Reactions 1680, p192 - 2 Dec 2017
Various toxicities: case report
A 53-year-old woman developed thyroiditis, transient
Cushing syndrome (CS), corticotroph deficiency and
hypophysitis leading to various complications, during co-
administration of nivolumab and ipilimumab.
The woman, who had a history of stage 4 melanoma of
BRAF-wild type. She was initiated on first line of treatment with
ipilimumab 1 mg/kg and nivolumab 3 mg/kg every three weeks
[routes not stated]. At six weeks of treatment, after three
injections, she developed transient thyrotoxicosis with
elevated free T3 and T4, which was associated with
undetectable levels of thyroid-stimulating-hormone. A
hypoechogenic thyroid gland was observed, which was
consistent with acute thyroiditis. She also developed
hyperthyroidism followed by hypothyroidism with
undetectable levels of thyroid-stimulating hormone. She
required hormone substitution with levothyroxine sodium [L-
thyroxin]. During week 9 of treatment , she showed
amenorrhoea and weight gain of over 25 pounds, polyuria-
polydipsia, weakness, decreased libido and emotional lability.
Tests revealed elevated cortisol and adrenocorticotropic
hormone (ACTH). Her other biochemical tests were normal,
and a fourth nivolumab and ipilimumab infusion was initiated.
A physical examination three weeks after the fourth infusion
showed central obesity, elevated blood pressure, mild fever,
red abdominal striae, facial plethora, proximal myopathy, a
rounded face and a buffalo hump. Her symptoms were
consistent with CS. Her hormonal tests showed highly
elevated urinary free cortisol (5363 µg/24h), serum cortisol
(696 nmol/L), midnight serum cortisol, late-night levels of
salivary cortisol. Hence, ACTH dependent CS was confirmed.
The woman’s treatment with nivolumab and ipilimumab
was discontinued. Enlargement of the pituitary was observed
on the MRI, which had been normal two months ago.
Hypophysitis was suspected. An inferior petrosal sinus
sampling was conducted to confirm the ACTH dependent CS.
Her transient CS lasted over a month. During week 16, seven
weeks after CS diagnosis, she experienced fatigue, decreased
appetite, depression, headache and muscle pains. Tests
showed decreased levels of morning circulating ACTH and
cortisol. She was then initiated on hydrocortisone treatment.
Her nivolumab was re-initiated twice a month at week 22. Her
corticotroph deficiency was permanent. Her hypophysitis and
thyroiditis were thought to have developed from the
synergistic effect of nivolumab and ipilimumab.
Author comment: "Hypophysitis was preceded in our case
by thyroiditis, suggesting a synergic effect with blockade
combinations." "We report the first case of transient CS
caused by pituitary ACTH transient release in a patient
receiving combined immune checkpoint blockade."
Lupu J, et al. Transient pituitary ACTH-dependent Cushing syndrome caused by
an immune checkpoint inhibitor combination. Melanoma Research 27: 649-652,
No. 6, Dec 2017. Available from: URL: http://doi.org/10.1097/
CMR.0000000000000405 - France
Reactions 2 Dec 2017 No. 16800114-9954/17/1680-0001/$14.95 Adis © 2017 Springer International Publishing AG. All rights reserved