The broad spectrum of cardiovascular adverse events related to immune check point inhibitors

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.S Andres ◽  
J Baksi ◽  
R Khattar ◽  
S.D Rosen ◽  
A.R Lyon
Keyword(s):  
Heart Failure ◽  
Adverse Effects ◽  
Adverse Events ◽  
Broad Spectrum ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Supraventricular Arrhythmias ◽  
Single Centre Study ◽  
Check Point Inhibitors ◽  
Ct Coronary Angiogram

Abstract Background Immunotherapy is one of the latest and most exciting developments in cancer treatment. Immune checkpoint inhibitors (ICI) have shown to have impressive positive results on several tumours such as melanoma, renal cancer and lung cancer, among others. Along with its benefits come the adverse effects which, concerning the heart, myocarditis is the most well-known and feared event. Yet, the spectrum of cardiovascular adverse events (CVAE) is much broader, ranging from heart failure to arrhythmias, but this has not been well documented until know. Objective Describe the broad spectrum of CVAE related to ICI Methods Observational retrospective, single centre study. We evaluated all the patients that have been referred to the cardio oncology (CO) unit and were under ICI treatment. The referred patients underwent a day case assessment with cardiovascular tests (blood tests, ECG, resting echocardiogram in all cases and MRI, stress echo or CT coronary angiogram if needed). The results were discussed in the multidisciplinary team meeting and the patients were then reviewed by one of the doctors in the team. The conclusions of the assessment were then communicated to the oncology team. Results From the year 2011 until December 2019, 71 patients receiving immunotherapy were referred to the CO unit. Three patients were excluded because they were referred for having an intracardiac tumour, leaving 68 for analysis. The first patient was referred in 2014 and during the first 3 years only 7 patients were reviewed in the CO unit. The frequency increased dramatically in 2017 to 17, 19 in 2018 and 25 in 2019. 21 patients were receiving Nivolumab, 24 on Ipilimumab, and 23 (34%) on combined therapy. The most frequent tumour was Melanoma (26/68, 38%). Regarding the CVAE: 22 patients (32%) were referred for investigtion of myocarditis. 6 had a diagnosis of definite myocarditis, 5 probable and 4 possible. Other CVAE (20/68, 29%) were the supraventricular arrhythmias including atrial fibrilation (20/68, 29%). 8 patients presented with non-inflammatory heart failure with new LVEF drop, 4 with chest pain, and 4 others with syncope. 1 patient developed pulmonary hypertension. Conclusions Myocarditis still remains the most frequent CVAE related to ICI, but the spectrum is broader than initially described. Supraventricular arrhythmias and non-inflammatory LVEF disfunction were very frequent in this series and we suspect that the incidence will increase as cardiologist and oncologists start considering them as probable adverse effects of this treatment. Funding Acknowledgement Type of funding source: None

scholarly journals Cutaneous Events Associated with Immunotherapy of Melanoma: A Review

2021 ◽  
Vol 10 (14) ◽  
pp. 3047
Author(s):  
Lorenza Burzi ◽  
Aurora Maria Alessandrini ◽  
Pietro Quaglino ◽  
Bianca Maria Piraccini ◽  
Emi Dika ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Stage Iii ◽  
Check Point ◽  
Check Point Inhibitors

Immunotherapy with checkpoint inhibitors significantly improves the outcome for stage III and IV melanoma. Cutaneous adverse events during treatment are often reported. We herein aim to review the principal pigmentation changes induced by immune check-point inhibitors: the appearance of vitiligo, the Sutton phenomenon, melanosis and hair and nail toxicities.

Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 84-84
Author(s):  
Kushal Naha ◽  
Lakshmi Manogna Chintalacheruvu ◽  
Donald C. Doll ◽  
Sowjanya Naha
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Confidence Interval ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Randomized Controlled ◽  
Dermatologic Adverse Events

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.

Abstract 12978: Identification of Cardiovascular Adverse Effects Associated With Midostaurin - A WHO Pharmacovigilance Database Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Arrush Choudhary ◽  
Ali Manouchehri ◽  
Javid Moslehi ◽  
Joe-elie Salem
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Adverse Effects ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Qt Prolongation ◽  
Reporting Odds Ratio ◽  
Pericardial Disease ◽  
Global Database

