What is the management protocol for a patient on pembrolizumab (pembrolizumab) with severe hypothyroidism, characterized by a Thyroid-Stimulating Hormone (TSH) level greater than 100 and a free Triiodothyronine (fT3) level of 2 pg/ml?

Management of Severe Hypothyroidism in a Patient on Pembrolizumab Maintenance

For a patient on pembrolizumab with severe hypothyroidism (TSH >100, fT3 2 pg/ml), immediate initiation of levothyroxine replacement therapy at a dose of 1.6 mcg/kg/day is recommended, with careful monitoring and dose adjustments every 4-6 weeks until TSH normalization. 1, 2

Initial Assessment and Management

• Confirm diagnosis: TSH >100 with low fT3 (2 pg/ml) confirms severe hypothyroidism
• Evaluate for hypophysitis: Check ACTH and morning cortisol levels before starting thyroid replacement 1
• Initial levothyroxine dosing:
  • For patients <70 years without cardiac disease: 1.6 mcg/kg/day
  • For elderly patients or those with cardiac conditions: Start lower at 25-50 mcg/day 2
  • Adjust dose based on clinical response and laboratory values

Critical Considerations

• Rule out adrenal insufficiency: Always check for adrenal insufficiency before initiating thyroid hormone replacement 1

  • If adrenal insufficiency is suspected or confirmed, start corticosteroids (hydrocortisone) several days BEFORE thyroid hormone replacement to prevent precipitating adrenal crisis 1
  • Morning cortisol and ACTH levels should be evaluated

• Continue pembrolizumab: Immune checkpoint inhibitor (ICPi) therapy can generally be continued in patients with hypothyroidism once hormone replacement is initiated 1

  • Only consider holding pembrolizumab if patient is clinically unstable or severely symptomatic

Monitoring Protocol

• Initial phase:

  • Monitor thyroid function tests every 4-6 weeks until stable 1, 2
  • Adjust levothyroxine dose in increments of 12.5-25 mcg until optimal replacement is achieved

• Target values:

  • TSH: 0.5-2.0 mIU/L for most adults
  • Free T4: Within normal range
  • Free T3: Within normal range 2

• Long-term monitoring:

  • Once stable, monitor thyroid function every 3-6 months while on pembrolizumab
  • Continue to monitor for other immune-related endocrinopathies

Additional Management Considerations

• Patient education:

  • Take levothyroxine on an empty stomach, 30-60 minutes before breakfast
  • Avoid taking with calcium, iron supplements, or antacids (separate by at least 4 hours)
  • Medication will likely be lifelong as pembrolizumab-induced hypothyroidism is typically permanent 1

• Symptom management:

  • Beta-blockers (propranolol or atenolol) may be needed for symptomatic relief during initial treatment 1
  • Consider endocrinology consultation, especially if multiple endocrine abnormalities are present

Special Situations

• If patient is unwell or has severe symptoms:

  • Consider temporarily holding pembrolizumab until hormone levels are stabilized 1
  • Hospitalization may be necessary for patients with myxedema or severely symptomatic hypothyroidism

• If multiple pituitary hormone deficiencies:

  • Obtain MRI of the brain with pituitary/sellar cuts to evaluate for hypophysitis 1
  • Comprehensive endocrine evaluation including LH, FSH, testosterone/estradiol as indicated

Remember that thyroid dysfunction is a common immune-related adverse event with pembrolizumab, and hypothyroidism is typically permanent, requiring lifelong hormone replacement therapy.