Ursodeoxycholic acid and bezafibrate were useful for steroid-refractory, immune-related hepatitis: a case report

Abstract Background Immune checkpoint inhibitors have shown clinically significant antitumor efficacy and have been approved for the treatment of various kinds of advanced malignancies. On the other hand, these immunotherapies show unique adverse events, termed “immune-related adverse events,” which are distinctly associated with conventional cytotoxic chemotherapy. Hepatotoxicity is recognized as an immune-related adverse event; prompt treatment with corticosteroids is recommended. However, some cases are refractory to steroids. Here, we report the first case (to our knowledge) of steroid-refractory immune-related hepatitis that was successfully treated with ursodeoxycholic acid and bezafibrate. Case presentation A 68-year-old Asian man, came to our hospital for the treatment of malignant melanoma involving the gingiva and presenting with multiple lymph node and bone metastases was administered nivolumab as a first-line treatment. Two months into treatment, the patient developed diarrhea as a result of immune-related colitis; the colitis was treated successfully with prednisolone 60 mg/ day, resulting in improvement in the patient’s symptoms. However, when steroids were being tapered, acute elevation of liver enzymes was observed. Autoimmune hepatitis was suspected as an immune-related adverse event, and treatment with intravenous prednisolone 60 mg/ day was reinitiated. However, restoration of the steroid treatment failed to improve the patient’s liver enzymes. On the basis of histological findings from liver biopsy and exclusion of other etiologies such as viral infection and other drug-induced hepatitis, steroid-refractory hepatic immune-related adverse event was deemed the most likely cause of the patient’s acute hepatitis. In general, mycophenolate mofetil or tacrolimus is known to provide benefits in cases of steroid-refractory hepatitis. We therefore decided to add oral ursodeoxycholic acid and bezafibrate in consideration of the patient’s background of repeated aspiration pneumonia. Administration of this regimen resulted in an improvement in liver function, which remained normal even after tapering of prednisolone. Conclusions Ursodeoxycholic acid and bezafibrate may be useful for treatment of steroid-refractory immune-related adverse event hepatitis.

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Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819884196 ◽

2019 ◽

Vol 12 ◽

pp. 175628481988419 ◽

Cited By ~ 15

Author(s):

Uday N. Shivaji ◽

Louisa Jeffery ◽

Xianyong Gui ◽

Samuel C. L. Smith ◽

Omer F. Ahmad ◽

...

Keyword(s):

Early Intervention ◽

Adverse Events ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Management Strategies ◽

Intestinal Barrier ◽

Common Side Effect ◽

Drug Induced ◽

Immune Balance ◽

Steroid Refractory

Background: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. Methods: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. Results: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. Conclusion: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis.

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Treatment-related adverse events of combination immune checkpoint inhibitors: Systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15060 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15060-e15060

Author(s):

Robin Park ◽

Laércio Lopes da Silva ◽

Ivy Riano ◽

Cagney Cristancho ◽

Anwaar Saeed

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Related Adverse Event ◽

Adverse Event Data ◽

Cancer Types ◽

Grade 3

e15060 Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

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Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Nature Medicine ◽

10.1038/s41591-021-01387-6 ◽

2021 ◽

Author(s):

Lewis Au ◽

◽

Annika Fendler ◽

Scott T. C. Shepherd ◽

Karolina Rzeniewicz ◽

...

Keyword(s):

Colorectal Cancer ◽

Adverse Event ◽

Checkpoint Inhibitors ◽

Temporal Association ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Vaccination Programs ◽

Patients With Cancer ◽

Related Adverse Event ◽

Pd1 Blockade

AbstractPatients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.

