Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors

Wang, Daniel; Salem, Joe‐Elie; Cohen, Justine V.; Chandra, Sunandana; Menzer, Christian; Ye, Fei; Zhao, Shilin; Das, Satya; Beckermann, Kathryn E.; Ha, Lisa; Rathmell, W. Kimryn; Ancell, Kristin K.; Balko, Justin M.; Bowman, Caitlin; Davis, Elizabeth J.; Chism, David D.; Horn, Leora; Long, Georgina V.; Carlino, Matteo S.; Lebrun‐Vignes, Bénédicte; Eroglu, Zeynep; Hassel, Jessica C.; Menzies, Alexander M.; Sosman, Jeffrey A.; Sullivan, Ryan J.; Moslehi, Javid; Johnson, Douglas B.

doi:10.1001/jamaoncol.2018.3923

Cited by 1,659 publications

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“…The higher rate of treatment discontinuation in older patients that we observed is supported by a prior analysis showing a discontinuation rate of 17% in patients 65 years or older treated with ICIs across cancer types that could have significant cost‐effectiveness and treatment decision‐making implications . Although none of our patients experienced fatal toxic effects from ICIs, a systematic review and meta‐analysis did show that fatal toxic effects from ICIs increase with age …”

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Real‐World Treatment of Older Adults with Non–Small Cell Lung Cancer

Muchnik

Loh

Strawderman

et al. 2019

J American Geriatrics Society

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OBJECTIVE To evaluate the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in older patients with advanced non–small cell lung cancer (NSCLC) seen in routine clinical practice. DESIGN Retrospective study. SETTING Single academic institution and its affiliated centers. PARTICIPANTS Patients 70 years or older with advanced‐stage NSCLC seen between April 1, 2015, and April 1, 2017, and treated with ICIs. MEASUREMENTS Efficacy data included overall survival (OS) and time to treatment failure (TTF), stratified by age, comorbidities (Charlson Comorbidity Index [CCI]), and Eastern Cooperative Oncology Group Performance Status (ECOG PS), and estimated using the Kaplan‐Meier method and log‐rank test. Toxicity data included immune‐related adverse events (irAEs), need for glucocorticoids, and hospitalization. The associations of toxicity with age, CCI, and ECOG PS were evaluated using the exact χ2 test or Fisher exact test. RESULTS We included 75 patients (median age: 74 y; range, 70‐92 y); 53% had a CCI of 3 or higher; 49% had ECOG PS of 2 or higher. Median OS for the whole cohort was 8.2 months (ECOG PS 0‐1 vs ≥2: 13.7 vs 3.8 mo; p < .01). Median TTF was 4.2 months (ECOG PS 0‐1 vs ≥2: 5.6 vs 2.0 mo; p = .02). Overall, 37% of patients experienced irAE of any grade (a total of 37 events); 8% were grade 3 or higher (no ICI‐related deaths). Of those who discontinued ICIs (N = 64), 15% were due to irAEs. Of those who experienced irAEs, 64% required glucocorticoids. Hospitalizations during ICI treatment occurred in 72%. Toxicity generally did not differ by age, CCI, or ECOG PS. CONCLUSIONS Outcomes in our cohort were driven by ECOG PS rather than chronological age or comorbidities. The relatively high rates of ICI discontinuation, use of glucocorticoids, and hospitalization during ICI treatment in our study highlight the vulnerability of older adults with advanced NSCLC even in the immunotherapy era. J Am Geriatr Soc 67:905–912, 2019.

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Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Real‐World Treatment of Older Adults with Non–Small Cell Lung Cancer

Muchnik

Loh

Strawderman

et al. 2019

J American Geriatrics Society

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“…The incidence of diarrhoea is reported to be up to 13% for anti‐PD‐1/PD‐L1 therapy and 35% for anti‐CTLA‐4 therapy . Severe enterocolitis, which is one of the most frequent severe irAEs, is principally caused by anti‐CTLA‐4, and, in rare cases, leads to perforation and death . Patients may also experience abdominal pain, nausea, and/or vomiting; haematochezia and fever are less frequent symptoms .…”

Section: Introductionmentioning

confidence: 99%

Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

et al. 2019

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Aims Immune checkpoint inhibitors (ICIs) improve survival across a range of malignancies but are also associated with a spectrum of gastrointestinal (GI) immune‐related adverse events (GI‐irAEs). The aims of this study were to explore the diagnostic value of gastric and duodenal biopsies and to address considerations in the differential diagnosis. Methods and results We identified 39 patients who were treated with ICIs and had a subsequent upper GI biopsy. We recorded clinical data and endoscopic findings, and reviewed their gastric, duodenal and colonic biopsies. Twenty‐one (54%) patients were treated with an anti‐programmed cell death protein 1 (PD‐1)/anti‐programmed cell death ligand 1 antibody alone, and 17 (44%) patients were treated with a combination of anti‐cytotoxic T‐lymphocyte‐associated protein‐4 and anti‐PD‐1 antibodies. Thirty‐two (82%) patients presented with diarrhoea. Gastric alterations included periglandular inflammation and granulomas, and duodenal changes included villous blunting, intraepithelial lymphocytosis, granulomas, and neutrophilic activity. We recognised four patterns of colonic injury: (i) acute self‐limiting colitis; (ii) lymphocytic colitis; (iii) collagenous colitis; and (iv) apoptosis‐only. Twenty‐nine (74%) and 10 (26%) patients were diagnosed clinically as positive and negative for GI‐irAEs, respectively. Gastric periglandular inflammation (P = 0.004) and an increased number of colonic lamina propria mononuclear cells (P = 0.04) correlated with the clinical diagnosis of a GI‐irAE. Histological alterations associated with ICI injury were more often identified in upper GI biopsies (71%) than in colonic biopsies (65%). Conclusions The morphological spectrum of ICI‐related GI disease is broad, and mimics a range of infectious and inflammatory diseases. Gastric periglandular inflammation represents one of the more characteristic histological features of GI‐irAEs. The study underscores the importance of a comprehensive review of upper and lower GI biopsies for the diagnosis of GI‐irAEs.

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“…Encephalitis is an uncommon toxicity described in several case reports and case series . Neurologic toxicity can be treated with high‐dose corticosteroids, intravenous immunoglobulin, and/or plasmapheresis but may be fatal in severe cases .…”

Section: Introductionmentioning

confidence: 99%

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

et al. 2019

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Background Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life‐threatening immune‐related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies. Case Presentation We describe herein a patient with metastatic melanoma who developed epididymo‐orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo‐orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad‐spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next‐generation sequencing assay, was negative. He received high‐dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5‐week taper of oral steroids. Discussion Here, we report a case of epididymo‐orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents. Key Points Epididymo‐orchitis is a rare and potentially life‐threatening complication of anti‐programmed death protein 1 (anti‐PD‐1) therapy. For patients on anti‐PD‐1 therapy who develop either epididymo‐orchitis or epididymitis without clear infectious cause, immune‐related adverse events should be considered in the differential diagnosis. If severe, epididymo‐orchitis related to anti‐PD‐1 therapy may be treated with high‐dose corticosteroids.

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Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors

Abstract: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Cited by 1,659 publications

References 30 publications

Immune Checkpoint Inhibitors in Real‐World Treatment of Older Adults with Non–Small Cell Lung Cancer

Immune Checkpoint Inhibitors in Real‐World Treatment of Older Adults with Non–Small Cell Lung Cancer

Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

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