Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma

Okano, Yudai; Satoh, Tetsurou; Horiguchi, Kazuhiko; Toyoda, Minoru; Osaki, Aya; Matsumoto, Shunichi; Tomaru, Takuya; Nakajima, Yasuyo; Ishii, Sumiyasu; Ozawa, Atsushi; Shibusawa, Nobuyuki; Shimada, Takahiro; Higuchi, Tetsuya; Chikamatsu, Kazuaki; Yamada, Masanobu

doi:10.1507/endocrj.ej16-0161

Cited by 108 publications

(80 citation statements)

References 24 publications

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“…The report of nivolumab-induced hypophysitis by Okano et al was of great interest to us [1]. We have experienced four cases of isolated ACTH deficiency after nivolumab administration, suggesting that decreased sodium (Na) concentrations during nivolumab therapy may predict the acute development of isolated ACTH deficiency.…”

Section: Dear Editormentioning

confidence: 97%

Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]

et al. 2017

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The report of nivolumab-induced hypophysitis by Okano et al. was of great interest to us [1]. We have experienced four cases of isolated ACTH deficiency after nivolumab administration, suggesting that decreased sodium (Na) concentrations during nivolumab therapy may predict the acute development of isolated ACTH deficiency.The underlying diseases in these four patients were malignant melanoma (case 1) [2] or non-small cell lung carcinoma (cases 2-4) >stage 4 (Table 1). Nivolumab (2 mg/kg, every 3 weeks) was effective for treating the cancer in three patients (cases 1-3), while case 4 was considered to have progressive disease and the treatment was discontinued after the 6th administration. All patients experienced fatigue, appetite loss, nausea, and body pain from the 6th to 10th nivolumab administrations. All four patients had low blood pressure and hyponatremia with markedly low ACTH and cortisol levels on admission. Neither ACTH nor cortisol responded to CRH stimulation tests, and the cortisol reaction to the conventional-dose short ACTH stimulation test (250 μg) was lower than normal. Cortisol was secreted following prolonged-stimulation tests in cases 1 and 2 (not determined in cases 3 and 4). The secretion of other pituitary hormones was normal. Magnetic resonance imaging showed no abnormalities. Based on these findings, the patients were diagnosed with isolated ACTH deficiency induced by nivolumab treatment. Their symptoms resolved and general conditions improved promptly after initiation of hydrocortisone (15-20 mg/day). There was no appearance of polyuria after hydrocortisone replacement.Symptoms such as fatigue developed within 6 days after the last nivolumab treatment, and hydrocortisone was initiated from 7-14 days after treatment in three of the four patients. None of the apparent clinical symptoms that would indicate adrenal insufficiency had been observed at the last administration of nivolumab. However, we noted hyponatremia (serum Na levels <135 mEq/L) in two patients (cases 1 and 2) [3] in the absence of such symptoms. In addition, serum Na levels in three patients (cases 1-3) were clearly reduced by the time of the last administration. Hyponatremia could thus be the first manifestation indicating ACTH deficiency in patients treated with nivolumab, followed by other symptoms or physical findings. A previous report by Asano et al. showed that hyponatremia was frequently detected in elderly patients with hypopituitarism, most of whom had ACTH deficiency, and the mechanism of hyponatremia in these patients may have involved augmented release of arginine vasopressin due to impaired pituitary-adrenal axis function [4]. A similar mechanism may have been responsible for the nivolumab-induced hyponatremia in ACTH deficiency in the patients (54-76 years old) in our study.Adrenocortical failure caused by isolated ACTH deficiency may be life-threatening, especially in frail patients with cancer. Our cases highlight the importance of comparing serum Na levels before and during treatment, and measuring ACT...

