UNIVERSITA’ DI PISA
SCUOLA DI SPECIALIZZAZIONE IN MALATTIE DELL’APPARATO CARDIOVASCOLARE
Direttore: Prof Roberto Pedrinelli
Biohumoral and echocardiographic parameters in the prediction of
cardiovascular events or cardiotoxicity after cancer treatment with
immune checkpoint inhibitors
Candidato
Dr.ssa Serena Petricciuolo
PRIMO RELATORE ACCADEMICO
RELATORE
Prof. Roberto Pedrinelli
Prof. Raffaele De Caterina
CORRELATORE
ABSTRACT
Background and Aims: Immune checkpoint inhibitors (ICI) have revolutionized cancer
treatment, but have been associated with immune-related adverse events (irAEs). Early diagnosis of irAEs is important to enact early treatment. We aimed at analyzing the prognostic role of high-sensitivity cardiac troponin T (TnT-hs) and echocardiographic parameters, including 2D global longitudinal strain (GLS), in irAEs.
Methods and Results: We prospectively studied 30 lung cancer patients, 23 men (76%),
median age 68 (95% CI 58-73 years), before and after ICI therapies. Patients underwent a baseline and an 80-day (95% CI 65-107) follow-up examination, after an average 5 cycles of chemotherapy. At baseline, all patients had normal ejection fraction [57.2% (54.2-59.35)] and GLS [17.5 (15.9-19.5%)]. Median TnT-hs values across a first ICI cycle were 11 (8-19.5) and 14 (8.75-25.25) ng/L, respectively. Three (10%) patients died, and two (6%) had pericardial disease. Such major adverse CV events at follow-up all occurred in patients with baseline TnT-hs ≥14 ng/L - upper normal reference limit (p=0.01 vs patients with baseline TnT-hs<14 ng/L). TnT-hs values at baseline ≥14 ng/L were also associated with a higher (p=0.006) risk of ESC guidelines-defined cardiotoxicity. We found no correlation between basal TnT-hs values and changes in GLS (p=0.171); or between pre-/post-cycle changes in TnT-hs and changes in GLS (p=0.568). At receiver-operator curve (ROC) analysis, a TnT-hs value ≥14 ng/L was the best cut-off predicting all-cause mortality (AUC 0.807, sensitivity=100%, specificity=61%), CV events (AUC 0.865; sensitivity=100%, specificity=69%) and cardiotoxicity (AUC 0.739; sensitivity=80%, specificity=67%).
Conclusions: In early cancer treatment with ICI, baseline TnT-hs ≥14 ng/L, but not
pre-/post ICI TnT-hs changes or changes in echocardiographic parameters, including GLS, predicts CV events and cardiotoxicity.
Key words: cancer; chemotherapy; immune checkpoint inhibitors; cardiac troponin T;
INTRODUCTION
The development of immunotherapies in oncology since 1990s has revolutionized the management of an increasing number of advanced-stage malignancies previously burdened with a dismal prognosis1,2. Immune checkpoint inhibitors (ICIs), including monoclonal antibodies (mAbs) against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1), are now being routinely used in clinical settings and have shown unprecedented efficacy in treating multiple cancers3,4.
Pathophysiology of targets for immune checkpoint inhibitors
Dead cancer cells release neoantigens, captured by antigen-presenting cells (APC) and presented to T-lymphocytes together with major histocompatibility complex (MHC) molecules5. CD8+ and CD4+ T-cells in lymph nodes recognize the MHC I and MHC II complex neoantigens, respectively, are thus activated, and migrate to the tumor bed (Figure 1), where they recognize cancer cells through the interaction between neoantigen-MHC complex and T cell receptors (TCR) on T-cells5.
Co-stimulatory signals from the binding of B7 and CD28 can modulate the T-cell activation process. The same occurs with co-inhibitory signals from the binding between cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-L1) with their respective ligands, B7 and PD-1 ligand (PD-L1)6,7. In such cases, the cellular immune response is “turned off” by inhibitory receptors expressed on T-lymphocytes, for instance cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1), tethered to their corresponding ligands on cancer cells, e.g., programmed cell death 1 ligand-1 (PD-L1)8. Taking advantage from this process, tumor cells are not recognized and, consequently, not destroyed by the immune system, merely up-regulating the expression of PD-L19. ICIs “turn back on” the cellular immune response against cancer cells, counteracting these immune checkpoints9.
