Abstract
e15153 Background: Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPI). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently published by Piranavan et al. KEYNOTE-189 and CHECKMATE-067 trials reported a 21-29% hypocalcemia event rate. The purpose of our study is to identify the hypocalcemia incidence in patients receiving ICPI at a single institution with multiple sites. Also, we aimed to investigate hypoparathyroidism as the etiology in these patients, if hypocalcemia was detected. Methods: A chart review to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Results: Group 1 (N = 83) includes patients with no calcium altering conditions or medications. Group 2 (N = 98) includes patients on calcium supplements (N = 17), vitamin D (N = 44), bisphosphonates (N = 24), > stage IIIB CKD (N = 5), and bone metastasis (N = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (N = 1). No further workup was done to investigate the etiology as that patient passed away. Conclusions: Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.
Highlights
immune checkpoint inhibitors (ICPIs) are rapidly evolving targeted therapies against immune checkpoint molecules, i.e., PD1, PDL-1, and CTLA-4
Corrected calcium was estimated using Parent et al.’s formula, i.e., corrected calcium (0.8 ×) + serum calcium [7]. e incidence of hypocalcemia events was calculated from the initiation of immune checkpoint inhibitors until their last follow-up
To identify the incidence of hypocalcemia attributed to hypoparathyroidism and minimize the bias, we identified the factors that could potentially affect the serum calcium levels. e factors that were recognized are medications or medical conditions (preexisting diagnosis of hyperparathyroidism/ hypoparathyroidism, vitamin D deficiency, coexisting hypomagnesemia, hyperphosphatemia, >stage III B chronic kidney disease (CKD), parathyroidectomy, neck surgery/radiation therapy resulting in parathyroid abnormalities, paraneoplastic syndromes resulting in abnormal parathyroid hormone-related peptide (PTHrP) production, and cancerous lesions in bone) [8]
Summary
ICPIs are rapidly evolving targeted therapies (monoclonal antibodies) against immune checkpoint molecules, i.e., PD1, PDL-1, and CTLA-4. While CTLA-4 regulates early T-cell proliferation mainly in lymph nodes, PD-1 primarily suppresses T-cell activation in an immune response in peripheral tissues. ICPIs block these specific molecules and regulate the T-cell-mediated antitumor activity. As the PD-1 pathway blockade results in activation of quiescent antitumor T cells and decreased self-tolerance, CTLA-4 pathway blockade results in reduced T regulatory cell-mediated immunosuppression and hyperproliferation. A dual pathway blockade causes enhanced antitumor immune response due to synergism [1]. Loss of self-tolerance and decreased T-cell regulatory response may produce several immunerelated adverse events (IRAEs) through autoantibodies, autoreactive T cells, and enhanced cytokine expression, the exact pathophysiology is not yet known [2]. IRAEs are organ-specific toxicities and vary with ICPI therapy type. IRAEs are organ-specific toxicities and vary with ICPI therapy type. ey are most commonly noted in the skin followed by the gastrointestinal tract, liver, endocrine
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