Immunotherapy-induced isolated ACTH deficiency in cancer therapy

Abstract

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4,447 cancer patients treated with ICI antibodies, 37 (0.8%) [23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 yr)] were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n=20, 54.1%), followed by melanoma (n=8, 21.6%). The most commonly ICI antibody inhibitor reported was nivolumab (n=18, 48.6%), pembrolizumab (n=16, 43.2%) and ipilimumab (n=8, 21.6%). About half of the patients (n=19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n=10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

Rare clinical problem — isolated ACTH deficiency associated with chronic alcohol abuse

“…A similar mechanism of enhanced immune response was suggested as a reason for IAD reported in patients treated for cancer with use of monoclonal antibodies directed against immune checkpoint inhibitors (most frequently -nivolumab or pembrolizumab) [10]. In retrospective analysis, the prevalence of IAD as a side-effect was about 1% of treated patients, diagnosed at a median of 7.0 months after starting immunotherapy, with 6.0 months of median overall survival since IAD diagnosis [10]. The other causes of IAD include pituitary trauma [2], primary empty saddle [11], and cases of possible "exhaustion" of central CRH/ACTH resources, resulting in secondary adrenal insufficiency [12].…”

“…According to this concept, the ectopic expression of pituitary antigens present in tumours evokes a breakdown of immune tolerance, resulting in the production of autoantibodies (anti-PIT1), which are a marker of the disease and can harm pituitary cells. A similar mechanism of enhanced immune response was suggested as a reason for IAD reported in patients treated for cancer with use of monoclonal antibodies directed against immune checkpoint inhibitors (most frequently -nivolumab or pembrolizumab) [10]. In retrospective analysis, the prevalence of IAD as a side-effect was about 1% of treated patients, diagnosed at a median of 7.0 months after starting immunotherapy, with 6.0 months of median overall survival since IAD diagnosis [10].…”

Diagnostic strategies in adrenal insufficiency

“…ICIs besides their direct effect on adrenals, have been also associated with hypophysitis with an incidence of up to 17% of the cases [23–29,30 ▪▪ ]. Its prevalence generally depends on the dosage and specific drug class (anti-CTLA-4, anti-PD-1 or anti-PD-L1) [30 ▪▪ ,31].…”

Idiopathic Isolated Adrenocorticotropic Hormone Deficiency: A Single-Center Retrospective Study

“…(3) Patients with traumatic brain injury were also diagnosed with IIAD due to immune system attacks on exposed ACTH cells [12]. (4) Immune checkpoint inhibitors (ICIs) cause IIAD in 0.8 % of patients [13], because over-activated immune cells lead to autoimmune damage. (5) The formation of the empty sella may be related to autoimmunity [14].…”

“…▪ Patients with traumatic brain injury develop IAD due to immune system attack on exposed ACTH cells [12]; ▪ 0.8 % of patients developed IIAD after ICI therapy [13];…”