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Management of immune-related adverse events (irAEs)

  Related eLearning: Immunotherapies

This document is an evidence based summary to complement treatment protocols and includes background and rationale for specific point of care actions. It is not intended to be a comprehensive literature review of all available evidence.

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  • The immune related adverse event (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients

Key references used in the development and review of this document include:

  • NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicitiesr
  • Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upr
  • Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Updater
  • Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsr

Additional references are listed in the bibliography of the Reference section.

  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • Cardiac irAEs are uncommon but potentially fatal. Myocarditis, pericarditis, arrhythmias, vasculitis and VTE have been reported.
  • Immune related myocarditis is the most common cardiac irAE and is associated with an approximate 50% mortality rate, symptoms such as new onset dyspnoea and congestive heart failure particularly within the first 3 months of treatment administration should prompt investigations to exclude myocarditis or other causes.
  • Complications of myocarditis include congestive heart failure, cardiac arrhythmias and sudden cardiac death. NOTE: mortality can still be high with a normal LVEF
  •  irAEs can escalate quickly, close monitoring of patients is required.
  • Early consultation with a cardiologist is advisable with rapid investigations to exclude other causes.
  • Re-challenge with anti-PD-1 or anti-PD-L1 therapy with or without anti-CTLA-4 is not recommended for immune related cardiac toxicity regardless of whether the toxicity is low- or high-grade.
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs consider early use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF), infliximab or anti-thymocyte globulin (ATG) after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Cardiac toxicity Grade 1 Grade 2  Grade 3 to 4

Signs and symptoms:

  • chest pain
  • arrhythmia
  • palpitations
  • syncope
  • peripheral oedema
  • progressive or acute dyspnoea
  • pleural effusion
  • fatigue
  • nausea
  • may be associated with a general myositis or other irAE

Abnormal cardiac biomarker testing including abnormal ECG

Abnormal screening tests with mild symptoms 

Grade 3: moderately abnormal testing or symptoms with mild activity

Grade 4: moderate to severe decompensated heart failure, the need for medical intervention or life-threatening conditions 
Treatment with anti-PD- 1,
anti-PD-L1 or anti-CTLA-4		 Withhold treatment for work-up, as high mortality even in asymptomatic cases  Permanently discontinue treatment
Tests: 

All grades require work-up given risk of cardiac compromise and sudden cardiac death secondary to arrhythmia: ECG, troponin, BNP, TTE, CXR

Additional testing to be guided by cardiologist and may include coronary angiogram, cardiac MRI, cardiac biopsy

NOTE: mortality can still be high with a normal LVEF
Management

Consider hospitalising patient given risk of deterioration  

Cardiology consult 

Telemetry 

High-dose corticosteroids e.g. IV methylprednisolone 1 to 2 mg/kg/day or equivalent

Consider early institution of cardiac transplant rejection doses of corticosteroids (e.g. IV methylprednisolone 1 g/day) and the addition of other non-corticosteroid immunosuppressive therapy

Hospitalise patient

Referral to a cardiologist 

Telemetry 

Admit to coronary care unit for patients with elevated troponin or conduction abnormalities

Early (within 24 hours) initiation of high-dose corticosteroids e.g. IV methylprednisolone 1 to 2 mg/kg/day or equivalent

Consider early institution of cardiac transplant rejection doses of corticosteroids (e.g. IV methylprednisolone 1 g/day) and the addition of other non-corticosteroid immunosuppressive therapy

Hospitalise patient

Urgent referral to a cardiologist 

Admit to coronary care unit 

Early (within 24 hours) initiation of high-dose corticosteroids e.g. IV methylprednisolone 1 to 2 mg/kg/day or equivalent

Consider early institution of cardiac transplant rejection doses of corticosteroids (e.g. IV methylprednisolone 1 g/day) and the addition of other non-corticosteroid immunosuppressive therapy
Follow-up Follow-up determined in conjunction with cardiology and oncology teams
  • The immune related adverse event (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents, and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis-Pneumocystis jiroveci (carinii) in cancer patients
Thyroid dysfunction Grade 1  Grade 2 Grade 3 to 4
e.g. hypothyroidism, hyperthyroidism Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Symptomatic; thyroid suppression therapy/thyroid replacement indicated; limiting instrumental activities of daily living (ADL)

Grade 3: severe symptoms; limiting self-care ADL; hospitalisation indicated

Grade 4: life-threatening consequences; urgent intervention indicated
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Continue treatment Consider withholding treatment until symptoms resolve  Withhold treatment until symptoms resolve 
Tests

