Content uploaded by Marcin Kleibert
Author content
All content in this area was uploaded by Marcin Kleibert on Sep 01, 2022
Content may be subject to copyright.
Citation: Czarnecka, A.M.; Kleibert,
M.; Płachta, I.; Rogala, P.; W ˛agrodzki,
M.; Leszek, P.; Rutkowski, P.
Myocarditis Induced by
Immunotherapy in Metastatic
Melanoma—Review of Literature
and Current Guidelines. J. Clin. Med.
2022,11, 5182. https://doi.org/
10.3390/jcm11175182
Academic Editors: Francesco Massari
and Alessandro Rizzo
Received: 25 June 2022
Accepted: 22 August 2022
Published: 1 September 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Review
Myocarditis Induced by Immunotherapy in Metastatic
Melanoma—Review of Literature and Current Guidelines
Anna M. Czarnecka 1, * , Marcin Kleibert 1,2,3,† , Iga Płachta 1, 2, † , Paweł Rogala 1, Michał W ˛agrodzki 3,
Przemysław Leszek 4and Piotr Rutkowski 1
1
Department of Soft Tissue, One Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute
of Oncology, 02-781 Warsaw, Poland
2Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
3Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute
of Oncology, 02-781 Warsaw, Poland
4Department of Heart Failure and Transplantology, National Institute of Cardiology, 04-628 Warsaw, Poland
*Correspondence: anna.czarnecka@gmail.com
† These authors contributed equally to this work.
Abstract:
Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint
inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma
therapy, due to the significant prolongation of patients’ overall survival. These drugs act by activation
of inhibited immune responses of T lymphocytes against cancer cells. The mechanism responsible for
the therapy’s high efficacy is also involved in immune tolerance of the patient’s own tissues. The
administration of ICI therapy to a patient can cause severe immune reactions against non-neoplastic
cells. Among them, cardiotoxicity seems most important due to the high mortality rate. In this article,
we present the history of a 79 year-old patient diagnosed with melanoma who died due to myocarditis
induced by ICI therapy, despite the fast administration of recommended immunosuppressive therapy,
as an illustration of possible adverse events of ICI. Additionally, we summarize the mechanism,
risk factors, biomarkers, and clinical data from currently published guidelines and studies about
ICI-related myocarditis. The fast recognition of this fatal adverse effect of therapy may accelerate the
rapid introduction of treatment and improve patients’ outcomes.
Keywords:
Immune checkpoint inhibitor; adverse event; immunotherapy; melanoma; nivolumab;
myocarditis; cardiotoxicity; guidelines
1. Introduction
Over the past decades, significant progress in cancer therapy has been observed. The
shift from standard chemotherapy to targeted treatment, and recently to immunotherapy
has taken place. The number of patients eligible for this modern treatment is growing
rapidly with a simultaneous increase in the number of adverse events (AE) related to
immunotherapy. Most organs have been reported to be the targets of immune-related
toxicity induced by immune checkpoint inhibitors (ICI) used, e.g., in melanoma treat-
ment [
1
]. Unfortunately, biomarkers defining populations at risk are not well defined at
this point in time, but PD-1/PD-1L pathway proteins are known to be involved in AEs [
2
].
However, Weidhass et al. showed that germline (microRNA-based biomarker) predicts
grade 2 and higher irAEs (immune-related AEs) to anti-PD1/PDL1 therapy regardless of
the type of cancer [3].
Melanoma immunotherapy acts by disinhibition of T-cell function (Figure 1). It can
lead to overactivity of the immune system, which results in irAEs. In 2018, a meta-analysis
that showed the mortality rate among patients treated with ICI was published. It was
reported that 0.36% of those treated with anti–PD-1, 0.38% of those treated with anti–PD-
L1, 1.08% of those treated with anti–CTLA-4, and 1.23% of those treated with combined
J. Clin. Med. 2022,11, 5182. https://doi.org/10.3390/jcm11175182 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2022,11, 5182 2 of 15
anti–PD-1/ anti–PD-L1 and CTLA-4 died due to complications of the treatment. The type
of fatal irAE observed varied by regimen. It can manifest as e.g., colitis, pneumonitis,
hepatitis, neurotoxicity, or myocarditis [4].
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 2 of 16
Melanoma immunotherapy acts by disinhibition of T-cell function (Figure 1). It can
lead to overactivity of the immune system, which results in irAEs. In 2018, a meta-analysis
that showed the mortality rate among patients treated with ICI was published. It was re-
ported that 0.36% of those treated with anti–PD-1, 0.38% of those treated with anti–PD-
L1, 1.08% of those treated with anti–CTLA-4, and 1.23% of those treated with combined
anti–PD-1/ anti–PD-L1 and CTLA-4 died due to complications of the treatment. The type
of fatal irAE observed varied by regimen. It can manifest as e.g., colitis, pneumonitis, hep-
atitis, neurotoxicity, or myocarditis [4].
Figure 1. Mechanism of blockade of CTLA-4 or PD-1 signaling in tumor immunotherapy and exam-
ples of drugs used in melanoma therapy. CTLA-cytotoxic T cell antigen, PD-programmed cell death
protein, MHC-major histocompatibility complex, TCR-T-cell receptor, CD-cluster of differentiation
DC-dendritic cell
Cardiotoxicity is an infrequent irAE during melanoma treatment. Among cardiac-
related irAEs left ventricular dysfunction, heart failure, myocarditis, myocardial fibrosis,
takotsubo syndrome, QT prolongation, arrhythmias, heart block, cardiac arrest, acute cor-
onary syndrome, hypertension, and thromboembolism were reported [5–8]. The first spe-
cific case report of myocarditis during treatment with a PD-1/PD-L1 inhibitor was pub-
lished in 2014 [9]. Tadokoro et al. (2016) reported probably the first biopsy-proven case of
acute lymphocytic myocarditis that occurred after the administration of nivolumab [10].
As was mentioned, cardiac-related complications are not a common example of irAE. Ac-
cording to the safety databases of Bristol-Myers Squibb Corporate, the incidence of myo-
carditis was first reported to be 0.09% in patients treated with nivolumab, ipilimumab, or
both. Patients who received combination therapy with both antibodies had more severe
and frequent myocarditis than those who received nivolumab alone (0.27% versus 0.06%)
Figure 1.
Mechanism of blockade of CTLA-4 or PD-1 signaling in tumor immunotherapy and exam-
ples of drugs used in melanoma therapy. CTLA-cytotoxic T cell antigen, PD-programmed cell death
protein, MHC-major histocompatibility complex, TCR-T-cell receptor, CD-cluster of differentiation
DC-dendritic cell.
Cardiotoxicity is an infrequent irAE during melanoma treatment. Among cardiac-
related irAEs left ventricular dysfunction, heart failure, myocarditis, myocardial fibrosis,
takotsubo syndrome, QT prolongation, arrhythmias, heart block, cardiac arrest, acute coro-
nary syndrome, hypertension, and thromboembolism were reported [
5
–
8
]. The first specific
case report of myocarditis during treatment with a PD-1/PD-L1 inhibitor was published
in 2014 [
9
]. Tadokoro et al. (2016) reported probably the first biopsy-proven case of acute
lymphocytic myocarditis that occurred after the administration of nivolumab [
10
]. As was
mentioned, cardiac-related complications are not a common example of irAE. According to
the safety databases of Bristol-Myers Squibb Corporate, the incidence of myocarditis was
first reported to be 0.09% in patients treated with nivolumab, ipilimumab, or both. Patients
who received combination therapy with both antibodies had more severe and frequent
myocarditis than those who received nivolumab alone (0.27% versus 0.06%) [
11
]. Two retro-
spective studies showed a higher prevalence of cardiac events in patients treated with ICIs;
1.0% and 1.14%, respectively [
5
,
12
]. However, it often presents with a rapid course, with
almost 50% of patients experiencing a major adverse cardiovascular event, which results
in death or progression to end-stage dilated cardiomyopathy (rate: 12–50%) [
12
–
16
]. The
increasing number of cases of myocarditis as an adverse reaction is continuously reported.
In the Danish study, the 1-year risk of peri- or myocarditis was 1.8%, thus suggesting that
the risk may be higher than previously estimated [
17
]. The median time to onset was
reported to be 17 to 39 days following treatment; however, in an analysis by Matzen et al.,
the median time to onset of symptoms after initiation of ICI was 16 days, but with a wide
variation of 1 to 196 days, whereas Qin et al. in their institutional report showed that the
J. Clin. Med. 2022,11, 5182 3 of 15
time to irAE ranged from 1.5 to 54 weeks [
16
,
18
,
19
]. Jain et al. reported a wide spectrum of
cardiovascular irAEs after ICI therapy with absolute incidence rates of stroke (4.6%), heart
failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction
(0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%) [20].
Despite the growing number of cases, pathogenesis is still not known. In our article,
we describe the case of fulminant lethal myocarditis related to nivolumab therapy along
with PD-1/PD-L1 analysis in the heart. Additionally, we present the current knowledge
regarding the pathogenesis, biomarkers, clinical course, and treatment of this rare adverse
event during therapy.
