scholarly journals Graft Versus Host Disease Associated with Immune Checkpoint Inhibitors: A Pharmacovigilance Study and Systematic Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Lee S. Nguyen ◽  
Lisa Raia ◽  
Bénédicte Lebrun-Vignes ◽  
Joe-Elie Salem
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Previous History ◽  
World Health ◽  
Disproportionality Analysis ◽  
Host Disease ◽  
Significant Difference ◽  
History Of ◽  
Time To Onset

Background: In patients with allogenic hematopoietic stem cell transplantation (allo-HSCT), immune-checkpoint inhibitors (ICI) are used to treat malignancy recurrence. However, ICI are also associated with graft vs. host disease (GVHD). In this pharmacovigilance analysis, we aimed to characterize cases of GVHD associated with ICI, drawn from the World Health Organization pharmacovigilance database, VigiBase®, and from literature.Methods: We performed VigiBase® query of cases of GVHD associated with ICI. These cases were combined with those of literature, not reported in VigiBase®. The Bayesian estimate of disproportionality analysis, the information component, was considered significant if its 95% credibility interval lower bound was positive; denoting a significant association between GVHD and the suspected ICI. Time to onset between ICI and GVHD onset and subsequent mortality were assessed.Results: Disproportionality analysis yielded 93 cases of GVHD associated with ICI (61.8% men, median age 38 [interquartile range = 27; 50] years). Cases were mostly associated with nivolumab (53/93, 57.0%), pembrolizumab (23/93, 24.7%) and ipilimumab (12/93, 12.9%) monotherapies. GVHD events occurred after 1 [1; 5.5] injection of ICI, with a time to onset of 35 [IQR = 14; 176] days. Immediate subsequent mortality after GVHD was 24/93, 25.8%. There was no significant difference in mortality depending on the molecule (p = 0.41) or the combination regimen (combined vs. monotherapy, p = 0.60). Previous history of GVHD was present in 11/18, 61.1% in cases reported in literature.Conclusion: In this worldwide pharmacovigilance study, disproportionality yielded significant association between GVHD and ICI, with subsequent mortality of 25.8%. Previous history of GVHD was reported in more than half of cases.Clinicaltrials.gov identifier:NCT03492242

scholarly journals History of Radiation to the Neck Increases the Risk of Denovo Thyroid Dysfunction after Receiving Immune Checkpoint Inhibitors

Endocrines ◽  
2020 ◽  
Vol 1 (2) ◽  
pp. 82-89
Author(s):  
Koosha Paydary ◽  
Muhammad Zain Farooq ◽  
Ankit Mangla
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Previous History ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Disorder ◽  
Free T4 ◽  
History Of

Thyroid dysfunction is a common endocrine side effect of immune checkpoint inhibitors (ICI). We designed a retrospective study, including patients who received ICI for any cancer at our institution. Thyroid-stimulating hormone (TSH), free T4 levels, and time to development of thyroid dysfunction were measured, and medication used to treat thyroid dysfunction were identified. We reviewed the charts of 104 patients with complete records obtained from our tumor registry. A total of 91 patients were included in the analysis, after excluding 13 patients with a pre-existing thyroid disorder. Twenty-eight (30.77%) patients developed thyroid dysfunction after starting ICI. Race (p-0.048), age (p-0.014), history of radiation therapy (RT) to the neck (p-0.004), history of RT to the chest (p-0.012), and history of venous thrombosis (p-0.004) were significantly associated with thyroid dysfunction on univariate analysis. For multivariate analysis, the history of RT to the neck, adjusted for age, race, and sex, was significantly associated with thyroid dysfunction (adjusted OR-9.64, 95%CI: 1.88, 49.36, p-0.007). In patients receiving ICI for any type of cancer, the previous history of RT to the neck was significantly associated with the development of thyroid dysfunction after starting ICI.

