Anticancer immunotherapies, like immune checkpoint blockades, promise to revolutionize clinical oncology, enlisting patients’ own immune systems against tumors. But these new agents can also sometimes compromise immune self-tolerance, inducing “a novel syndrome of autoimmune/autoinflammatory side effects” referred to as immune-mediated adverse events.1
These events include dermatitis, enterocolitis, hepatitis, neuropathies, and endocrinopathies such as hypophysitis, thyroiditis, and adrenal insufficiency; endocrinopathies can involve hypothyroidism, hypopituitarism and hypogonadism.2-4
“With the expanding use of ipilimumab, oncologists are not only faced with most common side effects, such as diarrhea… but also with unusual adverse events, such as certain endocrinopathies,” noted Salvatore M. Corsello, MD, and colleagues of the Catholic University Endocrinology Unit in Rome, Italy.2 “Hypophysitis has emerged as a distinctive side effect of cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies, establishing a new form of autoimmune pituitary disease.”
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Pituitary dysfunction (hypophysitis and hypopituitarism) appears to be the most common immunotherapy-associated endocrinopathy.1 Symptoms and their severity vary, and symptoms are nonspecific: headache, fatigue, memory problems, weakness, insomnia, anorexia, chills, confusion, hallucinations, irritability, and erectile dysfunction or loss of libido.5
To date, some of the best documented immune-mediated endocrinopathies, including hypophysitis, have occurred with ipilimumab and tremelimumab, two monoclonal antibodies (mAbs) that target CTLA-4, a T-cell inhibitor involved in immune self-tolerance.3 Ipilimumab was approved by the US Food and Drug Administration (FDA) in 2011 for treating advanced melanomas; tremelimumab is undergoing clinical trials (Box 1). Hypophysitis has also been reported among patients undergoing programmed cell death protein 1 (PD-1) immune checkpoint blockade.1
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Box 1. Online Clinician and Patient Resources Because of its serious and potentially fatal immune-mediated toxicity profile, FDA approval of ipilimumab involved promulgation of a Risk Evaluation and Mitigation Strategy (REMS), which is available online at https://www.hcp.yervoy.com/pages/rems.aspx. The ipilimumab REMS website includes downloadable PDF-format digital documents meant to supplement the FDA boxed warning and prescribing information. The online resources include a detailed description of immune-mediated toxicities, a management guide, a nursing checklist for detecting immune-mediated toxicities in patients, and a patient-awareness wallet card listing symptoms of immune-mediated toxicities. |
Of the immune-mediated adverse events, only endocrinopathies appear to involve a high risk of irreversible toxicity.3 Yet even these side effects are frequently mild to moderate in severity and are reversible.3 But early detection and intervention are crucial, and as just noted, symptoms can be nonspecific.5 Patient monitoring and posttreatment follow-up, communication, and patient education are crucial for early detection and intervention (Box 2).3
Patients should be advised to immediately report new vision problems, such as blurry or double vision, eye pain, headaches, dizziness, fainting, fatigue, dark urine, or changes in libido, memory, or mood. Patients should be told not to treat such symptoms with over-the-counter medications or dietary supplements without first talking to their oncology team.6
