Skip to main content

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy

From: Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

DERMATOLOGIC Specialist referral?
Maculopapular rash/dermatitis
Grade Description Management  
1 Macules/papules covering <10% BSA with or without symptoms (e.g., pruritus, burning, tightness) • Continue ICI
• Oral antihistamines
   Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime
• Topical corticosteroids
   Class I topical corticosteroid (clobetasol propionate, halobetasol propionate, betamethasone dipropionate cream or ointment) for body; Class V/VI corticosteroid (aclometasone, desonide, hydrocortisone 2.5% cream) for face
 
2 Macules/papules covering 10–30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL • Continue ICI
• Non-urgent dermatology referral
• Oral antihistamines
   Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime
• Topical corticosteroids (see grade 1)
   As above
   Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime
3 Macules/papules covering >30% BSA with or without associated symptoms; limiting self-care ADL • Hold ICI
• Same day dermatology consult
• Rule out systemic hypersensitivity: CBC with differential, CMP
• Oral antihistamines
   Cetirizine/loratidine 10 mg daily (non-sedating); hydroxyzine 10-25 mg QID, or at bedtime
• Systemic corticosteroids
• Prednisone 0.5 – 1 mg/kg/day (or equivalent dose of methylprednisolone) until rash resolves to ≤ grade 1
Pruritus*
Grade Description Management
1 Mild or localized; topical intervention indicated • Emollients with cream or ointment based, fragrance-free products
   Class I topical corticosteroid (clobetasol propionate, halobetasol propionate, betamethasone dipropionate) for body; Class V/VI corticosteroid (aclometasone, desonide, hydrocortisone 2.5%) for face, AND oral antihistamines (e.g., cetirizine/loratidine 10 mg daily, hydroxyzine 10-25 mg QID, or at bedtime
 
2 Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriation, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL • Dermatology referral
• Class I topical steroid (clobetasol propionate, halobetasol propionate, betamethasone dipropionate) for body; class V/VI steroid (aclometasone, desonide, hydrocortisone 2.5%) for face, AND oral antihistamines (e.g., cetirizine/loratidine 10 mg daily, hydroxyzine 10-25 mg QID, or at bedtime
• Oral corticosteroids
   Prednisone 0.5 – 1 mg/kg/day (or equivalent of methylprednisolone) tapered over 2 weeks
3 Intense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroid or immunosuppressive therapy indicated • Dermatology referral
• GABA agonist (pregabalin, gabapentin 100-300 mg TID)
• Oral corticosteroid
   Prednisone 0.5 – 1 mg/kg/day (or equivalent of methylprednisolone) tapered over 2 weeks
Notes:
1. Grade 4 maculopapular rash/dermatitis is not included in CTCAE
*Recommendations provided are based on case reports, series and expert consensus. Use of suggested therapies must be discussed with medical oncology based on individual patient considerations. The impact of these therapies on the anti-tumor immune response and efficacy of cancer treatment is unknown and requires further research.
GASTROENTEROLOGICAL Specialist referral?
Colitis
Grade CTCAE description Management  
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated
[Grade 1 diarrhea frequency ≤ 4/day]
• Close follow up within 24–48 h for changes or progression
• Continue ICI
• If symptoms persist, start routine stool and blood tests
• Bland diet advisable during period of acute diarrhea
• Anti-diarrheal medication is optional but not highly recommended when infectious work-up is negative.
 
