Tesla is a 24-year-old woman diagnosed with stage IIIA Hodgkin lymphoma. She enrolled in a clinical trial where she received a combination of chemotherapy and immunotherapy with pembrolizumab, an anti-PD-1 antibody. The clinical trial protocol required three doses every three weeks. At baseline, her thyroid function tests (TFTs) were normal. When she presented for her third dose, her labs showed grade 2 hyperthyroidism.
What Would You Do?
Immune-related adverse events (irAEs) from immunotherapy treatments can range from mild to dose-limiting and, in rare cases, can be fatal. Although the dermatologic and gastrointestinal systems are most commonly affected, endocrine dysfunction secondary to inflammation can result in thyroid dysfunction, with hypothyroidism affecting up to 18% of patients and hyperthyroidism affecting up to 10% of patients receiving pembrolizumab.
The effect is physiologically driven by a different process than autoimmune thyroiditis; however, treatment typically follows the same guidelines. The American Society of Clinical Oncology (ASCO) recommends that all patients undergoing immunotherapy have routine TFTs at baseline and every four to six weeks or prior to each dose, even if asymptomatic. Presenting symptoms of endocrine dysfunction are often nonspecific, so nurses and providers should assess reports of these symptoms in the context of labs and exam findings to identify potential irAEs.
In cases of hyperthyroidism related to thyroiditis, ASCO recommends monitoring thyroid function more closely every two to three weeks, or more frequently if symptomatic. Patients may report palpitations, jitteriness, insomnia, anxiety, or weight loss. They may exhibit tremors, hyperactive reflexes, and tachycardia.
Treatment for grades 1 or 2 hyperthyroidism usually does not require holding immunotherapy or using steroids. Beta blockers can be prescribed for symptom relief. For grades 3 or 4 hyperthyroidism, hospitalization and steroids may be indicated and treatment should be held until symptoms return to baseline. In rare cases, hyperthyroidism persists over six weeks and a workup for Graves’ disease is indicated, with treatment following endocrine guidelines.
Hypothyroid patients may report fatigue, constipation, feeling cold, or depressed mood. For symptomatic patients with thyroid stimulating hormone greater than 10, the recommendations for treatment of hypothyroidism are close monitoring of TFTs and thyroxine replacement at 1.6 mcg/kg daily for most patients or stepwise dosing from 25 mcg up to 50 mcg for frail or older adults. For grades 3 or 4 hypothyroidism, characterized by severe symptoms including bradycardia and hypothermia, treatment should be held and hospitalization may be indicated for IV therapy.
As many as half of patients put on thyroid replacement may require long-term treatment following completion of immunotherapy.
Tesla’s TSI was negative. A positron emission tomography scan demonstrated improvement in her lymphoma but diffuse uptake in her thyroid was consistent with thyroiditis.
She was asymptomatic and, after an endocrinology consultation, was prescribed propranolol 10 mg twice daily and scheduled for weekly TFTs. One month later, her labs revealed grade 2 hypothyroidism. Her thyroid peroxidase antibody test was negative.
Again asymptomatic, she was prescribed levothyroxine 75 mcg daily while simultaneously tapering off the propranolol. She completed treatment without incident but continued taking levothyroxine for persistent hypothyroidism.
Although irAEs can be serious, early intervention based on detailed assessments by nurses and providers who are cognizant of the risks and symptoms related to immunotherapy can prevent dose limitations or delays and ensure patients achieve the best possible treatment outcomes.