TSH (option for FT4)

If both TSH and FT4 low, evaluate as per hypophysitis
Management

Close monitoring of thyroid function

Grade 1: Consider endocrine consultation for persistent thyrotoxicosis (>6 weeks)

Grade 2: Consider referral to an endocrinologist

Medical management as appropriate

Supportive care

Hyperthyroidism: initiate medical management for control of hyperthyroidism as appropriate (e.g. beta-blockers). Consider corticosteroids for symptomatic hyperthyroidism if not controlled with beta blockers

Hypothyroidism: administer thyroid hormone replacement therapy in symptomatic patients with elevated TSH or in asymptomatic patients with persisting TSH levels over 10 mIU/L (measured after 4 weeks)

Consider risk factors including cardiac disease and age >65 years for thyroid hormone replacement doses

As per Grade 2

Refer to an endocrinologist

Consider hospitalisation for severe cases

Hypothyroidism: administer hydrocortisone before initiating thyroid hormone replacement if uncertain about primary or central hypothyroidism

Myxoedema coma is a life-threatening emergency
Follow-up Continue routine monitoring

Continue routine monitoring

If treatment withheld and patient clinically improved (with or without hormone replacement), consider resuming immunotherapy treatment (unless advised to permanently discontinue treatment)

 As per Grade 2
Primary adrenal insufficiency (AI) Grade 1 Grade 2 Grade 3 and 4
  Asymptomatic or mild symptoms Moderate symptoms, able to perform ADL Severe symptoms, medically significant
or life-threatening consequences, unable to
perform ADL
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Consider withholding treatment until patient stabilised Withhold treatment until patient stabilised
Tests

UEC, CMP, BSL, AM cortisol and ACTH, renin and aldosterone

Consider ACTH stimulation test if indeterminate results

Evaluate for precipitating crises such as infection

Adrenal CT to rule out metastasis or haemorrhage (most common causes of primary AI)

Monitor patient for signs of adrenal crisis 
Management

Administer replacement therapy with hydrocortisone 15-20 mg/day in divided doses, 
titrate to maximum daily dose of 30 mg. Consider addition of fludrocortisone (0.5-0.1 mg/day)

Refer to an endocrinologist

Administer stress corticosteroid therapy (e.g. hydrocortisone 30-50 mg daily or prednisone
20 mg daily). Initiate fludrocortisone (0.5-0.1 mg/day). Decrease stress dose to maintenance after 2-3 days

Maintenance therapy as per Grade 1

Refer to an endocrinologist

Hospitalisation might be required

Administer IV stress corticosteroid therapy (hydrocortisone 50-100 mg every 6-8 hours. Taper stress dose to maintenance over 5-7 days.

Maintenance therapy as per Grade 1
Follow-up Continue routine monitoring

Continue routine monitoring

If treatment withheld and patient clinically improved (with or without hormone replacement), consider resuming immunotherapy treatment (unless advised to permanently discontinue treatment)

May need to continue steroids with mineralocorticoid component in the long term

 As per Grade 2
Suspicion of adrenal crisis Tests and management Follow-up
e.g. severe dehydration, hypotension, shock

Withhold treatment during work-up

Evaluate to exclude other causes, including sepsis 

Urgent referral to an endocrinologist

Urgent administration of IV corticosteroids with mineralocorticoid activity e.g. hydrocortisone until asymptomatic, then continue with physiologic dose in consultation with endocrinologist

If adrenal crisis ruled out, treat as symptomatic endocrinopathy

Consider recommencement of immunotherapy once crisis has resolved
Hypophysitis Grade 1 Grade 2 Grade 3 and 4
  Asymptomatic or mild symptoms Moderate symptoms, able to perform ADL Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Consider withholding treatment until patient stabilised Withhold treatment until patient stabilised
Tests

Full endocrine laboratory assessment (including AM cortisol + ACTH, TFTs, LH/FSH, testosterone or oestradiol, prolactin)

Consider MRI pituitary 
Management

Refer to an endocrinologist

Initiate replacement therapy if symptomatic

Refer to an endocrinologist

Administer replacement therapy

Administer corticosteroid therapy e.g. 1mg/kg/day oral prednisolone or equivalent until asymptomatic, then continue with physiologic dose in consultation with endocrinologist. Always start corticosteroids for several days before levothyroxine to avoid precipitating adrenal crisis

As per Grade 2

Hospitalisation might be required
Follow-up Continue routine monitoring

Continue routine monitoring

If treatment withheld and patient clinically improved (with or without hormone replacement), consider resuming immunotherapy treatment (unless advised to permanently discontinue treatment)

