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Background: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy with growing indications for treatment of various malignancies. Immune checkpoint inhibitors are monoclonal antibodies that block inhibitory pathways in immune cells, including cytotoxic T lymphocyte antigen-4 (CTLA4), programmed death 1 receptor (PD1), and programmed cell death ligand-1 (PDL1), to activate the immune system. However, these agents can disrupt self-tolerance and lead to immune-related adverse events. Fulminant myocarditis, a feared complication of ICIs, can be highly fatal, and there is a need for effective treatment options., Case Summary: A 70-year-old patient with recurrent metastatic disease of urothelial carcinoma subsequently developed fulminant myocarditis after receiving eight cycles of pembrolizumab. He developed cardiogenic shock and required inotropes and a percutaneous microaxial flow pump placement for temporary mechanical circulatory support. He received methylprednisolone initially and then was started on second-line immunosuppression agents, ruxolitinib and abatacept, for steroid-refractory myocarditis. Abatacept is thought to inhibit activation of T-cell CTLA4 and PD1/PDL1 pathways and reverse ICI-activated pathways. Ruxolitinib is a Janus kinase inhibitor that impairs immune activation through suppressing cytokine sensing and production and T-cell activation. After these treatments, the patient subsequently clinically improved and his myocarditis resolved., Discussion: This case highlights ICI myocarditis refractory to corticosteroids leading to treatment with second-line immunosuppression. As immunotherapies are increasingly applied to a broader range of cancers, further research is needed to evaluate the optimal treatment strategy for ICI-related myocarditis and other immune-related adverse events., Competing Interests: Conflict of interest: P.G. (last 2 years): consulting: Aadi Bioscience, AbbVie, Asieris Pharmaceuticals, Astellas, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Fresenius Kabi, G1 Therapeutics, Gilead Sciences, Guardant Health, ImmunityBio, Janssen, Lucence, Merck KGaA, MSD, Pfizer, PureTech, Roche, SeaGen, Silverback Therapeutics, and Strata Oncology and research funding to institution: ALX Oncology, Acrivon Therapeutics, Bavarian Nordic, Bristol Myers Squibb, Debiopharm Group, Genentech, G1 Therapeutics, Gilead Sciences, GSK, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, QED Therapeutics. J.J.M.: consulting: Novartis, Bristol-Myers Squibb, Deciphera, Takeda, AstraZeneca, Regeneron, Kiniksa Pharmaceuticals, Daiichi Sankyo, BeiGene, IQVIA, AskBio, Labcorp, Paladin, Bitterroot Bio, Repare Therapeutics, and Cytokinetics. J.-E.S. participated to advisory boards or consultancy from BMS, Novartis, Banook, EISAI, Bayer, IPSEN, AstraZeneca, and BeiGene. He has patents related to the treatment of ICI-related immune adverse events. J.J.M. and J.-E.S. are co-inventors of a patent related to the use of abatacept in the treatment of ICI myocarditis. S.B.: advisory board/consultant (with honorarium): Bristol-Myers Squibb and Incyte; research grants (to institution): Bristol-Myers Squibb, EMD-Serono, Merck, Novartis, Immune Design, Incyte, Oncosec, Nantkwest, Exicure, Nektar, Amphivena, Checkmate, Xencor, and 4SC; and stock/equity: Moderna. The other authors report no relevant conflicts of interest., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors., Clinicaltrials.gov Identifier: NCT02580058., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA)., Methods and Results: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed., Conclusion: This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements., Clinical Trial Registration: NCT03530215., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE., Materials and Methods: Suspected PAI-irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports., Results: From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were "definite PAI" and 406 "possible PAI." Patients were mainly male (58.1%) with a median age of 66 years (range, 30-95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6-576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between "definite" versus "possible" PAI group., Conclusion: Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency., (© AlphaMed Press 2020.)

Aims: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented., Methods and Results: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE., Conclusion: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP ( n  = 68) and HA ( n  = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p  = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The "Checkpoint Inhibitor Safety Working Group," a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Cardiotoxicity can be a complication of anthracycline- or trastuzumab-based therapy for breast cancer patients. Screening echocardiograms (ECHOs) and radionuclide ventriculograms (RVGs) are often performed before administration of these agents to evaluate cardiac function. Limited evidence for the clinical utility of these screening tests is available., Methods: Early-stage breast cancer patients diagnosed from 2006 to 2011 (n = 1,067) with baseline ECHOs/RVGs were identified in a single institution prospective registry. Medical record review was performed to obtain pre- and post-ECHO/RVG treatment plans, baseline ECHO/RVG results, cardiac risk factors, and cardiac events. Patients with cardiac history were excluded. ECHO/RVG abnormalities were defined as ejection fraction (EF) <55%, valvular disease, left ventricular hypertrophy, and diastolic dysfunction. Cardiac events were defined as heart failure, myocardial infarction, arrhythmia, valvular disease, or angina during or after chemotherapy., Results: Among 600 eligible patients, abnormal ECHO/RVG results were observed in 13 (2.2%, 1.2%-3.7%), including 9 with baseline EF <55%. There were no detected changes in treatment plans, although more frequent cardiac monitoring was recommended for 2 patients. There were no significant differences in age, race, menopausal status, smoking history, alcohol use, body mass index, or medical comorbidities between patients with abnormal and normal results. In follow-up (mean, 4.0 years; range, 0-8.3), 15 patients developed cardiac events (none of whom had had abnormal baseline ECHOs/RVGs)., Conclusion: Baseline ECHO/RVG in patients without prior cardiac history rarely yields an abnormality that prompts change in planned anthracycline- and/or trastuzumab-based treatment. Moreover, few cardiac events developed in this screened population in follow-up., Implications for Practice: Baseline cardiac function screening with echocardiograms or radionuclide ventriculograms is frequently performed before administration of anthracycline- or trastuzumab-based chemotherapy in breast cancer patients due to the relatively low cost and risk to patients and the concern for potential cardiotoxicity. However, at a population level, these tests can take up time and can add up to significant costs for both patients and the health care system. This study finds that in patients with no history of cardiac disease, baseline cardiac function screening rarely identifies abnormalities that change treatment plans. Moreover, few cardiac events develop in an average of 4 years of follow-up, including none in patients with abnormal baseline cardiac function screening results. This suggests that baseline cardiac function screening may have limited utility in chemotherapy planning in young breast cancer patients with no history of cardiac disease., (©AlphaMed Press.)