IMAR* | Possible presenting signs/symptoms | Recommended workup | Grade† | Management |
Always inform the patient’s oncology team so that the ICI can be withheld or discontinued. Inform the on-call oncology coverage for the patient if a decision is made to initiate systemic immunosuppression | ||||
Colitis prevalence 6–9: Anti-PD-(L)1: 1.5% Anti-CTLA-4: 8% Anti-PD-1+anti-CTLA-4: 7%–10% Rare but serious IMAR to consider: enterocolitis |
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| Grade 4: life-threatening consequences; urgent intervention indicated |
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Grade 3: >6 liquid stools per day OR within 1 hour of eating; limiting self-care ADL |
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Grade 2: 4–6 liquid stools per day over baseline, or ≥1 of:
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Dermatologic (rash, Stevens-Johnson syndrome or toxic epidermal necrolysis) prevalence (all dermatologic toxicities) 6 7 10 12 28 29: Anti-PD-(L)1: 9%–11% Anti-CTLA-4: 29%–50% Anti-PD-1+anti-CTLA-4: 23% Rare but serious IMAR to consider: Stevens-Johnson syndrome |
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| Grade 4: skin sloughing >30% BSA with associated symptoms (eg, erythema, purpura, epidermal detachment) |
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Grade 3: rash >30% BSA with moderate or severe symptoms |
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Grade 2: rash covering 10%–30% BSA, potentially symptoms of pruritus or tenderness |
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Adrenal insufficiency prevalence: see hypophysitis, which causes central/secondary adrenal insufficiency and other endocrinopathies Primary adrenal insufficiency is rare but can be serious |
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| Grade 3/4: severe symptoms:
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Grade 2: moderate symptoms:
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Hypophysitis prevalence 8 10–13 19 29–31: Anti-PD-(L)1: <1% Anti-CTLA-4: ≤10%–17% Anti-PD-1+anti-CTLA-4: 9% |
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| Grade 3/4: severe mass effect symptoms:
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Grade 2: moderate symptoms:
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Hypothyroidism prevalence 6–8 10 11 29 31: Anti-PD-(L)1: 5%–9% Anti-CTLA-4: <1% Anti-PD-1+anti-CTLA-4: 22% |
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| Grade 4: life-threatening consequences; urgent intervention required |
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Grade 3: severe symptoms; limiting self-care ADL; hospitalisation indicated | ||||
Grade 2: symptomatic; thyroid replacement indicated; limiting instrumental ADL | ||||
Hyperthyroidism prevalence 6–8 10 28 29 31: Anti-PD-(L)1: 1%–5% Anti-CTLA-4: <1% Anti-PD-1+anti-CTLA-4: 8% |
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Grade 4: life-threatening consequences; urgent intervention required |
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Grade 3: severe symptoms; limiting self-care ADL; hospitalisation indicated | ||||
Grade 2: symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL | ||||
Pneumonitis prevalence (most common lung toxicity) 6–8 10 17 28–31: Anti-PD-(L)1:<1%–4% Severe: 1%–2% Anti-CTLA-4: <1% Anti-PD-1+anti-CTLA-4: 6% |
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| Grade 3/4: severe new symptoms; limiting self-care ADL; new/worsening hypoxia; life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation) |
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Grade 2: symptomatic mild/moderate (cough, dyspnoea, chest pain); no hypoxia; vitals normal |
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Hepatitis prevalence 6–8 10 28 29 31: Anti-PD-(L)1: <1%–2% Anti-CTLA-4: 11% Anti-PD-1+anti-CTLA-4: 13% |
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| Grade 3/4: AST, ALT>5× ULN; total bilirubin>3× ULN |
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Grade 2: AST, ALT>3 to ≤5× ULN; total bilirubin>1.5 to ≤3× ULN |
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Encephalitis prevalence 6–8 10 28 31: Anti-PD-(L)1: <1% Anti-CTLA-4: <1% Anti-PD-1+anti-CTLA-4: <1% |
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| Grade 3/4: severe, limiting self-care and aids warranted |
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Grade 2: moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation) | ||||
Nephritis prevalence 6 7 10 28 29: Anti-PD-(L)1:<1%–1% Anti-CTLA-4: <1% Anti-PD-1+anti-CTLA-4: 2% |
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| Grade 4: creatinine>6× ULN |
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Grade 3: creatinine>3× baseline or >3–6× ULN | ||||
Grade 2: creatinine>1.5–3× baseline or >1.5–3× ULN |
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Pancreatitis prevalence 6–8 28 31: Anti-PD-(L)1: <1% Anti-CTLA-4: 1.3% Anti-PD-1+anti-CTLA-4: <1% |
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| Grade 4: life-threatening consequences; urgent intervention indicated |
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Grade 3: severe pain; vomiting; medical intervention indicated | ||||
Grade 2: elevated enzymes or radiographic findings only | ||||
Peripheral motor and sensory neuropathy prevalence 28: Anti-PD-(L)1:<1% Anti-PD-1+anti-CTLA-4: <1% |
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| Grade 4: life-threatening consequences; urgent intervention indicated |
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Grade 3: severe symptoms; limiting self-care ADL | ||||
Grade 2: moderate symptoms; limiting instrumental ADL |
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Myocarditis, pericarditis, arrhythmias prevalence (all cardiac toxicities) 10–12 14 29 30: Anti-PD-(L)1: <1%–5% Anti-PD-1+anti-CTLA-4: <1% |
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| Grade 4: moderate-to-severe decompensation, intravenous medication or intervention required, life-threatening conditions |
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Grade 3: moderately abnormal testing or symptoms with mild activity | ||||
Grade 2: abnormal screening tests with mild symptoms | ||||
Uveitis prevalence 12: Any ICI: <1% |
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| Grade 4: best-corrected visual acuity of 20/200 or worse in the affected eye |
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Grade 3: anterior uveitis with 3+ or greater cells; intermediate posterior or pan-uveitis | ||||
Grade 2: anterior uveitis with 1+ or 2+ cells |
G1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated.
G2: moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL.
G3: severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care ADL.
G4: life-threatening consequences; urgent intervention indicated.
*Prevalence of IMARs is for any-grade IMARs.
† CTCAE grade definitions18:
ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ALT, alanine aminotransferase; ANCA, antineutrophil cytoplasmic antibodies; AST, aspartate aminotransferase; BSA, body surface area; CBC, complete blood count; CK, creatine kinase; CNS, central nervous system; CRP, C reactive protein; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxic T-lymphocyte antigen-4; CXR, chest X-ray (roentgenogram); ECG, electrocardiogram; EEG, electroencephalography; ESR, erythrocyte sedimentation rate; HSV, herpes simplex virus; ICI, immune checkpoint inhibitor; ICU, intensive care unit; IMAR, immune-mediated adverse reaction; IVIG, intravenous immunoglobulin; LFT, liver function test; NSAID, non-steroidal anti-inflammatory drug; PCR, polymerase chain reaction; PD-1, programmed death-1; PD-L1, programmed death ligand 1; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TPO, thyroid peroxidase antibody; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine; ULN, upper limit of normal; UPCR, urine protein/creatinine ratio.