Endocrinopathies from checkpoint inhibitors: Incidence, outcomes, and management

Randol Kennedy; Hussein Awada; Naga Vura; Daniela Ciltea; Michael Morocco

doi:10.3949/ccjm.90a.22032

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Figure 1
Proposed mechanism of the programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 pathway (PD-L1). (MHC = major histocompatibility complex ; TCR = T-cell receptor.)

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TABLE 1

Common Terminology Criteria for Adverse Events (CTCAE)

Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Asymptomatic or mild symptoms or change in affected chronic condition from baseline (eg, diabetes mellitus)	Moderate symptoms; limiting age-appropriate instrumental activities of daily living	Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self-care activities of daily living	Life-threatening consequences; urgent intervention indicated	Death

Adapted from reference 18.

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TABLE 2

Thyroid dysfunction due to immune checkpoint inhibitors: American Society of Clinical Oncology guideline

Situation	Action
Screening	Thyroid function tests, ie, thyroid-stimulating hormone (TSH) with or without thyroxine (T4) every 4–6 weeks while on therapy
Asymptomatic hypothyroidism (grade 1), TSH > 4.5 and < 10 mIU/L	Monitor thyroid function tests routinely as above Continue immune checkpoint inhibitor
Symptomatic hypothyroidism (grade 2) or TSH persistently > 10 mIU/L	Start levothyroxine (1.6 μg/kg/day if age < 70; 25–50 μg/day if age > 70 or multiple comorbidities); monitor TSH every 6–8 weeks until TSH is at goal, then every 6–12 months unless symptoms change Consider holding immune checkpoint inhibitor until symptoms resolve Consider endocrine consultation for challenging presentation or for hormonal therapy
Severely symptomatic hypothyroidism (grade 3 or 4)	Hold immune checkpoint inhibitor until symptoms resolve Hospital admission usually required Endocrine consultation recommended to assist with rapid hormone replacement Hydrocortisone should be given in the event central hypothyroidism is considered Start on chronic levothyroxine therapy and monitor as above on discharge.
Asymptomatic or mildly symptomatic thyrotoxicosis (grade 1)	Continue immune checkpoint inhibitor Start beta-blocker Monitor TSH and T4 every 2–3 weeks after diagnosis for possible hypothyroidism transition (and treat as for primary hypothyroidism) Consider endocrine consult for persistent thyrotoxicosis (> 6 weeks)
Mildly symptomatic thyrotoxicosis (grade 2)	Consider holding immune checkpoint inhibitor until symptoms improve Consider endocrine consultation Start on beta-blockers Refer to endocrinologist for persistent thyrotoxicosis (> 6 weeks) for additional workup and possible medical thyroid suppression
Severely symptomatic thyrotoxicosis (grade 3 or 4)	Hold immune checkpoint inhibitor until symptoms resolve Endocrine consult for all patients Start on beta-blocker Hospitalization with endocrine consultation to be considered in severe cases to guide medical therapy

Adapted from reference 49.

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TABLE 3

Hypopituitarism due to immune checkpoint inhibitors: American Society of Clinical Oncology guideline

Situation	Action
Screening and workup	Routine thyroid function tests as outlined in Table 2 If central hypothyroidism is suspected, evaluate morning adrenocorticotropic hormone (ACTH) and cortisol as well as electrolytes ACTH stimulation testing can be falsely negative early in hypophysitis, as adrenal reserve declines slowly after pituitary stimulation is lost
Asymptomatic or mild symptoms (grade 1)	Consider holding immune checkpoint inhibitor until patient is stabilized on hormone replacement Endocrine consultation Initiate hormonal replacement for affected axis Adrenal insufficiency: corticosteroid replacement (hydrocortisone 15–20 mg in divided doses) No adrenal insufficiency: consider lower steroid dosing (average daily dosing over 2 months < 7.5 mg) due to report of reduced survival on higher dosing Initiate other hormone replacement after steroid initiation and only after adrenal insufficiency is corrected, to avoid crisis
Moderate symptoms (grade 2)	Consider holding immune checkpoint inhibitor until the patient is stabilized on hormone replacement Endocrine consultation Consider oral pulse-dose steroid therapy in patients with magnetic resonance imaging evidence of swelling or threatened optic chiasm compression; taper over 1 to 2 weeks, then maintenance steroid therapy Other hormonal replacement therapy as above
Severe symptoms (grade 3 or 4)	Hold immune checkpoint inhibitor until patient is stabilized on hormone replacement Endocrine consultation Hospitalize or refer to emergency department for normal saline (at least 2 L) and monitored free water replacement if the patient has diabetes insipidus Intravenous stress steroids (initial dosing: hydrocortisone 50–100 mg every 6 hours), then oral pulse-dose therapy tapered over 1–2 weeks in patients with magnetic resonance imaging evidence of significant swelling, optic chiasm compression, severe headache, or visual changes Taper stress-dose steroids to oral maintenance dose over 5–7 days Other maintenance therapy as above Patients should have a medical alert device as well as education on stress-dosing for sick days, when to seek medical attention for impending adrenal crisis, and use of emergency steroid injectables

