Greater Total Dose and Duration of Treatment with Bortezomib Are Associated with Higher Incidence of Chalazion and Other Ocular Side Effects
Authors: Ganesh Karuna , Batlevi Connie , Zhang Zhigang , Hassoun Hani , Lendvai Nikoletta , Landau Heather , Moskowitz Craig H. , Caron Philip , Motzer Robert , Giralt Sergio A , Hamlin Paul , Lichtman Stuart M. , Matasar Matthew J. , Portlock Carol S , Shukla Neerav , Wasserheit-Lieblich Carol , Zelenetz Andrew D. , Gerecitano John F. 
Published: October 2019

Abstract

Background: Use of the proteasome inhibitor bortezomib has been anecdotally noted to be associated with a number of ocular side effects, including chalazion, vascular events and conjunctivitis. This type of adverse event has not been characterized in the literature on bortezomib to date. In this retrospective study, we report the incidence of bortezomib-associated eye disease among patients treated at Memorial Sloan Kettering Cancer Center, and identify risk factors for development of ocular side effects.
Methods: A retrospective review was conducted to identify all patients treated with bortezomib at Memorial Sloan Kettering Cancer Center between February 1999 and August 2013. Patients with bortezomib-associated eye disease were identified using ICD-9 diagnosis codes as shown in table 1. Patients were included if eye disease occurred after the first date of bortezomib administration and until one week after the last date of administration. Other data collected included dates, total dose and route of bortezomib administration. To identify statistically significant correlations between disease incidence and other variables, FisherÕs exact test was applied to discrete variables, and Wilcoxon rank sum test was applied to continuous variables.
Table 1. Diagnosis codes used for identification of bortezomib-associated ocular disease. Diagnosis codes identified as “chalazion” Diagnosis codes identified as “other eye disease” Hordeolum Externum Blepharitis Chalazion Blepharoconjunctivitis Conjunctival Hemorrhage Conjunctivitis Acute Conjunctivitis Optic Neuritis Conjunctiva Vascular Abnormality Retinal Hemorrhage Eye Swelling or Mass Purulent Endophthalmitis Disorders of Eyelid Keratoconjunctivitis Arterial Branch Occlusion Retinal Vasculitis Vitreous Hemorrhage Mucopurulent Conjunctivitis Retinal Vascular Occlusion Conjunctivitis NEC Inflammation Eyelid NOS
Results: 1122 patients were administered bortezomib between February 1999 and August 2013 at Memorial Sloan Kettering Cancer Center. Patients received bortezomib as IV (78.5%) or SC (19.9%) injections (1.6% (18 patients) received both IV and SC injections). Total doses of bortezomib ranged from 5.1mg to 505.2mg (median dose 60.56 mg). 53 patients (4.7%) developed eye disease during the period of bortezomib administration. Of these, 23 (2.0%) developed chalazion, while 30 (2.7%) developed other eye disease. The median dose administered prior to the first episode of eye disease was 34.41mg (range 2.10-147.40mg). The median time from first dose of bortezomib to the first event was 106 days (range 1-2154 days). Incidence of eye disease was positively correlated both with higher cumulative dose of bortezomib (p<0.0001) and with greater total time on bortezomib (p<0.0001). In addition, patients who received bortezomib both intravenously and subcutaneously were statistically more likely to develop eye disease than those who received bortezomib only via one route (p<0.0001). Patients who were documented as having relevant eye disease preceding bortezomib administration were not found to be more likely to develop eye disease during bortezomib therapy than those with no prior history of eye disease. There was also no correlation between the incidence of multiple episodes of eye disease during bortezomib therapy and any of the variables tested.
Conclusions: Bortezomib is an important part of treatment regimens for many patients with multiple myeloma and lymphoma. However, its use is associated with side effects, most notably neuropathy, which sometimes necessitates dose reduction or drug discontinuation. In this study we document the incidence of bortezomib-associated eye disease in the total cohort of patients treated with bortezomib over 14.5 years at a large academic medical center. We find that the development of eye disease is associated with higher total dose and greater duration of bortezomib administration.

Disclosures
Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Hamlin:Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding.