Ipilimumab-induced hypophysitis: early Australian experience

To the Editor: We report two men aged in their 60s receiving ipilimumab for metastatic melanoma who presented with headache and constitutional symptoms after the third 3-weekly dose, and were diagnosed with ipilimumab-induced hypophysitis. Ipilimumab is a monoclonal antibody that binds to cytotoxic T lymphocyte-associated antigen 4, resulting in T-cell activation and proliferation. It was the first therapy to yield a survival benefit in metastatic melanoma,1 but at the cost of frequent immune-related adverse events.2

Patient 1 experienced headache, fatigue, postural lightheadedness, anorexia and asthenia. Morning blood test results before steroid administration were consistent with central hypocortisolism (serum cortisol, < 28 nmol/L [reference interval (RI), 70–650 nmol/L]; inappropriately normal adrenocorticotropic hormone [ACTH], 1.2 pmol/L [RI, 0–12.0 pmol/L]), hypothyroidism (low thyroid-stimulating hormone [TSH], 0.2 mIU/L [RI, 0.4–4.0 mIU/L]; low free thyroxine [FT4], 8.9 pmol/L [RI, 9.0–19.0 pmol/L]; normal free triiodothyronine [FT3], 4.7 pmol/L [RI, 2.6–6.0 pmol/L]), and hypogonadism (low testosterone, 2.8 nmol/L [9.5–28.0 nmol/L]; insufficiently raised follicle-stimulating hormone [FSH], 14.0 IU/L [RI, 1.0–12.0 IU/L]; luteinising hormone [LH] within RI, 3.7 IU/L [RI, 0.6–12 IU/L]). Insulin-like growth factor-1, growth hormone and prolactin levels were within RIs. Magnetic resonance imaging (MRI) scans of the brain excluded metastatic disease and demonstrated pituitary enlargement without chiasmal or infundibular involvement (Box). The patient was initially commenced on replacement hydrocortisone.

Patient 2 presented with severe headaches and emesis. Morning blood test results demonstrated central hypothyroidism (low TSH, 0.24 mIU/L [RI, 0.27–4.20 mIU/L]; FT4, 11.4 pmol/L [RI, 12.0–22.0 pmol/L]; and FT3, 2.8 pmol/L [RI, 3.0–7.8 pmol/L]) and hypogonadism (low testosterone [2.1 nmol/L] and inappropriately normal FSH [8.1 IU/L] and LH [3.9 IU/L]). Although morning cortisol and ACTH levels were initially adequate, the patient had been placed on high-dose dexamethasone because of suspicion of brain metastases, which were later excluded by lumbar puncture and brain MRI. The pituitary was not enlarged, but superior convexity was evident.

Both patients received a 3-week tapering course of prednisolone starting at 30 mg daily and weaned to replacement doses. They received thyroxine and, later, testosterone replacement. Ipilimumab was continued to include the standard fourth and final dose. The endocrine abnormalities persisted in both men at 3–6-month follow-up, despite normalisation of MRI findings (Box). For Patient 2, a subsequent insulin-tolerance test demonstrated a flat cortisol response consistent with corticotropic insufficiency due to hypophysitis, although suppression from exogenous steroids may have contributed. Both patients experienced tumour progression over the follow-up period.

Ipilimumab was registered by the Therapeutic Goods Administration in 2011 and funded by the Pharmaceutical Benefits Scheme from August 2013. Ipilimumab-induced thyroiditis and adrenalitis are common differential diagnoses to consider.4 Suprasellar extension is seen frequently,5 requiring urgent ophthalmic evaluation. There are no prospective data on whether high-dose steroids improve pituitary recovery or abrogate the tumour response to ipilimumab. Our cases demonstrated no short-term advantage. Interdisciplinary awareness of this condition is required to ensure that replacement glucocorticoids are started promptly on diagnosis and increased during periods of physiological stress, including surgery or chemotherapy.

Sagittal magnetic resonance imaging (MRI) scans

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T1-weighted sagittal MRI scans of Patient 1, showing symmetrical pituitary enlargement up to 9.3 mm in height with superior convexity and loss of the posterior pituitary bright spot at presentation (A) consistent with a diagnosis of autoimmune hypophysitis,3 followed by normalisation 6 months later (B). 