Atezolizumab-induced myositis and myocarditis in a patient with metastatic urothelial carcinoma

2020 ◽  
Vol 13 (12) ◽  
pp. e236357
Author(s):  
Mary Sessums ◽  
Siva Yarrarapu ◽  
Pramod K Guru ◽  
Devang K Sanghavi
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Basic Knowledge ◽  
Malignant Neoplasms ◽  
Diverse Range ◽  
History Of ◽  
Metastatic Urothelial Carcinoma ◽  
Acute Hypercapnic Respiratory Failure

Immune checkpoint inhibitors have revolutionised cancer therapy in the past decade. Although they have been indicated to treat a diverse range of malignant neoplasms, they are also associated with various immune-related adverse effects. We report the case of a 74-year-old man with a history of urothelial carcinoma who had atezolizumab-induced myocarditis and myositis resulting in acute hypercapnic respiratory failure, despite the discontinuation of atezolizumab and aggressive treatment with corticosteroids. This case highlights the importance of a multidisciplinary approach for early diagnosis and treatment of immune-related adverse events. Physicians must be aware of the risks associated with immune checkpoint inhibitors and have a basic knowledge regarding their management.

The Current Role of Immunotherapy in mCRPC: A Systematic Review

2021 ◽  
Vol 8 (7) ◽  
Author(s):  
Dalibey H ◽  
◽  
Hansen TF ◽  
Zedan AH ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Treatment Modalities ◽  
Significant Difference

Background: The development of immunotherapy has shown promising results in several malignant diseases, including prostate cancer, calling for a systematic review of the current literature. This review aims to evaluate the present data and prospects of immune checkpoint inhibitors in metastatic Castration Resistant Prostate Cancer (mCRPC). Methods: Articles were identified via a systematic search of the electronic database Pubmed, in accordance with the PICO process and following the PRISMA guidelines. Articles in English studying immune checkpoint inhibitors in patients with mCRPC published between March 2010 and March 2020 were eligible for inclusion. Endpoints of interest were Overall Survival (OS), Progression-Free Survival (PFS), clinical Overall Response Rate (ORR), and Prostate-Specific Antigen (PSA) response rate. Results: Ten articles were identified as eligible for inclusion. The studies primarily explored the use of Ipilimumab, a CTLA-4 inhibitor, and Pembrolizumab, a PD-1 inhibitor. These drugs were both used either as monotherapy or in combination with other treatment modalities. The largest trial included in the review demonstrated no significant difference in overall survival between the intervention and placebo. However, two studies presented promising data combing immunotherapy and immune vaccines. Grade 3 and 4 adverse events ranging from 10.1% to 82.3%, whit diarrhea, rash, and fatigue were the most frequently reported. Forty relevant ongoing trials were identified exploring immunotherapy with or without a parallel treatment modality. Conclusion: Overall, the current data shows that the effect of immune checkpoint inhibitors as monotherapy may have limited impact on mCRPC, and the results from ongoing combinational trials are eagerly awaited.

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

Circulation ◽  
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.

Potential role of serum proteome in predicting immune-related adverse events from immune checkpoint inhibitors in non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21218-e21218
Author(s):  
Leeseul Kim ◽  
Young Kwang Chae ◽  
Chan Mi Jung ◽  
Emma Yu ◽  
Alice Daeun Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Significant Difference ◽  
Nsclc Patients

e21218 Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.

Abstract 14600: Pre-existing Autoimmune Disease and the Risk for Cardiovascular and Non-cardiovascular Immune Mediated Adverse Events With Immune Checkpoint Inhibitors

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Charlotte Lee ◽  
Zsofia D Drobni ◽  
Amna Zafar ◽  
Raza M Alvi ◽  
Sean P Murphy ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Autoimmune Disease ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Cardiovascular Events ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Skin Toxicity ◽  
Significant Difference