To date, seven ICIs have been approved by the United States Food and Drug Administration: ipilimumab (an inhibitor of CTLA-4), nivolumab, cemipilimab and pembrolizumab (inhibitors of PD-1); atezolizumab, avelumab, and durvalumab (inhibitors of PD-L1) (Table 1)10. These drugs have shown remarkable results in treating advanced metastatic cancers, including melanoma, non-small cell lung cancer (NSCLC), renal cell
carcinoma, head and neck squamous cell carcinoma, urothelial cancer, refractory Hodgkin’s lymphoma, and malignancies with microsatellite instability11
. In order to improve their efficacy, combined ICIs, in particular ipilumab and nivolumab, are being used 12.
The blocking of the immune checkpoints achieves rapid tumor regression in some patients, but the systemic activation of autoreactive T cell can also damage host tissues13, causing a range of toxicities, such as thyroiditis, myositis, dermatitis, hypophysitis, colitis and hepatitis14. ICI’s clinical use increases the need for a better management of immune-related adverse events (irAEs)9. These are generally managed with corticosteroids and, less commonly, with other immunomodulatory agents15.
CARDIOTOXICITY ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITION
The first report of fulminant myocarditis shortly after combined ICI treatment was described in 2016 by Johnson et al., in a retrospective clinical trial population study, in which they defined the basic clinical and pathophysiological characteristics16. In a recent retrospective study of immune-related cardiovascular adverse events, using VigiBase – the World Health Organization’s (WHO) global database of individual case safety reports – in patients who had received ICI, the odds of myocarditis were 11 times more frequent than in patients who had not received ICI17. A cohort study of 964 patient from a multicenter registry reported a prevalence of 1.14%, which increased to as high as 2.4% for combination therapy with anti-PD-1/anti-CTLA-418. Therefore, ICI-associated myocarditis appears to be a class effect, and the incidence seems to be higher when patients are treated with a combination of ICIs16,18.
The prevalence of myocarditis after ICI has steadily increased over the years, thus relating the use of these drugs in a larger population of advanced cancer patients to the increased incidence of this complication19. A key limitation in this therapeutic area is the lack of robust techniques for the detection of ICI myocarditis and the lack of tools for risk stratification in patients once myocarditis has developed20.
Other inflammatory cardiovascular adverse events (irAEs) have been also associated with ICI treatment, particularly pericardial disease and vasculitis17. ICI-associated pericardial disease can present as pericarditis21,22, pericardial effusion21,23, or cardiac tamponade22,23. Non-inflammatory cardiovascular toxicities have been reported in individual cases. These include myocardial infarction24; coronary vasospasm25; asymptomatic non-inflammatory left-ventricular dysfunction26; Tako-tsubo-like syndrome with both the apical27,28 and basal variants29. There are also cases of patients developing arrhythmias, but this kind of side effect is common in the cancer population and should be correlated to other complications, e.g., acute thyroiditis17. Some case reports of ICI-associated third-degree atrioventricular block and conduction disease have been often reported secondary to myocarditis involving the conduction system30,31.
Troponin T
Patients likely to develop cardiac irAEs cannot be identified before ICI therapy. Therefore, early detection of them is important for improved management, particularly for ICI-related myocarditis10. Mahmood et al.18 showed how useful for surveillance is measurement of
high-sensitivity cardiac troponin T (TnT-hs) levels at baseline and after each cycle of ICI treatment, with this parameter being abnormal in 94% of ICI-myocarditis patients at clinical presentation. In contrast, Sarocchi et al.32 measured TnT levels at each nivolumab administration in 59 patients, and found elevations in only six patients, none of whom developed overt cardiac irAEs. These researchers mentioned possible reasons for a “false positive” elevation of Tn, including it being a consequence of a myocardial oxygen demand-supply mismatch due to worsening of the clinical status or the presence of subclinical ICI-induced myocarditis. An elevation of Tn indeed indicates the presence of myocardial injury, but it is does not identify the underlying cause. Therefore, myocarditis or other causes of myocardial injury should be always considered in cases presenting with elevated Tn, and these patients should be referred immediately to cardiologists for further evaluation18.
Natriuretic peptides B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are established biomarkers that aid in the diagnosis of heart failure and are often elevated in the setting of ICI-related myocarditis. Mahmood et al18 reported that 66% of the patients in their series with ICI-related myocarditis had elevated BNP or NT-proBNP levels. In contrast to TnT, the elevation in natriuretic peptides did not predict major adverse cardiovascular events (MACEs). Similar to Tn, this class of biomarkers is also nonspecific for ICI-related myocarditis, and prompt the need for evaluating the clinical picture along with imaging modalities to confirm the diagnosis33.
