Immunotherapy cardiotoxicity

ESC Guidelines

• Early toxicity typically inflammatory : ICI-associated myocarditis had early onset of symptoms (median of 30 days after initial exposure to ICI), and up to 50% died)
• > 90 days--> non-inflammatory HF,  MI, AV block, supraventricular and ventricular arrhythmias, new pulmonary artery hypertension, sudden death. Can be seen in association with ischaemic stroke, and VTE. Takotsubo-like syndrome, pericarditis, pericardial effusion, also described.
• Long term considerations in the clinic: progressive atherosclerosis, hypertension, 
• Highest risk of cardiac toxicity: ipilimumab+ nivolumab ( combination)

Class I recommendations:

-All patients on ICI treatment: CV risk assessment, troponin, BNP, NT-BNP, EKG

- pt on long term ICI management ( > 12 months) should have CV assessment every 6-12 months, particularly so for the high risk patient.

-High-risk patients should additionally have a TTE evaluation at baseline  and repeat if  symptoms. 

What falls under CV risk assessment:

• Physical examination, BP, NP (BNP or NT-proBNP), lipid profile, HbA1c, and ECG.

 

What is a high risk patient?

• Dual ICI
•  combination ICI-cardiotoxic therapy for example immunotherapy with herceptin, VEGF inhibitor or doxorubicin ( keynote 522); pembro + axitinib
•  ICI-related non-CV events
• prior Cancer therapy related cardiac dysfunction
•  known CAD.

Once started on therapy, ECG, cTn, and NP should be checked.

In patients who develop ECG abnormalities, new biomarker changes, or new cardiac symptoms at any time, prompt cardio-oncology evaluation is strongly recommended, including TTE for the evaluation of LVEF and GLS, and CMR when myocarditis is suspected.

Monitoring of cardiac function while on treatment for high risk:

-Serial ECG and cTn measurements should be considered before ICI doses 2, 3, and 4, and if normal, reduce to every three doses until completion of therapy to detect subclinical ICI-related CV toxicity

International cardio-oncology societ criteria for myocarditis

 Myocarditis diagnosis based on pathohistological findings i.e. “multifocal inflammatory cell infiltrates with overt cardiomyocyte loss by light microscopy”, or cardiac troponin elevation associated with 1 major criterion (cardiac MRI – CMR modified diagnostic Lake Louise criteria) or with 2 minor criteria after excluding acute coronary syndrome or acute infectious myocarditis . The five minor criteria include the “clinical syndrome”, ventricular arrhythmia +/− new conduction disease, decline in systolic function +/− regional wall motion abnormalities (non Takotsubo pattern), other IRAEs (myositis, myopathies) and “suggestive CMR”.

What treatment options are available in patients not responding to steroids in 24-48 hr?

1. TNF inhibitors: Infliximab is a monoclonal Ab, acts by blocking release of IL 1 and IL6. Typically single dose given 72 hr after steroids if symptoms not responding. Can repeat a second dose after 2 weeks. 5 mg/kg bwt single dose IV. Send quantiferon gold.

Effective in : colitis, ir rheumatologic AE

2. Vedolizumab: Integrin antagonist. Mostly ir GI enterocolitis.

Both agents equally effective in immune mediated diarrhea and colitis according to a small prospective trial. 

3. Mycophenolate: B and T cell suppression, widespread effectiveness in a variety of auotimmune conditions and transplant patients. Can be used for all immune mediated toxicities. But if colitis and diarrhea, prefer IV vedolizumab or infliximab.

4. IVIG: 2 gm per kg bwt daily for 1-3 days; broad spectrum use. Guillain-Barré syndrome (GBS), myasthenia gravis, neuropathies, rheumatologic conditions, blistering disorders, immune hematologic conditions, and many others (NCCN)

5. Plasmapheresis: GBS, myasthenia. Mixed results when used in all neuro irAE.

Hyperacute immunotherapy toxicity

 hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 

-9% developed toxicity at a median of 10 days; 82 patients studied retrospectively

-Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis)

-2% grade 5--> death

Reference

Fertility Counseling for immunotherapy

National Comprehensive Cancer Network guidelines advise that patients of reproductive age use effective birth control during and for at least 5 months after immunotherapy. Most clinical trials also required patients of reproductive age to use at least two anticonception methods while receiving anti‐PD‐1 or anti‐PD‐L1 agents up to 6 months after the last dose.