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Management guideline for rare irAEs (<1% incidence rate) and infusion-related reactions

Myotoxicity

Myocarditis

Infusion-related symptoms

International guideline (ASCO, ESMO and NCCN) recommendations for other irAEs^1-3 ^{^}

^{^} For detailed guidelines, please refer to original publication

Suspected myocarditis, pericarditis, large vessel vasculitis

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	Management	Grading/Assessment
Myocarditis	Discontinue immunotherapy ICU-level monitoring Temporary or permanent pacing as required High dose steroids (IV methylprednisolone 1g/day) for 3–5 days. If responsive, switch to oral prednisone (1 mg/kg/day) then taper slowly over 6–12 weeks If no improvement within 24–48 hours, consider additional immunosuppression: Abatacept Alemtuzumab Antithymocyte globulin Infliximab IVIG Methotrexate Mycophenolate mofetil Plasmapheresis	Immediate cardiology consultation (preferably cardio-oncology) ECG Telemetry monitoring Echocardiogram (if possible with LV strain measurement) Test for cardiac and non-cardiac biomarkers Evaluate for concomitant irAEs, myasthenia gravis, myositis Consider cardiac catheterisation and/or myocardial biopsy Consider viral titres
Pericarditis/Pericardial effusion	Consider myocarditis as a contributor If myocarditis is not present, manage as per cardiology guidelines

ECG, electrocardiogram; ICU, intensive care unit; irAEs, immune-related adverse events; IV, intravenous; IVIG, intravenous immunoglobulin; LV, left ventricle; NCCN, National Comprehensive Cancer Network.

Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis*

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Grading	Management	Assessment
	All grades warrant workup and intervention	ECG Troponin, CPK to rule out concurrent myositis Alternative reasons should be ruled out Elevated troponin should be serially monitored and bring attention to potential myositis, myasthenia, and myocarditis BNP Echocardiogram Chest X-ray Consider: stress test, cardiac catheterisation, cardiac MRI
Grade 1: Abnormal biomarker testing No symptoms No ECG abnormalities	Hold immunotherapy and recheck troponin after 6 hours. Consider resuming once normalised or deemed unrelated to immunotherapy
Grade 2: Abnormal biomarker testing Mild symptoms New ECG abnormalities without conduction delay	Discontinue immunotherapy Early initiation of high-dose corticosteroids (1–2 mg/kg/day of prednisone, oral or IV depending on symptoms) Admit for cardiology consultation Consider transfer to coronary care unit for those with elevated troponin or conduction abnormalities Consider a pacemaker For patients with no immediate response to high-dose corticosteroids, consider methylprednisolone (1 g/day) and addition of either mycophenolate, infliximab, or antithymocyte globulin Consider abatacept or alemtuzumab in life-threatening cases
Grade 3: Abnormal biomarker testing Moderate symptoms or new conduction delay
Grade 4: Moderate to severe decompensation IV medication or intervention required Life-threatening condition

*Treatment recommendations are based on anecdotal evidence and the life threatening nature of cardiovascular complications. Holding checkpoint inhibitor therapy is recommended for all grades of complications. The appropriateness of rechallenging remains unknown. Note that infliximab has been associated with heart failure and is contraindicated at high doses (5 mg/kg) in patients with moderate-severe heart failure.

ASCO, American Society of Clinical Oncology; BNP, B-type natriuretic peptide; CPK, creatine phosphokinase; ECG, electrocardiogram; IV, intravenous; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging.

Myocarditis

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Grading	Management and assessment (first 3 days)
IR-myocarditis	Management Treat cardiovascular complications according to cardiology guidelines Hold immunotherapy until diagnosis is confirmed IV methylprednisolone 500–1,000 mg/day for first 3 days	Assessment Cardiac troponin Continuous ECG monitoring; cardiography Cardiac MRI Consider urgent coronary angiography and endomyocardial biopsy if clinically unstable
Management escalation
Uncomplicated IR-myocarditis Troponin reduction by >50% from peak No heart failure, CHB or ventricular arrhythmias at the end of day 3	In most cases, permanently discontinue immunotherapy MDT review with oncology and cardio-oncology before restarting immunotherapy Convert to oral prednisolone 1 mg/kg/day with a weekly reducing schedule of 10 mg/week if patient is stable Weekly ECG and cardiac troponin monitoring
Complicated IR-myocarditis Steroid resistant: troponin rising or <50% reduction from peak Haemodynamic instability: heart failure, cardiogenic shock, CHB or ventricular tachyarrhythmias	Permanently discontinue immunotherapy Continue IV methylprednisolone 1,000 mg/day Add 2L immunosuppressive: tocilizumab 8mg/kg or MFF 3L options: ATG, alemtuzumab, abatacept Ongoing treatment of cardiac complications Consider mechanical circulatory support if cardiogenic shock Pacing for CHB Beta-blocker therapy for tachyarrhythmias

2L, second-line; 3L, third-line; ATG, antithymocyte globulin; CHB, complete heart block; ECG, electrocardiogram; ESMO, European Society for Medical Oncology; IR, immune-related; IV, intravenous; MFF, mycophenolate motefil; MDT, multidisciplinary team; MFF, mycophenolate motefil; MRI, magnetic resonance imaging.

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Grading	NCCN²	ASCO¹
Grade 1  Mild transient reaction Infusion interruption not indicated Intervention not indicated	Continue immunotherapy Consider premedication (acetaminophen, H2 blockers, and diphenhydramine)
Grade 2 Therapy or infusion interruption indicated but responds promptly to symptomatic treatment Prophylactic medication indicated for ≤24 hours	Continue immunotherapy Treat per institutional guidelines Consider holding or reduce rate of infusion to 50% Consider premedication (acetaminophen, H2 blockers, and diphenhydramine) Consider corticosteroids	Consider holding immunotherapy temporarily and reducing rate of infusion to 50% (or per institutional guidelines) Offer symptomatic treatment with antihistamines, NSAIDs, opioids, IV fluids Offer premedication (acetaminophen and an antihistamine per institution guidelines)
Grade 3 Prolonged reaction (not rapidly responsive to symptomatic medication and/or brief interruption of infusion) Recurrence of symptoms following initial improvement Hospitalisation indicated for other clinical sequelae	Discontinue immunotherapy Treat per institutional guidelines Consider alternate agents in therapeutic class Admit patient	Hold immunotherapy, reduce infusion rate to 50% (or per institutional guidelines) Offer symptomatic treatment with antihistamines, NSAIDs, opioids, IV fluids Consider antihistamines and corticosteroid medication Hospitalisation for other clinical sequelae
Grade 4 Life-threatening Urgent intervention indicated		Discontinue immunotherapy ICU-level inpatient care

ASCO, American Society of Clinical Oncology; H2, histamine-2 receptor antagonists; IV, intravenous; ICU, intensive care unit; IV, intravenous; NCCN, National Comprehensive Cancer Network; NSAIDs, non-steroidal anti-inflammatory drugs.

References:

Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed April 2025.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed April 2025.
Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed April 2025.
OPDIVO^® (nivolumab) Product Information, BMS Hong Kong.
YERVOY^® (ipilumab) Product Information, BMS Hong Kong.

A. Cardiac irAEs

NCCN grading and management 2

ASCO grading and management 1

ESMO grading and management 3

B. Infusion-related reactions

Grading and management (NCCN and ASCO) 1,2