy was performed immediately, decreasing the IOP to 9 mmHg. Surgery was then rapidly performed to remove the cataract. This intervention was tricky as the lens appeared to be liquefied and under pressure. The anterior capsule burst when the surgeon tried to initiate the anterior flap. But surgery was completed and an IOL was implanted in the capsular bag.
One month after surgery, the LE had recovered a visual acuity of 20/32, due to persistent corneal opacity. The IOP of the LE had normalized at 12 mmHg. However, on examination, white lens opacities were noted in the RE that had not been there the month before, the visual acuity of the RE had decreased to 20/40 and the IOP of the RE was normal, at 13 mmHg. Laser iridotomy was performed immediately, to prevent the occurrence of angle-closure glaucoma in the RE, and cataract surgery was performed rapidly, with no complications. There were no post-operative complications, visual acuity was 20/20 for the RE and 20/25 for the LE, due to corneal scarring. IOP values normalized, at 11 mmHg for the RE and 12 mmHg for the LE. Case 3
A 65-year-old woman was treated for advanced lymphoma. She had no history of prior ocular disease.
The patient received erdafinitib with dose escalation from 2 mg daily to 9 mg daily. She was initially followed in the retinal department for asymptomatic subfoveal neuroretinal detachment due to erdafitinib (Fig. 3).
One month after the start of treatment, the patient complained of dry eyes. Her visual acuity was 20/25 for the RE and 20/25 for the LE. Slit-lamp biomicroscopy revealed superficial punctate keratitis in both eyes. OCT showed subfoveal serous neuroretinal detachment in both eyes. The patient was treated with sodium hyaluronate lubricating drops. Erdafitinib treatment was continued and the patient was followed up monthly. Her visual acuity was stable, as was her bilateral serous neuroretinal detachment.
Five months after the start of treatment, the patient’s visual acuity was stable in the RE, at 20/25, but had decreased in the LE, to 20/32. Slit lamp biomicroscopy showed corneal stromal thinning in the left eye, with no epithelial defect. Corneal thinning in the LE was measured at 269 m. Erdafitinib treatment was stopped, and local lubricant was prescribed.
Corneal pachymetry values significantly improved, returning to normal levels within four months (Fig. 4). The bilateral subfoveal serous neuroretinal detachment decreased significantly in size (Fig. 3), and the patient recovered a visual acuity of 20/25 in both eyes. On examination, she presented no cataracts at this point.
Eleven months after the start of treatment, the patient presented with vision loss in both eyes, with a visual acuity of 20/32 for the RE and 20/40 for the LE. Slit-lamp biomicroscopy revealed bilateral white cataracts. Intraocular pressure was 13 mmHg for the RE and 15 mmHg for the LE. Cataract surgery was rapidly performed, and the lenses of both eyes appeared to be liquefied and under pressure. dose of 6 mg for 5 weeks). Central pachymetry values were 469 and 493 m, for the right and left eyes, respectively. E and F: Right eye and left eye after 4 months at a daily dose of 6 mg; central pachymetry values were 486 and 493 m, for the right and left eyes, respectively. G and H: Right eye and left eye after 8 months at a daily dose of 6 mg, central pachymetry values were 500 and 504 m, for the right and left eyes respectively. M3, M5, M8, M12 = 3, 5, 8, 12 months after the start of treatment.
After surgery, the patient recovered a visual acuity of 20/20 for the RE and 20/25 for the LE.

