Hypercalcemia as an Immune-Related Adverse Event in a Patient Receiving Nivolumab and Ipilimumab for Metastatic Melanoma: A Case Report

Abstract

Hypercalcemia of malignancy is a well-known phenomenon in cancer patients, often associated with poor prognosis. The discovery of immune checkpoint inhibitors has revolutionised cancer therapy by improving prognosis in numerous different cancer types. Unfortunately, immune-related adverse events frequently arise, particularly with dual checkpoint inhibition. We present a case of severe hypercalcemia in a 65-year-old woman undergoing treatment for metastasised malignant melanoma. Eleven weeks after initiating ipilimumab-nivolumab, the patient developed severe hypercalcemia, along with inflammation and hepatitis. This was initially presumed to be due to hypercalcemia of malignancy, given the clinical examination, imaging findings and laboratory values potentially consistent with progressive disease. The hypercalcemia responded well to bisphosphonates, intravenous saline and methylprednisolone. Interestingly, fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) performed shortly after hospital discharge showed a complete metabolic remission, thereby making hypercalcemia of malignancy unlikely. Review of her medical history, imaging and laboratory revealed several features consistent with a sarcoid-like reaction. We hypothesise that this reaction led to elevated 1-alpha hydroxylase, thereby facilitating calcitriol-mediated hypercalcemia. In this report, we summarise previously published case reports on immune checkpoint inhibitor-induced hypercalcemia and discuss the various mechanisms that cause hypercalcemia in this rare immune-related adverse event. Immune checkpoint inhibitors can induce production of parathyroid hormone-related protein (PTHrP), calcitriol, and may cause hypocortisolaemia, all of which can disrupt calcium homeostasis. Through this case, we contribute to the growing body of evidence regarding hypercalcemia as an immune-related adverse event and aim to raise awareness among clinicians of this potential complication. Early recognition is critical for this life-threatening condition, as it can be refractory to conventional therapies and may necessitate corticosteroid therapy.