2 Abdominal pain; mucus or blood in stool
[Grade 2 diarrhea frequency 4–6/day]
• Hold ICI
• Outpatient stool and blood work; CRP, ESR, fecal calprotectin, lactoferrin, imaging and endoscopy are optional
• If diarrhea only, observe for 2–3 days. If no improvement start prednisone 1 mg/kg/day (or equivalent dose of methylprednisolone); anti-diarrheal medication is not recommended
• If diarrhea and colitis symptoms (abdominal pain +/− blood in BM), start prednisone 1 mg/kg/day (or equivalent dose of methylprednisolone)immediately
   If no improvement in 48 h, increase corticosteroid dose to prednisone 2 mg/kg/day (or equivalent dose of methylprednisolone)
   If patient improves
   ▪ Taper corticosteroid over 4–6 weeks may be needed
   ▪ Resume ICI when corticosteroid is tapered to ≤10 mg/day and patient remains symptom-free (grade ≤ 1)*
   ▪ Continue anti-PD-1 or anti-PD-L1 monotherapy
   ▪ If using combination anti-CTLA-4/anti-PD-1 immunotherapy, continue anti-PD-1 agent only
   ▪ ICI dose reduction is not recommended
• If colitis returns on resuming ICI:
   Grade ≤ 2: temporarily hold ICI
   Grade ≥ 3: permanently discontinue ICI

See note 5
3 and 4 Grade 3: Severe abdominal pain; change in bowel habits; medical intervention indicated; peritoneal signs
[Grade 3 diarrhea frequency ≥ 7×/day]
Grade 4: Life-threatening consequences; urgent intervention indicated
• Grade 3: withhold ICI; consider resuming ICI when corticosteroid is tapered to ≤10 mg/day and patient remains symptom-free (grade ≤ 1). Consider hospitalization
• Grade 4: permanently discontinue ICI and hospitalize
• Blood and stool infection work-up, inflammatory markers, imaging, endoscopy and GI consult
• Start intravenous prednisone 1-2 mg/kg/day (or equivalent dose of methylprednisolone) immediately
   If patient improves, follow instructions for ‘If patient improves’ for grade 2
• If refractory or no improvement on IV corticosteroid, start prednisone 2 mg/kg/day (or equivalent dose of methylprednisolone) for 3 days
• Consider other anti-inflammatory agents e.g. infliximab 5 mg/kg, which can be given again after two weeks if a second dose is needed. Vedolizumab may also be used (see Note 4 below).
 
Notes:
1. CBC with differential, CMP, ESR and CRP are recommended before starting immunotherapy, to provide baseline values for comparison over time. Despite the association between elevated ESR and CRP and colitis, some insurance companies may not cover these tests.
2. There is no proven role for prophylactic corticosteroids (budesonide) to prevent GI irAEs [45, 47].
3. Response to infliximab generally occurs within 1–3 days although some patients benefit from a second dose after 2 weeks. Prolonged oral prednisone taper may be required after infliximab administration. Whether infliximab reduces the antitumor efficacy of ipilimumab remains unknown [103].
4. Case reports of successful treatment of steroid-dependent immune-related colitis using vedolizumab indicate this may benefit certain patients.
5. A GI consult is warranted in any patient who meets criteria for grade 2 diarrhea/colitis with negative infectious stool work up.
Hepatitis
Grade CTCAE Description (Note 1) Management
1 AST, ALT > ULN -3xULN; total bilirubin > ULN-1.5xULN • Continue ICI
• CMP or hepatic function panel once weekly
• If liver enzyme and function tests are stable, reduce frequency of blood tests
 
2 AST, ALT >3- ≤ 5xULN; total bilirubin >1.5 - ≤ 3xULN • Hold ICI
• Rule out viral hepatitis, autoimmune disease, biliary obstruction, new metastasis or thrombosis
• Start prednisone 0.5-1 mg/kg/day (or equivalent dose of methylprednisolone) with 4 week taper
• Monitor CMP twice a week
• Liver biopsy is optional
• Resume ICI when corticosteroid taper to 10 mg/day (toxicity grade ≤ 1)
 
3 and 4 AST, ALT >5xULN; total bilirubin >3xULN • Permanently discontinue ICI
• Monitor CMP every 1–2 days
• Start prednisone 1–2 mg/kg/day
   If refractory after 3 days, consider mycophenolate
• If liver enzymes improve, taper corticosteroid over 4 weeks
• Consider liver biopsy
 
Notes:
1. Liver enzyme levels stated here are not defined in CTCAE and are instead drawn from reference [104]
2. In patients with liver metastasis, ICI can be used at baseline liver profile equivalent to grade 2. If ≥50% elevation in AST/ALT lasting for ≥1 week, permanently stop ICI.
 