Introduction: Midostaurin is an oral multiple tyrosine kinase inhibitor (TKI) approved for treatment of acute myeloid leukemia and systemic mastocytosis. Clinical trials have shown efficacy of midostaurin with few adverse events. Although midostaurin does cause QT-prolongation, other associated cardiovascular complications are unknown. The purpose of this study is to identify and characterize cardiovascular adverse events associated with midostaurin. Methods: We used VigiBase, WHO's global database of individual case safety reports, to evaluate the association between midostaurin and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC 025 is the lower end of the IC 95% credibility interval and an IC 025 value of more than zero is deemed significant. Results: We identified 153 adverse cardiovascular events reported in patients who received midostaurin. Midostaurin treatment was associated with higher reporting of QT prolongation (48 cases, IC 025 4.15), heart failure (38 cases, IC 025 1.90), atrial fibrillation (20 cases, IC 025 1.53), and pericardial disease (12 cases, IC 025 1.23). A majority of these adverse events occurred within 50 days of midostaurin initiation with midostaurin being the only suspected culprit medication. Fatalities occurred in 8.7%, 43.2%, and 42.1% of cases of QT prolongation, heart failure, and atrial fibrillation, respectively. Conclusions: Midostaurin can lead to severe and sometimes fatal cardiac toxicities in a subset of patients. Baseline electrocardiograms and echocardiograms would be prudent in patients starting midostaurin to characterize and monitor these adverse effects.

BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains

2019 ◽  
Vol 169 (1) ◽  
pp. 194-208 ◽  
Author(s):  
James L Weaver ◽  
Leah M Zadrozny ◽  
Kathleen Gabrielson ◽  
Kenrick M Semple ◽  
Katherine I Shea ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Clinical Effectiveness ◽  
Humanized Mice ◽  
Pituitary Insufficiency ◽  
Immune Mediated ◽  
The Difference

Abstract Checkpoint inhibitors represent a new class of therapeutics in the treatment of cancer that has demonstrated remarkable clinical effectiveness. However, some patients have experienced serious immune-mediated adverse effects including pneumonitis, hepatitis, colitis, nephritis, dermatitis, encephalitis, and adrenal or pituitary insufficiency. These adverse events were not predicted by nonclinical studies. To determine if bone marrow-liver-thymus (BLT) immune humanized mice could demonstrate these adverse effects, we studied the effect of nivolumab on 2 strains of BLT-humanized mice, NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug Tg(SV40/HTLV-IL3, CSF2)10-7Jic/JicTac (NOG-EXL). Mice were treated with 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days. BLT-NOG mice had significantly reduced survival compared with BLT-NOG-EXL mice. In spite of the difference in survival, both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell activation increased with concomitant loss of PD-1 detection. These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.

scholarly journals Inhibitors of immune checkpoints—PD-1, PD-L1, CTLA-4—new opportunities for cancer patients and a new challenge for internists and general practitioners

2021 ◽  
Author(s):  
Marek Z. Wojtukiewicz ◽  
Magdalena M. Rek ◽  
Kamil Karpowicz ◽  
Maria Górska ◽  
Barbara Polityńska ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Patients ◽  
General Practitioners ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Treatment Options ◽  
Immune Checkpoints ◽  
Major Step ◽  
Iatrogenic Complications ◽  
New Challenges

AbstractThe treatment of cancer patients with immune checkpoint inhibitors (ICI) (anti-CTLA-4, anti-PD-1, anti-PD-L1, combined therapy anti-PD-1/PD-L1 with anti-CTLA-4) has without doubt been a significant breakthrough in the field of oncology in recent years and constitutes a major step forward as a novel type of immunotherapy in the treatment of cancer. ICIs have contributed to a significant improvement in the outcome of treatment and prognosis of patients with different types of malignancy. With the expansion of the use of ICIs, it is expected that caregivers will face new challenges, namely, they will have to manage the adverse side effects associated with the use of these drugs. New treatment options pose new challenges not only for oncologists but also for specialists in other clinical fields, including general practitioners (GPs). They also endorse the need for taking a holistic approach to the patient, which is a principle widely recognized in oncology and especially relevant in the case of the expanding use of ICIs, which may give rise to a wide variety of organ complications resulting from treatment. Knowledge and awareness of the spectrum of immune-related adverse events (irAEs) will allow doctors to qualify patients for treatment more appropriately, prevent complications, correctly recognize, and ultimately treat them. Additionally, patients with more non-specific symptoms would be expected, in the first instance, to consult their general practitioners, as complications may appear even after the termination of treatment and do not always proceed in line with disease progression. Dealing with any iatrogenic complications, will not only be the remit of oncologists but because of the likelihood that specific organs may be affected, is likely to extend also to specialists in various fields of internal medicine. These specialists, e.g., endocrinologists, dermatologists, pulmonologists, and gastroenterologists, are likely to receive referrals for patients suffering from specific types of adverse events or will be asked to provide care in cases requiring hospitalization of patients with complications in their field of expertise. In view of these considerations, we believe that there is an urgent need for multidisciplinary teamwork in the treatment of cancer patients undergoing immunotherapy and suffering the consequent adverse reactions to treatment.