2. Clinical Background-Case Report
A 79-year-old patient, after resection of pT4b melanoma of the left foot two years
previously (weight: 96 kg, height: 164 cm, BSA: 2.09 m
2
, BMI: 35.7
kg
m2
), was referred to the
tertiary oncology center due to the presence of a nodular lesion of 37
×
31 mm in the 10th
segment of the left lung and a 9 mm nodule in the 2nd segment of the right lung in CT. Ad-
ditionally, the 3 mm lesion was found in the liver, and no metastatic changes were detected
in CNS. The patient had arterial hypertension and permanent atrial fibrillation treated
according to guidelines by a general practitioner. After excluding the BRAF mutation,
he was referred to immunotherapy and started treatment with nivolumab at a constant
dose of 240 mg every three weeks. The patient received three courses of treatment within
1.5 months
without any complications. However, some changes in laboratory results wors-
ened within this period (Table 1). On admission to the 4th treatment course, he reported a
well-being deterioration, according to the family report, it had lasted for 6 days—without
general practitioner intervention. He also reported severe headaches, weakness, loss of
appetite, and shortness of breath. In physical examination, no significant abnormalities
were observed.
Table 1.
Changes in selected laboratory parameters during immunotherapy. ALT-alanine transam-
inase, ASPAT-aspartate transaminase, CK-creatine kinase, CRP-C-reactive protein, LDH-lactate
dehydrogenase.
Parameter Reference Range Before Initiation of
Immunotherapy
After 3rd Course of
Nivolumab
On Admission to the
4th Course
ASPAT <50 (IU/L) 16 71 178
ALT <50 (IU/L) 10 49 207
CK <171 (IU/L) 60 - 2194
CRP <5 (mg/L) 2.8 - 6.1
LDH <247 (IU/L) 222 377 943
An urgent CT scan was performed which excluded pulmonary embolism, stroke,
pleural effusion, and CNS metastases. Due to the exacerbation of symptoms and chest
pain (very likely nonanginal), an ECG was performed which showed the presence of
atrial fibrillation (persistent), without apparent signs of myocardial ischemia. The cardiac
biomarkers presented a moderate increase in troponin T: 1.300 ng/mL (<0.014), CK-MB:
90.78 ng/mL (<6.22) and significant in NT-pro-BNP: 2396.0 pg/mL (<125). Echocardiogra-
phy revealed normal size and slightly reduced contractility of the left ventricle with basal
inferior wall hypokinesis and global EF 55–60%. Right ventricle size and contractility were
within normal ranges. A six hour follow-up evaluation proved a stable troponin level of
1.030 ng/mL.
A further MRI and endomyocardial biopsy (EMB) were planned; however, due to
the patient’s condition, limited access to MRI /EMB and autoimmune reaction related to
immunotherapy the treatment was started without further delay. The patient’s condition
was worsening gradually and in the evening, he developed delusions. The patient received
J. Clin. Med. 2022,11, 5182 4 of 15
steroid therapy (prednisolone 1 mg/kg) and acetylsalicylic acid (75 mg). Despite the rapid
start of steroid therapy, the patient died within 21 h of admission.
The autopsy report stated left foot melanoma recurrence, with metastases to the left
inguinal lymph node and both lungs (apT4bN1bM1) (Figure 2). The direct cause of death
was lymphocytic myocarditis (according to Dallas criteria) from T cells (CD3 (+), CD4 (+),
CD8 (+), PD-1 (+), CD20 (−)) (Figure 3).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 16
biomarkers presented a moderate increase in troponin T: 1.300 ng/mL (<0.014), CK-MB:
90.78 ng/mL (<6.22) and significant in NT-pro-BNP: 2396.0 pg/mL (<125). Echocardiog-
raphy revealed normal size and slightly reduced contractility of the left ventricle with
basal inferior wall hypokinesis and global EF 55–60%. Right ventricle size and contractility
were within normal ranges. A six hour follow-up evaluation proved a stable troponin
level of 1.030 ng/mL.
A further MRI and endomyocardial biopsy (EMB) were planned; however, due to the
patient’s condition, limited access to MRI /EMB and autoimmune reaction related to im-
munotherapy the treatment was started without further delay. The patient’s condition
was worsening gradually and in the evening, he developed delusions. The patient re-
ceived steroid therapy (prednisolone 1 mg/kg) and acetylsalicylic acid (75 mg). Despite
the rapid start of steroid therapy, the patient died within 21 h of admission.
The autopsy report stated left foot melanoma recurrence, with metastases to the left
inguinal lymph node and both lungs (apT4bN1bM1) (Figure 2). The direct cause of death
was lymphocytic myocarditis (according to Dallas criteria) from T cells (CD3 (+), CD4 (+),
CD8 (+), PD-1 (+), CD20 (−)) (Figure 3).
Figure 2. Histopathological presentation of primary lesion—malignant melanoma: Tumor com-
posed of epithelioid melanocytes (A), which show PD-L1 expression (B); whereas lymphoid cells in
the stroma present with PD-1 expression (C).
Figure 2.
Histopathological presentation of primary lesion—malignant melanoma: Tumor composed
of epithelioid melanocytes (
A
), which show PD-L1 expression (
B
); whereas lymphoid cells in the
stroma present with PD-1 expression (C).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 16
Figure 3. Histologic presentation of cardiotoxicity during nivolumab: H&E stain of the myocardium
shows patchy lymphocytic infiltrates associated with myocarditis and myocyte damage (A); immu-
nochemistry stain for CD3 (B), CD4 (C), and CD8 (D) highlights in brown T cells within the inflam-
matory infiltrate.
3. Review and Discussion
The first case series of ICI-related cardiotoxicities was a US and German study by
Heinzerling et al. (2016), including autoimmune myocarditis, cardiomyopathy, heart fail-
ure, cardiac fibrosis, and cardiac arrest [21]. Moslehi et al. described 101 cases reported in
VigiBase (http://www.vigiaccess.org/, accessed on 20 August 2022, the World Health Or-
ganization (WHO) database of individual safety case reports, whereas Salem et al. identi-
fied 122 cases, also reported in VigiBase [13,14]. Matzen et al. identified 87 cases of ICI-
induced myocarditis, and 39 among them were melanoma patients [16]. Rahouma et al.
performed a meta-analysis of 11 anti-PD/PD-L1 immunotherapy randomized clinical tri-
als (seven melanoma RCTs, three non-small-cell lung cancer RCTs, and one prostate can-
cer,) including five studies comparing mono-immunotherapy to chemotherapy, which
showed that cardiotoxicity was statistically insignificant (RR: 1.15; 95% CI: 0.73–1.80; p =
0.55) regardless the treatment regimen; either chemotherapy or dual immunotherapy [22].
All the ICIs can be responsible for development of myocarditis. In a retrospective study
among 752 patients by Voskens et al. (2013), one case of ipilimumab-induced myocardial
fibrosis was reported [7]. In a phase III trial of adjuvant ipilimumab after complete resec-
tion of high-risk stage III melanoma (EORTC 18071), one patient in the ipilimumab group
died because of myocarditis. It was probably the first reported death due to ICI-induced
myocarditis [23]. Also, a few more cases of fulminant myocarditis were reported, and
most of them were fatal [11,24–26]. Pericarditis and pericardial effusion were also men-
tioned. Apical ballooning and cardiomyopathy (a Takotsubo-like syndrome) or pericardi-
tis with pericardial effusion were also reported [27,28]. Scard et al. (2021), reported a case
of myocardial infarction (MI) in a patient who previously underwent MI and was treated
with triple coronary bypass implantation [18]. The first case of autoimmune myocarditis
as a side effect of pembrolizumab therapy was reported by Läubli et al. (2015), completely
Figure 3.
Histologic presentation of cardiotoxicity during nivolumab: H&E stain of the myocardium
shows patchy lymphocytic infiltrates associated with myocarditis and myocyte damage (
A
); im-
munochemistry stain for CD3 (
B
), CD4 (
C
), and CD8 (
D
) highlights in brown T cells within the
inflammatory infiltrate.
J. Clin. Med. 2022,11, 5182 5 of 15
3. Review and Discussion
The first case series of ICI-related cardiotoxicities was a US and German study by
Heinzerling et al. (2016), including autoimmune myocarditis, cardiomyopathy, heart fail-
ure, cardiac fibrosis, and cardiac arrest [
21
]. Moslehi et al. described 101 cases reported
in VigiBase (http://www.vigiaccess.org/, accessed on 20 August 2022, the World Health
Organization (WHO) database of individual safety case reports, whereas Salem et al. iden-
tified 122 cases, also reported in VigiBase [
13
,
14
]. Matzen et al. identified 87 cases of
ICI-induced myocarditis, and 39 among them were melanoma patients [
16
]. Rahouma et al.
performed a meta-analysis of 11 anti-PD/PD-L1 immunotherapy randomized clinical trials
(seven melanoma RCTs, three non-small-cell lung cancer RCTs, and one prostate cancer,)
including five studies comparing mono-immunotherapy to chemotherapy, which showed
that cardiotoxicity was statistically insignificant (RR: 1.15; 95% CI: 0.73–1.80;
p= 0.55
) re-
gardless the treatment regimen; either chemotherapy or dual immunotherapy [
22
]. All the
ICIs can be responsible for development of myocarditis. In a retrospective study among
752 patients by Voskens et al. (2013), one case of ipilimumab-induced myocardial fibrosis
was reported [
7
]. In a phase III trial of adjuvant ipilimumab after complete resection of
high-risk stage III melanoma (EORTC 18071), one patient in the ipilimumab group died
because of myocarditis. It was probably the first reported death due to ICI-induced my-
ocarditis [
23
]. Also, a few more cases of fulminant myocarditis were reported, and most
of them were fatal [
11
,
24
–
26
]. Pericarditis and pericardial effusion were also mentioned.
