Immune Checkpoint Inhibitor Myocarditis Research Articles

Mending Broken Hearts

Mending Broken Hearts

Practical cardiovascular imaging approach to diagnose immune checkpoint inhibitor myocarditis.

Immuno-oncology employs various therapeutic strategies that harness a patient's own immune system to fight disease and has been a promising new strategy for cancer therapy over the last decade. Immune checkpoint inhibitors (ICI), are monoclonal antibodies, that increase antitumor immunity by blocking intrinsic down-regulators of immunity, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1). Seven ICIs are currently approved by the Food and Drug Administration and have increased the overall survival for patients with various cancer subtypes. These are used either as single agents or in combination with other checkpoint inhibitors, small molecular kinase inhibitors or cytotoxic chemotherapies. There are also many other immune modifying agents including other checkpoint inhibitor antibodies that are under investigation in clinical trials.

Immune checkpoint inhibitor myocarditis: a systematic case study

Myocarditis is a life-threatening complication of immune checkpoint inhibitor therapy. Over the past ten years, drugs in this group have been used in the treatment of a wide range of hematological diseases and solid tumors. With steadily growing life expectancy of cancer patients, problems associated with treatment complications are increasingly coming to the fore. Since 2016, publications have appeared on cases of autoimmune myocarditis during checkpoint inhibitor therapy (CIT), among which there are quite a few single-center retrospective and observational studies. At the same time, the problem of diagnosis and treatment of immune checkpoint inhibitor myocarditis remains unresolved.This paper presents a review on the problem of immune checkpoint inhibitor myocarditis, as well as the results of a systematic analysis of PubMed database publications.

Abstract 13352: Decreased Absolute Lymphocyte Count and Increased Neutrophil Lymphocyte Ratio With Immune Checkpoint Inhibitors-associated Myocarditis

Introduction: Myocarditis due to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event (irAE). Hypothesis: Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil lymphocyte ratio (NLR) and the development of other irAEs; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods: This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI irAEs. We leveraged clinical testing where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events (MACE) was also tested. Results: In those who developed myocarditis, there was a decrease in ALC from baseline (1.6 K/μL, IQR 1.1-1.9) to admission (1.1 K/μL, IQR 0.7-1.3, p<0.001, Panel A). Similarly, among those who developed myocarditis, there was an increase in NLR from baseline (3.5, IQR 2.3-5.4) to admission (6.6, IQR 4.5-14.1, p<0.001, Panel B). There was no change in patients treated with an ICI who did not develop myocarditis. Among those who developed myocarditis, a greater decrease in ALC or increase in NLR was associated with a higher heart rate and a lower blood pressure at admission. In follow-up, there were 20 events; larger decreases in ALC or increases in NLR were associated with MACE (Panel C and D). Conclusions: A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR were associated with subsequent MACE.

Abstract 15833: Immune Checkpoint Inhibitor Myocarditis Subtypes are Determined by a Cd8-dependent Transcriptional Program

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing clinical use leads to higher rates of adverse immune related events (irAEs). One of those irAEs is the ICI-induced myocarditis (ICIM) - a rare phenomenon with an estimated mortality rate of up to 50%. We aimed to characterize the molecular changes of ICIM which are not yet understood completely. Methods: Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11) and virus-induced myocarditis (VIM, n=5). Results: Clinical analysis of 19 patients with ICIM showed an inconsistent presentation, e.g. an elevation of cardiac biomarkers (hsTnT, NT-proBNP, CK), a drop in leftventricular ejection fraction or late gadolinium enhancement in cMRI. We found 3784 (FDR <0.05) upregulated genes in ICIM. Among the genes that were related to antigen presentation and processing, we mainly found an upregulation of CD8. CD8-dependent clustering of ICI-patients, on the other hand, was associated with a number of immune cell-specific genes (compared to VIM: CXCL11 (log2 fc 3.24), CXCL9 (log2 fc 4.37), GBP6 (log2 fc 5.37), GBP5 (log2 fc 3.21). Analysis of high- and low-expressing CD8 positive biopsies identified two expression patterns, suggesting different pathological mechanisms for ICIM. Conclusion: Taken together, we were able to identify CD8 and CD8-associated genes as specifically regulated transcripts in ICIM. Moreover, based on the variable clinical phenotype, we propose that analysis of CD8 and CD8-dependent genes will be important to identify ICIM patients and to potentially sub-differentiate different phenotypes.

