Case Report: Fatal Multiorgan Failure and Heterochronous Pneumonitis Following Pembrolizumab Treatment in a Patient With Large-Cell Neuroendocrine Carcinoma of Lung

Immune checkpoint inhibitors have radically changed the landscape of antitumor therapies in several malignancies. Despite the long-term efficacy, severe immune-related adverse events (irAEs) were not uncommon. However, fatal simultaneous multiorgan failure was rare. Here, we described a patient who developed multiorgan failure, including fulminant myocarditis, myasthenia gravis crisis, hepatic dysfunction, and delayed pneumonitis after pembrolizumab therapy for lung large-cell neuroendocrine carcinoma. After failure of high-dose steroid treatment, implantation of cardiac pacemaker combined with high-dose steroids successfully controlled myocarditis caused by immune checkpoint inhibitors (ICIs). Delayed pneumonitis occurred unexpectedly, and it was treated successfully with steroids. With wild adoption of ICIs in clinical practice, investigations for predictive markers of irAEs are warranted, and more successful treatment strategies are worth sharing.

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Immune checkpoint inhibitors in large cell neuroendocrine carcinoma: current status

Oncotarget ◽

10.18632/oncotarget.24553 ◽

2018 ◽

Vol 9 (18) ◽

pp. 14738-14740 ◽

Cited By ~ 4

Author(s):

Aman Chauhan ◽

Susanne M. Arnold ◽

Jill Kolesar ◽

Hala Elnakat Thomas ◽

Mark Evers ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Large Cell ◽

Large Cell Neuroendocrine Carcinoma ◽

Current Status

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Durable response to combination radiotherapy and immunotherapy in EP-resistant lung large-cell neuroendocrine carcinoma with B2M and STK11 mutations: a case report

Immunotherapy ◽

10.2217/imt-2019-0166 ◽

2020 ◽

Vol 12 (4) ◽

pp. 223-227

Author(s):

Yi Qin ◽

Min Yu ◽

Lin Zhou ◽

Lili Jiang ◽

Meijuan Huang

Keyword(s):

Neuroendocrine Carcinoma ◽

Poor Prognosis ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Large Cell ◽

Large Cell Neuroendocrine Carcinoma ◽

Rare Tumor ◽

Limited Information ◽

Durable Response ◽

Combination Modes

Lung large-cell neuroendocrine carcinoma (LCNEC) is a rare tumor with poor prognosis. Despite the increasing prevalence of immune checkpoint inhibitors (ICIs) across a broad spectrum of solid tumors, very limited information is available about the efficacy in LCNEC. Here, we report a case of advanced lung LCNEC treated with combined radiotherapy and ICIs, which resulted in a durable response. We also focused on the impressive reaction of metastatic and primary lesions to two different combination modes of radiotherapy and ICIs.

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Effect of high-dose corticosteroid use on efficacy of immune checkpoint inhibitors in patients with renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4583 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4583-4583

Author(s):

Chris Labaki ◽

Sarah Abou Alaiwi ◽

Andrew Lachlan Schmidt ◽

Talal El Zarif ◽

Ziad Bakouny ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Cox Regression ◽

