What is the grade‑wise management of immune‑related adverse events in cancer patients receiving immune‑checkpoint inhibitor therapy?

Grade-Wise Management of Immune-Related Adverse Events in Cancer Patients Receiving Immunotherapy

The management of immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICPis) follows a standardized grade-based approach: continue therapy with monitoring for Grade 1, hold therapy and consider corticosteroids for Grade 2, permanently discontinue with high-dose corticosteroids for Grade 3, and immediately hospitalize with IV corticosteroids plus additional immunosuppression for Grade 4 toxicities. 1

General Management Framework by Grade

Grade 1 (Mild) Toxicities

Continue ICPi therapy with close monitoring:

• Maintain immunotherapy without interruption 1
• Implement weekly clinical follow-up and laboratory surveillance 1
• Initiate organ-specific supportive care (topical treatments for skin, antidiarrheals for colitis) 1
• Monitor for progression to higher grades requiring intervention 1

Key pitfall: Grade 1 toxicities can rapidly escalate, particularly with cardiac, neurologic, or ocular manifestations—maintain heightened vigilance even when continuing therapy 1

Grade 2 (Moderate) Toxicities

Hold ICPi and initiate corticosteroids:

• Temporarily discontinue immunotherapy immediately 1
• Administer prednisone 0.5-1 mg/kg/day (or equivalent) 1
• Strongly consider permanent discontinuation depending on organ system involved 1
• Consult appropriate subspecialty (dermatology, gastroenterology, endocrinology, etc.) 1
• Monitor weekly for improvement or progression 1

Resumption criteria after Grade 2 irAEs:

• May resume ICPi once toxicity downgrades to Grade 1 or less 1
• Corticosteroid taper must be below 10 mg/day prednisone equivalent 1
• Risk of recurrent irAEs is approximately 60% upon rechallenge, with 50% experiencing Grade ≥2 events 2, 3
• Patients with multisystemic initial irAEs have higher recurrence risk 2

Grade 3 (Severe) Toxicities

Permanently discontinue ICPi with high-dose corticosteroids:

• Immediately and permanently stop immunotherapy 1
• Administer prednisone 1-2 mg/kg/day (oral or IV based on severity and rapidity of onset) 1
• Strongly consider hospital admission based on clinical judgment 1
• Obtain urgent subspecialty consultation (hematology for cytopenias, cardiology for myocarditis, neurology for neurologic toxicities) 1
• Taper corticosteroids slowly over minimum 4-6 weeks once improved to Grade 1 1

If no improvement within 3-5 days or worsening occurs:

• Escalate to additional immunosuppressive agents (mycophenolate mofetil, infliximab, IVIG, rituximab, cyclosporine) 1
• For specific organ toxicities, consider targeted therapies (infliximab for colitis, IVIG for neurologic complications) 1

Grade 4 (Life-Threatening) Toxicities

Immediate hospitalization with aggressive immunosuppression:

• Permanently discontinue ICPi without exception 1
• Admit patient immediately with direct oncology involvement 1
• Administer IV methylprednisolone 1-2 mg/kg/day (or equivalent) 1
• Obtain emergent subspecialty consultation 1
• Initiate second-line immunosuppression early if no improvement within 48-72 hours 1
• Provide organ-specific supportive care and hemodynamic/respiratory support as needed 1

Second-line immunosuppressive options include:

• Infliximab 5 mg/kg for refractory colitis (avoid in cardiac or neurologic toxicities) 1
• IVIG for hematologic and neurologic complications 1
• Rituximab for severe hemolytic anemia or thrombocytopenia 1
• Mycophenolate mofetil or cyclosporine for refractory nephritis 1
• Plasma exchange for thrombotic thrombocytopenic purpura or severe myasthenia gravis 1

Organ-Specific Considerations

Dermatologic Toxicities

• Grade 1 (<10% BSA): Continue ICPi with topical emollients and mild-moderate potency topical corticosteroids 1
• Grade 2 (10-30% BSA or >30% BSA with mild symptoms): Hold ICPi, use high-potency topical corticosteroids, consider oral prednisone 0.5-1 mg/kg/day 1
• Grade 3 (>30% BSA with moderate-severe symptoms): Hold ICPi, consult dermatology, administer oral prednisone 1 mg/kg/day, may resume after downgrade to Grade 1 with prednisone <10 mg/day 1
• Grade 4 (severe consequences/hospitalization required): Permanently discontinue ICPi, admit patient, IV methylprednisolone 1-2 mg/kg/day, monitor for Stevens-Johnson syndrome/toxic epidermal necrolysis 1

Hematologic Toxicities (Autoimmune Hemolytic Anemia)