Apical ballooning and cardiomyopathy (a Takotsubo-like syndrome) or pericarditis with
pericardial effusion were also reported [
27
,
28
]. Scard et al. (2021), reported a case of
myocardial infarction (MI) in a patient who previously underwent MI and was treated
with triple coronary bypass implantation [
18
]. The first case of autoimmune myocarditis as
a side effect of pembrolizumab therapy was reported by Läubli et al. (2015), completely
regressing after high-dose corticosteroids [
29
]. The rate of adverse cardiovascular events
is reported to be low but when it occurs the severity is very high. Mahmood et al. pre-
sented that among patients who developed ICI-associated myocarditis, in nearly one-half
of cases incidence of grade 4 or 5 for cardiovascular adverse events was noted, graded
using the Common Toxicity Criteria for Adverse Events (version 4.0) [
12
]. By contrast, 4%
of cases of pneumonitis after anti-PD-1 or anti-PD-L1 treatment, were grade 4 or 5 [
30
].
Hofmann et al.
presented that the incidence of hepatitis during anti-PD-1 therapy was 2.2%
and only 18.2% of patients developed grade 4; no grade 5 was reported. Diarrhea and
colitis were only in grades 1–3 [
31
]. In a research study by Dearden et al., all
2 myocarditis
cases were grade 5, and no other treatment-related mortality was reported [
32
]. There is
no evidence that cardiac toxicity correlates with the ICI’s dose [
33
]. Interestingly, targeted
therapies used in melanoma treatment may also induce cardiotoxicity. BRAF/MEK in-
hibitors may cause reduction in left ventricular ejection fraction (5–11%), hypertension
(11–30%) or QT interval prolongation (0–5%) [
34
]. The summary of the most important
information about cases, which are mentioned above, is provided in supplementary data
(Table S1 in Supplementary Materials).
3.1. Diagnosis of Myocarditis
Myocarditis is an inflammatory disease of cardiac muscle that might occur as a result
of infections, predominantly viral, exposure to drugs, or immune system activation [
35
,
36
].
Its diagnosis is established using histological, immunological and immunohistochemical
criteria [
35
,
37
]. For patients who do not undergo EMB or have nondiagnostic findings on
EMB, myocarditis cannot be definitely diagnosed. However, in those cases a diagnosis of
clinically suspected myocarditis can be made if diagnostic criteria are met. Diagnosis of
myocarditis according to a 2013 position statement of the European Society of Cardiology
Working Group on Myocardial and Pericardial Diseases is shown in Table 2.
J. Clin. Med. 2022,11, 5182 6 of 15
Table 2. Criterias of diagnosis of myocarditis. Based on [35].
Definitive diagnosis Histology—EMB (according to
Dallas criteria [38])
Active myocarditis: an inflammatory infiltrate of
the myocardium with necrosis and/or
degeneration of adjacent myocytes not typical of
the ischemic damage associated with coronary
artery disease.
Borderline myocarditis: sparse inflammatory
infiltrate or myocytes without evident injury.
Diagnosis of clinically
suspected myocarditis [35]:
≥1 of the clinical presentations
of myocarditis
and
≥1 diagnostic criteria
(if the patient is asymptomatic,
≥2 diagnostic criteria are required)
Clinical presentations
- acute chest pain (pericarditis or
pseudo-ischemic)
- new-onset (days up to three months) or
worsening of dyspnea at rest or exercise,
and/or fatigue, with or without left and/or
right HF signs
- palpitation, and/or unexplained
arrhythmia symptoms and/or syncope,
and/or aborted sudden cardiac death
- unexplained cardiogenic shock
Diagnostic criteria
- ECG/Holter stress test features –first to
third degree AV block or bundle branch
block, ST/T wave change (ST elevation or
T wave inversion), sinus arrest, VT or VF,
asystole, AF, significantly reduced R wave
height, IVCD (widened QRS complex),
abnormal Q waves, low voltage, frequent
premature beats, or SVT
- elevated troponin T or troponin I.
- functional and structural abnormalities on
cardiac imaging (echocardiogram,
angiogram, or CMR—new, otherwise
unexplained abnormality of LV and/or RV
function (regional wall motion abnormality
or global systolic or diastolic dysfunction)
- tissue characterization by CMR—the
presence of updated Lake Louse criteria
suggests myocarditis
EMB—endomyocardial biopsy, HF—heart failure, AV—atrioventricular block, VT—ventricular tachycar-
dia, VF—ventricular fibrillation, AF—atrial fibrillation, IVCD—intraventricular conduction delay, SVT—
supraventricular tachycardia.
Myocarditis is often classified in terms of duration of symptoms. Acute myocarditis has
been defined as a condition with symptoms of heart failure developing over three months
or less, while chronic myocarditis has been defined as developing over >3 months [
39
].
Fulminant myocarditis is also differentiated as a subtype, it has a distinct onset, degree of
hemodynamic compromise but has a generally better prognosis than (sub)acute lympho-
cytic myocarditis symptoms [35,36].
3.2. Mechanism of ICI-Related Myocarditis, Biomarkers and Histopathology
The exact mechanism of cardiac IRAEs remains poorly understood; however, it is
likely related to the direct inhibition of PD-1 and CTLA-4. The PD-1/PD-L1 pathway
seems fundamental for the immune homeostasis within the myocardium and the cardiac
protection from T-lymphocytes. Deregulated immune cells were found to mislabel surface
structures such as cardiolipin as antigens, leading to subsequent targeting of normal
cardiomyocytes or other cells expressing these antigens. Therefore, a mechanism of action
for the ICIs resembles cardiovascular complications of patients with autoimmune diseases,
including systemic lupus erythematosus [21,40].
J. Clin. Med. 2022,11, 5182 7 of 15
Based on early animal models, it was demonstrated that after CTLA-4 inhibition
or PD-1 deletion, autoimmune myocarditis may develop [
41
]. PD-1 is known to protect
against tissue inflammation and murine cardiomyocytes damage [
42
]. It regulates a critical
checkpoint for autoimmune myocarditis and cardiomyocyte damage [41].
Moreover, PD-L2 deficiency has been described to predispose to exacerbation of my-
ocarditis in mice [
43
]. The damage to the gene encoding PD-1 in mice caused dilated
cardiomyopathy [
44
]. Knock-out of the PD-L1/PD-L2 genes or treatment with anti-PD-
L1 antibodies were shown to transform transient myocarditis into a lethal form of the
disease [
45
]. These observations were confirmed in the cell culture of human cardiomy-
ocytes. The blockage of PD-1 by nivolumab caused infiltration of the myocardium with T
lymphocytes and increased expression of inflammatory genes [46].
Another co-inhibitory molecule is a CTLA-4 which binds to CD80 (also known as B7.1)
or CD86 (also known as B7.2), with a ten-fold higher affinity than CD28 (co-stimulatory
molecule) [
47
]. Blockade of CTLA-4 has been shown to augment T-cell activation and
proliferation, which promotes anti-tumor immune response. This process may also promote
autoimmune reactions similar to complications caused by PD-, and PD-L1 antibodies.
There was an increased inflammation, enhanced serum markers of immune damage,
and increased infiltration of CD8
+
T cells in PD-1
−
/CD8
+
T cells compared to PD-1
+
/CD8
+
T cells in a CD8
+
T cell-mediated adoptive transfer model. PD-1 protects against inflamma-
tion and myocyte damage in T cell-mediated myocarditis [48].
One possible pathophysiologic mechanism of ICI-related myocarditis is that cardiac
myocytes may share targeted antigens with the tumor, therefore becoming targets of
activated T-lymphocytes resulting in lymphocytic infiltration of the myocardium [
11
].
However, this hypothesis seems unlikely due to the role of CTLA-4, PD-1, and PD-L1
molecules in immunology. The blockage of these proteins causes the overactivation of
lymphocytes and autoimmune reaction.
Under histological examination, we can observe infiltration of CD8
+
T-cells, CD68
+
macrophages, and signs of myocardial fibrosis [
29
,
49
]. Additionally, pericardial effusion
may develop both early and late during treatment and be symptomatic with tamponade,
or occur without any symptoms. In the case of pericardial effusion, heart biopsies show
infiltration of T-lymphocytes, mostly CD4+[50].
3.3. Clinical Presentation of ICI-Related Myocarditis
The signs and symptoms of ICI-related myocarditis are unspecific. At treatment initia-
tion no specific biomarkers of potential autoimmune risk may be evaluated directly, but
initial abnormal troponin levels, NT-proBNP and CK-MB indicating heart muscle damage
may be helpful in defining patients at risk of cardiac complications. As in our patient, the
myocarditis was manifested by physical deterioration, headache, and shortness of breath
initially. Despite the mild presentation of complaints, the course was fulminant, and the
patient died less than 24 h after admission. Due to the risk of acute course, it is important to
be aware of this rare complication of immunotherapy that can accelerate clinical diagnosis.