scholarly journals OP0276 CLINICAL PATTERNS AND FOLLOW-UP OF INFLAMMATORY ARTHRITIS AND OTHER IMMUNE-RELATED ADVERSE EVENTS INDUCED BY CHECKPOINT INHIBITORS. A MULTICENTER STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 172.1-172
Author(s):  
J. A. Gómez-Puerta ◽  
C. Perez-Garcia ◽  
D. Lobo Prat ◽  
R. Gumucio ◽  
F. Ojeda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Inflammatory Arthritis ◽  
Checkpoint Inhibitors ◽  
Wide Spectrum ◽  
Combined Therapy ◽  
Oncologic Outcome ◽  
Clinical Results ◽  
Oncologic Outcomes ◽  
Clinical Patterns

Background:Immune checkpoint inhibitors (ICI), such as anti-CTLA-4and anti-PD1/PD-L1 monoclonal antibodies, have produced impressive clinical results in different types of cancer. However, immune-related adverse events (irAEs) may develop a wide spectrum of disabling syndromes. Knowledge of different rheumatic irAEs induced by ICI is increasing over the last years, however clinical patterns, time to onset of different irAEs according to treatment and follow-up are less well known.Objectives:To describe different clinical patterns of rheumatic irAEs induced by ICI and their rheumatic and oncologic outcomes.Methods:We included consecutive patients with rheumatic irAEs from 3 different referral centers in Barcelona with special emphasis in articular irAEs. Four main clinical syndromes were identified: inflammatory arthritis (IA), non-inflammatory arthralgias (NIA), psoriatic arthritis (PsA)-like and polymialgia (PMR)-like. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response and outcome. Longitudinal visits were done from January 2017 to January 2020. Patients with other non–articular diagnosis were not included in the follow-up analysis.Results:We included 55 patients. A total of 34 patients were male (61.8%) with a mean age of 65.0 ± 11.4 years. Oncologic underlying diagnosis was lung carcinoma in 24 (43.6%) patients, followed by melanoma in 17 (29%), urothelial cancer in 4 (7.3%), breast in 2 (3.6%) and 2 (3.6%) acute myeloid leukemia among others. Seven (12.7%) patients received ICI as combined therapy. Different ICI were used including: Pembrolizumab in 21 (38.2%), Nivolumab 13 (23.6 %), Atezolizumab 6 (10.9%), Nivolumab + ipilimumab 5 (9.0%), Durvalumab 3 (5.5%), Pembrolizumab + epacadostat in 2 (3.6%), 2 anti TIM3, Atezolizumab+ Ibatasertib, Avelumab and Ipilimumab in one case each. 12 out of 55 patients had an underlying rheumatic disease before ICI treatment. Eleven patients developed other irAEs before or at the same time as rheumatic syndromes (mainly colitis and thyroiditis). Main rheumatic irAE included: IA in 23 (41.8%), NIA in 16 (29.1%), PsA-like in 6 (10.9%), PMR-like in 5 (9.1%) among others. Time from ICI to irAEs was 8.3 ± 8.4 months(mo). irAE presented earlier in patients with combined ICI therapy than in patients with monotherapy (6.5 ± 4.0 vs 8.6 ± 8.9 mo, p=NS, Figure 1A). Time (in mo) from ICI initiation to irAE onset was different according to treatments. For Nivolumab 10.0 ± 10.6, Anti TIM3 10.0 ± 1.4, Durvalumab 9.0 ± 2.0, Ipilimumab 7.98 ± 9.21, Pembrolizumab 7.28 ± 7.53, Avelumab 6.0 and Atezolizumab 4.4 ± 5.38 mo (Figure 1B). Time from ICI initiation and onset also differs among rheumatic irAEs (Figure 2). Mean time follow-up was 13.4 ± 10.9 mo. At the last visit, 45% were under GC, mean dose of 3.6 mg/d (range 0-40). DMARD were needed in 15% of patients (6 patients MTX, 1 with LEF and 1 SFZ). At the last visit, 11 (22.9%) patients remain with persistent arthritis, 25% intermittent flares and 52% had a self-limited pattern. Regarding oncologic outcome, 30.2% were on remission, 30.2% in partial response and 39.6% with tumor progression. Eleven (20%) of patients died.Conclusion:We described different clinical patterns according treatment and irAEs. Combined ICI therapy and patients treated with Atezolizumab had earlier onset of symptoms. Vasculitis and PMR-like syndromes appear in earlier phases. After a mean follow-up of around 1 year, one-quarter of the patients remain with persistent arthritis and 15% require DMARD therapy.Disclosure of Interests:Jose A. Gómez-Puerta Speakers bureau: Abbvie, BMS, GSK, Lilly, Pfizer, Roche, Carolina Perez-Garcia: None declared, David Lobo Prat: None declared, Roberto Gumucio: None declared, Fabiola Ojeda: None declared, Ana Milena Millán Arciniegas: None declared, Sebastian Rodriguez Garcia: None declared, Virginia Ruiz Speakers bureau: Lilly, Pfizer, Héctor Corominas Speakers bureau: Abbvie, Lilly, Pfizer, Roche

scholarly journals Therapeutic and Systemic Adverse Events of Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 axis for Clinical Management of NSCLC

