Immune Checkpoint Inhibitor Therapy-Toxicity Management

Immune related cardiac toxicity

• Summary
• Background
• Diagnosis
• Investigation
• Treatment/Management

Summary of Guideline

Immune related cardiovascular adverse events (irCVAE) are rare (<1% of immunotherapy recipients) and can manifest with myocarditis, pericarditis, significant cardiac rhythm disturbances (i.e. 2nd or 3rd degree heart block, VT/VF) and large vessel vasculitis, or a combination of these. Cases can be asymptomatic, but case-series report up to 50% mortality in people with moderate or severe symptoms. Management is base on expert opinion owing to the paucity of evidence and includes cessation of treatment, supportive cardiac care (for example for rhythm disturbance or heart failure) and immunosuppressive treatments.

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Background

Immune related cardiovascular adverse events (irCVAE) are rare (<1% of immunotherapy recipients) and can manifest with myocarditis, pericarditis, significant cardiac rhythm disturbances (i.e. 2nd or 3rd degree heart block, VT/VF) and large vessel vasculitis, or a combination of these. Cases can be asymptomatic, but case-series report up to 50% mortality in people with moderate or severe symptoms. Currently, there is minimal high-quality evidence to guide irCVAE prevention, assessment and management; hence, this guidance is based predominantly on published expert opinion.

Investigating for irCVAEs requires specialist cardiology and oncology input and therefore we would not expect this to be worked up in primary care. This guideline serves to support those clinicians investigating these treatments in secondary care and for information of primary care teams who may potentially see these patients during their follow up.

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Diagnosis

Presentation

• The median onset of irCVAE is 1-2 months after initiation of immunotherapy, but cases have been reported even after one year.
• The commonest associated irAEs are myositis and myasthenia gravis, but many cases involve only the cardiovascular system.
• Combination immunotherapy increases the risk of irCVAEs. Prior cardiovascular disease, diabetes and autoimmune diseases may also increase the risk.
• CTCAE grading can be used to crudely describe severity:
  • Grade 1: Asymptomatic with new cardiac biomarker or ECG abnormality (do we recommend a pre-therapy baseline Troponin I).
  • Grade 2: Abnormal cardiac investigations with ‘mild symptoms’
  • Grade 3 (severe): Moderately abnormal cardiac investigations or symptoms on mild activity
  • Grade 4 (life-threatening): Moderate to severe cardiovascular decompensation

Assessment
Consider irCVAEs in people receiving immunotherapy who present with:

• Chest pain (ischaemic or pericarditic)
• New breathlessness with no other clear cause (e.g. PE, pneumonia, anaemia)
• Palpitations associated with ventricular arrhythmias
• Syncope or presyncope with no other clear cause (e.g. dehydration, seizure)
• Asymptomatic new ECG abnormality or new cardiac biomarker elevation

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Investigation

In these cases, arrange urgent assessment with:

1. Full history and examination
2. 12-lead ECG
3. Routine blood testing including cardiac biomarkers (Troponin I)
4. Chest x-ray
5. Echocardiography

In cases of chest pain with troponin elevation, decompensated heart failure, severe rhythm disturbances (2nd or 3rd degree heart block, VT/VF) or suspected cardiac tamponade, seek urgent transfer to monitored cardiology or HDU setting. For less severe symptoms and/or investigation abnormalities compatible with irCVAE seek a cardiology opinion. The cardiology team may arrange other investigations (e.g. cardiac MRI) to complete assessment.

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Treatment/Management

Major considerations include:

1. Cessation of immunotherapy, probably permanently for grade 2+ irCVAE. Longer-term plans can be discussed with a cardio-oncology specialist.
2. Provision of supportive cardiology care for relevant syndrome (e.g. acute heart failure management, pacemaker implantation, pericardiocentesis)
3. Immunosuppressive therapy initially guided by grade of irCVAE and adjusted according to clinical response

Contacts
First line: Cardiology SpR or consultant on-call
Second line: Dr Ric Cubbon or Dr Rob Sapsford