Electrocardiography
New finding on the electrocardiogram (ECG) can help identifying myocarditis or pericarditis. This is especially important for patients receiving ICI, in particular if any of the following are noted: atrio-ventricular block, new prolongation of the PR interval, frequent premature ventricular complexes, ST depression or T-wave inversions33.
Echocardiography
Echocardiography is an important aid to diagnose IRAEs, in particular for myocarditis, and to monitor the response to treatment. Patients may present a normal left ventricular ejection fraction (LVEF) with abnormalities of diastolic parameters or new regional wall motion abnormalities34. Patients with a severe life-threatening syndrome of myocarditis may have depressed LVEF at presentation18. In the cohort of 35 patients with
ICI-those who developed MACEs had normal LVEF18. Supporting evidence of myocarditis is the presence of a new pericardial effusion, easily assessed by echocardiography. The current American Society of Clinical Oncology (ASCO) clinical practice guidelines for prevention and monitoring of cardiac dysfunction in survivors of adult cancers recommend obtaining a baseline echocardiogram before initiating any potentially cardiotoxic therapy35, but the specific ASCO guidelines for the management of IRAEs in patients with ICI therapy do not recommend for or against the routine use of echocardiography before initiating ICI36.
2D global longitudinal strain
The measurement of LV global longitudinal strain (GLS) has been extensively applied in the detection of cardiac injury with traditional cytotoxic chemotherapies and for the prediction of subsequent cardiac events after chemotherapy37,38. Specifically, GLS decreases acutely among patients with chemotherapy-induced cardiotoxicity39. There are no prospective data on the use of GLS in ICI-related myocarditis. A recent retrospective study showed how GLS is reduced in patients with ICI myocarditis among those presenting with both a preserved and reduced LFEF. In the follow-up, a decrease in GLS is strongly associated with MACEs in ICI myocarditis40. Additional work is needed to test if the GLS decrease occurs prior to the development of clinical myocarditis and if it can provide an early method of detection.
METHODS
Study population
Thirty patients with advanced lung cancer were prospectively enrolled within a single-institutional research study at the Cardiovascular Division of Pisa University Hospital, and
screened between September 2019 and March 2020 for a prospective,
electrocardiographic, echocardiographic and circulatory biomarker correlation study to assess factors predictive of the response and toxicity during ICI treatment.
The main inclusion criteria were as follows: age ≥18 years, histologically or cytologically confirmed lung cancer (non-small cell lung carcinoma – NSCLC –, adenocarcinoma, neuroendocrine lung cancer or pleural mesothelioma), clinical stage IIIb or IV (according to the Tumor-Node-Metastases – TNM – classification), previously treated or stable brain metastases assessed at least one month prior to treatment with ICI.
Nivolumab was administered at the dose of 240 mg every 15 days; pembrolizumab at the dose of 200 mg every 21 days; atezolizumab 1200 mg every 21 days; durvalumab 10 mg/kg every 44 days.
The study protocol required measurement of TnT-hs across each cycle to detect cardiac injury. TnT-hs was determined on frozen serum aliquots with a homogeneous sandwich immunoassay based on the ElectroChemiLuminiscence ImmunoAssay (ECLIA) technique on a COBAS apparatus (Roche). The hsTnT assay has a normal reference limit (upper 99th percentile of the normal value distribution) at 14 ng/L. BNP was measured on the ARCHITECT System, Abbott. The lower limit of detection is here at 100 pg/mL.
Follow-up echo data were obtained at 3 months from the first cycle with a scheduled global cardiology visit including a follow-up electrocardiographic, echocardiographic examination or global examination during the oncology visit. Renal function (estimated glomerular filtration rate, eGFR) was assessed with the Chronic kidney disease (CKD)-Epi formula.
Electrocardiography
All patients underwent an electrocardiographic examination with a standard 12-lead recording at the beginning of ICI treatment and at follow-up, evaluating changes in rhythm (new atrial fibrillation or other arrhythmias) and measuring the PR, QRS and QTc (Bazett) intervals.