In our case, the first symptoms occurred six days earlier, but it was ignored by the general
practitioner which delayed the beginning of treatment of myocarditis.
At presentation, most patients present with an abnormal electrocardiogram (ECG) and
cardiovascular symptoms, usually with elevated troponin, creatinine kinase MB or/and
B-type natriuretic peptide (BNP)/N-terminal prohormone of BNP (NT-pro BNP) levels.
It has been discussed, whether troponin T remains a good biochemical marker of my-
ocarditis, as it is found in fetal skeletal muscle and it might be less cardiac-specific than
troponin I in the presence of neuromuscular pathologies such as ICI-associated myosi-
tis [
51
]. In one study, it was observed that 94% of patients with ICI-related myocarditis
(
n= 35
) had an increased troponin level [
12
]. In our case, a high level of troponin was noted,
but the significant increasing tendency was not observed. ECG changes in myocarditis
are not specific and include ST-segment and T-wave abnormalities, conduction alterna-
tions such as bundle-branch blocks and AV conduction delays, and atrial and ventricular
J. Clin. Med. 2022,11, 5182 8 of 15
tachyarrhythmias. PR-segment depression and ST-segment elevation without reciprocal
changes were observed with pericardial inflammation [
52
]. In our patient, there were no
indications for interventional treatment according to ESC guidelines [
53
]. Interestingly,
the initiation of immunotherapy can induce changes in ECG parameters in melanoma
patients. It was recently evaluated by experts from “Essen Cardio-oncology Registry”
(ECoR). They showed that heart rate, PR time, QRS, and QTc did not differ when compar-
ing values before and after therapy started. However, QTd was prolonged after therapy
started (
32 ±16 ms vs. 47 ±19 ms
,n= 41, p< 0.0001). Subgroup analyses revealed pro-
longed QTd in patients that received combination immunotherapy with ipilimumab and
nivolumab (31
±
14 ms
vs. 50 ±14 ms
,n= 21, p< 0.0001), while QTd in patients with anti-
programmed
death 1 (PD-1)
inhibitor monotherapy did not change after therapy started.
QTd is prolonged in patients under ICI combination therapy, potentially signaling an
increased susceptibility to ventricular arrhythmias [54].
Echocardiographic examinations in the early stages of myocarditis are normal but can
have transient wall thickening with edema, impaired left and/or right ventricular functions
with preserved EF, or ventricular dilation. Traditionally, myocarditis unrelated to an ICI
presenting with a preserved EF is a comparatively benign entity; in contrast, data from
various research groups have shown that myocarditis related to an ICI is not [
55
,
56
]. As
in our case, despite slightly reduced contractility of left ventricle with basal inferior wall
hypokinesis, was symptomatic.
Cardiac MRI can show regional or globally increased T2-weighted signal with gadolin-
ium enhancement and/or myocardial injury through T1-based markers (including the
presence of late gadolinium enhancement following a non-ischemic distribution) [
15
,
34
].
Moreover, cardiac MRI may quantitate tissue injury, including edema, hyperemia, and
fibrosis, and can support the diagnosis of myocarditis (Lake Louis criteria) [
57
,
58
]. Based
on the Lake Louis criteria, when two or more of the three criteria are positive, myocar-
dial inflammation can be predicted with a diagnostic accuracy of 78% in patients with
myocarditis unrelated to ICI treatment The sensitivity and specificity of these criteria
should be verified in this group of patients but preliminary data suggest that they can
be useful in this indication [
12
]. Also, FDG-PET-CT imaging might be beneficial in con-
firming the diagnosis [
59
]. However, according to ESC guidelines EMB is still the gold
standard, and should be performed in any case of suspicion, especially among patients
with a life-threatening arrhythmia, LV dysfunction that does not improve 4–5 days after
onset of symptoms, exacerbating LV dysfunction within 4–5 days after onset of symptoms,
and recurrent myocarditis [
39
,
60
]. In our case, due to the inaccessibility to EMB, it was not
performed before the beginning of the immunosuppressive treatment. It seems that the
cardiac MRI or PET-CT may be used among patients who undergo EMB but it should be
verified in clinical studies.
3.4. Other Specific Organ Toxicities Associated with ICI
In a series by Heinzerling et al., five of the eight patients’ (63%) other organ sys-
tems were also affected by immune-related side effects, including autoimmune thyroiditis,
uveitis, colitis, hepatitis, and hypophysitis [
21
]. Similar observations were made by Ansari-
Gilani et al. [
61
]. Hepatitis was also associated with myocarditis in a case reported by
Samara et al. [
62
]. Patients who develop myasthenia gravis as the irAE, have been reported
to have a 16–37% chance of also having myocardial changes [
63
,
64
]. In Japanese patients
treated with immune checkpoint inhibitors, among twelve patients who developed myas-
thenia gravis, three presented with myocarditis [
65
]. Also, Bawek et al. presented a case
with myocarditis concomitant with myasthenia gravis; in addition, the patient was also di-
agnosed with myositis and hepatitis [
66
]. Moslehi et al. reported myositis/rhabdomyolysis,
myasthenia gravis, colitis, and severe cutaneous events (Stevens–Johnson syndrome, bul-
lous pemphigus, and skin necrosis) as the most frequent concurrent irAE [
14
]. A recent
systemic review showed that myocarditis and myositis have a propensity to occur together,
and ICI-induced myositis can be associated with myasthenia gravis in up to 40% of pa-
J. Clin. Med. 2022,11, 5182 9 of 15
tients [
64
]. Another concomitant neurologic irAE is axonal polyradiculoneuropathy, as
reported by Diamantopoulos et al. [
67
]. Koelzer et al., reported a case of lymphocytic
myocarditis as a part of systemic inflammation associated with ipilimumab and nivolumab
administration [
49
]. Some authors suggest that myocarditis is associated with response
to therapy [
68
]. However, a case of myocarditis with concomitant hyper-progression was
also described [
69
]. It is worth taking into account that not all cardiac and non-cardiac
manifestations occurring under ICI therapy are drug-related adverse events, therefore
differential diagnoses must be considered in order to avoid unnecessary cessation of ICI
treatment, which may have a major impact on overall patient prognosis [70].
3.5. Risk Factors for ICI-Related Myocarditis
The combination of ICI therapy is the most established risk factor. It was shown
that the risk of myocarditis increased by 4.74 among patients who received combination
(nivolumab + ipilimumab) therapy in comparison to monotherapy (nivolumab) [
11
]. In
a case series by Heinzerling et al., pre-existing pathology, including cardiac pathology
or peripheral arterial disease, was present in the majority of the patients (five out of
eight), but patients were free of symptoms when starting checkpoint inhibitor therapy [
21
].
Mahmood et al.
, in a retrospective study, implicated diabetes and perhaps pre-existing heart
disease as a risk factor for myocarditis [
12
]. Johnson et al. (2016) described two fatal cases
with fulminant myocarditis associated with the combination of ipilimumab with nivolumab,
and both patients were hypertensive but did not have other cardiac risk factors [
11
]. Other
authors also report pre-existing hypertension [
18
,
71
,
72
]. Some reported patients also
presented with coronary bypass implanted after MI, past cerebrovascular accidents, or
aortic aneurysms [
18
]. In a single-center study by Drobni et al., patients on ICIs were at
a threefold increased risk of MI and stroke due to increased aortic atherosclerotic plaque
burden, as compared with non-ICI patients [
73
]. Some authors suggest that patients with
baseline organ dysfunction, commonly excluded from clinical trials, represent a population
that may be more susceptible to adverse events [
74
]. However, in the population presented
by Shah et al. (2020), performance status at the time of initiation of immunotherapy
treatment did not show a significant association with toxicity [
75
]. Johnson et al. presented
a series of 30 patients with a range of pre-existing autoimmune disorders, treated with
ipilimumab for advanced melanoma. Interestingly, ipilimumab was active (20% response
rate), despite the fact that 43% of patients were on immunosuppressants at the time of
ipilimumab commencement. While 27% of patients experienced a flare of their autoimmune
disorder and 33% experienced grade 3–5 irAEs, no cardiac toxicity was observed [76].
3.6. Treatment of ICI-Related Myocarditis
The summary of recommended treatment guidelines is presented in figure (Figure 4).
The consensus for the initial steroid dose is an equivalent dose of (methyl)prednisolone
1–2 mg/kg for grade 2 or higher cardiotoxicity (Table 2) [
77
,
78
]. CTLA-4 agonist abatacept,
alemtuzumab, tocilizumab, rituximab, anti-thymocyte globulin, intravenous immunoglob-
ulins, tacrolimus, mycophenolate, azathioprine, methotrexate, cyclophosphamide, and
infliximab or plasmapheresis have been used in steroid-refractory cases of myocarditis,
although infliximab is not preferred at higher dosing given its association with cardiac
failure [
34
,
64
,
79
]. Matzen et al. compared fatality in identified cases and 55% treated
with high-dose steroids only were fatal versus 43% fatality in cases treated with other
immunosuppressive agents [
16
]. There is currently no consensus on the optimal immuno-
suppression treatment sequence, combination, and duration in steroid-refractory cases.
