Permanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy

Abstract

Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatmentrelated toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).

Case Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review

“…In the first case, CDI occurred in a patient affected by Merkel cell carcinoma who received avelumab (an anti-PD-L1 mAb) (22). In the second one, CDI was reported in a patient affected by lung cancer who received nivolumab (an anti-PD-1 mAb) (23), while in the third case, CDI was diagnosed in a patient affected by mesothelioma, who was treated with an experimental combination of tremelimumab (an anti-CTLA4 mAb) and durvalumab (an anti-PD-L1 mAb) (24).…”

Immune Checkpoint Inhibitors as a Threat to the Hypothalamus–Pituitary Axis: A Completed Puzzle

“…According to data from the WHO global database of individual case safety reports [ 53 ], between January 2011 and March 2019, a total of 6089 ICI-related endocrine AEs were reported, of which 1144 (18.8%) were pituitary events, including hypophysitis (835 reports), hypopituitarism (268 reports), pituitary enlargement (28), and other (13), while CDI was reported in 7 out of 1072 (0.7%) of the registered hypophysitis/hypopituitarism cases. Currently, the only clinical features of the damage induced to the posterior pituitary–hypothalamic axis by ICI are derived from 11 case reports that are available in the current literature (summarized in Table 2 ) [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. All of the patients, except two, were affected by solid malignancies ( N = 3, melanoma; N = 1, prostate cancer; N = 1, Merkel cell carcinoma; N = 1, non-small cell lung cancer; N = 1, pleural mesothelioma; N = 1 hypopharynx cancer; N = 1, bladder cancer); 10/11 (91%) patients were male, and the median age was 62.…”

“…However, other endocrine glands may be more rarely affected (adrenals, parathyroids, pancreas), and metabolic abnormalities have also been described [ 7 , 8 ]. Recently, central diabetes insipidus (CDI) has been reported as an irAE deriving from the dysfunction of posterior pituitary/hypothalamus in patients who are receiving treatment with ICI [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Herein, we briefly summarize the current evidence regarding ICI-induced injury to the hypothalamus–pituitary axis.…”

Endocrine adverse effects of immune checkpoint inhibitors

“…5 Given the association with pituitary dysfunction, along with results of plasma anti-diuretic hormone and water deprivation tests from recent case reports, this appears to be due to central and not nephrogenic diabetes insipidus. 18,19 Management Several guidelines make recommendations for the management of endocrine irAE, including the American Society of Clinical Oncology, European Society of Medical Oncology 20,21 and the Society for Endocrinology which has produced specific guidance for the management and assessment in the acute setting. 22 Although there is limited evidence to guide screening and management of irAE, there does seem to be general agreement between guidelines, summarised below.…”

“…Diabetes insipidus has been described in limited case reports with all cases associated with concurrent hypopituitarism 5 . Given the association with pituitary dysfunction, along with results of plasma anti‐diuretic hormone and water deprivation tests from recent case reports, this appears to be due to central and not nephrogenic diabetes insipidus 18,19 …”