Echocardiography
All patients underwent a complete transthoracic echocardiographic examination with a heart-dedicated machine (Philips iE33 ultrasound system, with 2.5–3.5 MHz transducers). Patients were examined in the left lateral decubitus, and data acquisition was performed with a matrix (M5S) probe at a depth of 16 cm in the apical (two-chamber, four-chamber, and long axis) and parasternal (long- and short-axis) views, according to current recommendations41,42.
Using standard M-mode and 2-D images in the parasternal long-axis views, we calculated LV dimensions, including end-diastolic/end-systolic LV diameters, the end-diastolic thickness of the interventricular septum and of the posterior wall. We used the body surface area (BSA) to correct LV mass calculations and derive the LV mass index (LVMI). We used both the apical 2- and 4-chamber views to evaluate the LV end-diastolic and end-systolic volumes and also the standard Simpson’s rule to calculate the LVEF. We performed spectral pulsed-wave Doppler analysis to assess LV diastolic function, measuring early (E-wave) and late (A-wave) trans-mitral velocities, the E/A ratio, and the E-wave deceleration time (DT). We performed TDI assessments, adjusting gain and frame rate to optimize tissue characterization41,42. We used 2D speckle tracking echocardiography (2D STE) (frame rate 45-90 frames/s, fps) to asses LV GLS, according to current standards42. Data sets were stored digitally in raw form, and exported to a workstation equipped with a commercial software. A value of -18% at the follow-up, or 15% relative reduction of GLS from baseline was considered indicative of subclinical cardiotoxicity according to the American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) Expert Consensus42.
Grading of myocardial injury/dysfunction
Myocardial injury/dysfunction was defined by the presence of abnormal multiparametric values including biomarkers, LV function and GLS parameters or clinical symptoms of Heart Failure (HF). Using the definition of cardiotoxicity applied in the CARDIOTOX trial, according to European Society of Cardiology (ESC) guidelines, different degrees of myocardial injury/dysfunction, requiring different treatment, were defined as illustrated in
Figure 243,44,45:
- Normal: no evidence of myocardial injury/dysfunction. Asymptomatic patients with normal biomarkers and LV function parameters;
- Mild: asymptomatic patients with LVEF ≥50% with elevated biomarkers or at least one additional abnormal echo parameter (increased LV end-systolic volume (ESV), left atrial area (LAA) >30 cm2, 10% decrease of LVEF to an LVEF <53%, average E/e’ >14, GLS >-18%, 15% relative reduction of GLS from baseline);
- Moderate: asymptomatic patients with LVEF ≥40% and <50% with or without biomarker increase or other LV function abnormalities;
- Severe: patients with asymptomatic LVEF<40% or clinical HF. Heart failure was defined as follows: HF with reduced ejection fraction (HFrEF): HF symptoms/signs and LVEF<40%; HF with mid-range ejection fraction (HFmrEF): symptoms/signs of HF with elevated NT-proBNP, LVEF 40–49% and at least one additional criterion (enlarged LA, LV hypertrophy, or other relevant diastolic function parameters); and HF with preserved ejection fraction (HFpEF): in presence of symptoms/signs of HF, elevated NT-proBNP, LVEF≥50%, and at least one additional criterion (enlarged LA, LV hypertrophy, or other diastolic dysfunction parameters)44.
Statistical analysis
We used the IBM SPSS Statistics (version 22, 2013) and R statistical software ( http://www.r-project.org/, version 3.4.4) for all calculations. Normal distribution was assessed with the Kolmogorov-Smirnov test; as all continuous variables had a non-normal distribution, they were expressed as medians and interquartile ranges (IQR). Mean differences between groups were evaluated through the Mann-Whitney U-test, while categorical variables were compared by the Chi-square test with the Yates correction. The strength of correlations was calculated by Spearman's rho values. Kaplan-Meier survival curves were derived. Univariate Cox regression analysis was performed to assess the prognostic value of troponin and GLS; multivariate analysis was not performed in agreement with the "one-in-ten" rule. Area under the curve (AUC) values were derived and compared through discrimination analysis. We considered two-tailed p values <0.05 as statistically significant.
RESULTS
The study population included 30 lung cancer patients treated with ICI (68 years, 95% CI 58-73 years) of whom n=23 (76%) were male. Demographic, bio-humoral and echocardiographic characteristics of the overall population divided into tertiles 1 and 2 combined vs tertile 3 are summarized in Table 2.
The median number of administrated cycles was 5 (range 2-16). All patients received the first cycle of ICI therapy. Fourteen patients (47%) received pembolizumab, eight (27%) nivolumab, four (13%) durvalumab, and four (13%) atezolizumab.