Decreased Absolute Lymphocyte Count and Increased Neutrophil/Lymphocyte Ratio With Immune Checkpoint Inhibitor-Associated Myocarditis.

BackgroundMyocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune‐related adverse event. Limited data have suggested an association between baseline and on‐treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune‐related adverse events; there are no data characterizing the role of ALC and NLR in ICI‐associated myocarditis.Methods and ResultsThis was a case control study of 55 patients with ICI myocarditis and 55 controls without any post‐ICI immune‐related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1–1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7–1.3 K/μL; P<0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3–5.4) to admission (6.6; interquartile range, 4.5–14.1; P<0.001). There was no statistically significant change in controls. In follow‐up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P<0.001) or increases in NLR (156.5% versus 65.1%; P=0.019) were associated with major adverse cardiac events.ConclusionsA reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

KEEPING IMMUNE CHECKPOINT INHIBITOR MYOCARDITIS IN CHECK: SIMULTANEOUS VENOARTERIAL ECMO AND IMPELLA SUPPORT AS A BRIDGE TO RECOVERY

As immunotherapy use in various malignancies expands, immune checkpoint inhibitor (ICI) myocarditis is a rare but potentially fatal complication requiring a high degree of clinical suspicion for early diagnosis and treatment. A 60 year-old female with colon cancer status post 3 months of nivolumab

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis

BackgroundThere is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. ObjectivesThis study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. MethodsThis study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. ResultsCases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). ConclusionsGLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms.

Immune checkpoint inhibitor therapy for malignancy has been associated with adverse events including myocarditis. It has been unclear if there are distinct pathologic grades of this myocarditis that are associated with distinct clinical outcomes. Cardiac tissue from ten patients with immune checkpoint inhibitor myocarditis (nine biopsies and one autopsy) were evaluated using immunohistochemistry for CD3, CD8, CD68, tryptase, PD-L1, and C4D. The immune checkpoint inhibitor myocarditis cases were classified as either high grade (>50 CD3+ cells/hpf) or low grade (≤50 CD3+ cells/hpf). The densities of macrophages, T cells, eosinophils, necrotic myocytes, and PD-L1+ macrophages and myocytes were compared between the two groups and with 13 cases of grade 2R acute cellular allograft rejection. Three patients were classified as high-grade myocarditis and seven as low grade. There were higher densities of CD3+ cells and CD8+ cells in high-grade immune checkpoint inhibitor myocarditis and rejection compared with low-grade myocarditis. The number of CD68+ macrophages was higher in high-grade myocarditis compared with low-grade myocarditis and rejection. For both grades of myocarditis, there was a higher CD68/CD3 ratio and a higher density of PD-L1+ macrophages and myocytes compared with rejection. Clinically, there were trends toward higher serum troponin levels and shorter interval from first immune checkpoint inhibitor treatment in the high-grade myocarditis group compared with the low-grade group. All the patients with high-grade myocarditis died, while all the patients with low-grade myocarditis were still living. These data suggest that immune checkpoint inhibitor myocarditis occurs in two forms, a high-grade form with increased inflammatory cell infiltration and a more fulminant clinical course, and a low-grade form with a lower degree of inflammatory cell infiltration and a more indolent clinical course. Compared with acute cellular rejection, immune checkpoint inhibitor myocarditis is characterized by a more lymphohistiocytic inflammatory infiltrate with an increased CD68/CD3 ratio and increased PD-L1+ macrophages and myocytes.

Association between EKG Alterations and Clinical Outcomes in Immune Checkpoint Inhibitor-Associated Myocarditis