Moreover, it should be taken into account that lymphocyte depletion associated with im-
munosuppressive therapy may induce the unleashing of aggressive melanoma and the
progression of the disease [
80
]. A recent study showed that the blockade of TNF
α
may lead
to preventing the manifestation of ICI-related cardiotoxicity [
81
]. Balanescu et al. (2020)
described for the first time the successful rechallenge with ICI after cured ICI-induced
J. Clin. Med. 2022,11, 5182 10 of 15
myocarditis. The patient, who developed myocarditis after the combination of nivolumab
and ipilimumab, was able to reinitiate monotherapy with nivolumab at short notice [82].
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 10 of 16
represent a population that may be more susceptible to adverse events [74]. However, in
the population presented by Shah et al. (2020), performance status at the time of initiation
of immunotherapy treatment did not show a significant association with toxicity [75].
Johnson et al. presented a series of 30 patients with a range of pre-existing autoimmune
disorders, treated with ipilimumab for advanced melanoma. Interestingly, ipilimumab
was active (20% response rate), despite the fact that 43% of patients were on immunosup-
pressants at the time of ipilimumab commencement. While 27% of patients experienced a
flare of their autoimmune disorder and 33% experienced grade 3–5 irAEs, no cardiac tox-
icity was observed [76].
3.6. Treatment of ICI-Related Myocarditis
The summary of recommended treatment guidelines is presented in figure (Figure
4).
The consensus for the initial steroid dose is an equivalent dose of (methyl)predniso-
lone 1–2 mg/kg for grade 2 or higher cardiotoxicity (Table 2) [77,78]. CTLA-4 agonist
abatacept, alemtuzumab, tocilizumab, rituximab, anti-thymocyte globulin, intravenous
immunoglobulins, tacrolimus, mycophenolate, azathioprine, methotrexate, cyclophos-
phamide, and infliximab or plasmapheresis have been used in steroid-refractory cases of
myocarditis, although infliximab is not preferred at higher dosing given its association
with cardiac failure [34,64,79]. Matzen et al. compared fatality in identified cases and 55%
treated with high-dose steroids only were fatal versus 43% fatality in cases treated with
other immunosuppressive agents [16]. There is currently no consensus on the optimal im-
munosuppression treatment sequence, combination, and duration in steroid-refractory
cases. Moreover, it should be taken into account that lymphocyte depletion associated
with immunosuppressive therapy may induce the unleashing of aggressive melanoma
and the progression of the disease [80]. A recent study showed that the blockade of TNFα
may lead to preventing the manifestation of ICI-related cardiotoxicity [81]. Balanescu et
al. (2020) described for the first time the successful rechallenge with ICI after cured ICI-
induced myocarditis. The patient, who developed myocarditis after the combination of
nivolumab and ipilimumab, was able to reinitiate monotherapy with nivolumab at short
notice [82].
Figure 4. Management of cardiovascular toxicities, including myocarditis, pericarditis, arrhythmias,
impaired ventricular function with heart failure, and vasculitis. Based on [78]; G1—grade 1, G2—
G1: elevated
troponin
hold ICPi
+
recheck troponin 6 hours later
+
admit patient for cardiology consultation
consider resuming ICPi, if
troponin level
normalized
or elevation is believed
not to related to ICPi
≥G2
hold ICPi
+
early (within 24h) initiate high-dose CS (1-2
mg/kg/d of prednisolone, oral or IV)
+
admit patient for cardiology consultation
No immediate response to
corticosteroids:
higher doses of CS
(methylpredisolone 1g every day)
+
addition of either MMF, infliximab,
or ATG
Life-threating
cases:
consider
abatacept
or
alemtuzumab
elevated troponin
or conduction
abnormalities
transfer to a coronary patient unit
new conduction
delay consider a pacemaker
Figure 4.
Management of cardiovascular toxicities, including myocarditis, pericarditis, arrhythmias,
impaired ventricular function with heart failure, and vasculitis. Based on [
78
]; G1—grade 1, G2—
grade 2 (see Table 3), ICIs—immune checkpoints inhibitor, CS—corticosteroid, MMF—mycophenolate
mofetil, ATG—anti-thymocyte globulin.
Table 3.
Grading of cardiovascular toxicities, including myocarditis, pericarditis, arrhythmias,
impaired ventricular function with heart failure, and vasculitis. Based on [78].
G1 Abnormal cardiac biomarker testing without symptoms and with no
ECG abnormalities
G2 Abnormal cardiac biomarker testing with mild symptoms or new ECG
abnormalities without conduction delay
G3 Abnormal cardiac biomarker testing with either moderate symptoms or new
conduction delay
G4 Moderate to severe decompensation, IV medication or intervention required,
life-threatening conditions
3.7. Follow-Up and Surveillance of Patients
The cardiac history should be taken from all patients before initiation of ICI therapy.
Additionally, the measurement of troponin level and ECG should be performed [
47
]. The
patients with concomitant cardiac diseases or initial troponinemia have non-ICI-related
myocardial damage and are more susceptible to myocarditis. In one study, the authors
measured the troponin level one time per week for 6 weeks (from the first dose of ICI) [
13
].
In any case of elevation of this cardiac biomarker during follow-up, the patient should be
consulted with a cardiologist and an echocardiogram should be done. A cardiac biopsy
should be considered if there is any sign of myocarditis in an echocardiogram or cardiac
MRI [
13
]. However, in many cases elevation of troponin during immunotherapy can be
not associated with myocarditis. Melanoma was reported to be the second most frequent
cancer associated with cardiac metastases, after mesothelioma, so the progression of the
disease and heart failure related to increasing after-load should be always taken into
consideration [
83
,
84
]. Also, Kurzhals et al. (2021) reported elevations of serum troponin T
levels in 28% of patients with advanced skin cancer prior to the beginning of the therapy,
and the pre-therapeutic elevated troponin T concentrations were not associated with the
J. Clin. Med. 2022,11, 5182 11 of 15
development of myocarditis [
85
]. However, if and how the extent to which metastatic
melanoma per se is associated with increased serum troponin T concentrations needs to
be confirmed in larger studies. The potential risk of long-term cardiotoxicity has not been
established yet, due to the lack of sufficient long-term data as most of these agents have
been approved in the last few years [40].
4. Conclusions
Cardiotoxic AEs, initially reported as very rare, are more often becoming recognized
as the use of immune checkpoint inhibitors is expanded outside clinical trials in general
everyday practice. At the start of immunotherapy treatment, no specific biomarkers of
potential autoimmune cardiac risk are known at this point in time, but initial abnormal
troponin, NT-proBNP and CK/CK-MB levels indicating heart muscle damage may be
helpful in defining patients at risk. As in our patient, the myocarditis was manifested by
physical deterioration, ECG abnormalities or chest pain.
Monitoring of patients with pre-existing cardiac disorders and risk factors is essential
in everyday practice and may accelerate the diagnosis and rapid initiation of treatment
for myocarditis. Special attention needs to be focused on patients who have already
experienced one immune-related adverse event such as colitis, pneumonitis, hepatitis, neu-
rotoxicity, and hyper- or hypothyroidism. In any case of cardiac signs or symptoms, prompt
evaluation is essential which can ensure fast initiation of treatment for myocarditis. It can
reduce the risk of death due to this complication and allow reinitiating the immunotherapy
after curing the myocarditis in some cases. More research on autoimmunity biomarkers is
needed. Prospective translational trials could help to define patients at risk. Serum-based
biomarkers that are easily obtained in routine practice should be considered.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jcm11175182/s1, Table S1. Description of case of cardiac compli-
cations of immunotherapy.
Author Contributions:
Conceptualization—A.M.C. and P.R. (Piotr Rutkowski); methodology—
A.M.C., P.R. (Paweł Rogala) and M.W.; software—A.M.C., M.K., I.P. and M.W.; formal analysis—I.P.,
M.K. and A.M.C.; investigation—A.M.C., P.R. (Paweł Rogala), P.R. (Piotr Rutkowski) and M.W.;
resources—P.R. (Piotr Rutkowski); data curation—A.M.C., I.P. and M.K.; writing—A.M.C., M.K.,
I.P., P.R. (Paweł Rogala), and M.W., P.L. and P.R. (Piotr Rutkowski); visualization—M.W., I.P. and
M.K.; supervision—P.R. (Piotr Rutkowski) and A.M.C.; project administration—A.M.C.; funding
acquisition—P.R. (Piotr Rutkowski). All authors have read and agreed to the published version of
the manuscript.
Funding: Maria Skłodowska—Curie National Institute of Oncology statutory founding (MEiN).
Institutional Review Board Statement:
The study was approved by Ethics Committee of Maria
Sklodowska-Curie National Research Institute of Oncology (protocol code: 13/2008, date of ap-
proval:4/03/2008).
Informed Consent Statement:
This is retrospective non-interventional study and all the data ana-
lyzed were collected as a part of routine clinical practice for diagnosis and treatment. The patient
signed an informed consent form for treatment as per the standard operating procedures in our
hospitals. In addition, the patient was diagnosed and treated following the national guidelines and
policies. The treatment was covered according to the reimbursement regulations of National Health
Fund (NFZ, Poland), based on the recommendations of the Polish Agency for Health Technology
Assessment and Tariff System (AOTMiT).
Data Availability Statement:
All data are available for research cooperation purposes from the PI of
the study upon DTA approval.
