Beyond the Expected: Life-Threatening Immune-Related Adverse Events from Checkpoint Blockade — A Case Series

Abstract Background: Immune checkpoint inhibitors (ICIs) have transformed the management of multiple solid tumors, but their use is accompanied by immune-related adverse events (irAEs) that can affect virtually any organ system. Although most irAEs are low-grade, a minority are severe or life-threatening and require prompt recognition. We describe three patients who developed distinct, uncommon, high-severity irAEs during ICI therapy. Methods: We report a retrospective case series of three patients treated with programmed death-1 (PD-1) or PD-1/PD-ligand 1 (PD-L1)–directed therapy at a tertiary oncology referral center. Clinical, laboratory, and imaging data were extracted from the medical record and are presented descriptively. Results: Case 1, a 54-year-old man with resected clear-cell renal-cell carcinoma receiving adjuvant pembrolizumab, developed ICI-induced hypophysitis after 13 cycles, presenting with severe hyponatremia and biochemical evidence of central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency; pituitary MRI was normal. Hormone replacement was initiated and the patient remained disease-free at 1-year follow-up. Case 2, a 74-year-old woman on maintenance pembrolizumab after trimodality therapy for esophageal adenosquamous carcinoma, presented with fulminant insulin-deficient diabetes and diabetic ketoacidosis (DKA); C-peptide was nearly undetectable. She required prolonged subcutaneous insulin and permanent discontinuation of immunotherapy. Case 3, a 68-year-old woman receiving dostarlimab with chemotherapy for metastatic high-grade serous endometrial carcinoma, developed an extensive maculopapular eruption after the second dose. Skin biopsy showed full-thickness epidermal necrosis; high-dose systemic corticosteroids produced gradual resolution over 2–3 months, and dostarlimab was permanently discontinued. Conclusions: ICI therapy can produce rare, severe, and organ-specific irAEs—including hypophysitis, fulminant diabetes with DKA, and extensive cutaneous eruptions—that may occur after variable latency and can mimic other acute medical conditions. Awareness of these presentations, coupled with a low threshold for endocrine and dermatologic evaluation, allows earlier diagnosis and may reduce irAE-associated morbidity. Keywords: immune checkpoint inhibitors; immune-related adverse events; hypophysitis; fulminant diabetes; diabetic ketoacidosis; cutaneous toxicity; pembrolizumab; dostarlimab