An analysis of early morning acth levels in the first case of pembrolizumab-induced adrenalitis as a delayed immune-related event (dire) – case study.

The aim: The levels of adrenocorticotrophic hormone (ACTH) are elevated in primary adrenal failure (Addison’s disease) with a peak in the early morning hours. This also occurs under hydrocortisone replacement therapy due to the unphysiological substitution regime. The aim was to study ACTH levels under two different replacement regimens. This is exemplified in a patient with adrenalitis after immunotherapy for malignant melanoma (MM), since (elevated) levels of ACTH and its cleavage product alpha-melanocyte stimulating hormone (α-MSH) raise concerns since receptors for both hormones can be expressed in melanoma cells.
Material and methods: A female with MM had immunotherapy with pembrolizumab and developed adrenalitis with Addison crisis about one year after discontinuation of this therapy (delayed immune-related event = DIRE). ACTH levels were measured hourly (4-8 a.m.) during a “conventional” hydrocortisone replacement therapy and during a therapy with dual-release hydrocortisone.
Results: Salient differences between the morning ACTH profiles under the “conventional” hydrocortisone replacement regimen with 10-5-5 mg/die compared to the single-dose regimen with 20 mg dual-release hydrocortisone were not discernible.
Conclusion: DIRE could be an underestimated problem in immunotherapy and could put the patients at hazard. Especially in case of an endocrinological DIRE concerning the adrenocorticotrophic axis, life-threatening situations can arise for the patients. As for the special situation with M. Addison and MM, where hormonal feedback mechanisms may cause further problems beyond the normal hormonal replacement therapy, we observed no salient differences in the early morning ACTH profiles under different hydrocortisone replacement regimens.