ENDOCRINE Specialist referral?
Hypophysitis
Grade CTCAE Description* Management
1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated • Hold ICI if ≥ grade 2 irAE until work up is completed and appropriate hormone replacement is started
• If central adrenal insufficiency: start physiologic steroid replacement: Hydrocortisone ~10 mg/m2 (HC 15 mg am, 5 mg at 3 pm)
   Periodic assessment (e.g., every 3 months in the first year, every 6 months thereafter): clinical monitoring and repeat hormone levels (am cortisol and ACTH and/or low dose cosyntropin stimulation test) to assess recovery
• If central hypothyroidism: start thyroid hormone (levothyroxine 1mcg/kg)
   Repeat thyroid function testing 6–8 weeks after initiation of thyroid hormone and then periodically (e.g., every 3 months in the first year and every 6 months thereafter) to assess recovery
• If central hypogonadism, repeat hormone levels in 2–3 months and consider testosterone in men or HRT in women if appropriate for cancer type
For severe/life-threatening symptoms such as adrenal crisis, severe headache, visual field deficiency:
• Hospitalize as appropriate.
• High dose corticosteroid (prednisone 1 mg/kg/day) (or equivalent dose of methylprednisolone) in the acute phase, followed by taper over 1 month.
• Adrenal crisis should be managed per standard guidelines.
• If central hypothyroidism, replace thyroid hormone (see above) after corticosteroids have been initiated
2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL
3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent intervention indicated
Note: In the uncommon scenario of MRI findings without pituitary deficiency, consider high dose corticosteroids for prevention of hormonal dysfunction.
* Hypophysitis is not defined in CTCAE Version 4.0. This classification is drawn from the CTCAE category ‘Endocrine disorders – Other’.
Hypothyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated • Hold ICI for ≥grade 3 irAEs
• ICI can be continued after resolution of symptoms to grade 2 or better.
• Start standard thyroid replacement therapy: initial dose can be the full dose (1.6 mcg/kg) in young, healthy patients, but a reduced dose of 25 -50mcg should be initiated in elderly patients with known cardiovascular disease.
• Repeat TSH and free T4 testing after 6–8 weeks and adjust thyroid hormone dose accordingly. If TSH is above reference range, increase thyroid hormone dose by 12.5 mcg to 25 mcg
• After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s status changes
• After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s status changes
2 Symptomatic; thyroid replacement indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL; hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated
Hyperthyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated • Hold ICI for ≥ grade 3 irAEs
• Standard therapy for hyperthyroidism should be followed
Thyroiditis is self-limiting and has 2 phases:
   In the hyperthyroid phase, patients may benefit from beta blockers if symptomatic (e.g., atenolol 25–50 mg daily, titrate for HR < 90 if BP allows). Monitor closely with regular symptom evaluation and free T4 testing every 2 weeks.
   Introduce thyroid hormones (see hypothyroidism management) if the patient becomes hypothyroid (low free T4/T3, even if TSH is not elevated).
Graves’ disease should be treated per standard guidelines.
2 Symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL; hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated
Note: High dose corticosteroids (1 mg/kg/day) are not routinely required.
Type 1 diabetes (CTCAE defines hyperglycemia not diabetes)
Grade CTCAE Description Management
1 Fasting glucose > ULN - 160 mg/dL (>ULN - 8.9 mmol/L) Type 1 DM with diabetic ketoacidosis: Hold ICI; hospitalize and initiate treatment per standard guidelines.
Type 1 DM without diabetic ketoacidosis: Hold ICI for hyperglycemia ≥ grade 3. Treat with insulin and continue ICI when patient recovers to grade 1.
• Treat with insulin per standard guidelines and restart ICI when patient recovers to grade 1.
• Provide patient education on diet and lifestyle modification, and blood glucose testing
2 Fasting glucose >160–250 mg/dL (>8.9–13.9 mmol/L)
3 Fasting glucose >250–500 mg/dL (>13.9–27.8 mmol/L); hospitalization indicated
4 Fasting glucose >500 mg/dL (>27.8 mmol/L); life-threatening consequences
PULMONARY Specialist referral?
Pneumonitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only • Consider holding ICI
• Consider pulmonary and infectious disease consultations
• Reimage at least prior to every cycle of ICI treatment (at least every 3 weeks)
   If repeat imaging shows resolution of radiographic findings, no further CT imaging is necessary; resume therapy with close follow-up
   If evidence of progression, treat at higher grade
   If no change, consider continued therapy with close follow-up for new symptoms
• If symptoms develop, treat at higher grade
• Self-monitor symptoms and oxygen saturation (using personal pulse oximeter) every 2–3 days; weekly clinic visits
• If chest imaging abnormalities resolve, consider resuming treatment with close follow-up
2 Symptomatic; limiting instrumental ADL; medical intervention indicated • Hold ICI
• Consider hospitalization
• Pulmonary consultation for bronchoscopy with bronchoalveolar lavage. Consider biopsies for atypical lesions
• Initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent)
   Day 2–3 of corticosteroids/supportive care: If symptoms improve to ≤ grade 2, start slow steroid taper over >1 month. If symptoms do not improve, or worsen, treat as grade 3–4
• Consider drug re-challenge if symptoms and imaging abnormalities resolve