Checkpoint Inhibitors ◽

Univariate Analysis ◽

High Dose ◽

Line Of Therapy

4583 Background: The use of High-Dose Corticosteroids (HDC) has been linked to poor outcomes in patients with lung cancer treated with immune checkpoint inhibitors (ICIs) (Ricciuti B, JCO, 2019). There is no data on the effect of HDC on renal cell carcinoma patients (RCC) treated with immunotherapy. We hypothesized that HDC use would be associated with worse outcomes in RCC patients receiving ICIs. Methods: This study evaluated a retrospective cohort of patients with RCC at Dana-Farber Cancer Institute in Boston, MA. Clinical information including demographics, IMDC risk score, RCC histology, steroid administration, ICI regimen, line of therapy, time to treatment failure (TTF) and overall survival (OS) were collected. Patients were divided into those receiving HDC (prednisone ≥10 mg or equivalent for ≥ 1 week, HDC group) or not receiving HDC (No-HDC group). HDC administration was evaluated in relation to TTF and OS in a univariate analysis (Log-rank test) and a multivariate analysis (Cox regression). Results: 190 patients with RCC receiving ICIs were included, with a median age of 59 years. HDC were administered to 56 patients and 134 patients received no (N= 116) or only low-dose (N=18) steroids. In the HDC group, 40 patients received steroids for immune-related adverse events, 8 for other cancer-related indications, and 8 for non-oncological indications. There was no difference in TTF between the HDC and No-HDC groups (12-mo TTF rate: 34.8 vs. 32.3%, respectively; log-rank p=0.65). Similarly, there was no difference in OS between the HDC and No-HDC groups (36-mo OS rate: 56.7 vs. 62.4%, respectively; log-rank p=0.97). After adjusting for IMDC risk group, RCC histology, ICI regimen type, and line of therapy, TTF and OS did not differ in the HDC group as compared to No-HDC group (HR=1.14 [95%CI: 0.80-1.62], p=0.44 and HR=1.17 [95%CI: 0.65-2.11], p=0.59, respectively). Conclusions: In this retrospective study of patients with RCC treated with ICIs, administration of high-dose corticosteroids was not associated with worse outcomes.[Table: see text]

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Abstract 12563: Retrospective Analysis of Cardiovascular Events With the Use of Immune Checkpoint Inhibitors

Circulation ◽

10.1161/circ.142.suppl_3.12563 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tushar Tarun ◽

Brian P Bostick ◽

Deepa Baswaraj ◽

Nishchayjit Basra ◽

Meeshal Khan ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Retrospective Analysis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Multiple Organ ◽

Fulminant Myocarditis ◽

Organ Systems ◽

History Of

Introduction: Immune checkpoint inhibitors have emerged as a promising, novel therapy for multiple malignancies. Immune-related adverse reactions pose a serious concern with use of these agents and reportedly involve multiple organ systems, notably cardiotoxicity. Early identification and management of these adverse events is essential in the prevention of morbidity and mortality. Hypothesis: Immune checkpoint inhibitors cause multiple cardiotoxic effects, and patients with prior cardiac history have a higher likelihood of cardiotoxicity. Methods: 1. A retrospective analysis of 150 patients was performed who had received immunotherapy with either the cytotoxic T lymphocyte associated antigen 4 inhibitors (CTLA4) or with the programmed cell death inhibitors (PD1) or programmed death-ligand 1 (PD-L1) inhibitors for a period of two years at a Tertiary health Care from 7/1/2016-6/30/2018. 2. Patients' cardiac diagnoses prior to the initiation of therapy were noted and included, including history of heart failure, coronary artery disease, atrial fibrillation, and sudden cardiac arrest. 3. Patients’ clinic visits and hospitalizations with admitting and discharge diagnosis, electrocardiogram, echocardiogram, troponin T, and NT-proBNP were reviewed. Results: 6% of patients had new onset heart failure (both preserved and reduced), 1.3% had evidence of myocardial infarction, 2% had new atrial fibrillation with rapid ventricular rate, and 0.6% had fulminant myocarditis. Of patients with new cardiac events, 60% had a history of cardiac disease, which was significantly higher than in patients without (p< 0.05). There were no age or sex differences between the groups with and without cardiotoxicity. Conclusion: Immunotherapy with immune checkpoint inhibitors have broadened the horizon for treatment of multiple solid and hematological malignancies. Nonetheless, new adverse effects on multiple organ systems, specifically cardiac involvement, occur with these therapies, which are important and potentially detrimental toxicities. Patients with a history of prior cardiovascular disease have higher likelihood to develop cardiotoxicity.

