Endocrine Abstracts

Ipilimumab, a monoclonal antibody against CTLA-4, is licenced for the treatment of metastatic melanoma (dose of 3 mg/kg for four cycles intravenously). It can cause immune-related adverse reactions (IRAEs) in multiple organs, with hypophysitis the most common endocrine IRAE. We carried out a retrospective analysis of 171 ipilimumab-treated patients in one centre for endocrinopathies.

Results: Nine cases (six female, mean age 64 years, range 42–76) of ipilimumab-induced hypopituitarism were identified (incidence 5.3%). Mean time to hypophysitis was 64 days (17–188 days, mean 3.4 cycles) post-commencement of ipilimumab. All patients were identified at clinic visits or presented acutely; fatigue, headache and blurred vision were the most common symptoms. At diagnosis, three patients were hyponatraemic; hormone deficiencies were: eight cortisol (no recovery), eight TSH (four recovered), seven gonadotrophin (three recovered), no DI. Seven patients had IGF-1 measured (two high, two low). Five patients had low TSH (0.03–0.54;NR0.55–4.78 mU/l) with low normal fT4 (12.7–15.5; NR10–22 pmol/l) the month before diagnosis. Five patients’ MRI scans demonstrated enlarged pituitary; follow-up scans showed normal pituitary in three, one reduced pituitary size and one empty sella. Four patients had additional IRAEs (three colitis, one dermatitis, one hepatitis). Four patients received high dose glucocorticoids (2-methylprednisolone, 2-dexamethasone), with no difference in hormone recovery, however one developed diabetes mellitus and another steroid psychosis. No other endocrinopathy was diagnosed.

Discussion: In our series, the incidence of ipilimumab-hypophysitis was approximately 5%. Cases occurred from the first cycle to several months after treatment completion. A normal pituitary on MR does not exclude hypopituitarism. The low TSH documented a month prior to clinical presentation may be a valuable marker of early hypophysitis and represent an opportunity for earlier diagnosis. Treatment with high dose glucocorticoids (as recommended by manufacturers) is of uncertain value and can lead to side effects. Hypopituitarism is rarely reversible and not a reason to discontinue ipilimumab.