Three (10%) patients died, 2 (6%) of cardiac arrest and pericardial tamponade, both with previous coronary artery disease, and 1 (3%) of non-cardiologic primary causes. Pulmonary embolism occurred in 1 (3%) patient. Pleural effusion occurred in 3 (10%) patients, causing, in 2 cases, acute respiratory failure and heart failure. None of the 30 patients treated with ICI had myocarditis.
A total of 132 blood samples were available for TnT-hs. Median TnT-hs values across a first ICI cycle were 11 (8-19.5) and 14 (8.75-25.25) ng/L, respectively. Detailed characteristics of the echocardiographic and electrocardiographic parameters of the patients with hsTnT ≥14 ng/L and <14 ng/L before beginning ICI and at follow-up are shown in Table 3.
Two (6%) patients had prolonged QTc, 2 (6%) had premature ventricular complexes at the follow-up and none had atrioventricular block. Six patients showed disease progression. A combined therapy was administered to 3 patients, using nivolumab together with two anticancer drugs (carboplatinum and permetrexed), and none of them had cardiovascular side effects.
We found a significant correlation between TnT-hs basal value and the composite CV endpoint, including CV death, stroke/transient ischemic attack, pulmonary embolism and heart failure (HR 1.09, 95% CI 1.03-1.14, p=0.001). There was also a significant correlation (HR 1.08, 95% CI 1.02-1.13, p=0.008) between basal TnT-hs and the risk of ESC guidelines-defined cardiotoxicity, as defined in the recent CARDIOTOX trial.
Patients having any of such major adverse CV events at follow-up all had a baseline TnT-hs ≥14 ng/L (p=0.01) vs patients with baseline TnT-TnT-hs<14 ng/L. TnT-TnT-hs values at baseline
≥14 ng/L – coinciding with the upper normal reference limit – were also associated with a higher (p=0.006) risk of cardiotoxicity. In particular, 10 (33%) patients developed moderate or severe cardiotoxicity (Figure 2).
We found no correlation between basal TnT-hs values and GLS (p=0.375), basal TnT-hs values and GLS changes (p=0.171); or between pre-/post-cycle changes in TnT-hs and GLS (p=0.568). We found no correlation between basal GLS and CV endpoints (p=0.145); and between basal GLS and the risk of cardiotoxicity (p=0.256).
At receiver-operator curve (ROC) analysis, a TnT-hs value ≥14 ng/L was the best cut-off predicting all cause death (AUC 0.807, sensitivity 100%, specificity 61%), CV events (AUC 0.865; sensitivity 100%, specificity 69%). We found similar results for the other endpoint of cardiotoxicity (AUC 0.739; sensitility 80%, specificity 67%). Therefore, we found a relationship between basal TnT-hs value ≥14 ng/L before starting ICI and the composite CV endpoint (P=0.001; Log Rank 10.3) on the one hand; and the cardiotoxicity endpoint (P = 0.032; Log Rank 4.7) on the other (Figure 3).
DISCUSSION
Few prospective studies have evaluated irAEs in ICI therapy, despite the fact that such occurrences frequently complicate therapy and require drug discontinuation in 40% of patients12,46. No data are available to define the best cardiac monitoring strategy for detection and risk stratification of complications in ICI patients32. Ours is a prospective study in a selected population of advanced cancer patients (lung cancer) showing the important role of TnT-hs evaluation at the beginning of ICI treatment. IrAEs are most common in the first weeks (79 days, interquartile range 60-108) after the beginning of therapy as reported in previous studies18,47. At ROC-analysis we found that a TnT-hs value ≥14 ng/L was the best cut-off predicting all cause death, CV events, and cardiotoxicity. All patients had normal ECG and normal LVEF in the absence of abnormalities of regional wall motion at the beginning of therapy, so we consider basal levels of TnT-hs above normal limits as due to the possible presence of a myocardial oxygen demand-supply mismatch or to comorbidities, such as heart disease in a chronic phase in patients with CV risk factors48,49,50. There were no differences between pre-/post-cycle TnT-hs values (∆% TnT-hs pre/postcycle = 9.1% (IC 95% 0.6-13.66%) p=1.0.
In our study, patients with TnT-hs ≥14 ng/L had a higher prevalence of CV risk factors, such as diabetes (p=0.006) and hypertension (p=0.017) compared with patients with normal TnT-hs. Moreover, 2 patients who died of CV death both had a history of previously revascularization and TnT-hs ≥14ng/L.
