For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory ...approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.
IMPORTANCE: Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate ...of approximately 1% to 7%. OBSERVATIONS: The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear. CONCLUSIONS AND RELEVANCE: Acute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.
The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing ...new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4-1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs.
Immune checkpoint inhibitors have greatly improved clinical outcomes in multiple cancer types and are increasingly being used in earlier disease settings and in combination with other therapies.1 ...However, high-grade immune-related adverse events can occur. Patients had a wide spectrum of age (median 69 years range 20-90), cancer types (most commonly melanoma and lung cancer), and geographical location (appendix). Supplementary Material 1 JD Wolchok, PD-1 blockers, Cell, Vol. 162, 2015, 937 2 DB Johnson, JM Balko, ML Compton, Fulminant myocarditis with combination immune checkpoint blockade, N Engl J Med, Vol. 375, 2016, 1749-1755 3 L Heinzerling, PA Ott, FS Hodi, Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy, J Immunother Cancer, Vol. 4, 2016, 50 4 M Escudier, J Cautela, N Malissen, Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity, Circulation, Vol. 136, 2017, 2085-2087 5 M Lindquist, VigiBase, the WHO global ICSR database system: basic facts, Drug Inf J, Vol. 42, 2008, 409-419
The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of ...the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications.
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.
Limited data are available for immune‐related adverse events related to primary adrenal insufficiency. This article characterizes such events using Vigibase, the WHO's global database of individual case safety reports.
Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different ...immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.
In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs 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. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540.
We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 95% CI 9·36–13·43; IC025 3·20), pericardial diseases (12 800 vs 95, 3·80 3·08–4·62; IC025 1·63), and vasculitis (33 289 vs 82, 1·56 1·25–1·94; IC025 0·03), including temporal arteritis (696 vs 18, 12·99 8·12–20·77; IC025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 3·13–8·40; IC025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 56% of 87 patients), whereas myocarditis (42 41% of 103 patients) and vasculitis (42 60% of 70 patients) were more commonly reported in patients with melanoma (χ2 test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001).
Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).
The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014–2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.
Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, ...there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or as a result of anticancer therapy. Much attention has focused on heart failure; however, other cardiotoxicities, notably cardiac rhythm disorders, can occur without underlying cardiomyopathy.
Supraventricular tachycardias occur in cancer patients treated with cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs) such as ibrutinib. Ventricular arrhythmias, with a subset of them being torsades-de-pointes (TdP) favored by QTc prolongation have been reported: this may be the result of direct hERG-channel inhibition or a more recently-described mechanism of phosphoinositide-3-kinase inhibition. The major anticancer drugs responsible for QTc prolongation in this context are KIs, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, and selective estrogen receptor modulators.
Anticancer drug-induced cardiac rhythm disorders remain an underappreciated complication even by experienced clinicians. Moreover, the causal relationship of a particular anticancer drug with cardiac arrhythmia occurrence remains challenging due in part to patient comorbidities and complex treatment regimens. For example, any cancer patient may also be diagnosed with common diseases such as hypertension, diabetes or heart failure which increase an individual's arrhythmia susceptibility. Further, anticancer drugs are generally usually used in combination, increasing the challenge around establishing causation.
Thus, arrhythmias appear to be an underappreciated adverse effect of anticancer agents and the incidence, significance and underlying mechanisms are now being investigated.
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