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

2019 ◽  
Vol 12 ◽  
pp. 175628481988419 ◽  
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.

scholarly journals Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217260
Author(s):  
Tommaso Morelli ◽  
Kohei Fujita ◽  
Gil Redelman-Sidi ◽  
Paul T Elkington
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Treatment ◽  
Common Side Effect ◽  
Inflammatory Immune Response ◽  
New Framework

Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

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

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21712-e21712 ◽  
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.

Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 341-341 ◽  
Author(s):  
Nicola Personeni ◽  
Tiziana Pressiani ◽  
Antonio Capogreco ◽  
Arianna Dal Buono ◽  
Antonio D'Alessio ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Subsequent Treatment ◽  
Drug Induced ◽  
Increased Risk ◽  
Grade 3

341 Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.

Combination therapy with vincristine, immunoglobulin and glucocorticosteroid (VIG regimen) is very effective for the management of grade 3/4 or steroid-refractory immune-related adverse events (irAE) secondary to PD-1 blockade.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14577-e14577
Author(s):  
Zhan-Hong Chen ◽  
Li Wei ◽  
Tian-tian Wang ◽  
Qu Lin ◽  
Xiangyuan Wu
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Continuous Infusion ◽  
Clinical Improvement ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Inpatient Setting ◽  
Improvement Rate ◽  
Grade 3 ◽  
Steroid Refractory

e14577 Background: The management of grade 3/4 or steroid-refractory immune related adverse events (irAE) is based on a paucity of retrospective data analysis. Our initial experience with the combination therapy with Vincristine (VCR), immunoglobulin (IVIG) and glucocorticosteroid (VIG regimen) showed clinical improvement in a wide variety of irAEs. As a result, we recommend the use of VIG regimen for the management of grade 3/4 or steroid-refractory irAEs. Methods: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The components of VIG regimens are as follows: Methylprednisolone (MP) 2-10mg/kg for 3days, VCR 1.4mg/m2 (≤2mg) continuous infusion for 4-8 hours on day 3 once a week with Immunoglobulin (IVIG) 0.4g/kg for 3-5 days. The dose of MP and IVIG will be reduced quickly after irAE improves. VCR 1.4mg/m2 once a week will be used for 1 to 3 times according to the improvement. Clinical improvement was defined as either: documentation of resolution of symptoms and normalisation of biochemical tests or hospital discharge within 14 days. Results: A total of 25 patients had grade3/4 or steroid-refractory irAEs after receiving immune checkpoint inhibitors and then received VIG regimen. Among them, 22 patients have been significantly improved, with an improvement rate of 88%. Twenty-three patents were treated in the inpatient setting (92%). The index grade 3/4 irAE was pneumonitis in 28%, immune mediated hepatotoxicity(IMH) in 28%, rash/SJS/TEN in 24%, cerebritis in 8 % and one case each of ITP, Near blindness and severe oral mucositis. In 7 patients with severe IMH, the range of total bilirubin was 80-481umol/L and ALT 35-5000u/L. Six patients with IMH recover well but one patient did not recover to normal due to IMH complicated with pneumonitis and TEN . Clinical improvement was noted in 22/25 patients (88%), 11 patients (44%) required a single dose, while 12 patients (48%) required two doses, 2 patients(8%) required three doses of VCR 1.4mg/m2 continuous infusion for 4-8 hours. What is impressive is that the two patients with encephalitis were significantly relieved within 2 weeks after using the VIG regimen. One patient with TEN (SCORETEN 3)was significantly improved and discharged from our hospital 11 days after using the VIG regimen. A patient with near-blind eyesight recovered to normal 3 days after using the VIG regimen. Conclusions: VIG regimen may be an effective therapeutic option for the management of grade3/4 or steroid-refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the efficacy and safety of VIG regimen.

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

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Sachiyo Onishi ◽  
Masahiro Tajika ◽  
Hideaki Bando ◽  
Yuki Matsubara ◽  
Waki Hosoda ◽  
...  
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Ursodeoxycholic Acid ◽  
Liver Enzymes ◽  
Checkpoint Inhibitors ◽  
Drug Induced ◽  
Related Adverse Event ◽  
First Case ◽  
Clinically Significant ◽  
Steroid Refractory

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.

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

2017 ◽  
Vol 25 (3) ◽  
pp. 551-557 ◽  
Author(s):  
Chipman RG Stroud ◽  
Aparna Hegde ◽  
Cynthia Cherry ◽  
Abdul R Naqash ◽  
Nitika Sharma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Improvement ◽  
Median Time ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Inpatient Setting ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Immune Mediated ◽  
Steroid Refractory

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 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 one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days. Results Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/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). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1–238.5) at baseline to 109.3 mg/L (21.5–350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25–149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1–27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period. Conclusions Tocilizumab may be 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.

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

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