Bortezomib ocular toxicities: Outcomes with ketotifen
Authors: Michael Dennis, Asaf Maoz, David Hughes, Vaishali Sanchorawala, J. Mark Sloan, Shayna Sarosiek
Journal: American Journal of Hematology (2018)

Bortezomib, a first-in-class proteasome inhibitor, is frequently used in the treatment of multiple myeloma (MM), systemic light chain (AL) amyloidosis, and other hematologic conditions.1-3 Common and dose-limiting toxicities associated with bortezomib include peripheral neuropathy, thrombocytopenia, rash, and gastrointestinal toxicity.3, 4 Ocular symptoms related to bortezomib are known to occur, but are not often reported. The most common ocular side effects include chalazion and conjunctivitis.4 Ocular symptoms are often refractory to conservative management and discontinuation of bortezomib may be required.4, 5 Based on anecdotal experience at our center, patients with bortezomib-associated eye disorders are treated with ketotifen ophthalmic solution, an H1 antihistamine and mast cell stabilizer. This report describes the frequency of ocular symptoms associated with bortezomib, the time to development of symptoms, and the rate of bortezomib discontinuation in a cohort treated with ketotifen. We performed a single-center retrospective study of all patients with plasma cell disorders being treated with bortezomib-based therapy at Boston Medical Center between January 1, 2014 and December 31, 2017. One hundred forty-five patients were identified. Six were excluded due to lack of data. Of the remaining 139 patients included in the study, 21 patients (15%) developed ocular toxicity and were initiated on ophthalmic ketotifen solution. The patient characteristics of the group with ocular toxicity were compared to the remaining 118 patients (Table 1). The mean age for the group with ocular toxicity and the group without toxicity was 58 years (range, 33-73) and 63 years (range, 39-92), respectively. Of the 21 patients that developed ocular toxicity, 13 patients (62%) were black, 4 patients (19%) were white, and 3 patients (14%) were Hispanic compared to 65 black patients (55%), 42 white patients (36%), and 7 Hispanic patients (6%) in those without ocular toxicity. MM was the most common plasma cell disorder in both groups (57% and 64%), followed by AL amyloidosis (33% and 30%). Thirteen females (62%) and eight males (38%) developed ocular symptoms compared with 41 females (35%) and 77 males (65%) that did not (P = 0.02). There was no significant difference in age, race/ethnicity, or plasma cell disease between patients with or without ocular toxicity. The majority of ocular complaints were bilateral (62%). Symptoms were highly variable, with eight different symptoms being reported (Supplementary Table 1). Eyelid swelling, conjunctival injection, and discharge were among the most common. Eyelid erythema, pruritus, dry eyes, burning/pain, and blurry vision were also noted. The most common clinical diagnoses were chalazion/hordeolum (n = 10, 48%), blepharitis (n = 6, 29%), and conjunctivitis (n = 3, 14%). The treatment regimens for patients with ocular complaints, as well as any modifications that were made after ocular complaints developed, are shown in Table 1. The dose of bortezomib was the same for all patients (1.3 mg/m2) with most patients receiving weekly bortezomib. Two patients received twice weekly dosing. On average, symptoms developed after 13 cumulative doses (corresponding to the fourth cycle of chemotherapy). The range was highly variable, with one patient developing symptoms after three doses while another developed symptoms after 32. Three patients (14%) completed the planned bortezomib therapy before symptoms developed. There was no change in treatment for the majority of patients (n = 12, 57%). Two patients (10%) had the frequency of bortezomib reduced. Four patients (19%) stopped receiving bortezomib and switched to another regimen due to ocular symptoms. One patient switched from bortezomib to ixazomib and had a recurrence of blepharitis. All patients received ketotifen ocular solution with supportive care when ocular toxicity developed. The patient demographics in this report are consistent with the general population of patients with MM and AL amyloidosis, demonstrating a predominance of males and black patients with an average age of 60-70 years.1, 6 There was no significant difference in race noted between patients with ocular toxicity and those without, but there was a trend toward increased prevalence of symptoms in minority groups. The lack of significance in these racial differences may be related to the small sample size. A significant difference in the rate of ocular symptoms did exist between males and females, with an increased prevalence in females (P = 0.02). This finding, as well as the difference in racial prevalence, should be explored further in larger prospective trials. Unique to this study was also the finding that ocular complaints occurred in some patients up to 5 weeks after bortezomib cessation. This observation highlights the need for continued monitoring for development of ocular symptoms after the last exposure to bortezomib. Additionally, in contrast to previously published literature,4, 5 our study found that the majority of patients were able to continue bortezomib despite ocular side effects. The reason for this difference is not completely clear but may be related to the use of ketotifen for symptom management. Although there are no published reports of ketotifen in this setting, it is routinely used at our institution with good effect. The exact pathophysiology of ocular toxicity is not yet understood. However, multiple studies have suggested an inflammatory etiology,4, 5 which would support a role for the anti-histamine and mast cell stabilization properties of ketotifen. Further research is needed to investigate this potential biological explanation, as well as the benefits of ketotifen. In addition, additional investigation is needed to determine whether the newer proteasome inhibitors, such as carfilzomib and ixazomib, have the same ocular safety profile as bortezomib. In summary, our study contributes to the post-marketing surveillance of bortezomib, confirming the presence of ocular toxicities in 15% of patients during and after treatment. We report an increased risk of ocular toxicity in females and the potential use of ketotifen to mitigate ocular side effects and allow continued used of bortezomib. We recommend vigilance in monitoring for ocular side effects during and after bortezomib treatment with rapid institution of supportive care, including consideration of ketotifen, in an effort to prevent interruptions in bortezomib therapy. There are no conflicts of interest to disclose. M.D., A.M., and S.S. have reviewed the cases, analyzed results, and authored the manuscript. J.M.S, V.S., and S.S were involved in the clinical care of patients in this series. All authors were involved in the review, editing, and approval of the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.