(pulmonary and infectious disease)
3 Severe symptoms; limiting self-care ADL; oxygen indicated • Permanently discontinue ICI
• Hospitalize; consider ICU care
• Pulmonary consultation for bronchoscopy with bronchoalveolar lavage. Consider biopsies for atypical lesions
• Initiate methylprednisolone IV, 2 mg/kg/day
• Day 2–3 of corticosteroids/supportive care:
   If no clinical improvement, add infliximab or cyclophosphamide, mycophenolate mofetil or IVIG
   If clinical improvement: reduce corticosteroids to 1 mg/kg/day and slowly taper over >2 months.
• Drug re-challenge:
   Grade 3: Consider drug re-challenge on a case-by-case basis after discussions weighing risk/benefit with the patient and only if symptoms and imaging abnormalities resolve
   Grade 4: Permanent y discontinue ICI

(pulmonary and infectious disease)
4 Life-threatening respiratory compromise; urgent intervention indicated (e.g., intubation)
Notes:
1. Consider prophylactic antibiotics for pneumocystis pneumonia (PCP) for patients receiving at least 20 mg methylprednisolone or equivalent for ≥4 weeks
2. Consider calcium and vitamin D supplementation with prolonged steroid use
3. All patients with grade 2–4 pneumonitis receiving steroids should also be on proton pump inhibitor therapy for GI prophylaxis
4. T-spot testing should be undertaken to exclude tuberculosis in any patient being considered for anti-TNF therapy, prior to starting anti-TNF treatment.
Sarcoidosis
Grade CTCAE Description Management
1 Not defined in CTCAE • Consider holding ICI
• Close follow-up
• Consider corticosteroids
• Hold ICI
• Consider corticosteroid therapy for patients with sarcoidosis grade 2 or higher and any of the following:
   progressive radiographic change
   persistent and/or troublesome pulmonary symptoms
   lung function deterioration: TLC decline of ≥10%, FVC decline of ≥15%; DLCO decline of ≥20%
   concomitant involvement of critical extrapulmonary organ systems
   sarcoid-related hypercalcemia
• Corticosteroid dose: prednisone 1 mg/kg (or IV equivalent of methylprednisolone) for grade 2 sarcoidosis or severe cases requiring hospitalization. Taper steroids over 2–4 months, depending on response