The presence of diabetes mellitus, obstructive sleep apnea and obesity were associated with a higher risk of myocarditis caused by ICI also in the largest study of IrAEs18, while another recent retrospective study identified a history of acute coronary syndrome (ACS), HF or advanced age as additional important risk factors for the development of IrAEs51. We could not find any correlation between basal TnT-hs values and GLS changes (p=0.171); or between pre-/post-cycle changes in TnT-hs and GLS (p=0.568). This is in line with a recent retrospective study in which ICI patients with myocarditis had a GLS decrease compared with control subjects (p<0.001)40. None of our patients had symptomatic myocarditis.
As take-home messages, and in accordance with ASCO guidelines, we therefore suggest an evaluation of basal TnT-hs before beginning ICI also in asymptomatic patients: indeed, a basal value of TnT-hs is useful to indicate which patients must receive an accurate CV evaluation before and during this therapy, also on the basis of risk factors and
comorbidities36. In our study neither serial TnT-hs measurements nor multiparametric echocardiographic evaluation at follow-up (despite these latter showing changes in LV function) provided any additional prognostic information.
Study limitations
We acknowledge several limitations of our study. Ours is a prospective study with a limited number of selected patients with lung cancer and a short follow-up. Our follow-up duration, however, is compatible with data from all previous analyses showing that irAEs and cardiotoxicity were diagnosed in ICI patient at a median of 34-65 days18,47.
The small number of patients precluded the addition of other covariates such as the presence of specific risk factors and possible associations of outcomes with any specific single therapeutic agent here used. We found TnT-hs as a predictors of CV prognosis and the cut off of 14 ng/L as an excellent cut-off to predict a worse CV outcome. We cannot, however, exclude that additional parameters among those evaluated by us might also predict CV events or cardiotoxicity, due to a type II statistical error.
For all these reasons, the present has to be considered a pilot study to identify predictors of immunotherapy-related CV deterioration.
WHAT’S NEW
Our study was a prospective analysis finding that baseline TnT-hs ≥14 ng/L, but not pre-/post ICI cycle TnT-hs changes or basal echocardiographic parameters, including GLS before the beginning of the therapy, predicts CV events and cardiotoxicity in early cancer treatment with ICI.
By applying the CARDIOTOX scheme in ICI patients and considering the progression to moderate or severe states at follow up, we found a correlation to basal TnT-hs with worse CV outcomes. This biomarker may be therefore applicable in larger prospective studies.
CONCLUSIONS
The real incidence of early and late cardiotoxicity associated with immune checkpoint blockade is largely unknown. The routine assessment of TnT-hs in cancer patients before starting ICI is therefore important. When TnT-hs values are ≥14 ng/L, especially in the presence of one or more risk factors or a previous history of heart disease, consultation with a cardiologist is fundamental to increase the likelihood of early diagnosis of heart disease and the enactment of timely treatment for irAEs.
Prospective larger studies are needed to verify the accuracy of further additional biomarkers (e.g., growth differentiation factor (GDF)-15) and of parameters derived from cardiac magnetic resonance in patients with TnT-hs ≥14 ng/L to improve baseline evaluation and guide early and late follow-up in subjects at risk.