Background Immune checkpoint inhibitors (ICIs) have revolutionized oncologic care. Myocarditis is an uncommon but frequently fatal complication of ICI use. There is need for improved methods of detection and risk stratification of ICI myocarditis. Both the QRS duration and the QTc interval on EKG are widely used, standardized, and easily interpretable measures; there are no data on the utility of these measures among patients with ICI myocarditis. Hypothesis We hypothesized that ICI myocarditis is associated with EKG abnormalities and that such abnormalities would correlate with worse clinical outcomes. Methods From a multicenter international registry, we compared the PR interval, QRS duration, and QTc interval from 110 ICI myocarditis cases and 178 controls. Where available, we measured these parameters from cases and controls prior to starting ICI and also while on ICI but prior to the development of myocarditis (for cases). The association between EKG measures and major adverse cardiac events (MACE) was tested. Cases and controls were compared using the pair-wise Wilcoxon rank-sum test with Bonferroni correction, MACE Kaplan-Meier curves were compared with the log-rank test, and hazard ratios (HR) were determined using the Cox proportional hazards model. Results The PR interval, QRS duration, and QTc interval were similar between cases and controls both prior to ICI and after initiation of ICI but prior to myocarditis (in cases). At presentation with myocarditis, cases had a similar PR interval, but longer QRS duration (107±22 ms vs 91±19 ms; p 110 ms conferred a 2.6-fold increased risk of MACE (95% confidence interval [CI] 1.5-4.4; p 450 ms also conferred a 2.6-fold increased risk (95% CI 1.3-5.1; p=0.003; figure B). Conclusions Increases in QRS duration and QTc interval, but not PR interval, were observed in ICI myocarditis and were each associated with increased risk of MACE. Measurement of these standardized and widely available parameters may be helpful in diagnosing ICI myocarditis and identifying those with ICI myocarditis at elevated risk of MACE.

Steroid-Refractory Immune Checkpoint Inhibitor-Associated Myocarditis

Background Immune checkpoint inhibitors (ICIs) are a paradigm shift in cancer care, leveraging the immune system to target cancer cells. Myocarditis is an uncommon, highly morbid, and poorly understood complication of ICI therapy. We present a case of steroid-refractory ICI myocarditis and discuss management. Case An 88-year-old man with metastatic melanoma who had recently started pembrolizumab (anti-PD-1 antibody) reported fatigue. Testing revealed a creatine kinase of 3,005 U/L (normal Discussion Reports have indicated that myocarditis develops in 0.4-1% of ICI recipients. Mortality is estimated at 17-40%, far exceeding the approximately 4% mortality associated with non-ICI lymphocytic myocarditis. There are currently no prospective data to guide management. Expert opinion recommends therapy with high-dose glucocorticoids, followed by other immunosuppressive agents in cases of steroid-refractory disease, including anti-TNFα agents (infliximab), mycophenolate mofetil, intravenous immunoglobulin, plasmapheresis, tacrolimus, or anti-thymocyte globulin. Conclusion ICI myocarditis carries a high morbidity and mortality. Expert opinion recommends high-dose steroids as the initial therapy and the addition of other classes of immunosuppression in refractory cases. Prospective studies are critically needed to define the optimal treatment regimen.

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys. Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29. Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans. We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.

Immune checkpoint inhibitor myocarditis.

The purpose of this study is to summarize and highlight the recent literature regarding immune checkpoint inhibitor myocarditis. The use of immune checkpoint inhibitors, a promising form of immunotherapy, is rapidly increasing in oncology. These drugs have been recently found to cause a fulminant myocarditis associated with a high-case fatality rate. Most patients present early in the course of treatment with positive cardiac biomarkers. Endomyocardial biopsy findings resemble high-grade cardiac transplant rejection. Treatment requires cessation of immunotherapy, aggressive immunosuppression, and hemodynamic stabilization. Immune checkpoint inhibitor myocarditis is a newly described entity. Although relatively uncommon compared with other immune-related adverse events associated with these drugs, it is associated with the highest rate of mortality.

DECREASED GLOBAL LONGITUDINAL STRAIN WITH MYOCARDITIS FROM IMMUNE CHECKPOINT INHIBITORS AND OCCURRENCE OF MAJOR ADVERSE CARDIAC EVENTS

Myocarditis is a serious and poorly characterized complication from immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving chemotherapy. There are no data on the use of GLS in ICI myocarditis. We compared

IMMUNE CHECK POINT INHIBITOR MYOCARDITIS MIMICKING ACS

Myocarditis is a rare but life-threatening complication of immune checkpoint inhibitors (ICI). We report a case of ICI myocarditis which was misdiagnosed as ACS. A 71-year-old gentleman was transferred for acute shortness of breath for 2 days. He had dynamic ST-segment elevation in inferior leads