≥ 2
Notes: To date, there are no studies focusing on management of sarcoidosis as a side effect of checkpoint inhibitor therapy. Current recommendations are based on clinical experience and case report publications.
RHEUMATOLOGIC/MUSCULOSKELETAL [78] Specialist referral?
Inflammatory arthritis
Grade CTCAE Description (Note 1) Management
1 Mild pain with inflammatory symptoms (Note 2), erythema, or joint swelling (Note 3) • Continue ICI
• Analgesics: NSAIDs: naproxen 500 mg BID or meloxicam 7.5–15 mg daily orally for 4–6 weeks
• If NSAIDs ineffective, consider prednisone 10–20 mg daily for 2–4 weeks
• Consider intra-articular corticosteroid injection only if ≤2 joints affected and low dose prednisone (10 mg/day) and NSAIDs not effective
• If no improvement in 2–4 weeks, escalate to grade 2 management
• Conduct serial rheumatologic examinations (2 weeks, 4 weeks, then 4–6 weekly) and functional assessment at follow-up
 
2 Moderate pain associated with signs of inflammation, erythema, or joint swelling; limiting instrumental ADL • Consider holding ICI
• Rheumatology referral to confirm inflammatory arthritis, assess need for intra-articular injection and examine for signs of early bone damage
• Prednisone 20 mg daily for 2–4 weeks, increase to 1 mg/kg/day, or equivalent. If no response in 2–4 weeks. Escalate to grade 3 management
• If symptoms improve, taper corticosteroid over 4–8 weeks or until grade 1
3 Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage (e.g., erosion); disabling; limiting self-care ADL • Hold ICI
• Rheumatology referral
• Prednisone 1 mg/kg/day or equivalent for 2–4 weeks, or until symptoms improve to grade 1
• Consider additional immunosuppression (Note 4) (e.g. methotrexate [Note 5], sulfasalazine, leflunomide). Consider anti-cytokine therapy (e.g. TNF-inhibition) [Note 6]
• If symptoms improve, taper corticosteroid over 4–8 weeks/until grade 1; if symptoms do not improve in 4–6 weeks: permanently discontinue ICI
Notes:
1. CTCAE includes separate listings for arthritis, joint effusion and arthralgia although there is overlap in presenting symptoms such as pain and effects on ADL
2. Joint stiffness after sleep or inactivity, improvement of symptoms with movement or heat.
3. Joint swelling refers to the clinical finding on examination, and may encompass soft tissue swelling, joint effusion or synovitis.
4. Before initiation of these drugs, screening for hepatitis B and C should be performed
5. Methotrexate should be administered at a starting dose of 15 mg weekly, with daily folic acid supplementation. Titrate up to a maximum of 25 mg weekly, or switch to injectable methotrexate if patient cannot tolerate orally
6. Before anti-cytokine therapy, evaluation for latent/active TB should be performed
INFUSION REACTIONS Specialist referral?
Grade CTCAE Description Management
1 Mild transient reaction; infusion interruption not indicated; intervention not indicated • Drug infusion rate may be decreased, or infusion temporarily interrupted, until resolution of the event
• Consider reducing the rate of infusion upon re-initiation or subsequent infusions
• Non-steroidal anti-inflammatory drugs (NSAIDs, e.g. acetaminophen), antihistamines, opioids, and corticosteroids may be used per investigator/ institutional guidelines
• Consider premedication for subsequent infusions per investigator/ institutional guidelines
 
