Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm

Argentiero, Antonella; Solimando, Antonio Giovanni; Ungaro, Valentina; Laforgia, Mariarita; Strippoli, Sabino; Pinto, Dario; Negri, Antonio; Ferraiuolo, Simona; Zito, Alfredo; Guida, Michele

doi:10.3389/fonc.2020.583781

Cited by 9 publications

(10 citation statements)

References 49 publications

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“…In one phase II trial, investigating the use of pembrolizumab in patients with recurrent or relapsed TETs, 9.1%, 6.1%, 12.1%, and 3.0% of the patients developed myocarditis, MG, hepatitis, and thyroiditis, respectively [ 14 ]. There is a case report of a fatal immune-related storm in a thymoma patient treated with pembrolizumab, leading to hepatotoxicity accompanied by lymphocytosis, thrombocytopenia, and thyroid dysfunction [ 15 ]. Multiple organ damage was also involved in our case.…”

Section: Discussionmentioning

confidence: 99%

Camrelizumab-Related Lethal Arrhythmias and Myasthenic Crisis in a Patient with Metastatic Thymoma

Zhang

Gyawali

Liu

et al. 2022

Case Reports in Cardiology

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Immune checkpoint inhibitors (ICIs) have emerged in recent years as promising treatment options for several malignant tumors. However, ICI therapy has also been associated with various immune-related adverse events (irAEs), especially for patients with preexisting autoimmune status, which sometimes can be life-threatening. A 68-year-old woman diagnosed with metastatic thymoma was treated with camrelizumab, a new ICI, as her antitumor protocol. Eleven days after the first dose of camrelizumab, the patient was admitted to our hospital with symptoms of dyspnea, fatigue, and poor appetite. Workups on admission indicated dramatically elevated transaminase, troponin I, creatine kinase, and a new-onset conduction abnormality on electrocardiography. After detailed evaluation, ICI-related myocarditis, myositis, and hepatitis were diagnosed, and therapies including intravenous methylprednisolone were administered. Coronary angiography was performed to exclude acute coronary syndrome due to dynamic electrocardiography changes on day 3. She lapsed into a coma with respiratory muscle failure on the next day, which was highly suspected of myasthenic crisis. Mechanical ventilation and higher dose of methylprednisolone plus intravenous immunoglobulin were applied immediately. However, the third atrioventricular block occurred within the same day, and an urgent temporary pacemaker was placed. More seriously, refractory ventricular tachycardia (VT) occurred subsequently, and even multiple antiarrhythmic drugs used in combination failed to alleviate the VT storm. On day 5 of hospitalization, she suffered from ventricular fibrillation and died of cardiac arrest. In clinical practice, close follow-up should be conducted after ICI treatment, especially for patients already with or at high risk for autoimmune disorders. A multidisciplinary team approach is of importance for better management of patients with multiple organ involvement.

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Section: Discussionmentioning

confidence: 99%

Camrelizumab-Related Lethal Arrhythmias and Myasthenic Crisis in a Patient with Metastatic Thymoma

Zhang

Gyawali

Liu

et al. 2022

Case Reports in Cardiology

View full text Add to dashboard Cite

show abstract

“…In one phase Ⅱ trial, investigating the use of pembrolizumab in patients with recurrent or relapsed TETs, 9.1%, 6.1%, 12.1% and 3.0% of the patients developed myocarditis, MG, hepatitis and thyroiditis, respectively [13]. There is a case report of a fatal immune-related storm in a thymoma patient treated with pembrolizumab, leading to hepatotoxicity accompanied by lymphocytosis, thrombocytopenia and thyroid dysfunction [14].…”

Section: Discussionmentioning

confidence: 99%

Camrelizumab-related lethal arrhythmias and myasthenic crisis in a patient with metastatic thymoma: a case report