Introduction: The use of immune checkpoint inhibitors (ICIs) is associated with an increase in cardiovascular events. The mechanism is likely related to immune activation and inflammation. Patients with pre-existing autoimmune disease have a baseline increased risk for cardiovascular disease and have been traditionally excluded from clinical trials of ICIs. There is limited data on the cardiovascular and non-cardiovascular safety of ICIs in these patients. Methods: This was a retrospective study of 2845 patients treated with an ICI at the Massachusetts General Hospital. This cohort was screened by individual chart review for patients with a diagnosis of an autoimmune disease prior to ICI therapy. These autoimmune patients were compared to controls at a 1:2 ratio. Baseline characteristics and risk of cardiovascular and non-cardiovascular immune related adverse events (iRAEs) were compared. Cardiovascular events were a composite of myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), stroke, transient ischemic attack (TIA), deep venous thrombosis (DVT), pulmonary embolism (PE), or myocarditis. Results: 93 patients had a diagnosis of an autoimmune disease prior to ICI. These patients were more likely to be older and to have a history of coronary artery disease, heart failure, chronic kidney disease, hypertension and diabetes mellitus. There were 12 events over a median follow-up period of 300 days. There was no significant difference in composite of cardiovascular events in follow-up (13 vs. 9.1%, autoimmune vs. none, P =0.41). The individual cardiovascular event rates were as follows: MI (4.3 vs. 0.5%, P =0.04), PCI (0 vs. 0.5%, P =1), CABG (0. vs. 0.5%, P =1), stroke (0 vs. 0%), TIA (0 vs. 0.5%, P =1), DVT (5.4 vs. 2.2%, P =0.17), PE (1.1 vs. 4.8%, P =0.17), and myocarditis (2.2 vs. 1.1%, P =0.60). There was an increased rate of pneumonitis (14 vs. 4%, P <0.001) and skin toxicity (16 vs. 0%, P <0.001). Conclusions: Patients with pre-existing autoimmune disease treated with an ICI had a higher baseline cardiovascular risk but did not have a significant increase in cardiovascular events in an unadjusted analysis. These patients did, however, have an increased rate of pneumonitis and skin toxicity after ICI.

scholarly journals Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors

2019 ◽  
Vol 38 (4) ◽  
pp. 1200-1206 ◽  
Author(s):  
Yosuke Ando ◽  
Takahiro Hayashi ◽  
Reiko Sugimoto ◽  
Seira Nishibe ◽  
Kaori Ito ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Heart Disease ◽  
Anticancer Agents ◽  
Immune Checkpoint ◽  
Odds Ratio ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
History Of ◽  
Cancer Associated Thrombosis

SummaryPurpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT incidence and associated risk factors in patients receiving ICI. Methods Patients administered nivolumab or pembrolizumab at Fujita Health University Hospital from April 2017 to March 2018 were enrolled. We collected retrospective data regarding age, sex, cancer type, BMI, medical history, laboratory data at treatment initiation, medications, and computed tomography (CT) interpretations from electronic medical records. Results We identified 122 eligible participants from 135 patients receiving nivolumab or pembrolizumab. Ten patients (8.2%) developed CAT. A history of venous thromboembolism (VTE) or arterial thromboembolism (ATE) was a risk factor for CAT incidence (odds ratio: 6.36, P = 0.039). A history of heart disease may be a risk factor for CAT incidence (odds ratio 6.56, P = 0.052). Significantly higher usage of antiplatelet and anticoagulant therapy was noted in patients who developed CAT (60%) than in those who did not (13.4%, p < 0.01). Conclusion High (8.2%) CAT incidence during ICI administration suggested that ICI is not associated with a lower blood clot risk than other anticancer agents investigated in previous studies. For patients with VTE, ATE, or heart disease history, it is crucial to consider the possibility of CAT even with antiplatelet therapy.

Optimizing Sequence of PD-L1 Immune-Checkpoint Inhibitors and Radiation Therapy in Bladder Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 295-302
Author(s):  
Côme Tholomier ◽  
Gautier Marcq ◽  
Surashri Shinde-Jadhav ◽  
Mina Ayoub ◽  
Jia Min Huang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radiation Therapy ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Tumor Growth Rate ◽  
Significant Difference ◽  
Rate Of Response

