IRREVERSIBLE RETINAL PIGMENT EPITHELIUM TOXICITY ASSOCIATED WITH FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITOR THERAPY

This paper documents a novel cause of retinal pigment epithelium toxicity from a fibroblast growth factor inhibitor. The damage resulted in a scotoma and reduced visual acuity.

Abstract

Purpose:

Erdafitinib is a fibroblast growth factor receptor inhibitor indicated for the treatment of cancer. A case of fibroblast growth factor receptor inhibitor–associated retinopathy that resulted in significant visual symptoms and chronic subretinal abnormalities is reported.

Methods:

A 73-year-old man with a history of relapsed multiple myeloma was treated with erdafitinib. Soon after his fourth treatment cycle, he developed blurred vision in both eyes. Therapy with erdafitinib was subsequently discontinued.

Results:

Funduscopic examination and optical coherence tomography of both eyes revealed multifocal subretinal fluid in the macula of both eyes. Eleven weeks after cessation of the erdafitinib, the visual acuity improved but the patient reported bilateral annular scotomas. Evaluation was notable for resolution of the subretinal fluid with the development irregular subfoveal thickening in both eyes. The patient's symptoms improved, but the subfoveal abnormalities were persistent at 14 months follow-up.

Conclusion:

Erdafitinib may be associated with permanent retinal pigment epithelium toxicity.

Erdafitinib and pemigatinib are the first selective fibroblast growth factor receptor (FGFR) inhibitors approved for use in the United States.^1,2 FGFR inhibitors are a new class of targeted anticancer agents. The indications for FGFR inhibitors are contingent on FGFR gene alterations. Multiple neoplasms have been found to have FGFR alterations including some bladder cancers, cholangiocarcinomas, and multiple myelomas. Retinopathy, accompanied by mild visual symptoms, which resolve on cessation of therapy without permanent ocular sequelae, is one recognized adverse effect of FGFR inhibitors.^1–3 The typical ocular findings of FGFR inhibitor retinopathy includes bilateral symmetric, foveal, or multifocal macula serous detachments. A clinical trial investigating erdafitinib in urothelial carcinoma noted serous detachments in 21% of patients.³ This report describes a unique case of FGFR inhibitor–associated retinopathy that resulted in significant visual symptoms and chronic subretinal alterations, likely due to long-lasting retinal pigment epithelium (RPE) dysfunction.

Case Report

A 73-year-old man was referred for ophthalmic evaluation with symptoms of blurred vision in both eyes. The patient's medical history included relapsed IgA kappa multiple myeloma with an FGFR3/IGH-activating mutation, and he was a participant in the MyDRUG study (NCT03732703) subprotocol D1 cohort with 6 mg oral erdafitinib daily. His other study medications included 20 mg dexamethasone with 4 mg ixazomib weekly and 4 mg pomalidomide for 21 days per month. Before initiation of the study, the patient was asymptomatic with a visual acuity of 20/25 in both eyes. His ophthalmic examination was notable for mild nuclear sclerosis in both eyes. The optical coherence tomography (OCT) images were unremarkable in both eyes. The subfoveal choroidal thickness was 210 μm and 180 μm in the right and left eye, respectively (Figure 1).

Fig. 1.

Infrared and optical coherence tomography of both eyes at baseline. Normal infrared reflectance and optical coherence tomography in the right (A) and left (B) eyes obtained at the baseline visit, before starting erdafitinib. Subfoveal choroidal thickness measured 210 μm on the right eye and 180 μm on the left eye.

The patient's visual symptoms began after his fourth cycle of study medications. The visual acuity had decreased to 20/70 in the right eye and 20/50 in the left eye. The nuclear sclerosis was stable in both eyes. Fundus examination revealed multiple pockets of yellow–orange elevations within the macula and fovea. The infrared reflectance (IR) displayed multiple foci of hyperreflectivity surrounded by a hyporeflective circumference. The OCT uncovered multifocal pockets of subretinal fluid with associated thickening of the ellipsoid zone (EZ) and interdigitation zone (IZ) in both eyes. The subfoveal choroidal thickness increased to 350 μm in the right eye and 300 μm in the left eye (Figure 2).

Fig. 2.

Infrared and optical coherence tomography of both eyes following initiation of erdafitinib. IR and OCT in the right (A) and left (B) eyes after the initiation of erdafitinib. The IR highlights the development of multifocal lesions with a hyperreflective focus and hyporeflective circumference both eyes. These lesions are distributed within the arcades of the macula. OCT is notable for dome-shaped accumulations of subretinal fluid with hyperreflective, thickened ellipsoid, and interdigitation zones. Subfoveal choroidal thickness is 350 μm on the right eye and 300 μm on the left eye.

Erdafitinib was discontinued while the patient continued the same dose of all his other study medications (20 mg dexamethasone with 4 mg ixazomib weekly and 4 mg pomalidomide for 21 days per month). Three weeks after two additional monthly cycles, he reported improvement in his vision but complained of a “donut-shaped” shadow that had developed in the center of his vision of both eyes. At this follow-up visit, the visual acuity was 20/40 in the right eye and 20/25 in the left eye. The nuclear sclerosis was unchanged in both eyes. Fundus examination was notable for subfoveal hyperpigmentation of the RPE in both eyes. The multifocal serous detachments within the macula and fovea were not visible. The IR and OCT confirmed resolution of the subretinal fluid in all areas of the macula. However, there was focal thickening of the EZ and IZ in the superior nasal macula. At the fovea, the EZ thickening had resolved, but there was residual hyperreflective dissection of the IZ from the apical RPE. The subfoveal choroidal thickness decreased to 290 μm and 240 μm in the right and left eye, respectively (Figure 3).