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Section: Dear Editormentioning

confidence: 97%

Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]

et al. 2017

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“…Among pituitary dysfunctions, the incidence of secondary adrenocortical insufficiency, secondary hypothyroidism, and secondary hypogonadism were 6.1%, 7.6%, and 7.5%, respectively (3). Pituitary enlargement has been seen in irAE-related hypophysitis (10) similarly to cases of idiopathic autoimmune hypophysitis (9). Higher expression of CTLA-4 in the pituitary gland was reported to be related to severe hypophysitis, based on type II or type IV allergy by anti-CTLA-4 antibodies (11).…”

Section: Discussionmentioning

confidence: 99%

Thyrotoxicosis and Adrenocortical Hormone Deficiency During Immune-checkpoint Inhibitor Treatment for Malignant Melanoma

Ariyasu

Inaba

Ota

et al. 2018

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“…We speculate that nivolumab-induced cancer cell destruction might cause reconstruction of the immune system, which somewhat resembles graft versus host disease. Immune checkpoint inhibitors are currently available and there have been three reports who developed eosinophilia during nivolumab therapy without any good response to the drug; two had adrenal insufficiency (4,5), and one had "eosinophilia and systemic symptom syndrome" (3). Therefore, this Figure 1.…”

Section: Immuno-checkpoint Inhibitor-associated Hyper-eosinophilia Anmentioning

confidence: 99%

“…With regard to drug-induced eosinophilia by immune-checkpoint inhibitors, there have been only three reports with nivolumab therapy (3)(4)(5). In these reports, eosinophilia was evaluated as an adverse event (AE), and might be an early indicator before the onset of symptoms of adrenal insufficiency or eosinophilia and systemic symptom syndrome (3)(4)(5). We report herein a case of hyper-eosinophilia due to nivolumab therapy for an advanced lung adenocarcinoma.…”

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confidence: 99%

Immuno-checkpoint inhibitor-associated hyper-eosinophilia and tumor shrinkage

et al. 2018

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Hyper-eosinophilia is defined as an absolute eosinophil count of more than 1500/mm3 (1). Drug-induced hyper-eosinophilia can develop within a few weeks of the start of therapy and is associated with potentially lethal clinical complications, mainly cardiac, cutaneous, neurologic or pulmonary (2). Hypereosinophilia associated with cancer chemotherapy seems to be very rare. With regard to drug-induced eosinophilia by immune-checkpoint inhibitors, there have been only three reports with nivolumab therapy (3-5). In these reports, eosinophilia was evaluated as an adverse event (AE), and might be an early indicator before the onset of symptoms of adrenal insufficiency or eosinophilia and systemic symptom syndrome (3-5). We report herein a case of hyper-eosinophilia due to nivolumab therapy for an advanced lung adenocarcinoma. Of particular interest is in the patient, that, the occurrence of hyper-eosinophilia was observed at the same time of shrinkage of the primary lesion of the disease. We discuss that hypereosinophilia caused by nivolumab therapy may be an immune reaction associated with favorable immune response.A 61-year-old male was referred to our hospital due to incidentally detected abnormal nodule on chest radiograph. He was diagnosed as having lung adenocarcinoma pathologically, however, neither epidermal growth factor receptor mutation nor anaplastic lymphoma kinase fusion gene was identified. Due to small but multiple metastases in brain, he received gamma-knife therapy for the metastatic cites, and two lines of systemic chemotherapy, carboplatin + pemetrexed + bevacizumab, docetaxel + bevacizumab. But the primary tumor and mediastinal lymphadenopathy did not respond and enlarged ( Figure 1A). Therefore, the patient received nivolumab therapy (15 mg/kg, q14 days) as the third-line therapy, although immunostaining was evaluated as negative for PD-L1. Six weeks after the initiation of nivolumab therapy, the patient noted to have an eczema-like skin eruption over back, neck and upper thorax.

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Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma

Cited by 108 publications

References 24 publications

Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]

Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]

Thyrotoxicosis and Adrenocortical Hormone Deficiency During Immune-checkpoint Inhibitor Treatment for Malignant Melanoma

Immuno-checkpoint inhibitor-associated hyper-eosinophilia and tumor shrinkage

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