Zhang

Gyawali

Liu

et al. 2021

Preprint

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Immune checkpoint inhibitors (ICIs) have emerged in recent years as a promising treatment option for several malignant tumors. However, ICI therapy has also been associated with various immune-related adverse events (irAEs), especially with pre-existing autoimmune status, which sometimes can be life-threatening. A 68-year-old woman diagnosed with metastatic thymoma was treated with camrelizumab as her initial anti-tumor protocol at a nearby hospital. On 11 days after the first dose of camrelizumab, the patient was admitted to our hospital with symptoms of dyspnea, fatigue, and poor appetite. Workup on admission indicated dramatically elevated transaminase, troponin I, creatine kinase, and creatine kinase MB and a new-onset conduction abnormality on electrocardiography. She had no other underlying disease prior to ICI treatment; therefore, ICI-related myocarditis, myositis and hepatitis were diagnosed, and intravenous methylprednisolone (80mg/day) and other supporting treatments were administered sequentially. Coronary angiography was performed on day 3 of hospitalization, but no abnormality was detected. On the same day, she lapsed into a coma with respiratory muscle failure, which was highly suspected of myasthenic crisis. Therefore, mechanical ventilation and higher dose of methylprednisolone (1 g/day) plus intravenous immunoglobulin (20g/day) were applied immediately. The third artrioventricular block occurred abruptly and an urgent temporary pacemaker was placed. Repeated ventricular tachycardia (VT) occurred, and even multiple antiarrhythmic drugs used in combination failed to alleviate the VT storm. On day 5 of hospitalization, she suffered from ventricular fibrillation and die of cardiac arrest. In conclusion, close follow-up should be conducted after ICI treatment, especially for patients already with or at high risk for autoimmune disorders. Once diagnosed with severe irAEs, prompt high dose of glucocorticoid alone or in combination with other immunomodulators if necessary should be administered. A multidisciplinary team approach is of importance for better management of patients with multiple organs involvement.

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“…Fortunately, fulminant hepatitis due to ICI hepatotoxicity remains very rare. A small number of cases have now been reported, although full exclusion for other causes for liver failure was not conducted in all of these published reports, making an alternate cause for liver failure possible (albeit unlikely) 24,67 . Fulminant hepatitis has been described in patients with a range of primary malignancies; patients with and without liver metastases; and after both initial exposure to ICI but also after re-challenge, following prior successful treatment of a milder episode of ICI hepatotoxicity 68 .…”

Section: Fulminant Hepatitismentioning

confidence: 99%

“…Generally, the clinical presentation has been characterized by very high transaminases, liver synthetic dysfunction, and jaundice, with hepatic encephalopathy either at presentation or developing within days of presentation, despite treatment with immunosuppression (high-dose corticosteroid and MMF). Three cases resulted in death due to progressive liver failure, one despite escalation of treatment to include plasma exchange 24,67,69 . Two patients recovered after successful use of either plasma exchange, 68 or antithymocyte globulin 70 .…”

Section: Fulminant Hepatitismentioning

confidence: 99%

“…A small number of cases have now been reported, although full exclusion for other causes for liver failure was not conducted in all of these published reports, making an alternate cause for liver failure possible (albeit unlikely). [24,67] Fulminant hepatitis has been described in patients with a range of primary malignancies; patients with and without liver metastases; and after both initial exposure to ICI but also after rechallenge, following prior successful treatment of a milder episode of ICI hepatotoxicity. [68] It is reported following exposure to either ICI monotherapy or combination therapy, but it is notable that the vast majority of cases reported, and all of those which include a full assessment for alternate causes for liver failure, have occurred after either combination or very close sequential anti-CTLA-4/ PD-1 therapy.…”

Section: Fulminant Hepatitismentioning

confidence: 99%

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Checkpoint inhibitor hepatotoxicity: pathogenesis and management

2023

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Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients. Although ICI-associated hepatotoxicity is clinically and pathologically distinct from idiopathic autoimmune hepatitis, our understanding of its pathogenesis continues to evolve. Pending greater understanding of the pathophysiology, mainstay of management remains through treatment with high-dose corticosteroids. This approach works for many patients, but up to 30% of patients with high-grade hepatotoxicity may not respond to corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, and rare cases of fulminant hepatitis due to ICI hepatotoxicity have been reported. Optimal management for these challenging patients remains uncertain. Herein, we review the current understanding of pathogenesis of ICI-associated toxicities, with a focus on hepatotoxicity. Based on the existing literature, we propose evolving management approaches to incorporate strategies to limit excess corticosteroid exposure, and address rare but important presentations of cholestatic hepatitis and fulminant liver failure. Finally, as ICI hepatotoxicity frequently occurs in the context of treatment for advanced malignancy, we review the impact of hepatotoxicity and its treatment on cancer outcomes, and the overall safety of re-challenge with ICI, for patients who may have limited treatment options.

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Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm

Cited by 9 publications

References 49 publications

Camrelizumab-Related Lethal Arrhythmias and Myasthenic Crisis in a Patient with Metastatic Thymoma

Camrelizumab-Related Lethal Arrhythmias and Myasthenic Crisis in a Patient with Metastatic Thymoma

Camrelizumab-related lethal arrhythmias and myasthenic crisis in a patient with metastatic thymoma: a case report

Checkpoint inhibitor hepatotoxicity: pathogenesis and management

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