Pembrolizumab- and ipilimumab-induced diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency: a case report

Abstract

Background Several human monoclonal antibodies directed against immune checkpoints, including T lymphocyte antigen 4 and programmed cell death protein 1, have been implemented for cancer treatment in order to promote effector T cell response to tumors. Despite the antitumor activity of these agents, a significant number of patients demonstrated immune-related adverse events that affected the functions of multiple organs, including the endocrine system. We report the first case of immune checkpoint inhibitor–induced simultaneous diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency following combination treatment with immune checkpoint inhibitors. Case presentation A 70-year-old Thai man with no previous history of diabetes mellitus was diagnosed with stage IVB non–small cell lung with pleural and liver metastases. After 14 weeks of combination treatment with pembrolizumab and ipilimumab, he presented with fatigue, nausea, and vomiting. Laboratory investigation revealed random plasma glucose 794 mg/dl, serum ketone 6.3 mmol/L, bicarbonate 13 mmol/L, and high anion gap 24 mmol/L. New-onset diabetes mellitus and diabetic ketoacidosis were diagnosed. Insulin therapy was initiated a favorable outcome within 10 hours. Despite improvement of hyperglycemia, the patient had persistent nausea and hyponatremia. Further investigation revealed cortisol 0.8 μg/dl and adrenocorticotropic hormone 21.7 pg/ml. His other pituitary hormone levels were normal, except for mild elevation of gonadotropin hormone. Magnetic resonance imaging of the pituitary showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, resulting in an improvement of his symptoms. Conclusion Our patient developed new-onset diabetes mellitus, diabetic ketoacidosis, and isolated adrenocorticotropic hormone deficiency during cancer treatment with pembrolizumab and ipilimumab. The present case highlights the need for physicians to be aware that immune-related adverse events can occur in multiple organs at the same time.

Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management

“…Most ICIs-DM cases are observed during treatment with PD-1/PD-L1 inhibitors either alone or in combination with other immunotherapies. On the contrary, a few ICIs-DM cases are reported for patients exposed to CTLA-4 inhibitor monotherapy (7,11,70). Patients with advanced tumors are more likely to receive first-line systemic immunotherapy, and may receive combination of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.…”

“…Mechanisms of the 3 immunotherapy agents are different from each other and ICIs alone or in combination with chemotherapy are conventional first- or second-line therapies. This has been attributed to favorable survival durations and tolerance for many types of malignancies, including metastatic melanoma ( 6 ), advanced non-small cell lung cancer ( 7 ), Hodgkin lymphoma ( 8 ), metastatic renal cell carcinoma ( 9 ), and unresectable hepatocellular carcinoma ( 10 ). Despite the efficacy of immunotherapy, immune-related adverse events (irAEs), often involving endocrine tissues including pneumonitis, hypophysitis, thyroiditis, colitis, pancreatitis, and autoimmune diabetes, have emerged as potential challenges to patients ( 11 , 12 ).…”

“…Most of these events have been described as a case report ( Table 1 ). Cancer patients treated with ICIs present with symptoms collectively described as ICIs-associated pancreatic AEs including abdominal pain, vomiting, dyspepsia, irregular stools, and large daily glucose fluctuations ( 7 , 13 , 32 ). ICIs-associated pancreatic AEs are rare, however they result in poor quality of life and affect safety of patients.…”

Immune checkpoint inhibitor–induced diabetes mellitus with pembrolizumab

“…The variability in autoantibody status further indicates the poorly understood nature of the mechanism of ICI-induced DM 32 33. Similarly, the NOD mouse model indicated there was no correlation between autoantibody levels and the development of autoimmune diabetes in subjects receiving PD-1/PD-L1 inhibitors 12.…”

Fulminant ACTH decrease following diabetic ketoacidosis induced by immune checkpoint inhibitor combination therapy with nivolumab and ipilimumab: A case report

“…Table 5 shows cases reporting hypophysitis and T1D. [3,[21][22][23][24][25][26][27][28][29][30][31][32] ICIs are anti-PD-1 monotherapy, anti-PD-L1 monotherapy, and combination therapy of anti-PD-1/anti-PD-L1 and anti-CTLA-4. No cases with hypophysitis and T1D due to ipilimumab monotherapy were reported.…”