MON-348 Isolated ACTH Deficiency after Administrating Immune Checkpoint Inhibitors: Report of Three Cases and Review of Literature

Abstract [Introduction] Immune checkpoint inhibitors (ICIs) are widely used for the treatment of several malignancies. Despite their effectiveness, they may cause immune-related adverse effects on endocrine organs. Here we describe three cases of isolated ACTH deficiency (IAD) that has occurred after ICI therapy. [Case presentation] Case 1: An 80-year-old female patient with advanced melanoma received nivolumab (NIVO) (3 mg/kg intravenously (IV) every two weeks) for 16 weeks, followed by ipilimumab (3 mg/kg IV every three weeks). After the third injection of ipilimumab, she was alert but complained of general fatigue and anorexia. Her laboratory tests revealed hyponatremia (Na 126 mEq/l), hypoglycemia (Glu 65 mg/dl), low ACTH (ACTH <2.1 pg/ml), hypocortisolemia (cortisol (F) 3.6 µg/dl), and inflammation (white blood cell (WBC) 9,000/µl and C-reactive protein 12.87 mg/dl). Case 2: A 52-year-old diabetic male patient on sulfonylurea for the past two years was given 13 courses of NIVO (3 mg/kg IV every two weeks) for the treatment of recurrent lung cancer but could not proceed with the 14th treatment because of general malaise, appetite loss, and slight fever (37ºC). About three weeks after the 13th injection, he went into hypoglycemic coma (Glu 32 mg/dl) and received intravenous glucose. On admission, his Glasgow Coma Scale score was 14 (E4V4M6). Laboratory tests showed hyponatremia (Na 133 mEq/l), low ACTH (ACTH <2.1 pg/ml), and hypocortisolemia (F 0.2 µg/dl), but no leukocytosis (WBC 6,000/µl). Case 3: A 67-year-old male patient received NIVO (3 mg/kg IV every two weeks) as third-line therapy for advanced gastric cancer. After the seventh course of treatment, he complained of general fatigue, anorexia, joint pain, and palpitations. His blood laboratory test was unremarkable with normal serum sodium (Na 140 mEq/l). Six days later, he returned due to persistent symptoms. Laboratory investigation revealed hyponatremia (Na 135 mEq/l), normoglycemia (Glu 88 mg/dl), low ACTH (2.7 pg/ml), and hypocortisolemia (F 0.8 µg/dl), but no inflammation (WBC 3,200/µl). In all three cases, magnetic resonance imaging showed no abnormalities and endocrinological tests confirmed the clinical diagnosis of IAD. All of them were discharged on a physiological replacement dose of hydrocortisone. [Discussion] A recent report suggested that hyponatremia can be an early manifestation of ICI-induced IAD. Indeed, in Cases 1 and 2, adrenal insufficiency was suspected due to hyponatremia and hypoglycemia, although in Case 2, sulfonylurea presumably also contributed to the development of hypoglycemia. In Case 3, however, serum sodium and glucose levels were normal when he initially became symptomatic. This case illustrates the importance of suspecting IAD in ICI-treated patients who present with non-specific symptoms, such as malaise, even in the absence of hyponatremia or hypoglycemia.