A Case Series of Rare Immune-Mediated Adverse Reactions at the New Mexico Veterans Affairs Medical Center
Background: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several solid tumors. The use of ICIs is expected to rise as a growing number of indications are approved for their use by the US Food and Drug Administration and with the increasing number of patients with cancer. Unfortunately, ICIs are associated with the development of immune-mediated adverse reactions (IMARs). About 5% to 10% of patients developing severe toxicities requiring treatment postponement or discontinuation. IMARs can affect any organ, but most frequently the skin and endocrine glands are involved.
Case Presentation: We present a case series of IMARs observed at the New Mexico Veterans Affairs Medical Center. First, we present a case of grade 4 myocarditis in an 84-year-old man receiving chemoimmunotherapy for lung adenocarcinoma to demonstrate the rapid progression of this rare condition. Second, we present a case of uveitis in a 70-year-old man with superficial bladder cancer undergoing treatment with pembrolizumab. Finally, we present a case of a 63-year-old man with pleuritis and organizing pneumonia secondary to dual ICI treatment (nivolumab and ipilimumab) for mesothelioma. A discussion regarding the epidemiology of these IMARs, expected course, and optimal management follows each rare toxicity described.
Conclusions: Though these toxicities are uncommon, they serve as a reminder to clinicians across specialties that IMARs can drive the acute deterioration of any organ, and consideration of toxicities secondary to ICIs should be considered for any atypical presentation of unclear etiology.
Discussion
ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.18 The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.
Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.19 This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.20 Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.
CONCLUSIONS
ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.
It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.