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Challenge of immune-mediated adverse reactions in the emergency department

Emergency Medicine Journal ◽

10.1136/emermed-2018-208206 ◽

2019 ◽

Vol 36 (6) ◽

pp. 369-377 ◽

Cited By ~ 4

Author(s):

Gregory A Daniels ◽

Angela D Guerrera ◽

Donna Katz ◽

Jayne Viets-Upchurch

Keyword(s):

Immune System ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Adverse Reactions ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

High Dose ◽

Clear Understanding ◽

Immune Mediated ◽

Multiple Drugs

Multiple drugs of a new class of cancer treatments called immune checkpoint inhibitors, which work by enabling the immune system to attack tumour cells, have been approved for a variety of indications in recent years. Immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 and programmed death-1, are part of the normal immune system and regulate immune activation. Treatment with inhibitors of these checkpoints can significantly improve response rates, progression-free survival and overall survival of patients with cancer; it can also result in adverse reactions that present similarly to other conditions. These immune-mediated adverse reactions (IMARs) are most commonly gastrointestinal, respiratory, endocrine or dermatologic. Although patients’ presentations may appear similar to other types of cancer therapy, the underlying causes, and consequently their management, may differ. Prompt recognition is critical because, with appropriate management, most IMARs resolve and patients can continue receiving immune checkpoint inhibitor treatment. Rarely, these IMARs may be life-threatening and escape detection from the usual evaluations in the emergency environment. Given the unusual spectrum and mechanism of IMARs arising from immune checkpoint inhibitors, emergency departmentED staff require a clear understanding of the evaluation of IMARs to enable them to appropriately assess and treat these patients. Treatment of IMARs, most often with high-dose steroids, differs from chemotherapy-related adverse events and when possible should be coordinated with the treating oncologist. This review summarises the ED presentation and management of IMARs arising from immune checkpoint inhibitors and includes recommendations for tools and resources for ED healthcare professionals.

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The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919875549 ◽

2019 ◽

Vol 11 ◽

pp. 175883591987554 ◽

Cited By ~ 2

Author(s):

Marco Tucci ◽

Anna Passarelli ◽

Annalisa Todisco ◽

Francesco Mannavola ◽

Luigia Stefania Stucci ◽

...

Keyword(s):

Renal Function ◽

Interstitial Nephritis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acute Interstitial Nephritis ◽

Clinical State ◽

High Dose ◽

Systemic Symptoms ◽

The Impact

Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with a number of types of cancer, but the frequent development of immune-related adverse effects (irAEs) can worsen the outcome. The most common irAEs involve the gastrointestinal, cutaneous, and endocrine systems, but nephrotoxicity, resulting from damage to the tubule-interstitial compartment, may occur in some patients. The early phases of acute interstitial nephritis (AIN) are characterized by systemic symptoms that indicate a poor clinical state as well as a mild deterioration of renal function. Tubular injury is due to a direct effect mediated by cytotoxic CD8+ T cells, which sustain the local production of pro-inflammatory cytokines that progressively impair renal function. The treatment of AIN is mainly based on high-dose steroids, which in most instances leads to the recovery of renal function. However, the premature discontinuation of ICI therapy may prevent the impact of treatment on the clinical progression of the malignancy. Adequately addressing irAEs requires a standardized therapy that is based on the results of large clinical trials.

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Case Report: Cardiac Toxicity Associated With Immune Checkpoint Inhibitors

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.727445 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ru Chen ◽

