Table 5 Cases of Immune Checkpoint Inhibitors Induced Primary Adrenal Insufficiency, Cushing’s Disease, Hypoparathyroidism and Diabetes Insipidus

Reports No.

6

1

1

3

Cases No.

6

1

1

3

Gender

Male = 3; Female = 2;

Not reported =1

Female = 1

Male = 1

Male = 3

Age (years)

Median = 52; Mean + SD = 51.2 + 4.7 Range 43–56

53

73

Median = 62; Mean + SD = 61.7 + 11.5 Range = 50–73

Pertinent medical history

PHx EndoD: NR = 6

FHx EndoD: NR = 6

HX AutoD: NR = 6

PHx EndoD: NR

FHx EndoD: NR

Hx AutoD: NR

PHx EndoD: NR

FHx EndoD: NR

Hx AutoD: No

PHx EndoD: NR = 3

FHx EndoD: NR = 3

Hx AutoD: NR = 3

Type of cancer (all metastatic)

Melanoma = 3; RCC = 1; Lung adenoCa = 1; NSCLC = 1

Melanoma

Melanoma

Prostate Ca = 1;

Melanoma = 1;

Merkel cell Ca = 1.

Check point inhibitor(s)

Ipilimumab =2; Nivolumab =3; Pembrolizumab =1

Ipilumumab + Nivolumab

Nivolumab +Ipilimumab

C1: Ipilimumab.

C2: Ipilimumab

C3: Avelumab

ICI Drug D/C?

Yes = 1; Not reported = 5

Yes = 1 at 12 wks.

Not reported =1

Clinical presentation

Fatigue, weight loss, anorexia, nausea, vomiting, headache, etc

Anorexia, weakness

Paresthesia, weakness, etc

C1: Polydipsia, polyuria

C2: Polydipsia, polyuria

C3: Polydipsia, polyuria.

Onset (weeks) after 1st dose

Median = 10 Mean + SD =14.92 + 14 Range = 1.5–36

14 wks

6 wks

Median = 12; Mean + SD = 3 + 16; Range = 3–16

Biochemical tests

↑ACTH in 5; ↓cortisol in 4; Synactin test +ve & + ve adrenal Ab in 1 without cortisol.

In 1 cosyntropin stimulation test was negative and pt. had enlarged adrenal glands preceded by secondary adrenal \insufficiency.

9wks: slight ↑ in cortisol;

12 wks: ↑ACTH, ↑cortisol, ↑[cortisol]_u. Abnormal low dose dexamethasone suppression test.

16 wks: ↓ACTH, cortisol. 6wks: ↓TSH, ↑FT4, FT3. Then ↓TSH, FT4, FT3. ↓LH, estradiol. Normal PRL.

↓Calcium, undetectable PTH, ↑ phosphate₄,

↓vitamin D, magnesium

7wks: ↓TSH, ↑FT4, FT3, then ↓TSH, FT4, FT3.

C1: ↓ACTH, cortisol, TSH, FT4, FT3, LH & FSH. Normal glucose.

C2: ↓ACTH, cortisol, TSH, FT4, FT3, LH & FSH. Normal glucose. Water deprivation test: partial diabetes insipidus

C3: ↑[sodium],[osmolality]_s, ↓[osmolality]_u.

Normal glucose

Diagnosis

Primary adrenal insufficiency

Cushing’s disease, then 2^o adrenal insufficiency. Thyroiditis, then

hypothyroidism.

2^o hypogonadism.

Primary hypoparathyroidism

Diabetes insipidus

Imaging MRI/CT

MRI brain: 2 normal & 2 enlarged pituitary.

Abd CT scan: atrophied adrenals; enlarged in 1

MRI pituitary at 12 wks: enlarged

EKG: prolonged QT interval

MRI pituitary: Normal in all

CTCAE grade reported

Severity not reported in all:

Not reported

Not reported;

Not reported in all.

Therapy at onset at diagnosis

iv steroids in 4.

Oral steroids in 2. Florinef in 2

Wk5: LT4

Wk16: HCT & LT4.

iv calcium gluconate, then oral vitamin D & Ca carbonate. LT4.

C1: High dose steroidsC2: HCT, LT4 & desmopressin. C3: Desmopressin

Outcome

5 discharged on steroids.

1 NR.

HCT & LT4.

Calcium carbonate + calcitriol

LT4.

C1: NR. C2: HCT, LT4 & desmopressin; C3: Desmopressin D/C