J. Clin. Med. 2022,11, 5182 12 of 15
Conflicts of Interest:
PRu Financial Interests: Blueprint Medicines—advisory board; BMS—invited
speaker, advisory board; Merck—advisory board, invited speaker; MSD—invited speaker, advisory
board; Novartis—invited speaker; Pierre Fabre—invited speaker, advisory board; Sanofi—advisory
board, invited speaker; BMS—institutional research grant; Pfizer—institutional research grant; Non-
financial Interests: ASCO, Officer; Polish Society of Surgical Oncology, Member of Board of Directors.
Travel reimbursement and fees and speaker honoraria: AMC—BMS, MSD, Pierre Fabre, Novartis,
Roche. Other—declared none.
References
1.
Kennedy, L.B.; Salama, A. A review of cancer immunotherapy toxicity. CA A Cancer J. Clin.
2020
,70, 86–104. [CrossRef] [PubMed]
2.
Jia, X.-H.; Geng, L.-Y.; Jiang, P.-P.; Xu, H.; Nan, K.-J.; Yao, Y.; Jiang, L.-L.; Sun, H.; Qin, T.-J.; Guo, H. The biomarkers related
to immune related adverse events caused by immune checkpoint inhibitors. J. Exp. Clin. Cancer Res.
2020
,39, 284. [CrossRef]
[PubMed]
3.
Weidhaas, J.; Marco, N.; Scheffler, A.W.; Kalbasi, A.; Wilenius, K.; Rietdorf, E.; Gill, J.; Heilig, M.; Desler, C.; Telesca, D.; et al.
Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy. J. Immunother. Cancer
2022
,10, e003625. [CrossRef]
[PubMed]
4.
Wang, D.Y.; Salem, J.E.; Cohen, J.V.; Chandra, S.; Menzer, C.; Ye, F.; Zhao, S.; Das, S.; Beckermann, K.E.; Johnson, D.B.; et al. Fatal
Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol.
2018
,4,
1721–1728. [CrossRef] [PubMed]
5.
Zimmer, L.; Goldinger, S.M.; Hofmann, L.; Loquai, C.; Ugurel, S.; Thomas, I.; Schmidgen, M.; Gutzmer, R.; Utikal, J.;
Heinzerling, L.; et al.
Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur.
J. Cancer 2016,60, 210–225. [CrossRef]
6.
Oldfield, K.; Jayasinghe, R.; Niranjan, S.; Chadha, S. Immune checkpoint inhibitor-induced takotsubo syndrome and diabetic
ketoacidosis: Rare reactions. BMJ Case Rep. 2021,14, e237217. [CrossRef]
7.
Voskens, C.J.; Goldinger, S.M.; Loquai, C.; Robert, C.; Kaehler, K.C.; Al, E.; Dummer, R. The price of tumor control: An analysis
of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One
2013
,8, e53745.
[CrossRef]
8.
Tomita, Y.; Sueta, D.; Kakiuchi, Y.; Saeki, S.; Saruwatari, K.; Sakata, S.; Jodai, T.; Migiyama, Y.; Akaike, K.; Hirosako, S.; et al.
Acute coronary syndrome as a possible immune-related adverse event in a lung cancer patient achieving a complete response to
anti-PD-1 immune checkpoint antibody. Ann. Oncol. 2017,28, 2893–2895. [CrossRef]
9.
Heery, C.R.; Coyne, G.H.O.; Madan, R.A.; Schlom, J.; Von Heydebreck, A.; Cuillerot, J.-M.; Sabzevari, H.; Gulley, J.L. Phase I
open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies.
J. Clin. Oncol. 2014,32 (Suppl. 15), 3064. [CrossRef]
10.
Tadokoro, T.; Keshino, E.; Makiyama, A.; Sasaguri, T.; Ohshima, K.; Katano, H.; Mohri, M. Acute Lymphocytic Myocarditis with
Anti-PD-1 Antibody Nivolumab. Circ. Heart Fail. 2016,9, e003514. [CrossRef]
11.
Johnson, D.B.; Balko, J.M.; Compton, M.L.; Chalkias, S.; Gorham, J.; Xu, Y.; Hicks, M.; Puzanov, I.; Alexander, M.;
Moslehi, J.J.; et al.
Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N. Engl. J. Med.
2016
,375, 1749–1755. [CrossRef]
[PubMed]
12.
Mahmood, S.S.; Fradley, M.G.; Cohen, J.V.; Nohria, A.; Reynolds, K.L.; Heinzerling, L.M.; Sullivan, R.; Damrongwatanasuk, R.;
Chen, C.; Neilan, T.G.; et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J. Am. Coll. Cardiol.
2018
,71,
1755–1764. [CrossRef] [PubMed]
13.
Salem, J.E.; Manouchehri, A.; Moey, M.; Lebrun-Vignes, B.; Bastarache, L.; Pariente, A.; Gobert, A.; Spano, P.; Balko, J.;
Moslehi, J.J.; et al.
Cardiovascular toxicities associated with immune checkpoint inhibitors: An observational, retrospective,
pharmacovigilance study. Lancet Oncol. 2018,19, 1579–1589. [CrossRef]
14.
Moslehi, J.J.; Salem, J.E.; Sosman, J.A.; Lebrun-Vignes, B.; Johnson, D.B. Increased reporting of fatal immune checkpoint
inhibitor-associated myocarditis. Lancet 2018,391, 933. [CrossRef]
15.
Tajiri, K.; Aonuma, K.; Sekine, I. Immune checkpoint inhibitor-related myocarditis. Jpn. J. Clin. Oncol.
2017
,48, 7–12. [CrossRef]
16.
Matzen, E.; Bartels, L.E.; Løgstrup, B.; Horskær, S.; Stilling, C.; Donskov, F. Immune checkpoint inhibitor-induced myocarditis in
cancer patients: A case report and review of reported cases. Cardio-Oncol. 2021,7, 27. [CrossRef]
17.
D’Souza, M.; Nielsen, D.; Svane, I.M.; Iversen, K.; Rasmussen, P.V.; Madelaire, C.; Fosbøl, E.; Køber, L.; Gustafsson, F.;
Andersson, C.; et al.
The risk of cardiac events in patients receiving immune checkpoint inhibitors: A nationwide Danish
study. Eur. Heart J. 2020,42, 1621–1631. [CrossRef]
18.
Scard, C.; Nguyen, J.-M.; Varey, E.; Moustaghfir, I.; Khammari, A.; Dreno, B. Cardiac adverse events associated with anti-PD-1
therapy in patients treated for advanced melanoma: Relevance of dosing troponin T levels. Eur. J. Dermatol.
2021
,31, 205–212.
[CrossRef]
19.
Qin, Q.; Patel, V.G.; Wang, B.; Mellgard, G.; Gogerly-Moragoda, M.; Zhong, X.; Parikh, A.B.; Leiter, A.; Gallagher, E.J.;
Galsky, M.D.; et al.
Type, timing, and patient characteristics associated with immune-related adverse event development in
patients with advanced solid tumors treated with immune checkpoint inhibitors. J. Clin. Oncol.
2020
,38 (Suppl. S15), e15160.
[CrossRef]
J. Clin. Med. 2022,11, 5182 13 of 15
20.
Jain, P.; Bugarin, J.G.; Guha, A.; Jain, C.; Patil, N.; Shen, T.; Stanevich, I.; Nikore, V.; Margolin, K.; Dowlati, A.; et al. Cardiovascular
adverse events are associated with usage of immune checkpoint inhibitors in real-world clinical data across the United States.
ESMO Open 2021,6, 100252. [CrossRef]
21.
Heinzerling, L.; Ott, P.A.; Hodi, F.S.; Husain, A.N.; Tajmir-Riahi, A.; Tawbi, H.; Pauschinger, M.; Gajewski, T.F.; Lipson, E.J.;
Luke, J.J. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J. Immunother. Cancer
2016
,4, 50. [CrossRef]
[PubMed]
22.
Rahouma, M.; Karim, N.A.; Baudo, M.; Yahia, M.; Kamel, M.; Eldessouki, I.; Abouarab, A.; Saad, I.; Elmously, A.;
Gaudino, M.; et al.
Cardiotoxicity with immune system targeting drugs: A meta-analysis of anti-PD/PD-L1 immunotherapy
randomized clinical trials. Immunotherapy 2019,11, 725–735. [CrossRef] [PubMed]
23.
Eggermont, A.M.; Chiarion-Sileni, V.; Grob, J.J.; Dummer, R.; Wolchok, J.D.; Schmidt, H.; Hamid, O.; Robert, P.; Richards, J.;
Testori, A.; et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A
randomised, double-blind, phase 3 trial. Lancet Oncol. 2015,16, 522–530. [CrossRef]
24.
Saibil, S.D.; Bonilla, L.; Majeed, H.; Sotov, V.; Hogg, D.; Chappell, M.A.; Cybulsky, M.; Butler, M.O. Fatal Myocarditis and
Rhabdomyositis in a Patient with Stage Iv Melanoma Treated with Combined Ipilimumab and Nivolumab. Curr. Oncol.
2019
,26,
e418–e421. [CrossRef] [PubMed]
25.
Yamaguchi, S.; Morimoto, R.; Okumura, T.; Yamashita, Y.; Haga, T.; Kuwayama, T.; Yokoi, T.; Hiraiwa, H.; Kondo, T.;
Sugiura, Y.; et al.
Late-Onset Fulminant Myocarditis with Immune Checkpoint Inhibitor Nivolumab. Can. J. Cardiol.