BACKGROUND: New bladder preserving strategies are needed for muscle invasive bladder cancer (MIBC). Combined therapy of immune-checkpoint inhibitors and radiation was shown to have synergistic antitumoral effects in preclinical studies. OBJECTIVES: We aim to evaluate whether the sequence of administration of this combined therapy impacts antitumoral response. METHODS: We developed an in-vivo syngeneic MIBC mouse model where murine bladder cancer cells (MB49) were injected subcutaneously in the right flank of C57BL/6 mice. Mice were then randomized to the following treatments: control, anti-programmed cell death ligand 1 (PD-L1) alone, radiation alone (XRT) consisting of 6.25 Gy x2 fractions, concurrent anti-PD-L1 with XRT, neoadjuvant anti-PD-L1 followed by XRT, or XRT followed by adjuvant anti-PD-L1 therapy. Tumor growth, survival, and rate of response were analyzed. RESULTS: Total of 60 mice were randomized. One-way analysis of variance showed statistically significant difference in tumor growth rate across the treatment arms (p = 0.029). Importantly, timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) did not alter either tumor growth or survival (p > 0.05). The rate of response was also similar in each combination arm (p > 0.05). CONCLUSION: Combining anti-PD-L1 immunotherapy and radiation therapy offers optimal antitumoral responses. Timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) does not appear to affect outcomes. Whether the toxicity profile differs across various sequential deliveries of combination therapy requires further evaluation.

Implementation of a pharmacy consult service for evaluation of immune checkpoint inhibitor related adverse events at a large community hospital

2020 ◽  
pp. 107815522097026
Author(s):  
Jeff Kamta ◽  
Bren Magruder ◽  
Lisa Hymel
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Primary Outcome ◽  
Checkpoint Inhibitors ◽  
Delayed Presentation ◽  
Consult Service ◽  
Organ Systems ◽  
History Of ◽  
Secondary Outcomes

Introduction Immune checkpoint inhibitors (ICI) are novel oncolytic therapies associated with various immune related adverse events (irAEs) affecting multiple organ systems, which may have a delayed presentation. Identification of irAEs and prompt initiation of appropriate treatment represents a challenge to clinicians. The purpose of this study was to evaluate the effectiveness of a pharmacy consult service in identification and management of irAEs. Methodology: This was a single center, retrospective study. Patients included were: ≥18 years old, admitted as inpatients, and reported a history of cancer treatment within the last year. A pharmacy consult was developed and implemented for patients who reported a history of ICI therapy within the last year. Education regarding the consult service was provided to select physicians, nurses, and all pharmacists. Primary outcome: percent of admitted patients reporting ICI therapy within the last year, who required pharmacist intervention for an irAE. Secondary outcomes: types of interventions performed, percentage of recommendation acceptance, pharmacist time spent. Results Fifty-one patients received a pharmacy immunotherapy consult. Seventeen patients (33%) met the primary outcome. Thirty-three separate recommendations were made by pharmacists for these 17 patients. The secondary outcomes of interventions made and percentage accepted (n; % accepted): Initiation/adjustment of steroid therapy (20; 40%), placement of a consult for oncology or other specialist (10; 70%), other therapeutic interventions (3; 67%). Average time spent by pharmacist on initial consultations (SD): 29 minutes (15). Conclusion A pharmacy consult service may help to increase identification of patients receiving immune checkpoint inhibitors and initiate timely interventions.

scholarly journals Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients

2021 ◽  
Author(s):  
Han-sang Baek ◽  
Chaiho Jeong ◽  
Kabsoo Shin ◽  
Jaejun Lee ◽  
Dong-Jun Lim ◽  
...  
Keyword(s):  
Subclinical Hypothyroidism ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Hazard Ratio ◽  
Cancer Type ◽  
Significant Difference ◽  
The Difference ◽  
Lower Hazard

Abstract Background Immune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival. Methods Patients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary’s Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction. Results Among the 196 patients, 66 (33.7%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (38 months vs. 13 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.520 (p = 0.007). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for morbidity of 0.309 (p = 0.001). Patients with thyrotoxicosis showed a worse hazard ratio for morbidity than those without thyroid irAE, although the difference was not statistically significant. Conclusions It was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

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