Address for
Correspondence: Prof. Dr. Johnson Francis, MBBS, MD, DM,
FACC, FRCP Edin, FRCP London, Senior Consultant Cardiologist,
Baby Memorial Hospital, Kozhikode, Kerala, India, PIN 673017.
Email: pulikkottil2002@hotmail.com
Abstract
Immune checkpoint inhibitors (ICI) are a promising group of
novel anti cancer drugs. They are monoclonal antibodies
targeting cytotoxic T lymphocyte-associated antigen 4
(CTLA-4), programmed cell death 1 (PD-1) and its ligand
(PD-L1). This group of drugs have been useful in a wide
variety of malignancies with an otherwise poor prognosis.
Important drugs in this class are ipilimumab, nivolumab,
pembrolizumab and atezolizumab. Though they are excellent
therapeutic options in several malignancies, some
immune-related adverse effects have been noted, of which
autoimmune myocarditis is potentially life threatening.
Pathology of ICI‐associated myocarditis is characterized by
intense infiltration by T lymphocytes and macrophages. Severe
myocarditis will mandate suspension of ICI treatment and
initiation of high dose corticosteroids (prednisolone or
methylprednisolone).
Keywords: Immune Checkpoint Inhibitors, Myocarditis
Myocardial dysfunction leading to heart failure is one of
the well known adverse effects of cancer chemotherapy,
especially with anthracycline group of drugs [1]. Immune
checkpoint inhibitors (ICI) are a promising group of novel
anti cancer drugs. They are monoclonal antibodies targeting
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4),
programmed cell death 1 (PD-1) and its ligand (PD-L1). This
group of drugs have been useful in a wide variety of
malignancies with an otherwise poor prognosis. Important drugs
in this class are ipilimumab, nivolumab, pembrolizumab and
atezolizumab [2]. Though they are excellent therapeutic
options in several malignancies, some immune-related adverse
effects have been noted, of which autoimmune myocarditis is
potentially life threatening [3].
Anti-CTLA-4 monoclonal antibodies were the first generation
ICIs. Ipilimumab was the prototype of this class of monoclonal
antibodies. Anti-PD-1 monoclonal antibodies were the second
generation. Nivolumab and pembrolizumab target PD-1 while
atezolizumab, avelumab and durvalumab target PD-L1 [2].
Therapeutic blockade of immune checkpoints by these drugs can
alter immunological tolerance and give rise to autoimmune or
inflammatory side effects known collectively as
'immune-related adverse events'. Of these, endocrinopathies
involving the thyroid and pituitary have high risk of
irreversible toxicity. Cardiac immune-related adverse events
are less common than those which affect other organ systems.
PD-1 is expressed in human hearts as well as in the hearts of
mice. PD-1 deficiency has been shown to produce fatal
myocarditis in certain types of mice [4]. Though myocarditis
is a rare adverse effect of ICIs, due to the increasing number
of cancers being treated with these drugs, the chance of
occurrence of myocarditis is also increasing. But due to the
low prevalence, it has been difficult to assess ICI-associated
myocarditis in any single clinical trial. Hence Checkpoint
Inhibitor Safety Working Group has recently conducted a
workshop and summarized their findings and proposed steps [5].
Pathology of ICI‐associated myocarditis is characterized by
intense infiltration by T lymphocytes and macrophages [6]. The
rather rapid onset of myocarditis after initiation of ICIs
would also suggest the presence of a pre-existing factor that
was held in check by the pathway targeted by the treatment
[5]. ICI‐associated myocarditis occurs early during treatment
and is more common with combination ICI, though two thirds of
cases occurred following monotherapy [7].
American Society of Clinical Oncology Clinical Practice
Guideline has addressed the management of immune-related
adverse events in patients treated with ICIs including
myocarditis [8]. The symptoms to look for include chest pain,
palpitations, peripheral edema, fatigue and breathlessness.
Baseline evaluation would include and ECG and cardiac troponin
estimation. Additional testing based on symptoms may be
echocardiogram, chest X-ray and B-type natriuretic peptide
estimation. Cardiac magnetic resonance imaging (CMR) with late
gadolinium enhancement may be considered in selected cases.
Cardiac catheterization is useful in assessing the hemodynamic
status and histological documentation of myocarditis with
endomyocardial biopsy.
Severe myocarditis will mandate suspension of ICI treatment
and initiation of high dose corticosteroids (prednisolone or
methylprednisolone). Tapering of corticosteroids is done over
a course of 4 to 6 weeks. In refractory cases addition of
mycophenolate, infliximab or antithymocyte globulin may be
considered [9].
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