2 Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤24 h.
3 Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae • Permanently discontinue ICI
• For severe/life-threatening reactions, manage the patient as clinically appropriate (e.g. antihistamines, oxygen, fluids, opioids, corticosteroids, bronchodilators, etc.) per investigator/ institutional guidelines
Refer to allergist to prevent potential future reactions
4 Life-threatening consequences; urgent intervention indicated
CARDIOVASCULAR Specialist referral?
Grade CTCAE Description Management
1 Abnormal cardiac biomarker testing, including abnormal ECG • Recommend baseline ECG and cardiac biomarker assessment (BNP, troponin) to establish if there is a notable change during therapy
• Mild abnormalities should be observed closely during therapy

if abnormal
2 Abnormal screening tests with mild symptoms • Control cardiac diseases (e.g. heart failure, atrial fibrillation) optimally
• Control cardiac disease risk factors proactively (including hypertension, hyperlipidemia, discontinue smoking, and monitor diabetes)
3 Moderately abnormal testing or symptoms with mild activity • BNP > 500 pg/ml, troponin >99% institutional normal, new ECG findings (QTc prolongation, new conduction disease, or ST-T wave changes)
• Consider withholding ICI
   If a period of stabilization is achieved and definite cardiac toxicity was not identified, it may be reasonable to consider re-challenging the patient with ICI, with heightened monitoring.
• If confirmed cardiac injury or decompensation, hold ICI therapy until stabilized.
• Optimally treat identified cardiac conditions
• Consider corticosteroids if myocarditis suspected (Note 2)
4 Moderate to severe decompensation, intravenous medication or intervention required, life threatening conditions • Permanently discontinue ICI
• If myocarditis is identified, consider high-dose corticosteroids (1 mg/kg methylprednisolone (IV) for at least several days) until improved to grade ≤ 1, after that consider at least 4–5 weeks of tapering doses (Note 2).
• Add additional immunosuppressive agents in severe refractory cases.
• Give additional supportive treatments, including appropriate treatment of heart failure. Additional treatment of detected cardiac conditions should be provided.*
Notes:
1. Grades outlined here are not drawn from CTCAE.
2. Patients with confirmed myocarditis (or in cases of reasonable suspicion) should receive emergent high-dose corticosteroids. Until data are available (e.g., cut-off levels of troponin) to determine when to start corticosteroids in patients with possible (as opposed to confirmed) myocarditis, this decision should be made on a case by case basis. The importance of active, ongoing consultation with a cardiologist to discuss the risk/benefit of continuing ICI therapy, starting corticosteroids, or instituting other cardiac treatments, cannot be overstated.
* Other therapies for management of myocarditis or pericarditis (viral based therapy, immunoglobulins, or plasmapheresis) are speculative at this point in time.
HEMATOLOGIC Specialist referral?
Anemia  
Grade CTCAE Description Management  
1 Hgb < LLN - 10.0 g/dL; <LLN - 6.2 mmol/L; <LLN - 100 g/L • Monitor closely while continuing ICI  
2 Hgb <10.0–8.0 g/dL; <6.2–4.9 mmol/L; <100 - 80 g/L • Monitor closely while continuing ICI
• Evaluate for possible causes and refer to hematology if no obvious cause if identified

if no cause identified
3 Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated • Hold ICI
• Consider Coombs testing and evaluation for hemolytic anemia
• Consider re-treating with ICI if hemolytic anemia responds promptly (within a few days) to corticosteroids
4 Life-threatening consequences; urgent intervention indicated • Permanently discontinue ICI
Notes:
1. No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
2. If unexplained anemia does not respond to steroids, consider bone marrow biopsy.
Thrombocytopenia (CTCAE defines decreased platelet count not thrombocytopenia)
Grade CTCAE Description Management
1 <LLN - 75,000/mm3; <LLN-75.0 x 10e9 /L Progressive or grade 3 unexplained thrombocytopenia: consider work up for autoimmune disease and rule out DIC or other cause of thrombocytopenia that may be related to underlying disease
Precipitous development of thrombocytopenia: consider steroid intervention pending clinical condition (brain metastases, colitis, etc.) and evaluate for immune-mediated thrombocytopenia
• Permanently discontinue ICI for clinically significant, steroid-refractory ICI-associated thrombocytopenia
 