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Table 1. ICIs and their Federal Drug Administration (FDA)-approved indications as of December 2018
ICI FDA
Approval Year
Target Types of Cancers with FDA Approval for Treatment
Ipilimumab 2011 CTLA-4 Melanoma (unresectable or metastatic)
Renal cell carcinoma (advanced or metastatic) Microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer
Nivolumab 2014 PD-1 Melanoma (unresectable or metastatic) or as adjuvant
Squamous NSCLC (metastatic)
Renal cell carcinoma (advanced)
Classical Hodgkin’s lymphoma (relapsed)
Head and neck squamous cell carcinoma (recurrent or metastatic)
Urothelial carcinoma (advanced or metastatic)
Microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer Hepatocellular carcinoma (refractory)
Renal cell carcinoma (advanced or metastatic)
Pembrolizumab 2014 PD-1 Melanoma (unresectable or metastatic)
NSCLC (metastatic)
Head or neck squamous cell carcinoma (recurrent or metastatic)
Classical Hodgkin’s lymphoma (refractory)
Urothelial carcinoma (locally advanced or metastatic)
Microsatellite instability-high or mismatch repair deficient solid tumours and colorectal cancer
Gastric or gastroesophageal junction adenocarcinoma (locally advanced or metastatic)
Primary mediastinal large B cell lymphoma (refractory)
Hepatocellular carcinoma
Merkel cell carcinoma (recurrent or metastatic)
Atezolizumab 2016 PD-L1 Urothelial carcinoma (locally advanced or metastatic)
NSCLC (metastatic)
Durvalumab 2017 PD-L1 Urothelial carcinoma (locally advanced or metastatic)
NSCLC (unresectable Stage III)
Avelumab 2017 PD-L1 Merkel cell carcinoma (metastatic)
Urothelial carcinoma (locally advanced or metastatic)
Cemiplimab 2018 PD-1 Cutaneous squamous cell carcinoma (metastatic)
1
Table 2. Demographic and baseline clinical characteristics of cancer patients treated with Immune Checkpoint Inhibitors Overall TnT-hs ≥14 ng/L TnT-hs<14 p value (N = 30) (N = 13) (N = 17) Age 68 (59-75) 69 (63-77) 60.5 (53.5-72) 0.015 Male 23 (76.7) 12 (92.3) 10 (62.5) 0.062 BMI (kg/m2) 25.76 (23.68-28.23) 27.88(25.05-30.03) 23.14-27.37) 0.144 BSA (m2) 1.9 (1.7-2) 2 (1.8-2.05) 1.8 (1.7-1.9) 0.059 SBP (mmHg) 120 (120-137) 120 (115-135) 122.5 (120-138.75) 0.329 DBP (mmHg) 80 (70-85) 75 (70-82.5) 80 (70-88.75) 0.398 Saturation 98 (96.5-99) 98 (96-99) 98 (97-99) 0.682 Heart rate 80 (73.5-93) 76 (64-88.5) 84.5 (73.5-96.5) 0.449 CV risk factor Hypertension 13 (43.3) 9 (69.2) 4 (25) 0.017 Diabetes 6 (20) 5 (38.5) 0 0.006 Current or prior smoking 27 (90) 12 (92) 14 (82) 1 Dyslipidemia 12 (40) 7 (53.8) 4 (25) 0.142 COPD 1 (3.3) 0 1 (0.05) 0.359 Chronic kidney disease 3 (10) 2 (15.4) 0 0.104 Coronary artery disease 4 (13.3) 2 (15.4) 1 (6.3) 0.422
Current or prior atrial fibrillation
3 (10) 2 (15.4) 1 (6.3) 0.422
Lung cancer
Squamous 7 (23) 3 4 (23) Mesothelioma 3 (10) 2 (3) 1 (0.05) Neuroendocrine 1 (0.03) 0 1 (0.05) Prior chemotherapy 15 (50) 5 (38.5) 9 (56.3) Prior radiation 8 (26.7) 4 (30.8) 3 (18.8) Metastases 21 (70) 12 (92.3) 8 (50) Bioumoral characteristics Creatinine 0.86 (0.80-1.15) 1.14 (0.99-1.69) 0.82 (0.67-0.85) 0.004 Creatinine Clearance (mL/min kg) 77 (64.5-100.5) 61.5 (38.5-75.75) 88.7 (69.47-104.8) 0.004 TnT-Hs (ng/l) 11 (8-19.5) 23 (15-29) 8.5 (7-11) Hemoglobin 12.3 (11.5-14) 12.3 (11.1-13.6) 12.65(11.52-14.3) 1 Echocardiographic parametres LV EDVi (ml/m2) 108 (72.5-125) 117 (65-130) 101 (75.5-119) 0.779 LV ESVi (ml/m2) 43 (29.5-57.5) 58 (35-63) 36 (28.5-51) 0.374 EF (%) 57.2 (54.2-59.35) 56.1 (52.5-57.6) 57.7 (55-61.57 0.288 GLS (%) - 17.5 (15.9-19.5) - 18 (15-20) - 17.3 (16.12-20.2) 0.559 LAVi (cm2/m2) 16.3 (14-27.5) 29 (19.9-42.2) 14.7 (11.87-16.52) 0.001
