ABSTRACT

We report two patients who developed toxic keratopathy following high-dose cytarabine chemotherapy and whose symptoms resolved following topical loteprednol etabonate 0.5% treatment. A 25-year-old woman and a 26-year-old man with acute myeloid leukemia were referred to our department with symptoms of ocular discomfort, photophobia, and blurred vision after consolidation chemotherapy. Central corneal epithelial microcysts were observed bilaterally in both patients, and in vivo confocal microscopy showed highly reflective disseminated granular and irregular intraepithelial opacities, mainly in the basal epithelial layers. Loteprednol etabonate 0.5% relieved both patients’ symptoms in less than a week, and the microcysts disappeared in 2 to 3 weeks of treatment. Although there is no standardized treatment protocol for cytarabine-induced corneal toxicity, dexamethasone 0.1% and prednisolone phosphate 1.0% were reported to be effective in the resolution of discomfort and symptoms. In the two patients we report herein, loteprednol etabonate 0.5% four times daily was also effective in suppressing the symptoms.

Introduction

Cytarabine is an anti-metabolite used mainly in the treatment of acute non-lymphoblastic leukemia. Corneal toxicity related to cytarabine treatment is dependent on the concentration and duration of treatment and is encountered in patients receiving high-dose intravenous treatment, particularly for consolidation therapy in acute myeloid leukemia (AML).^1,2 Following intravenous infusion, the drug penetrates the blood-brain barrier and reaches the cornea via both the aqueous and tears.¹ Cytarabine-induced corneal toxicity is characterized by corneal epithelial microcyst formation. The corneal toxic keratopathy is reversible without permanent damage or scarring, and vision usually returns to baseline. The resolution of symptoms is within 10 to 14 days and follows the desquamation of the affected cell line. Although uncommon, cytarabine-induced corneal toxicity has also been reported with low-dose treatment regimens.³ While there is no standard treatment protocol for cytarabine-induced corneal toxicity, dexamethasone and prednisolone drops have been reported effective in treatment.^1,4,5 In this report we want to emphasize that loteprednol etabonate, a topical soft steroid, is also as effective as dexamethasone and prednisolone in the treatment of cytarabine-induced corneal toxicity.

Discussion

Cytarabine-based consolidation chemotherapy was proven mandatory in preventing relapses after achieving complete remission in AML patients.⁶ A high-dose (3 doses of 6 g/m² daily) cytarabine regimen was reported to be superior to low-dose cytarabine regimens (5 doses of 0.4 g/m² or 0.1 g/m²) for consolidation.⁷ Ocular symptoms develop within 1 week after the initiation of cytarabine treatment and can be prevented with the use of topical corticosteroids. Patients usually complain of tearing, photophobia, foreign body sensation, and sometimes reduced visual acuity. At slit-lamp biomicroscopy, conjunctival hyperemia, superficial punctate keratopathy, and corneal epithelial microcysts with or without conjunctival punctate staining can be noted.

The exact mechanism of corneal microcyst formation is unknown. Since cytarabine inhibits DNA polymerase during the S-phase of cell division, daughter transient amplifying cells that migrate centripetally to populate the basal layer of the corneal epithelium are expected to be more vulnerable to cytarabine toxicity. Since the peripheral epithelial stem cells have a longer cell cycle time compared to the central basal cells, they may not be equally sensitive to the toxic effect of cytarabine; thus, the peripheral cornea typically remains clear, and there remains a clear corneal zone free from microcyts at the corneal periphery.¹ Basal cells are displaced to more superficial layers of the cornea and are desquamated with dynamic turnover and sustained proliferation, hence the resolution of symptoms occurs. In the first few symptomatic days, IVCM shows hyperreflective opacities 8 to 20 µm in size in the basal cell layer. In the following 4 to 9 days, these hyperreflective opacities move to the superficial layers, also affecting the wing-cells and the apical cells. Guthoff et al.⁸ also showed intraepithelial highly reflective elements were visualized only in the basal layer in IVCM on first symptomatic day, but at days 9 to 14 they mainly presented in more superficial layers. Histologically, these opacities were shown to represent degenerate cells with pyknotic nuclei intermixed with cytoplasmic debris.⁹

The incidence of cytarabine-induced corneal toxicity was reported to be around 85-92% without topical corticosteroid prophylaxis.¹⁰ In this case, topical steroids are started 1 day before initiation of treatment and are continued throughout the therapy. Topical corticosteroid eye drops have been reported to reduce the incidence to 8-16%.^2,10 Although the mechanism of action is unknown, corticosteroid eye drops were hypothesized to render the corneal epithelial cells less susceptible to the effects of cytarabine by inducing a partial reduction in DNA replication.² In a randomized, double-masked trial that compared placebo to prophylactic steroid use, corticosteroids prevented the development of conjunctival hyperemia and visual reduction, and significantly reduced the degree of microcyst formation.² Additionally, prophylactic topical corticosteroid use certainly relieves the symptoms of cytarabine-induced corneal toxicity, such as tearing, photophobia, and foreign body sensation. Betamethasone sodium phosphate 0.1%, dexamethasone 0.1%, and prednisolone phosphate 1% eye drops have been recommended for prophylaxis against cytarabine-induced corneal toxicity.^1,2 In our two patients, loteprednol etabonate 0.5% eye drops were also quite effective in suppressing the patients’ symptoms and relieving photophobia. Since these patients are already immunosuppressed, loteprednol etabonate 0.5% use may reduce the risk of secondary infection at the ocular surface, as well as minimizing the risk of short-term topical corticosteroid-induced side effects such as intraocular pressure elevation.

The use of topical 2-deoxycytidine, a competitive inhibitor of cytarabine, has also been shown to be effective in the management of the dose-related corneal toxicity of systemic cytarabine. However, this drug is not commercially available.¹¹ Artificial tear drops, on the other hand, can help relieve symptoms by diluting cytarabine in tears; therefore, the addition of topical lubricants to topical corticosteroid prophylaxis is usually recommended.⁴

Acute anterior uveitis and optic neuropathy are the other rare complications of high dose cytarabine treatment.¹² High dose cytarabine treatment used in conjunction with total-body irradiation in the setting of induction for hematopoietic cell transplantation can rarely induce retinal microvascular damage with capillary nonperfusion, neovascularization, vitreous hemorrhage, and macular edema.¹³

In summary, ophthalmologists should be aware of the signs and symptoms of cytarabine-induced ocular toxicity, whereas oncologists need to know the importance of seeking ophthalmology consultation for initiation of topical corticosteroid treatment together with frequent lubrication in patients who need to receive high-dose chemotherapy regimens with cytarabine. Once cytarabine-induced keratopathy is diagnosed, topical soft steroids such as loteprednol etabonate 0.5% eye drops and frequent lubrication may also be as effective as topical dexamethasone and prednisolone eye drops in relieving ocular discomfort, photophobia, and foreign body sensation.