2 <75,000–50,000/mm3; <75.0–50.0 x 10e9 /L
if no cause identified
3 <50,000–25,000/mm3; <50.0–25.0 x 10e9 /L
4 <25,000/mm3; <25.0 x 10e9 /L
Note: No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
RENAL Specialist referral?
Nephritis
Grade CTCAE Description Management
1 Creatinine level increase of >0.3 mg/dL; creatinine 1.5–2.0× above baseline • Continue ICI but initiate work-up to evaluate possible causes and monitor closely  
2 Creatinine 2 - 3× above baseline • Hold ICI
   Resume when creatinine decreased to ≤grade 1 (Note 2)
• Consider timing of event and response to treatment when making a decision
• Start corticosteroids (Note 3)
• Discontinue ICI for persistent or recurrent elevation
 
3 Creatinine >3 x baseline or >4.0 mg/dL; hospitalization indicated • Hold ICI
• Consider resuming treatment if grade 3 resolves (Note 2) and cause of event is confirmed. Timing of event and response to treatment should be considered in making a decision
• Start corticosteroids (Note 3)
• Discontinue ICI for persistent or recurrent elevation
 
4 Life-threatening consequences; dialysis indicated • Permanently discontinue ICI
• Start corticosteroids (Note 3)
Notes:
1. Grades are those listed under ‘acute kidney injury’ in CTCAE [33].
2. Consider using increase from baseline rather than absolute value for creatinine monitoring, especially in patients with primary renal carcinoma or other baseline renal conditions.
3. For persistent creatinine elevation ≥ grade 2 with no other identifiable cause, start corticosteroids. Dose and schedule should be individualized and based on grade. Taper corticosteroids when creatinine improves to grade 1.
NEUROLOGIC Specialist referral?
Encephalopathy/Leukoencephalopathy/Reversible posterior leukoencephalopathy syndrome (PRES)
Grade CTCAE Description Management
1 Mild symptoms • Hold ICI and initiate diagnostic work-up
• Consider permanent discontinuation of ICI if AE worsens or does not improve
 
2 Moderate symptoms; limiting instrumental ADL • Hold ICI
• Start 0.5–1.0 mg/kg/day methylprednisolone equivalents PO or IV once infection has been excluded
• Consider permanent discontinuation of ICI if AE worsens or does not improve.
3 Severe symptoms; limiting self-care ADL • Permanently discontinue ICI
• Start 1–2 mg/kg/day methylprednisolone equivalents IV and prophylactic antibiotics
• Consider plasmapheresis if no improvement or symptoms worsen after 3 days
4 Life-threatening consequences; urgent intervention indicated • Permanently discontinue ICI
• Start 1–2 mg/kg/day methylprednisolone equivalents IV and prophylactic antibiotics
• Consider plasmapheresis if no improvement or symptoms worsen after 3 days
• Contact intensive care unit

and contact intensive care unit
Notes: CTCAE provides grading criteria for encephalopathy, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (PRES). For all these irAEs, ICI therapy may be continued for grade 1 irAEs. However, ≥ grade 2 events require an ICI hold, and referral to neurology. For events of ≥ grade 3 severity, ICI should be permanently discontinued, IV corticosteroids administered, and plasmapheresis considered if there is no improvement, or symptoms worsen, after 3 days.
Peripheral motor and sensory neuropathy
Grade CTCAE Description Management
1 See CTCAE for grade definitions for each disorder • Continue ICI
• Consider permanent discontinuation of ICI if AE worsens or does not improve
 
