Title: ADRENOCORTICOTROPIC HORMONE (ACTH) DEFICIENCY WITH PEMBROLIZUMAB THERAPY: AN IMMUNE-RELATED ADVERSE EVENT?
Abstract: SESSION TITLE: Drug-Induced Lung Injury Pathology Case PostersSESSION TYPE: Case Report PostersPRESENTED ON: 10/19/2022 12:45 pm - 01:45 pmINTRODUCTION: The development of immune check point inhibitors (ICIs) has revolutionized cancer treatment. Tumor cells can evade T-cell mediated cell death, by expressing checkpoint proteins such as PD-L1, PD-1, CTLA-4. These then bind to corresponding sites on T cells and inactivate them, evading the body's immune system. ICIs are monoclonal antibodies that inhibit these T cell inhibitory signaling pathways. Immune related adverse events (IRAEs) are common side effects of these medications.1CASE PRESENTATION: A 62-year-old white female was diagnosed with stage IV-A NSCLC with widespread metastasis in March 2021. Her lung biomarkers showed PD-L1 (20%) and PTEN deletion. She was started on dexamethasone 4 mg twice daily for intracranial metastasis at diagnosis then whole brain irradiation. Dexamethasone tapered off. Based on lung biomarkers, she was started on pembrolizumab for 9 cycles. Her baseline laboratory values were a TSH of 3.16 UIU/ML and free T4 of 0.8 NG/DL. ACTH was 15 pg/mL and total cortisol was 3.4 mcg/dL, off dexamethasone. Two months later, her ACTH was 39 pg/mL and cortisol was 8.2 mcg/dL. Five months after diagnosis PET/CT showed improvement in metastatic disease. Unfortunately, she developed cardiac tamponade from malignant pericardial effusion, requiring intervention. Pemetrexed was later added. Eight months after diagnosis, she developed worsening fatigue, nausea and vomiting. She presented to the emergency department hypotensive at 75/25 mmHg. Laboratory values showed a potassium of 4.2 mmol/L, a sodium of 134 mmol/L, bicarbonate of 25 mmol/L, cortisol of <1mcg/dL, ACTH of < 5 pg/mL, TSH 1.30 UIU/ML. Given high index of suspicion of ACTH deficiency, she was re-started on corticosteroids, leading to eventual improvement and discharge home after a short hospital stay.DISCUSSION: ICIs have rapidly evolved as treatment for advanced solid malignancies. Pembrolizumab is a PD-1 inhibitor. It was approved by the FDA in 2014.2 Endocrinopathies are common toxicities related to ICIs. Hypophysitis (inflammation of the pituitary gland) was thought to be associated solely with ipilimumab, however cases are now noted with newer ICIs such as pembrolizumab.3 Anti PD-1 /anti PD-L1 do not produce dose dependent cytotoxicity unlike anti-CTLA-4.1 A Mayo clinic cohort study from 2012-2016 showed the incidence of hypophysitis with pembrolizumab at about 1.7%.4 The risk factors include male gender and history of autoimmunity.2 The median time to onset of symptoms was about 26 weeks with anti-PD1 (pembrolizumab).1MRI of pituitary gland is usually performed to assess for metastasis. However, normal brain imaging does not rule out hypophysitis.2CONCLUSIONS: A high index of suspicion for IRAEs is warranted, due to a multiorgan involvement. ICI therapies vary based on grades- Grade 1 and 2, can continue ICI with close monitoring. Grades > 2, ICI is stopped, and high dose systemic steroids initiated.2Reference #1: Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol. Jul 2021;17(7):389-399.Reference #2: Elia G, Ferrari SM, Galdiero MR, et al. New insight in endocrine-related adverse events associated to immune checkpoint blockade. Best Pract Res Clin Endocrinol Metab. Jan 2020;34(1):101370.Reference #3: Doodnauth AV, Klar M, Mulatu YS, Malik ZR, Patel KH, McFarlane SI. Pembrolizumab-Induced Hypophysitis With Isolated Adrenocorticotropic Hormone (ACTH) Deficiency: A Rare Immune-Mediated Adverse Event. Cureus. Jun 5 2021;13(6):e15465.DISCLOSURES: No relevant relationships by Navitha RameshNo