Discussion

This case series demonstrates that FGFR inhibitors can affect the cornea, causing dry eye syndrome (reported with many targeted agents [3]), corneal ulcers and stromal thinning. We show that FGFR inhibitors can affect the lens, causing acute-onset white cataracts, with a rapid increase in lens volume inducing angle-closure glaucoma in one patient and necessitating urgent medical and surgical care. Our findings also confirm that FGFR inhibitors can induce subfoveal serous retinal detachment.
Five of the 41 patients treated with erdafitinib had severe dry eye syndrome, five developed subfoveal serous retinal detachment, and three developed severe corneal adverse events threatening vision and necessitating changes to erdafitinib treatment (its cessation or a change in dose). Two of the three patients with severe corneal events developed bilateral acute-onset white cataracts in the months following the corneal adverse event and a few months after the end of erdafitinib treatment. The other patient had cataract surgery before the start of the trial. One of these three patients had bilateral subfoveal serous retinal detachment. This condition is more frequent than adverse corneal and lens events, but must be addressed rapidly as it can cause vision loss and precede other adverse effects.
FGFs are small proteins that bind and activate FGFRs. FGFRs are transmembrane proteins with an intracellular tyrosine kinase domain that transduce extracellular signals in various intracellular cascades involved in the regulation of cell survival, proliferation and differentiation [3]. FGFs are potent mitogens, with effects on cell survival, and mutations of FGFRs are frequently observed in malignant cells. Drugs targeting FGFRs are considered promising for use in the treatment of patients with malignant tumors.
Unlike previously developed anticancer drugs, targeted agents are generally well tolerated. They are thought to be more specific and less toxic than traditional cytotoxic chemotherapy. However, ocular toxicity has been reported for many approved targeted agents. This ocular toxicity can be explained by the expression of many of the targeted molecules in ocular tissues as well as in tumors. FGFR expression has been reported in the cornea, the lens and the retina [7]. The fragile balance of growth factors and other signaling molecules within the eye can easily be disrupted by targeted agents blocking signaling pathways.
FGFs play an active role in corneal wound healing, by increasing the proliferation of epithelial stem cells in the limbal region [8]. Furthermore, FGFs are present in tears and can rapidly induce epithelial healing rapidly as they come into direct contact with the erosion. Presumably, agents blocking FGFR signaling can also disturb this signaling in normal cells expressing FGFR, delaying epithelial healing. In case 2, the corneal toxicity of erdafitinib caused a chronic ulcer, resulting in corneal scarring and a loss of visual acuity. These three cases of corneal stromal thinning implicate FGFs in the complex mechanisms maintaining the thickness, structure and refractive properties of the cornea. The full or partial reversibility of stromal tissue thinning over a few months following the modification of erdafitinib treatment indicates that this treatment did not cause a definitive destruction of stromal tissue.
FGFs are also involved in lens homeostasis. The reasons for the appearance of cataracts only in patients with severe corneal adverse events and only several months after the end of erdafitinib treatment are unclear. FGFs are required to induce lens differentiation from ectoderm and these molecules play a crucial role in every stage of adult lens development [9]. In the presence of high concentrations of FGFs in the vitreous cavity, lens cells undergo a complex transformation that ensures lens transparency. These cells elongate, and produce crystallin proteins, which fill the cells, and all the organelles are destroyed to minimize light scattering [10]. The central role of FGFs in lens development, homeostasis and transparency suggests that erdafitinib, an FGFR inhibitor, played a causal role in the acute cataracts observed in two of our patients.
FGF is a neurotrophic factor known to be present in the retina, its expression levels being highest in Müller glial cells and the RPE. The blocking of this signaling pathway, might therefore be expected to cause a degeneration of the RPE and Müller cells, and, thus, serous retinal detachment [11].
There are currently no clear guidelines concerning FIIN-2 the ocular toxicity of FGFR inhibitors. We would encourage investigators to request a baseline examination and corneal and retinal follow-up by an ophthalmologist for all patients treated with FGFR inhibitors. We believe that the early recognition and management of these adverse ocular reactions are necessary, to prevent the complication of blindness. Lubricants should be generally sufficient for the treatment of mild dry eye syndrome. However, in cases of corneal thinning, chronic corneal ulcer or acute cataract, FGFR inhibitor treatment should be stopped, or the dose decreased.
Corneal thinning and acute-onset white cataracts associated with FGFR inhibitor use are reported here for the first time. Left untreated, these adverse events could have severe consequences for vision, such as corneal scarring and acute angle-closure glaucoma. Follow-up should be pursued even after the end of FGFR inhibitor treatment, as cataracts can appear a few months later.

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