2 • Hold ICI
• Refer to neurology
• Consider permanent discontinuation of ICI if AE worsens or does not improve
3 • Permanently discontinue ICI
• Start 1–2 mg/kg/day methylprednisolone equivalents IV, and prophylactic antibiotics
4
Notes: CTCAE provides grading criteria for peripheral motor neuropathy and sensory motor neuropathy. For all these irAEs, ICI therapy may be continued for grade 1 irAEs. However, ≥ grade 2 events require an ICI hold and referral to neurology. For events of ≥ grade 3 severity, ICI therapy should be permanently discontinued and IV corticosteroids administered.
OPHTHALMOLOGIC
Uveitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only • Continue ICI
• Ophthalmology referral within 1 week
• Start lubrication drops (artificial tears)
2 Anterior uveitis; medical intervention indicated • Hold ICI
• Ophthalmology referral within 2 days, prior to initiating uveitis treatment
• Coordinate treatment with ophthalmologist (topical corticosteroids, cycloplegic agents, systemic corticosteroids)
3 Posterior or pan-uveitis (Note 1) • Permanently discontinue ICI
• In carefully selected cases it may be appropriate to restart treatment, cautiously, depending on severity, systemic response to immunotherapy and ocular response to topical, local or systemic prednisone (prescribed in coordination with ophthalmologist)
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating treatment. Co-ordinate treatment with specialists
• Consider systemic corticosteroids in addition to intravitreal/periocular corticosteroids/topical corticosteroid treatment as recommended by ophthalmologist

URGENT
4 Blindness (20/200 or worse) in the affected eye • Permanently discontinue ICI
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating any treatment. Co-ordinate treatment with specialists
• Consider systemic corticosteroids in addition to intravitreal /periocular corticosteroids/topical corticosteroid treatment as recommended by ophthalmologist

URGENT
Note: Unlike anterior uveitis, posterior uveitis can be asymptomatic but nonetheless proceed to visual loss.
Episcleritis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic observations only • Continue ICI
• Ophthalmology referral within 1 week
• Start lubrication drops (artificial tears)
2 Symptomatic, limiting instrumental ADL; moderate decrease in visual acuity (20/40 or better) • Hold ICI
• Ophthalmology referral within 2 days, prior to initiating uveitis treatment
• Coordinate treatment with ophthalmologist (topical steroids, cycloplegic agents, systemic steroids) (See Note)
3 Symptomatic, limiting self- care ADL; marked decrease in visual acuity (worse than 20/40) • Permanently discontinue ICI
• In carefully selected cases it may be appropriate to restart treatment, cautiously, depending on severity, systemic response to immunotherapy and ocular response to topical, local or systemic prednisone (prescribed in coordination with ophthalmologist)
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating treatment (See Note). Co-ordinate treatment with specialists.
• Consider systemic steroids in addition to intravitreal /periocular steroids /topical steroid treatment as recommended by ophthalmologist

URGENT
4 Blindness (20/200 or worse) in the affected eye • Permanently discontinue ICI
• URGENT ophthalmology referral (preferably uveitis specialist) prior to initiating any treatment (See Note). Co-ordinate treatment with specialists.
• Consider systemic steroids in addition to intravitreal /periocular steroids /topical steroid treatment as recommended by ophthalmologist

URGENT
Notes: IMPORTANT: Starting treatment with steroids prior to conducting an eye exam may worsen ocular conditions that are due to infection (e.g., herpetic keratitis/uveitis) or may mask accurate diagnosis and severity grading when the patient is examined by an ophthalmologist.
Blepharitis
Grade CTCAE Diagnosis Management
Not defined in CTCAE • Puffy eyelids may indicate early preseptal cellulitis, which requires systemic antibiotic treatment. Warning signs (eyelid swelling with pain and erythema, proptosis, pain with eye movements, movement restriction/diplopia, vision changes) should prompt urgent ophthalmology referral
• In the absence of warning signs, start warm compresses and lubrication drops and refer to ophthalmology, especially if symptoms do not improve

URGENT if warning signs
  1. [Note: Recommended management of uncommon dermatologic immune-related adverse events is presented in Additional file 1: Table S1]