relevant relationships by Uba Udeh SESSION TITLE: Drug-Induced Lung Injury Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: The development of immune check point inhibitors (ICIs) has revolutionized cancer treatment. Tumor cells can evade T-cell mediated cell death, by expressing checkpoint proteins such as PD-L1, PD-1, CTLA-4. These then bind to corresponding sites on T cells and inactivate them, evading the body's immune system. ICIs are monoclonal antibodies that inhibit these T cell inhibitory signaling pathways. Immune related adverse events (IRAEs) are common side effects of these medications.1 CASE PRESENTATION: A 62-year-old white female was diagnosed with stage IV-A NSCLC with widespread metastasis in March 2021. Her lung biomarkers showed PD-L1 (20%) and PTEN deletion. She was started on dexamethasone 4 mg twice daily for intracranial metastasis at diagnosis then whole brain irradiation. Dexamethasone tapered off. Based on lung biomarkers, she was started on pembrolizumab for 9 cycles. Her baseline laboratory values were a TSH of 3.16 UIU/ML and free T4 of 0.8 NG/DL. ACTH was 15 pg/mL and total cortisol was 3.4 mcg/dL, off dexamethasone. Two months later, her ACTH was 39 pg/mL and cortisol was 8.2 mcg/dL. Five months after diagnosis PET/CT showed improvement in metastatic disease. Unfortunately, she developed cardiac tamponade from malignant pericardial effusion, requiring intervention. Pemetrexed was later added. Eight months after diagnosis, she developed worsening fatigue, nausea and vomiting. She presented to the emergency department hypotensive at 75/25 mmHg. Laboratory values showed a potassium of 4.2 mmol/L, a sodium of 134 mmol/L, bicarbonate of 25 mmol/L, cortisol of <1mcg/dL, ACTH of < 5 pg/mL, TSH 1.30 UIU/ML. Given high index of suspicion of ACTH deficiency, she was re-started on corticosteroids, leading to eventual improvement and discharge home after a short hospital stay. DISCUSSION: ICIs have rapidly evolved as treatment for advanced solid malignancies. Pembrolizumab is a PD-1 inhibitor. It was approved by the FDA in 2014.2 Endocrinopathies are common toxicities related to ICIs. Hypophysitis (inflammation of the pituitary gland) was thought to be associated solely with ipilimumab, however cases are now noted with newer ICIs such as pembrolizumab.3 Anti PD-1 /anti PD-L1 do not produce dose dependent cytotoxicity unlike anti-CTLA-4.1 A Mayo clinic cohort study from 2012-2016 showed the incidence of hypophysitis with pembrolizumab at about 1.7%.4 The risk factors include male gender and history of autoimmunity.2 The median time to onset of symptoms was about 26 weeks with anti-PD1 (pembrolizumab).1MRI of pituitary gland is usually performed to assess for metastasis. However, normal brain imaging does not rule out hypophysitis.2 CONCLUSIONS: A high index of suspicion for IRAEs is warranted, due to a multiorgan involvement. ICI therapies vary based on grades- Grade 1 and 2, can continue ICI with close monitoring. Grades > 2, ICI is stopped, and high dose systemic steroids initiated.2 Reference #1: Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol. Jul 2021;17(7):389-399. Reference #2: Elia G, Ferrari SM, Galdiero MR, et al. New insight in endocrine-related adverse events associated to immune checkpoint blockade. Best Pract Res Clin Endocrinol Metab. Jan 2020;34(1):101370. Reference #3: Doodnauth AV, Klar M, Mulatu YS, Malik ZR, Patel KH, McFarlane SI. Pembrolizumab-Induced Hypophysitis With Isolated Adrenocorticotropic Hormone (ACTH) Deficiency: A Rare Immune-Mediated Adverse Event. Cureus. Jun 5 2021;13(6):e15465. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh
Publication Year: 2022
Publication Date: 2022-10-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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