Abstract

Background

Immune-related hypophysitis (IH) occurs in up to 19% of melanoma patients treated with anti-CTLA-4 antibodies (ipilimumab and tremelimumab) alone, or in combination with anti-PD1 antibodies. There are no strict criteria available to define IH, but pituitary hormone (ACTH +/- TSH) deficiency and MRI evidence of a swollen pituitary gland are pathognomonic. Diagnosis can be difficult since patients may not be symptomatic, and while endocrine-related adverse events associated with checkpoint inhibitors are generally irreversible,  early detection is needed to avoid life-threatening adrenal crisis and may enable recovery of some hormone function. Optimal treatment is not defined.

Method

We performed a retrospective cohort study of patients treated with ipilimumab alone or in combination with nivolumab at a tertiary melanoma referral centre between January 2015 and September 2018. The primary outcomes were IH incidence and the potential reversibility of hormone axis deficiency.

Results

35 patients received ipilimumab+/-nivolumab, 5 (15%) developed IH at a median of 20 weeks (range 13-28) after initiating treatment. All patients developed a deficiency in thyrotrophic and corticotrophic axes. Two patients had evidence of gonadotrophic deficiency. Two asymptomatic patients presented with hyponatraemia at the initial diagnosis, while the other three patients had normal sodium level.  Three patients received a high dose of corticosteroids, two patients were commenced on physiological dose of steroids, and all patients received synthetic thyroxine (levothyroxine), two patients required testosterone replacement.   One patient, diagnosed early with mild symptoms (fatigue and headache) and started on physiological dose of steroids, recovered both thyrotrophic and gonadotrophic function.

Conclusion

Real world incidence of IH appears to be similar to prospective clinical trial data. The physiological dose of steroids can be used in patients with no life-threatening symptoms. Recovery of the thyroid is possible; however, adrenal recovery seems to be a rare event.