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Delayed cytokine release syndrome after neoadjuvant nivolumab: a case report and literature review

Immunotherapy ◽

10.2217/imt-2020-0329 ◽

2021 ◽

Author(s):

Aaron T Ciner ◽

Howard S Hochster ◽

David A August ◽

Darren R Carpizo ◽

Kristen R Spencer

Keyword(s):

Adverse Event ◽

Checkpoint Inhibitors ◽

Corticosteroid Treatment ◽

Hemodynamic Instability ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Related Adverse Event ◽

Neoadjuvant Immunotherapy ◽

Appropriate Treatment ◽

High Index Of Suspicion

Aim: Cytokine release syndrome (CRS) is an infrequently described immune-related adverse event of checkpoint inhibitors (CPI). CPI-induced CRS typically presents with fevers, hemodynamic instability and organ dysfunction within 2 weeks of the last treatment cycle. Case study: We report an unusual case of delayed and severe CRS occurring postoperatively in a patient with hepatic-limited metastatic colorectal cancer who received neoadjuvant immunotherapy. After a negative workup for alternative causes, he received prolonged corticosteroid treatment with symptom resolution. Conclusion: CPI-induced CRS can mimic sepsis and clinicians should maintain a high-index of suspicion to diagnose this immune-related adverse event early and initiate appropriate treatment. As use of perioperative immunotherapy increases, the potential role of surgery to trigger CRS in this case warrants further investigation.

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Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000144 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000144 ◽

Cited By ~ 6

Author(s):

Sarah Abou Alaiwi ◽

Wanling Xie ◽

Amin H Nassar ◽

Shaan Dudani ◽

Dylan Martini ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Median Time ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Safety And Efficacy ◽

Clinically Significant

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.

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Adverse Event Circumstances and the Case of Drug Interactions

Healthcare ◽

10.3390/healthcare7010045 ◽

2019 ◽

Vol 7 (1) ◽

pp. 45 ◽

Cited By ~ 3

Author(s):

Theodoros G. Soldatos ◽

David B. Jackson

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Drug Interactions ◽

Drug Targets ◽

Drug Induced ◽

Related Factors ◽

Human Phenotype ◽

Potential Applications ◽

Patient Responses ◽

Multiple Drugs

Adverse events are a common and for the most part unavoidable consequence of therapeutic intervention. Nevertheless, available tomes of such data now provide us with an invaluable opportunity to study the relationship between human phenotype and drug-induced protein perturbations within a patient system. Deciphering the molecular basis of such adverse responses is not only paramount to the development of safer drugs but also presents a unique opportunity to dissect disease systems in search of novel response biomarkers, drug targets, and efficacious combination therapies. Inspired by the potential applications of this approach, we first examined adverse event circumstances reported in FAERS and then performed a molecular level interrogation of cancer patient adverse events to investigate the prevalence of drug-drug interactions in the context of patient responses. We discuss avoidable and/or preventable cases and how molecular analytics can help optimize therapeutic use of co-medications. While up to one out of three adverse events in this dataset might be explicable by iatrogenic, patient, and product/device related factors, almost half of the patients in FAERS received multiple drugs and one in four may have experienced effects attributable to drug interactions.

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Incidence and prediction of checkpoint inhibitor immune-related nephrotoxicity.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.91 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 91-91

Author(s):

Jonathan D Sorah ◽

Tracy L. Rose ◽

Roshni Radhakrishna ◽

Vimal Derebail ◽

Matthew I. Milowsky

Keyword(s):

Autoimmune Disease ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Kidney Injury ◽