Stroke Volume Index 59 (43.5-70) 62.4 (46-70) 56.5 (42.25-74.75) 0.983
E/e' average 7.6 (6.3-8.9) 8.1 (7-9.7) 7.1 (5.4-8.5) 0.100
TAPSE 20 (18.5-23) 20 (18-24) 21.5 (18.2-23) 0.268
2
Table 3. Echocardiographic and electrocardiographic parameters
All pre TnT1≥14ng/L TnT1<14ng/L All follow-up TnT2≥14ng/L TnT2<14ng/L
LVEDVi(ml/m2) 108 (72.5-125) 117 (65-130) 101 (75.5-119) 99 (73-117) 95 (76.5-113) 99 (60-116) LVESVi(ml/m2) 43 (29.5-57.5) 58 (35-63) 36 (28.5-51) 46 (34-53) 46 (37.5-53) 46 (29-59) EF (%) 57.2 (54.2-59.35) 56.1 (52.5-57.6) 57.7 (55-61.57 52.6 (48-57) 48 (46-54) 53 (51-60) GLS (%) - 17.5 (15.9-19.5) - 18 (15-20) - 17.3 (16.12-20.2) -16.7 (14.5-18.3) - 15.7 (15.2-16.8) - 17.5 (14-19) LAVi (cm2/m2) 16.3 (14-27.5) 29 (19.9-42.2) 14.7 (11.87-16.52) 17.3 (13-22) 18 (17-28) 16 (12-21) SV Index 59 (43.5-70) 62.4 (46-70) 56.5 (42.25-74.75) 52 (39-66) 40 (39-62) 52 (32-66) E/A 0.7 (0.6-0.85) 0.75 (0.7-0.8) 0.7 (0.6-0.9) 0.7 (0.5-0.8) 0.57-0.82) 0.8 (0.6-0.8) velE 61.2 (49.6-72.5) 62.4 (60.8-77.8) 56.5 (49-73.2) 62 (47.6-77.2) 62.2(54.2-71.8) 60.15 (43-78) velA 80 (74.7-93.8) 82.9(75.5-102.8) 79.5 (70.8-89.5) 85 (72-96.5) 89.6 (71-110) 86 (71-95) dec time 158.4 (120-195) 151.4 (110-194) 159.2 (119.7-206.7) 183 (151-208) 221 (167-278) 181(145-198) Aortic radice 32 (30-34) 31.5 (30.2-33.7) 31.5 (29.2-34) 33 (31-35.5) 34 (31-34) 32 (31-35.7) e'septal 6.2 (5.4-8.4) 6.3 (5.5-7.7) 6.2 (5.2-9.2) 6.3 (4.8-7) 6.3 (4-6.7) 6.3 (5.45-7.4) e' lateral 8.6 (6.8-10) 7.9 (6.9-9.5) 8.7 (6.8-12.1) 8.3 (6.2-10) 5.7 (4.3-9.8) 8.85 (7.2-10.5) E/e' average 7.6 (6.3-8.9) 8.1 (7-9.7) 7.1 (5.4-8.5) 8.7 (6.6-11.8) 10.6 (8.4-15.2) 7.6 (6.3-9.7) TAPSE 20 (18.5-23) 20 (18-24) 21.5 (18.2-23) 18 (17-20) 15 (14.5-16.5) 19 (18-21) PR 149 (131-180) 164 (119.5-192) 150.5 (137.7-168.7) 160 (139-182) 168 (123-190) 160 (140-184) QRS 97 (83.5-111) 95.5 (85.2-117.2) 93.5 (83-104.7) 93 (80-110) 94 (82.5-155.5) 89 (80-105) QTc 403 (390-418) 401 (389-416) 402.5 (390.2-419) 407 (393-426) 426 (407-463) 400 (393-424) 3 3
Dec time, deceleration time; EF, ejection fraction; GLS, global longitudinal strain; LVEDV, left ventriclular end diastolic volume; LVESV, left ventricular end systolic volume; LAVi, left atrial volume index; LV, left ventricular; TAPSE, tricuspid annular plane excursion; TnT-hs, Troponin T high sensitive.
Figure 1. Cell surface receptors and ligands at immune checkpoints.
(A) Interactions between CTLA-4/B7 and PD-1/PD-L1 inhibit T cell-mediated tumor cell killing. (B) Blockade of CTLA-4, PD-1, and PD-L1 results in T cell activation and proliferation, which reactivates T cell-mediated tumor cell killing.
Figure 2. Kaplan Meier curves for pre-TnT-hs ≥14 ng/L with CV events and pre-TnT-hs ≥14 ng/L with
Figure 3. Prevalence of graded cardiotoxicity in patients with TnT-hs ≥14ng/L and TnT-hs <14ng/L
throughout the follow-up.
