Management guideline for rare irAEs (<1% incidence rate) and infusion-related reactions1,2,8
BMS-recommended management guidelines for cardiac irAEs1,2,8
When NIVO is administered in combination with IPI, IPI should also be withheld if NIVO is withheld. Cardiac or cardiopulmonary symptoms require assessment for potential myocarditis
| Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|
| Myocarditis definition | Symptoms with mild to moderate activity or exertion | Severe symptoms at rest or minimal activity or exertion
Intervention indicated |
Life-threatening consequences
Urgent intervention indicated (e.g. continuous IV therapy or mechanical haemodynamic support) |
| Dual NIVO + IPI
or NIVO alone1,8 |
Permanently discontinue | ||
| Monitoring | Hospitalise with cardiac monitoring | Hospitalise to intensive cardiac monitoring | |
| Consultation/test | Urgent cardiology consultation for evaluation and management:
For Grade 3–4 reactions, myocardial biopsy if feasible |
||
| Medication | Prompt initiation of 2 mg/kg/day methylprednisolone IV or equivalent | Immediate initiation of 2 mg/kg/day methylprednisolone IV or 1 g IV bolus | |
| Additional therapeutic management | – | Consider adding a second immunosuppressive agent
Additionally, for Grade 4: Hospitalise/transfer to institution with intensive cardiac monitoring expertise |
|
| Follow-up2 | If improved:
For Grade 2 reactions, retreatment may be considered after recovery and completion of steroid taper |
||
| If symptoms worse, intensify treatment according to grade | If no improvement, consider additional immunosuppressive agent | ||
BNP, brain natriuretic peptide; ECG, electrocardiogram; IPI, ipilimumab; IV, intravenous; MRI, magnetic resonance imaging; NIVO, nivolumab
BMS-recommended management guidelines for infusion reactions1,2,8
Infusion-related reactions were graded according to NCI CTCAE Version 4.03
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| NIVO alone | Interrupt or slow the rate of infusion1 | Interrupt or slow the rate of infusion1 | Immediately and permanently discontinue infusion1 |
| Monitoring | Remain bedside and monitor patient until symptoms resolve | ||
| IV saline solution | – | Begin an IV infusion of normal saline | |
| Medication | – | Corticosteroid may also be administered as appropriate | Diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed |
| Additional therapeutic management | – | Treat the patient with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325–1000 mg
Bronchodilator therapy as appropriate |
Recommend administration of bronchodilators
SC epinephrine: 0.2–1 mg of a 1:1000 solution or IV epinephrine (slow injection): 0.1–0.25 mg of a 1:10,000 solution |
| Resume NIVO infusion | – | When symptoms resolve, restart the infusion at 50% of the original infusion rate
No further complications (>30 minutes): increase to 100% infusion rate Recurring symptoms: no further nivolumab infusion at that visit, administer diphenhydramine 50 mg IV |
– |
| For late-occurring hypersensitivity symptoms (e.g. localised/generalised pruritus <1 week after treatment), symptomatic treatment may be given (e.g. oral antihistamine or corticosteroids) | |||
| Follow-up | Prophylactic pre-medications are recommended for future infusions:
|
– | |
IV, intravenous; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NIVO, nivolumab; SC, subcutaneous
International guideline (ASCO, ESMO and NCCN) recommendations for other irAEs5–7^
^ For detailed guidelines, please refer to original publication
Myocarditis,6 pericarditis,6 arrhythmias, impaired ventricular function with heart failure, vasculitis5,7 and cardiomyopathy7
For pericarditis/pericardial effusion, if myocarditis not present, manage as per usual recommendations6
| Immunotherapy | Consider hold and permanently discontinue after Grade 14,5
or Permanently discontinue6,7 |
|---|---|
| Consultation | Immediate6 consultation with a cardiologist is recommended5 |
| Monitoring/testing |
|
| Medication |
High-dose corticosteroids (1–2 mg/kg oral or IV prednisone) initiated rapidly depending on symptoms5 and Consider early institution of cardiac transplant rejection doses of corticosteroids (methylprednisolone 1 g/day) and the addition of immunosuppressive agents. For life-threatening cases, consider additional immunosuppression5:
or Methylprednisolone IV 500–1000 mg/day for 3–5 days6,7 and switch to oral prednisolone 1mg/kg/day6 (for uncomplicated immune-related myocarditis7), then taper slowly over 6–12 weeks based on clinical response and improvement of biomarkers.6 If no improvement within 24–28 hours on steroids, consider further interventions6:
Second-line options include7:
Third-line options include7:
|
| Admission | Admit patient and immediately transfer to a coronary unit for patients with elevated troponin or conduction abnormalities5
or ICU-level monitoring6 |
| Additional consideration | Consider management of cardiac symptoms according to ACC/AHA guidelines and with guidance from cardiology5
For new conduction delay, consider a pacemaker5 |
ACC, American College of Cardiology; AHA, American Heart Association; ATG, anti-thymocyte globulin; BNP, brain natriuretic peptide; CXR, chest X-ray; ECG, electrocardiogram; ECMO extracorporeal membrane oxygenation; ICU, intensive care unit; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LVAD, left ventricular assist device; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging
|
ASCO |
|||
|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3 | Grade 4 |
| Abnormal cardiac biomarker testing without symptoms and with no ECG abnormalities | Abnormal cardiac biomarker testing with mild symptoms or new ECG abnormalities without conduction delay | Abnormal cardiac biomarker testing with either moderate symptoms or new conduction delay | Moderate to severe decompensation, IV medication or intervention required, life-threatening conditions |
ASCO, American Society of Clinical Oncology; ECG, electrocardiogram; IV, intravenous
Infusion-related reactions5,6
Clinicians should consult the prescribing information for each individual immunotherapy agent for recommendations regarding premedication to prevent infusion reactions
| Grade 1 (mild6) | Grade 2 (moderate6) | Grade 3 (severe6) | Grade 4 (severe6) | |
|---|---|---|---|---|
| Immunotherapy | Continue immunotherapy5
or Hold until symptom resolved, then resume as tolerated6 |
Hold (temporarily5) or slow the rate of infusion6 Once return to ≤ Grade 1, consider resuming at an infusion rate of 50% or per institutional guidelines5 |
As Grade 2
or Discontinue offending immunotherapy6 |
Permanently5 discontinue offending immunotherapy5,6 |
| Monitoring/testing | Perform a physical examination, monitor vital signs,6 pulse oximetry and perform an ECG if patient experiences chest pain or sustained tachycardia5,6 | |||
| Intervention | Consider premedication with acetaminophen and an antihistamine5 (H2 blockers and diphenhydramine6) with subsequent/future infusions5,6 | Offer or consider prophylactic/symptomatic treatment with5,6:
Hospitalisation for other clinical sequelae5; |
ICU level inpatient care5;
Treat per institutional guidelines6 |
|
ECG, electrocardiogram; ICU, intensive care unit; IV, intravenous; NSAID, non-steroidal anti-inflammatory drug
|
ASCO5 |
NCCN6 |
|
|---|---|---|
| Grade 1 (mild6) | Mild transient reaction; infusion interruption not indicated;
intervention not indicated |
Reactions typically transient |
| Grade 2 (moderate6) | Therapy or infusion interruption indicated but responds promptly to symptomatic treatment;
prophylactic medication indicated for ≤24 hours |
Reactions typically respond promptly to symptomatic treatment and require medication for ≤24 hours |
| Grade 3 (severe6) | Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion);
recurrence of symptoms following initial improvement; hospitalisation indicated for other clinical sequelae |
Reactions are often more prolonged with limited responsiveness to intervention or infusion interruption.
Symptoms can reoccur following initial improvement Hospitalisation indicated; life-threatening consequences; urgent intervention |
| Grade 4 (severe6) | Life-threatening consequences; urgent intervention indicated |
ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol-Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- NCI-CTCAE v4, National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
- Champiat S, et al. Ann Oncol 2016;27:559–574.
- Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 3.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 2023.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