Retrospective Chart Review ◽

Tumor Type ◽

True Incidence ◽

Platinum Based Chemotherapy ◽

Increased Risk ◽

Clinically Significant

91 Background: Immune checkpoint inhibitors (ICIs), through inhibition of self-tolerance, have the potential to cause immune-related adverse events that can affect any organ, including the kidneys. Our study aimed to better characterize the incidence of and predictive characteristics for immune-related nephrotoxicity. Methods: All patients at the University of North Carolina (UNC) who received ICIs between April 2014 and December 2018 for any malignancy were identified. Patients on dialysis or those who received concurrent platinum-based chemotherapy were excluded. Any patient who subsequently had a clinically significant acute kidney injury (AKI), defined as a doubling or more of baseline creatinine, was included for analysis. A retrospective chart review was performed to determine the cause of AKI. Any uncertain cases were reviewed by two nephrologists for expert consensus (R.R. and V.D.). Results: 1766 patients received an ICI during the study period. 123 (7%) patients had AKI within one year of the first ICI dose. 14 were due to immune-related nephrotoxicity (11% of patients with AKI and 0.8% of all ICI patients). Pre-existing autoimmune disease was more likely in patients with immune-related nephrotoxicity than in those with non-immune AKI (14% vs 3%, p = 0.04). Similarly, concurrent or prior other immune-related adverse events were more common in patients with immune-related AKI (57% vs 6%, p = 0.01). Patients with immune-related AKI were more likely to see a nephrologist (57% vs 23%, p = 0.007) and had a more profound increase in creatinine from baseline (median 2.6 vs 1.6, p = 0.02). Age, sex, urinalysis findings, and primary tumor type were not associated with increased risk. Conclusions: The true incidence of ICI related nephrotoxicity is difficult to ascertain due to the many confounders that contribute to AKI in this population. Severe immune-related nephrotoxicity is rare, but patients with preexisting autoimmune disease or history of immune-related adverse events are at increased risk.

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Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Frontiers in Pharmacology ◽

10.3389/fphar.2021.663088 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhuo Ma ◽

Jie Pei ◽

Ximu Sun ◽

Lihong Liu ◽

Wenchao Lu ◽

...

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Reporting System ◽

Checkpoint Inhibitors ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Interquartile Range ◽

Event Reporting

Introdution: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies.Objective: To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death.Methods: Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated.Results: We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54–69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC025 = 2.11 and ROR 4.87 [4.51–5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6–70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12–114), p = 0.003).Conclusion: ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.

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Immunotherapy-induced endocrinopathies: assessment, management and monitoring

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819896182 ◽

2019 ◽

Vol 10 ◽

pp. 204201881989618 ◽

Cited By ~ 5

Author(s):

Edson Nogueira ◽

Tom Newsom-Davis ◽

Daniel L. Morganstein

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Mechanism Of Action ◽

Checkpoint Inhibitors ◽

Hormone Deficiency ◽

High Dose ◽

Multiple Organs ◽

Immune Mediated

Immunotherapy with checkpoint inhibitors has transformed the treatment of cancer, but frequently results in immune-mediated adverse events affecting multiple organs, amongst which endocrine adverse events are frequent. The patterns of endocrine adverse events differ between inhibitors of the CTLA-4 and PD-1/PD-L1 pathways, but most frequently involve the thyroid and pituitary with insulin deficient diabetes also emerging as an important adverse event. These frequently result in long-lasting hormone deficiency requiring replacement. This review explores the mechanism of action of checkpoint inhibitors and details the expected endocrine adverse events and typical presentations. The effect of high-dose glucocorticoids therapy to treat nonendocrine adverse events is also discussed.

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Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21712 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21712-e21712 ◽

Cited By ~ 1

Author(s):

Chipman Robert Geoffrey Stroud ◽

Cynthia R. Cherry ◽

Abdul Rafeh Naqash ◽

Nitika Sharma ◽

Sulochana Devi Cherukuri ◽

...

Keyword(s):

Adverse Events ◽

Clinical Improvement ◽

Median Time ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Immune Checkpoint Blockade ◽

Inpatient Setting ◽

Immune Mediated ◽

Steroid Refractory

e21712 Background: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events (irAEs) is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid-refractory irAEs. Methods:The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over 1 hour. C-reactive protein was drawn at first nivolumab infusion and at q 2 weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital d/c within 7 days. Results:Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All pts were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, cytokine release syndrome/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). Median CRP at initial tocilizumab dose was 100.5 mg/L (2.0 -350.4). Clinical improvement was noted in 27/34 pts (79.4%). 52.9% of pts required a single dose, while 35.3% required two, 8.8% required three and 1 pt required 4 doses. Twenty seven doses were given in the inpatient setting (49.1%). Median time to discharge was 4 days (range 1-27). Seventy four percent of pts were discharged home. For the 55 doses of tocilizumab that were delivered there was a cost savings of $147,174.94 (WAC) during the 18 month period versus infliximab 5 mg/kg IV dose. Conclusions: Tocilizumab is a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.

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