• Grade 1: Continue ICPi with close laboratory monitoring 1
• Grade 2: Hold ICPi and strongly consider permanent discontinuation, prednisone 0.5-1 mg/kg/day 1
• Grade 3: Permanently discontinue ICPi, consult hematology, prednisone 1-2 mg/kg/day, consider admission, transfuse RBCs only to maintain hemoglobin 7-8 g/dL, supplement with folic acid 1 mg daily 1
• Grade 4: Permanently discontinue ICPi, admit patient, consult hematology, IV prednisone 1-2 mg/kg/day, add rituximab/IVIG/cyclosporine/mycophenolate if no improvement 1

Critical drug avoidance in hemolytic anemia: Immediately discontinue fludarabine (contraindicated and can be life-threatening), avoid ciprofloxacin and other fluoroquinolones, use penicillins/rifampin with extreme caution 4

Ocular Toxicities (Uveitis)

• Grade 1 (asymptomatic): Continue ICPi, refer to ophthalmology within 1 week, artificial tears 1
• Grade 2 (anterior uveitis requiring intervention): Hold ICPi temporarily, urgent ophthalmology referral, topical corticosteroids and cycloplegic agents, may resume once systemic corticosteroids <10 mg/day 1
• Grade 3 (posterior/panuveitis): Permanently discontinue ICPi, urgent ophthalmology referral, systemic plus intravitreal/periocular/topical corticosteroids 1
• Grade 4 (vision 20/200 or worse): Permanently discontinue ICPi, emergent ophthalmology referral, IV methylprednisolone 1-2 mg/kg/day plus local corticosteroids, consider infliximab for refractory cases 1

Renal Toxicities (Acute Kidney Injury)

• Grade 1 (creatinine 1-1.5× baseline): May hold temporarily while evaluating alternative etiologies (IV contrast, medications, volume status) 1
• Grade 2 (creatinine 1.5-3× baseline): Hold ICPi, consult nephrology, rule out other causes, prednisone 0.5-1 mg/kg/day, permanently discontinue if worsening or no improvement, taper over 4-6 weeks if improved 1
• Grade 3-4 (creatinine >3× baseline or requiring dialysis): Permanently discontinue ICPi, consult nephrology, evaluate alternative causes, prednisone 1-2 mg/kg/day, add mycophenolate if no improvement within 2-5 days, taper over minimum 4 weeks 1

Cardiovascular Toxicities (Myocarditis/Arrhythmias)

• Any grade myocarditis requires immediate ICPi discontinuation due to high mortality risk 1
• Grade 2-3: Hold ICPi permanently, admit patient, consult cardiology, obtain troponin/BNP/ECG/echocardiogram, prednisone 1-2 mg/kg/day, consider pulse-dose methylprednisolone 1 g daily × 3-5 days for severe cases 1
• Grade 4: Permanently discontinue ICPi, admit to ICU, cardiology consultation, hemodynamic/respiratory support, IV methylprednisolone 1-2 mg/kg/day or pulse-dose therapy, add IVIG or other immunosuppression if refractory 1

Critical pitfall: Cardiovascular irAEs have mortality rates exceeding 25-50% and can present with nonspecific symptoms (fatigue, malaise) that mask the severity—maintain extremely low threshold for cardiac workup 1, 5

Corticosteroid Tapering Principles

Taper duration based on initial toxicity grade:

• Grade 2 toxicities: Taper over minimum 3-4 weeks once downgraded to Grade 1 1
• Grade 3-4 toxicities: Taper over minimum 4-6 weeks once downgraded to Grade 1 1
• Never taper faster than 10 mg/week prednisone equivalent 1
• Monitor closely for toxicity flare during taper—if occurs, increase back to previous effective dose 1

Rechallenge Considerations After irAEs

Rechallenge is generally not recommended after Grade 3-4 irAEs due to high recurrence risk and lack of survival benefit 6, 2, 3

If rechallenge considered after Grade 2 irAEs:

• Ensure complete resolution to Grade 0-1 before rechallenge 2, 3
• Corticosteroids must be tapered to <10 mg/day prednisone equivalent 1
• Patients with multisystemic initial irAEs have significantly higher recurrence risk 2
• Approximately 60% will experience recurrent or new irAEs, with 50% being Grade ≥2 2, 3
• No survival benefit demonstrated for rechallenge versus permanent discontinuation in most studies 3

Absolute contraindications to rechallenge:

• Grade 4 irAEs of any type 1, 6
• Grade 3-4 myocarditis, neurologic toxicities, or pneumonitis 1
• Any life-threatening irAE requiring ICU admission 1