Fig. 3.

Infrared and optical coherence tomography imaging of both eyes eleven weeks after cessation of erdafitinib. IR and OCT in the right (A) and left (B) eyes obtained 11 weeks after the erdafitinib was discontinued. The IR demonstrates resolution of the multifocal lesions illustrated in Figure 2. There is poorly demarcated hyperreflectivity at the fovea in both eyes. The OCT images show resolved subfoveal fluid in both eyes. There is normalization of the ellipsoid zone, with hyperreflective dissection of the interdigitation zone from the apical retinal pigment epithelium in each eye (arrows). Subfoveal choroidal thickness is 290 μm on the right eye and 240 μm on the left eye.

The patient continued with 12 additional cycles of the same dose of all his study medications, including the same weekly 20 mg dose of dexamethasone, without erdafitinib. At his fourteen-month evaluation, the patient's vision was unchanged, despite progression of the right cataract. His symptoms of a central shadow had resolved. The OCT showed persistent dissection of the IZ from the apical RPE at the fovea in both eyes. The IR images revealed poorly demarcated hyperreflective signals at the fovea of both eyes (Figure 4). The subfoveal choroidal thickness had continued to decrease to 200 μm on the right eye and 230 μm on the left eye.

Fig. 4.

Infrared and optical coherence tomography imaging of both eyes fourteen months after cessation of erdafitinib. IR and OCT in the right (A) and left (B) eyes obtained 14 months after the erdafitinib was discontinued. The IR confirms complete resolution of the extrafoveal lesions in both eyes. There is a poorly demarcated hyperreflective signal at the fovea in both eyes. The OCT reveals persistent hyperreflective dissection of the interdigitation zone from the apical retinal pigment epithelium in each eye (arrows). Subfoveal choroidal thickness measured 200 μm on the right eye and 230 μm on the left eye.

Discussion

FGFRs influence important cellular processes by several signal transduction pathways.⁴ Genetic alterations in these signaling cascades have been detected in a variety of tumors.⁵ Erdafitinib is an FGFR inhibitor that was approved in 2019 by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic urothelial carcinoma.^1,2 It is currently being investigated in other cancers with FGFR gene alterations, such as some forms of multiple myeloma.⁶

As with mitogen-activated protein kinase (MEK) inhibitors, the downstream pathways of FGFR inhibitors include the mitogen-activated protein kinase (MAPK) pathway. So, it is not surprising that the retinopathy described with FGFR inhibitors resembles that associated with MEK inhibitors. MEK-associated retinopathy is characterized by bilateral serous retinal detachments which are self-limited and mildly, if at all, symptomatic. OCT imaging of these retinal detachments typically reveal SRF underlying a thickened EZ and IZ.^1,3,7 The retinopathy may be multifocal within the arcades or isolated to the fovea.

Clinical trials of FGFR inhibitors reported, without images, bilateral retinal detachments and pigment epithelial detachments which resolved on drug cessation. Prikh et al¹ published the first description of retinopathy secondary to an FGFR inhibitor, erdafitinib, which was corroborated by contemporaneous images. The pattern of retinal detachments in their patient was subfoveal, unlike the multifocal distribution in this report. Alekseev et al³ demonstrated a case of multifocal retinopathy related to FGFR inhibitor, pemigatinib. The clinical features and course of these two prior cases resemble classic MEK inhibition–associated retinopathy. The course of retinopathy in the current report differed in several ways. The patient was symptomatic with decreased visual acuity and an annular scotoma in both eyes. Persistent dissection of the IZ from the apical RPE also developed. To the best of my knowledge, this is the first documented case of chronic subretinal alterations associated with a MAPK cascade inhibitor.

The diagnosis of central serous retinopathy is in the differential diagnosis, especially because treatment included dexamethasone, and there was an increase in choroidal thickness. However, central serous retinopathy was considered unlikely because the only medication discontinued was erdafitinib, and both the serous retinal detachments and choroidal thickness improved with follow-up, despite continuing the same dose of dexamethasone each month. The association of increased choroidal thickness with the serous retinal detachments could indicate that central serous retinopathy and FGFR inhibitor–induced retinopathy share a similar mechanism.

Although current knowledge regarding the pathogenesis of retinopathy associated with MAPK pathway inhibition is limited, studies suggest an underlying dysfunction of the RPE.^4,7,8 Since FGFR inhibitors act further upstream on the FGFR-MAPK pathway than MEK inhibitors, they also inhibit other signal transduction pathways. It is, therefore, plausible that additional mechanisms may contribute to FGFR inhibitor–associated cellular injury, possibly leading to RPE damage not seen with MEK inhibitors.

The subfoveal lesions described in this case could represent either a proliferation of the RPE cells or unphagocytized material. Longitudinal reflectivity profile analysis as described by Nti et al⁸ might further help differentiate the precise nature of the material. Regardless, the structural changes likely indicate a chronic dysfunction at the RPE-photoreceptor interface which could result from RPE toxicity. The foveal location of the lesions also supports a primary RPE mechanism. It has been postulated that undigested material tends to collect in the foveal region because of the increased load executed by the greater foveal photoreceptor to RPE cell ratio.⁸

In conclusion, this report describes a patient who developed multifocal serous retinal detachments with thickened EZ and IZ following the use of erdafitinib. Fourteen months after stopping erdafitinib, the patient had persistent subfoveal lesions despite resolution of the serous retinal detachments. This case highlights the need for effective monitoring of patients treated with FGFR inhibitors because the associated retinopathy could be chronic and detrimental to vision.