Poster Presentation ESA-SRB Conference 2015

Endocrine collateral damage (#207)

Amy Hsieh 1 , Greg Hockings 1 , Elisabeth Nye 1 2
  1. Greenslopes private Hospital, Brisbane, QLD, Australia
  2. Frankston Hospital , Melbourne , Victoria , Australia

Monoclonal antibodies such as Ipilimumab (against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) and nivolumab (against programmed death protein 1 [PD-1]), block inhibitory regulatory T cell molecules and  achieve anti-tumour effect by enhanced T cell activation at the cost of autoimmunity1,2,3,4,5. We report a case of presumed autoimmune hypophysitis and type 1 diabetes after treatment with ipilimumab and nivolumab for metastatic melanoma. 

A 54-year-old woman presented with seizures and confusion. Medical history included melanoma with intracranial metastases treated with craniotomy, radiation and a course of ipilimumab nine weeks prior. MRI excluded new cerebral lesions but showed an enlarged pituitary not present previously. Static anterior pituitary function evaluation revealed hypopituitarism involving the pituitary-thyroid and pituitary-gonadal axes (T4 of 6.2 pmol/L with TSH of 1.2 mIU/L; low gonadotrophins of FSH 8 IU/L and LH 1 IU/L). ACTH insufficiency was suspected but could not be established due to concurrent dexamethasone therapy (cortisol < 35 nmol/L, ACTH < 5 ng/L).  A clinical diagnosis of ipilimumab-induced hypophysitis (IH) was made. 

Despite complications, the patient completed the ipilimumab course and then received nivolumab. Five weeks later, she presented with severe symptomatic hyperglycaemia (serum glucose 21.7 mmol/L) and ketoacidosis (pH  6.91, serum beta-hydroxybutyrate 9.4 mmol/L), requiring an insulin infusion. Abdominal CT showed a normal pancreas with no radiological evidence of pancreatitis or metastasis. The acute presentation with hyperglycaemia, ketoacidosis and low C-peptide levels led to the diagnosis of presumed autoimmune diabetes. Serum autoantibodies (IA2 and GAD65) were negative.

There is little data on nivolumab-induced autoimmune diabetes. It has been reported in one recent study6. This is the first report of ipilimumab-induced hypophysitis followed by apparent nivolumab-induced type 1 diabetes. These are uncommon adverse events of immunotherapy but are expected to rise in incidence as immunotherapy becomes more prevalent.

  1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
  2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26.
  3. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122-33.
  4. Weber J, Ka ̈hler K, Hauschild A. Management of Immune-Related Adverse events and Kinetics of response with ipilimumab. Journal of Clinical Oncology 2012 Nov20;30(21):2691-7
  5. Gettinger S, Horn L, Gandhi et al. Overall Survival and Long-Term Safety of Nivolumab. Journal of Clinical Oncology 2015 Apr 20.
  6. Hughes J, Vudattu N, Sznol M et al. Precipitation of Autoimmune Diabetes with Anti-PD-1 Immunotherapy. Diabetes Care 2015; 38:e55–e57