Ling Peng ◽

Zhihua Qiu ◽

Yan Wang ◽

Fen Wei ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Troponin I ◽

Systemic Corticosteroid ◽

Checkpoint Inhibitors ◽

Cardiac Conduction ◽

Fulminant Myocarditis ◽

Cancer Type ◽

Life Threatening ◽

The Subject

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancer. Along with the development of ICIs, immune-related adverse effects (irAEs) have been the subject of wide attention. The cardiac irAE, a rare but potentially fatal and fulminant effect, have been reported recently. This article retrospectively reviewed 10 cases from our hospital with cardiac irAEs, with severity ranging from asymptomatic troponin-I elevations to cardiac conduction abnormalities and even fulminant myocarditis. In our series, all the cases were solid tumors and lung cancer was the most frequent cancer type (4,40%). In total, three (30.0%) patients experienced more than one type of life-threatening complication. A systemic corticosteroid was given to nine patients (90.0%). The majority of cases (7, 70%) were performed at an initial dose of 1–2 mg/kg/day. Two (20.0%) patients were admitted to ICU, three (30.0%) patients were put on mechanical ventilation, two (20.0%) patients received the plasma exchange therapy, and one patient was implanted with a pacemaker. Two (20.0%) of the patients succumbed and died, with a median duration of 7.5 days (IQR5.0–10.0) from diagnosis of cardiac irAE to death. Based on these results, we recommend that clinicians be alert to cardiac irAEs, including performing cardiovascular examinations before ICI treatment to accurately diagnose suspected myocarditis, enabling immediate initiation of immunosuppressive therapy to improve prognosis.

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Case Report: A Case of Trimethoprim/Sulfamethoxazole-Triggered Hypotensive Shock: Cytokine Release Syndrome Related to Immune Checkpoint Inhibitors and Drug-Induced Hypersensitivity Syndrome

Frontiers in Oncology ◽

10.3389/fonc.2021.681997 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tetsuya Urasaki ◽

Makiko Ono ◽

Toshiaki Mochizuki ◽

Koichi Takeda ◽

Aya Nishizawa ◽

...

Keyword(s):

Immune Checkpoint ◽

Interstitial Pneumonitis ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hypersensitivity Syndrome ◽

High Dose ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Drug Induced ◽

Prophylactic Administration

Currently, only a few reports exist on the cytokine release syndrome (CRS) as one of the severe immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Notably, it is very rare that grade 4 CRS related to ICI therapy overlaps with the drug-induced hypersensitivity syndrome (DiHS). A 46-year old woman with metastatic kidney cancer had grade 3 interstitial pneumonitis induced by four cycles of combination therapy of anti-programmed death-1 and anti-cytotoxic T lymphocyte-4 antibodies after right cytoreductive nephrectomy. Prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) was started concomitantly with prednisolone therapy to treat the interstitial pneumonitis. She developed hypotensive shock when reducing the dosage of prednisolone, and required intubation and ventilation using vasopressors at the intensive care unit. She subsequently exhibited prominent leukocytosis and an increased level of C-reactive protein, suggesting markedly increased cytokine levels. Interestingly, facial edema and erythema increased in association with pyrexia, leukocytosis, liver dysfunction, and renal failure, suggesting that she developed DiHS. She received hemodialysis three times, a plasma exchange, and anti-interleukin-6 therapy to treat severe renal dysfunction, a thrombotic thrombocytopenic purpura-suspected condition, and possible grade 4 CRS, respectively. Although these therapies did not elicit sufficient effects, high-dose administration of intravenous immunoglobulin was successful. With steroid mini-pulse therapy and the subsequent administration of prednisolone, she recovered successfully. To the best of our knowledge, this is the first report that ICIs and TMP/SMX can induce hypotensive shock accompanied with CRS and DiHS during immunosuppressive therapy for an irAE. Importantly, the prophylactic administration of TMP/SMX should be performed cautiously to avoid severe drug reactions such as CRS or DiHS.

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Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Case Reports in Oncological Medicine ◽

10.1155/2021/8870334 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Lindsey Teal ◽

Jeffrey Yorio

Keyword(s):

Liver Metastases ◽

Uveal Melanoma ◽

Fulminant Hepatic Failure ◽

Immune Checkpoint ◽

Hepatic Failure ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

High Dose ◽

Hepatic Perfusion ◽

Percutaneous Hepatic Perfusion

Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.

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