2018
,
34, 812.e1–812.e3. [CrossRef]
26.
Arangalage, D.; Delyon, J.; Lermuzeaux, M.; Ekpe, K.; Ederhy, S.; Pages, C.; Lebbé, C. Survival After Fulminant Myocarditis
Induced by Immune-Checkpoint Inhibitors. Ann. Intern. Med. 2017,167, 683–684. [CrossRef]
27.
Geisler, B.P.; Raad, R.A.; Esaian, D.; Sharon, E.; Schwartz, D.R. Apical ballooning and cardiomyopathy in a melanoma patient
treated with ipilimumab: A case of takotsubo-like syndrome. J. Immunother. Cancer 2015,3, 4. [CrossRef] [PubMed]
28.
Yun, S.; Vincelette, N.D.; Mansour, I.; Hariri, D.; Motamed, S. Late Onset Ipilimumab-Induced Pericarditis and Pericardial
Effusion: A Rare but Life Threatening Complication. Case Rep. Oncol. Med. 2015,2015, 794842. [CrossRef]
29.
Läubli, H.; Balmelli, C.; Bossard, M.; Pfister, O.; Glatz, K.; Zippelius, A. Acute heart failure due to autoimmune myocarditis under
pembrolizumab treatment for metastatic melanoma. J. Immunother. Cancer 2015,3, 11. [CrossRef]
30.
Naidoo, J.; Wang, X.; Woo, K.M.; Iyriboz, T.; Halpenny, D.; Cunningham, J.; Chaft, J.; Segal, N.; Callahan, M.;
Hellmann, M.D.; et al.
Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J. Clin. Oncol.
2017
,35,
709–717. [CrossRef]
31.
Hofmann, L.; Forschner, A.; Loquai, C.; Goldinger, S.M.; Zimmer, L.; Ugurel, S.; Schmidgen, M.I.; Gutzmer, R.; Utikal, J.S.;
Göppner, D.; et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur. J. Cancer
2016
,
60, 190–209. [PubMed]
32.
Dearden, H.; Au, L.; Wang, D.Y.; Zimmer, L.; Eroglu, Z.; Smith, J.L.; Cuvietto, M.; Khoo, C.; Atkinson, V.; Lo, S.; et al. Hyperacute
toxicity with combination ipilimumab and anti-PD1 immunotherapy. Eur. J. Cancer 2021,153, 168–178. [CrossRef] [PubMed]
33.
Shulgin, B.; Kosinsky, Y.; Omelchenko, A.; Chu, L.; Mugundu, G.; Aksenov, S.; Pimentel, R.; DeYulia, G.; Kim, G.; Peskov, K.; et al.
Dose dependence of treatment-related adverse events for immune checkpoint inhibitor therapies: A model-based meta-analysis.
OncoImmunology 2020,9, 1748982. [CrossRef] [PubMed]
34.
Arangalage, D.; Degrauwe, N.; Michielin, O.; Monney, P.; Özdemir, B.C. Pathophysiology, diagnosis and management of cardiac
toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors. Cancer Treat. Rev.
2021
,100, 102282. [PubMed]
35.
Caforio, A.L.; Pankuweit, S.; Arbustini, E.; Basso, C.; Gimeno-Blanes, J.; Felix, S.B.; Fu, M.; Heliö, T.; Heymans, S.;
Elliott, P.M.; et al.
Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the
European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2013,34, 2636–2648.
36. Cooper, L.T. Myocarditis. New Engl. J. Med. 2009,360, 1526–1538. [CrossRef]
37.
Richardson, P. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on
the Definition and Classification of cardiomyopathies. Circulation 1996,93, 841–842.
38.
Aretz, H.T.; Billingham, M.E.; Edwards, W.D.; Factor, S.M.; Fallon, J.; Fenoglio, J.J.; Olsen, E.G.; Schoen, F.J. Myocarditis.
A histopathologic definition and classification. Am. J. Cardiovasc. Pathol. 1987,1, 3–14.
39.
Cooper, L.T.; Baughman, K.L.; Feldman, A.M.; Frustaci, A.; Jessup, M.; Kuhl, U.; Levine, G.; Narula, J.; Starling, R.C.;
Virmani, R.; et al.
The role of endomyocardial biopsy in the management of cardiovascular disease: A scientific statement
from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by
the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur. Heart J.
2007
,
28, 3076–3093.
40.
Lobenwein, D.; Kocher, F.; Dobner, S.; Gollmann-Tepeköylü, C.; Holfeld, J. Cardiotoxic mechanisms of cancer immunotherapy–A
systematic review. Int. J. Cardiol. 2020,323, 179–187.
41.
Grabie, N.; Gotsman, I.; Dacosta, R.; Pang, H.; Stavrakis, G.; Butte, M.J.; Keir, M.E.; Freeman, G.J.; Sharpe, A.H.; Lichtman, A.H.
Endothelial Programmed Death-1 Ligand 1 (PD-L1) Regulates CD8 + T-Cell–Mediated Injury in the Heart. Circulation
2007
,116,
2062–2071. [PubMed]
42.
Seko, Y.; Yagita, H.; Okumura, K.; Azuma, M.; Nagai, R. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the
development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc. Res.
2007
,75, 158–167. [CrossRef] [PubMed]
J. Clin. Med. 2022,11, 5182 14 of 15
43.
Li, S.; Tajiri, K.; Murakoshi, N.; Xu, D.; Yonebayashi, S.; Okabe, Y.; Yuan, Z.; Feng, D.; Inoue, K.; Aonuma, K.; et al. Programmed
Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice. Int. J. Mol. Sci.
2021
,22, 1426. [PubMed]
44.
Nishimura, H.; Okazaki, T.; Tanaka, Y.; Nakatani, K.; Hara, M.; Matsumori, A.; Sasayama, S.; Mizoguchi, A.; Hiai, H.;
Minato, N.; et al.
Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice. Science
2001
,291, 319–322. [PubMed]
45.
Nishimura, H.; Nose, M.; Hiai, H.; Minato, N.; Honjo, T. Development of Lupus-like Autoimmune Diseases by Disruption of the
PD-1 Gene Encoding an ITIM Motif-Carrying Immunoreceptor. Immunity 1999,11, 141–151.
46.
Tay, W.T.; Fang, Y.-H.; Beh, S.T.; Liu, Y.-W.; Hsu, L.-W.; Yen, C.-J.; Liu, P.-Y. Programmed Cell Death-1: Programmed Cell
Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response
In Vitro. Int. J. Mol. Sci. 2020,21, 2399.
47.
Hu, J.R.; Florido, R.; Lipson, E.J.; Naidoo, J.; Ardehali, R.; Tocchetti, C.G.; Lyon, A.R.; Padera, R.; Johnson, D.; Moslehi, J.; et al.
Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc. Res. 2019,115, 854–868.
48.
Tarrio, M.L.; Grabie, N.; Bu, D.-X.; Sharpe, A.H.; Lichtman, A.H. PD-1 Protects against Inflammation and Myocyte Damage in T
Cell-Mediated Myocarditis. J. Immunol. 2012,188, 4876–4884.
49.
Koelzer, V.H.; Rothschild, S.I.; Zihler, D.; Wicki, A.; Willi, B.; Willi, N.; Voegeli, M.; Cathomas, G.; Zippelius, A.; Mertz, K.D.
Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors—an autopsy study. J. Immunother.
Cancer 2016,4, 13.
50.
Saade, A.; Mansuet-Lupo, A.; Arrondeau, J.; Thibault, C.; Mirabel, M.; Goldwasser, F.; Oudard, S.; Weiss, L. Pericardial effusion
under nivolumab: Case-reports and review of the literature. J. Immunother Cancer 2019,7, 266. [CrossRef]
51.
Ang, E.; Mweempwa, A.; Heron, C.; Ahn, Y.; Rivalland, G.; Ha, L.Y.; Deva, S. Cardiac Troponin I and T in Checkpoint
Inhibitor–associated Myositis and Myocarditis. J. Immunother. 2021,44, 162–163. [PubMed]
52.
Arponen, O.; Skyttä, T. Immune checkpoint inhibitor-induced myocarditis not visible with cardiac magnetic resonance imaging
but detected with PET-CT: A case report. Acta Oncol. 2020,59, 490–492. [PubMed]
53.
Ibanez, B.; James, S.; Agewall, S.; Antunes, M.J.; Bucciarelli-Ducci, C.; Bueno, H.; Caforio, A.; Crea, F.; Goudevenos, F.;
Widimský, P.; et al.
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-
segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment
elevation of the European Society of Cardiology (ESC). Eur. Heart J. 2018,39, 119–177. [PubMed]
54.
Pohl, J.; Mincu, R.-I.; Mrotzek, S.M.; Hinrichs, L.; Michel, L.; Livingstone, E.; Zimmer, L.; Wakili, R.; Schadendorf, D.;
Rassaf, T.; et al.
ECG Changes in Melanoma Patients Undergoing Cancer Therapy–Data from the ECoR Registry. J. Clin. Med.
2020,9, 2060.
55.
Ammirati, E.; Cipriani, M.; Moro, C.; Raineri, C.; Pini, D.; Sormani, P.; Mantovani, R.; Varrenti, M.; Pedrotti, P.; delle
Miocarditi, R.L.; et al.
Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multi-
center Lombardy Registry. Circulation 2018,138, 1088–1099.
56.
Awadalla, M.; Mahmood, S.S.; Groarke, J.D.; Hassan, M.Z.; Nohria, A.; Rokicki, A.; Murphy, S.; Mercaldo, N.; Zhang, L.;
Neilan, T.G.; et al.
Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related
Myocarditis. J. Am. Coll. Cardiol. 2020,75, 467–478.
57.
Friedrich, M.G.; Sechtem, U.; Schulz-Menger, J.; Holmvang, G.; Alakija, P.; Cooper, L.T.; White, J.A.; Abdel-Aty, H.;
Gutberlet, M.
;
Prasad, S.; et al. Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper. J. Am. Coll. Cardiol.
2009
,53,
1475–1487.
58.
Olimulder, M.A.; van Es, J.; Galjee, M.A. The importance of cardiac MRI as a diagnostic tool in viral myocarditis-induced
cardiomyopathy. Neth. Heart J. 2009,17, 481–486.
59.
Nensa, F.; Kloth, J.; Tezgah, E.; Poeppel, T.D.; Heusch, P.; Goebel, J.; Nassenstein, K.; Schlosser, T. Feasibility of FDG-PET in
myocarditis: Comparison to CMR using integrated PET/MRI. J. Nucl. Cardiol. 2018,25, 785–794.
60.
Hazebroek, M.R.; Everaerts, K.; Heymans, S. Diagnostic approach of myocarditis: Strike the golden mean. Neth. Heart J.
2014
,22,
80–84.
61.
Ansari-Gilani, K.; Tirumani, S.H.; Smith, D.A.; Nelson, A.; Alahmadi, A.; Hoimes, C.J.; Ramaiya, N.H. Myocarditis associated
with immune checkpoint inhibitor therapy: A case report of three patients. Emerg. Radiol. 2020,27, 455–460. [PubMed]
62.
Samara, Y.; Yu, C.L.; Dasanu, C.A. Acute autoimmune myocarditis and hepatitis due to ipilimumab monotherapy for malignant
melanoma. J. Oncol. Pharm. Pract. 2018,25, 966–968.
63.
Fukasawa, Y.; Sasaki, K.; Natsume, M.; Nakashima, M.; Ota, S.; Watanabe, K.; Takahashi, Y.; Kondo, F.; Kozuma, K.; Seki, N.
Nivolumab-Induced Myocarditis Concomitant with Myasthenia Gravis. Case Rep. Oncol. 2017,10, 809–812. [PubMed]
64.
Pathak, R.; Katel, A.; Massarelli, E.; Villaflor, V.M.; Sun, V.; Salgia, R. Immune Checkpoint Inhibitor–Induced Myocarditis with
Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases. Oncologist 2021,26, 1052–1061. [PubMed]
65.
Suzuki, S.; Ishikawa, N.; Konoeda, F.; Seki, N.; Fukushima, S.; Takahashi, K.; Uhara, H.; Hasegawa, Y.; Inomata, S.;
Matsui, M.; et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 2017,89, 1127–1134.
66.
Bawek, S.J.; Ton, R.; McGovern-Poore, M.; Khoncarly, B.; Narvel, R. Nivolumab-Induced Myasthenia Gravis Concomitant with
Myocarditis, Myositis, and Hepatitis. Cureus 2021,13, e18040.
67.
Diamantopoulos, P.T.; Tsatsou, K.; Benopoulou, O.; Bonou, M.; Anastasopoulou, A.; Mastrogianni, E.; Gogas, H. Concomitant
development of neurologic and cardiac immune-related adverse effects in patients treated with immune checkpoint inhibitors for
melanoma. Melanoma Res. 2020,30, 484–491.
J. Clin. Med. 2022,11, 5182 15 of 15
68.
Shalata, W.; Peled, N.; Gabizon, I.; Saleh, O.A.; Kian, W.; & Yakobson, A. Associated Myocarditis: A Predictive Factor for
Response? Case Rep. Oncol. 2020,13, 550–557.
69.
Barham, W.; Guo, R.; Park, S.S.; Herrmann, J.; Dong, H.; Yan, Y. Case Report: Simultaneous Hyperprogression and Fulminant
Myocarditis in a Patient with Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy. Front.
Immunol. 2021,11, 561083.
70.
Arangalage, D.; Pavon, A.G.; Özdemir, B.C.; Michielin, O.; Schwitter, J.; Monney, P. Acute cardiac manifestations under immune
checkpoint inhibitors—beware of the obvious: A case report. Eur. Heart J.-Case Rep. 2021,5, ytab262.
71.
Fazel, M.; Jedlowski, P.M. Severe Myositis, Myocarditis, and Myasthenia Gravis with Elevated Anti-Striated Muscle Antibody
following Single Dose of Ipilimumab-Nivolumab Therapy in a Patient with Metastatic Melanoma. Case Rep. Immunol.
2019
,
2019, 2539493.
72.
Wakefield, C.; Shultz, C.; Patel, B.; Malla, M. Life-threatening immune checkpoint inhibitor-induced myocarditis and myasthenia
gravis overlap syndrome treated with abatacept: A case report. BMJ Case Rep. 2021,14, e244334. [PubMed]
73.
Drobni, Z.D.; Alvi, R.M.; Taron, J.; Zafar, A.; Murphy, S.P.; Rambarat, P.K.; Mosarla, R.C.; Lee, C.; Zlotoff, D.A.; Raghu, V.K.; et al.
Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque. Circulation
2020
,
142, 2299–2311.
74.
Kanz, B.A.; Pollack, M.H.; Johnpulle, R.; Puzanov, I.; Horn, L.; Morgans, A.; Sosman, J.A.; Rapisuwon, S.; Conry, R.M.;
Eroglu, Z.; et al.
Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. J. Immunother.
Cancer 2016,4, 60. [PubMed]
75.
Shah, K.P.; Song, H.; Ye, F.; Moslehi, J.J.; Balko, J.M.; Salem, J.-E.; Johnson, D.B. Demographic Factors Associated with Toxicity in
Patients Treated with Anti–Programmed Cell Death-1 Therapy. Cancer Immunol. Res. 2020,8, 851–855. [PubMed]
76.
Johnson, D.B.; Sullivan, R.J.; Ott, P.A.; Carlino, M.S.; Khushalani, N.I.; Ye, F.; Buchbinder, E.; Mudigonda, T.; Spencer, K.;
Clark, J.I.; et al.
Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA
Oncol. 2016,2, 234–240.
77.
Haanen, J.B.A.G.; Carbonnel, F.; Robert, C.; Kerr, K.M.; Peters, S.; Larkin, J.; Jordan, K. Management of toxicitiesfrom immunother-
apy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017,28, iv119–iv142.
78.
Schneider, B.J.; Naidoo, J.; Santomasso, B.D.; Lacchetti, C.; Adkins, S.; Anadkat, M.; Atkins, M.; Mammen, J.; Naing, A.;
Bollin, K.; et al.
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy:
ASCO Guideline Update. J. Clin. Oncol. 2021,39, 4073–4126.
79.
Guo, C.W.; Alexander, M.; Dib, Y.; Lau, P.K.; Weppler, A.M.; Au-Yeung, G.; Lee, B.; Khoo, C.; Mooney, D.; Joshi, S.B.; et al.
A closer
look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies. Eur. J. Cancer
2019
,
124, 15–24.
80.
Norwood, T.G.; Lenneman, C.A.; Westbrook, B.C.; Litovsky, S.H.; McKee, S.B.; Conry, R.M. Evolution of Immune Checkpoint
Blockade–Induced Myocarditis Over 2 Years. JACC Case Rep. 2020,2, 203–209.
81.
Michel, L.; Helfrich, I.; Hendgen-Cotta, U.B.; Mincu, R.-I.; Korste, S.; Mrotzek, S.M.; Spomer, A.; Odersky, A.; Rischpler, C.;
Herrmann, K.; et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur. Heart J.
2021,43, 316–329.
82.
Balanescu, D.V.; Donisan, T.; Palaskas, N.; Lopez-Mattei, J.; Kim, P.Y.; Buja, L.M.; McNamara, D.M.; Kobashigawa, J.A.;
Durand, J.-B.; Iliescu, C.A. Immunomodulatory treatment of immune checkpoint inhibitor-induced myocarditis: Pathway toward
precision-based therapy. Cardiovasc. Pathol. 2020,47, 107211. [PubMed]
83.
Benassaia, E.; Vallet, A.; Rouleau, E.; Ederhy, S.; Robert, C. Troponin increase during immunotherapy: Not always myocarditis.
Eur. J. Cancer 2021,157, 424–427.
84. Bussani, R.; De-Giorgio, F.; Abbate, A.; Silvestri, F. Cardiac metastases. J. Clin. Pathol. 2007,60, 27–34. [CrossRef] [PubMed]
85.
Kurzhals, J.K.; Graf, T.; Boch, K.; Grzyska, U.; Frydrychowicz, A.; Zillikens, D.; Terheyden, P.; Langan, E.A. Serum Troponin
T Concentrations Are Frequently Elevated in Advanced Skin Cancer Patients Prior to Immune Checkpoint Inhibitor Therapy:
Experience from a Single Tertiary Referral Center. Front. Med. 2021,8, 691618.