2021 ◽  
Vol 30 ◽  
pp. 096368972110415
Author(s):  
Jing Chen ◽  
Yaser Alduais ◽  
Baoan Chen
Keyword(s):  
Monoclonal Antibodies ◽  
Adverse Effects ◽  
Adverse Events ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Critical Parameters ◽  
Small Cell Lung ◽  
Randomized Controlled ◽  
Google Search

Non-small-cell lung cancer takes up the majority of lung carcinoma-caused deaths. It is reported that targeting PD-1/PD-L1, a well-known immune evasion checkpoint, can eradicate tumor. Checkpoint inhibitors, such as monoclonal antibodies, are actively employed in cancer treatment. Thus, this review aimed to assess the therapeutic and toxic effects of PD-1/PD-L1 inhibitors in treatment of NSCLC. So far, 6 monoclonal antibodies blocking PD-1/PD-L1 interaction are identified and used in clinical trials and randomized controlled trials for NSCLC therapy. These antibody-based therapies for NSCLC were collected by using search engine PubMed, and articles about the assessment of adverse events were collected by using Google search. Route of administration and dosage are critical parameters for efficient immunotherapy. Although antibodies can improve overall survival and are expected to be target-specific, they can cause systemic adverse effects in the host. Targeting certain biomarkers can limit the toxicity of adverse effects of the antibody-mediated therapy. Clinical experts with knowledge of adverse effects (AEs) of checkpoint inhibitors can help manage and reduce mortalities associated with antibody-based therapy of NSCLC.

Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management

2018 ◽  
pp. 13-19 ◽  
Author(s):  
Shilpa Grover ◽  
Osama E. Rahma ◽  
Nikroo Hashemi ◽  
Ramona M. Lim
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Effective Management ◽  
Rule Out

Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of checkpoint blockade. These adverse events can be severe enough to require interruption or withdrawal of immune checkpoint blockade therapy. Patients with immune-related adverse effects require early recognition with an evaluation to rule out alternative etiologies and effective management to minimize complications. This article reviews the gastrointestinal and hepatic toxicities of the antibodies that target immune checkpoints CTLA-4 and PD-1/PD-L1 and provides an approach to their diagnosis and management.

scholarly journals Immunotherapy-related adverse events (irAEs): extraction from FDA drug labels and comparative analysis

JAMIA Open ◽  
2018 ◽  
Vol 2 (1) ◽  
pp. 173-178 ◽  
Author(s):  
QuanQiu Wang ◽  
Rong Xu
Keyword(s):  
Adverse Events ◽  
Broad Spectrum ◽  
Checkpoint Inhibitors ◽  
Endocrine System ◽  
Biological Mechanisms ◽  
Fold Enrichment ◽  
Improved Outcomes ◽  
Organ Systems ◽  
Treatment Research ◽  
Target Effects

Abstract Objectives Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes in cancer patients. However, ICIs are associated with significant immune-related adverse events (irAEs) and the underlying biological mechanisms are not well-understood. To ensure safe cancer treatment, research efforts are needed to comprehensively detect and understand irAEs. Materials and methods We manually extracted and standardized irAEs from The U.S Food and Drug Administration (FDA) drug labels for six FDA-approved ICIs. We compared irAE profile similarities among ICIs and 1507 FDA-approved non-ICI drugs. We investigated how irAEs have differential effects on human organs by classifying irAEs based on their targeted organ systems. Finally, we identified broad-spectrum (nontarget-specific) and narrow-spectrum (target-specific) irAEs. Results A total of 893 irAEs were extracted. 31.4% irAEs were shared among ICIs as compared to the 8.0% between ICIs and non-ICI drugs. irAEs were resulted from both on- and off-target effects: irAE profiles were more similar for ICIs with same target than different targets, demonstrating the on-target effects; irAE profile similarity for ICIs with the same target is less than 50%, demonstrating unknown off-target effects. ICIs significantly target many organ systems, including endocrine system (3.4-fold enrichment), metabolism (3.7-fold enrichment), immune system (3.6-fold enrichment), and autoimmune system (4.8-fold enrichment). We identified 21 broad-spectrum irAEs shared among all ICIs, 20 irAEs specific for PD-L1/PD-1 inhibition, and 28 irAEs specific for CTLA-4 inhibition. Discussion and conclusion Our study presents the first effort toward building a standardized database of irAEs. The extracted irAEs can serve as the gold standard for automatic irAE extractions from other data resources and set a foundation to understand biological mechanisms of irAEs.

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