Adapted from reference 49.

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TABLE 4

Adrenal dysfunction due to immune checkpoint inhibitors: American Society of Clinical Oncology guideline

Situation	Action
Screening and workup	No screening recommended Workup for suspected adrenal insufficiency includes morning adrenocorticotropic hormone (> 2 times the upper limit of normal), cortisol (< 3 μg/dL), basic metabolic panel, renin, and aldosterone Adrenocorticotropic hormone testing can be considered for indeterminate results Rule out other causes such as infection or metastatic disease
Asymptomatic or mild symptoms (grade 1)	Consider holding the immune checkpoint inhibitor until the patient is stabilized on hormone replacement Endocrine consultation Start hydrocortisone treatment (15–20 mg in divided doses) and titrate to maximum 30 mg/day for residual adrenal insufficiency Most primary adrenal insufficiency cases will also require fludrocortisone (starting dose 0.1–0.5 mg/day) Patients should have a medical alert device as well as education on stress-dosing for sick days, when to seek medical attention for impending adrenal crisis, and use of emergency steroid injectables
Moderate symptoms (grade 2)	Consider holding immune checkpoint inhibitor until the patient is stabilized on hormonal replacement Endocrine consultation Initiate outpatient corticosteroid treatment 2–3 times the maintenance dose (hydrocortisone 30–50 mg/day; prednisone 20 mg/day) to manage acute symptoms and decrease stress dosing after 2 days Initiate fludrocortisone as above Patient education as above
Severe symptoms (grade 3 or 4)	Hold the immune checkpoint inhibitor until the patient is stabilized on hormonal replacement Endocrine consultation For inpatient management, normal saline (at least 2 L) with intravenous stress-dose steroids (initial dosing: hydrocortisone 50–100 mg every 6 hours), then taper to oral maintenance doses over 5–7 days Maintenance therapy as above Patient education as above

Adapted from reference 49.

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TABLE 5

Diabetes due to immune checkpoint inhibitors: American Society of Clinical Oncology guideline

Situation	Action
Screening and workup	Screening glucose at baseline and with each treatment cycle while on therapy and at follow-up visits for at least 6 months Monitor symptoms for hyperglycemia Other laboratory tests include urine or serum ketones (or both), anion gap on a metabolic panel, anti-glutamic acid decarboxylase antibody, anti-islet cell antibodies, C-peptide
Asymptomatic or mild symptoms (grade 1), or type 2 diabetes with fasting glucose < 160 mg/dL and no new evidence of ketoacidosis or pancreatic autoimmunity	Can continue immune checkpoint inhibitor with close clinical follow-up Refer to primary care physician for diabetes management
Moderate symptoms (grade 2), or type 2 diabetes with fasting glucose > 160–250 mg/dL and no new evidence of ketoacidosis or pancreatic autoimmunity	May hold immune checkpoint inhibitor until glucose control is obtained Urgent endocrine consultation for any patient with new-onset checkpoint inhibitor-associated diabetes Initiate insulin Refer to emergency department if unable to initiate therapy or if urgent outpatient specialist evaluation is unavailable
Severe symptoms (grade 3 or 4), or worsening glucose, glucose > 500 mg/dL, ketoacidosis, or other metabolic abnormality	Hold immune checkpoint inhibitor until glucose control is obtained to levels and symptoms similar to grade 1 Admit for diabetic ketoacidosis, volume and electrolyte resuscitation, and insulin initiation Endocrine consultation recommended for all patients Insulin therapy appropriate for all patients