Immunotherapy-linked Hypoparathyroidism Shows Need to Monitor Calcium

The case of a 71-year-old man with hypoparathyroidism and low calcium that was induced by the cancer immunotherapy Keytruda (pembrolizumab) was described in a recent study.

This is the third reported instance of Keytruda-induced hypoparathyroidism, highlighting the need for close monitoring of calcium and parathyroid hormone (PTH) levels in patients receiving the treatment, investigators said.

The case report, “Pembrolizumab Associated Hypoparathyroidism: A Single Case Report,” was published in the journal AACE Clinical Case Reports.

Hypoparathyroidism is caused by a deficiency of PTH, produced by the parathyroid glands, which modulates blood calcium levels. When insufficient PTH is secreted, blood calcium levels diminish, resulting in hypocalcemia — low levels of calcium.

Most cases of acquired hypoparathyroidism result from parathyroid gland damage during surgery, or autoimmune response, in which the body’s immune system attacks the glands. In turn, hypoparathyroidism resulting from medical treatment is very rare.

In this case, a 71-year-old man with stage IIIB lung cancer (it had spread to lymph nodes and/or to nearby structures and organs) developed hypoparathyroidism and hypocalcemia following treatment with Keytruda, by Merck (known as MSD outside of the U.S. and Canada). 

The patient received two different radiation treatments. Five years after his initial cancer diagnosis, high levels of PD-L1 — a protein expressed in some cancer cells that can prevent immune system attack by binding to PD-1 in immune T-cells — prompted the initiation of immunotherapy treatment with 200 mg dose Keytruda administered intravenously (IV, into the vein) every three weeks. Prior to the treatment, the patient had no history of abnormal calcium levels. (Keytruda works by targeting PD-1.)

After dose 13 of Keytruda, the patient’s blood calcium level had decreased from 9.2 mg/deciliter (dL) to 8.1 mg/dL, below the normal range of 8.5 to 10.5 mg/dL. Following dose 18, his calcium level was 7.7 mg/dL, and PTH level was 20.4 picograms (pg)/ml, within the normal range of 14 to 72 pg/ml. After 22 doses, calcium had dropped to 6.5 mg/dl and PTH to 4.3 pg/dl. 

At the time of presentation, the patient had been on Keytruda for 15 months. He experienced fatigue, weakness, and persistently low calcium and PTH levels, resulting in a diagnosis of Keytruda-induced hypoparathyroidism. He began treatment with daily oral calcium supplements — including 2,000 mg calcium carbonate, 2 g IV calcium gluconate, and three doses of 1 g IV calcium chloride — as well as 0.5 micrograms of the vitamin D form calcitriol. He also  received vitamin D weekly for six months, then every two weeks.

The treatment increased his calcium levels and alleviated his fatigue and weakness.

“It is not clear if this hypoparathyroidism will continue to be permanent even after the discontinuation of pembrolizumab [Keytruda] treatment or may potentially resolve over time,” the scientists wrote. The team added that “the dose-response relationship and the timing of pembrolizumab treatment and hypoparathyroidism can vary on a case-to-case basis.”