 As per Grade 2
Type 1 diabetes mellitus (T1DM) Tests and management Follow-up
 

If T1DM is suspected, treatment should be withheld during work-up for diabetic ketoacidosis (DKA)

Patients with new-onset T1DM should be tested for hemoglobin A1c, C-peptide and autoantibodies

Referral to an endocrinologist

DKA should be managed as per institutional guidelines and insulin for T1DM should be administered as per endocrinologist. No steroids should be prescribed

Continue routine monitoring

Consider recommencement of immunotherapy once patient has stabilised and insulin regimen has been instituted

Long term endocrinology input will be required for the management of T1DM
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • Although the number of bowel actions defines CTCAE grading of diarrhoea, clinicians should also account for other clinical features such as (but not limited to) duration, diarrhoea volume, abdominal pain and general constitution in their patient assessment. Diarrhoea frequency may underestimate degree of inflammation. CTCAE grading may not be the best reflection of the severity of gastrointestinal toxicity.r
  • Small bowel enteritis may present with diarrhoea, or with nausea/constitutional symptoms.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory immune-related enterocolitis consider use of steroid-sparing agents e.g. infliximab, vedolizumab after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carnii) in cancer patients
Gastrointestinal toxicity Grade 1 Grade 2 Grade 3 to 4

Signs and symptoms:

  • diarrhoea or more bowel movements than usual
  • blood or mucous in stools
  • dark, tarry, sticky stools
  • abdominal pain or tenderness
  • systemic symptoms

Diarrhoea: <4 stools per day over baseline

Colitis: asymptomatic

Diarrhoea: 4-6 stools per day over baseline; not interfering with ADL

Colitis: abdominal pain; mucous or blood in stool

Grade 3 diarrhoea: ≥7 stools per day over baseline; interfering with ADL

Grade 3 colitis: severe abdominal pain; peritoneal signs

Grade 4: life threatening diarrhoea or colitis or perforation
Treatment with anti-PD-1 or anti-PD-L1

Continue treatment at discretion of treating clinician

Withhold treatment

Grade 3: withhold treatment until Grade 0, or baseline. Consider retreatment at discretion of treating clinician

Grade 4: permanently discontinue treatment
Treatment with anti-CTLA-4 or anti-CTLA-4 and anti-PD-1

Continue treatment at discretion of treating clinician

Withhold treatment

Consider permanent discontinuation of anti-CTLA-4

Grade 3: permanently discontinue anti-CTLA-4 and withhold anti-PD-1 until Grade 0 or baseline. Consider retreatment with anti-PD-1 at discretion of treating clinician

Grade 4: permanently discontinue both anti-CTLA-4 and anti-PD-1
Tests

Stool cultures (including Clostridium difficile)

Evaluate to exclude other causes

Review concomitant medications that may alter gut microflora 

Consider TSH and celiac serologies if suspicious of immunotherapy-induced celiac disease

Stool cultures (including Clostridium difficile)

Consider faecal calprotectin in consultation with a gastroenterologist

Consider colonoscopy or flexible sigmoidoscopy in consultation with a gastroenterologist

Consider abdominal imaging in patients with signs and symptoms of colitis complications, such as bowel perforation or toxic megacolon

Evaluate to exclude other causes

Review concomitant medications that may alter gut microflora 

Consider TSH and celiac serologies if suspicious of immunotherapy-induced celiac disease

Stool cultures (including Clostridium difficile)

Faecal calprotectin in consultation with a gastroenterologist

Evaluate for GI perforation or peritonitis

Colonoscopy or flexible sigmoidoscopy in consultation with a gastroenterologist

Abdominal imaging is advised in patients with signs and symptoms of colitis complications, such as bowel perforation or toxic megacolon; however normal imaging results may not exclude significant colitis

Evaluate to exclude other causes

Review concomitant medications that may alter gut microflora 

Consider TSH and celiac serologies if suspicious of immunotherapy-induced celiac disease
Management

Symptomatic treatment
e.g. fluid replacement, consider loperamide

Symptomatic treatment e.g. fluid and electrolyte replacement

Administer corticosteroid therapy if immune-related diarrhoea/colitis is histologically confirmed or strongly suspected in the absence of an infectious aetiology, or if Grade 2 diarrhoea is persistent e.g. oral prednisolone 1 mg/kg/day or equivalent

Hospitalise patient 

Urgent referral to a gastroenterologist

Consult gastroenterologist for urgent scope, evaluate for perforation and peritonitis and toxic megacolon; do not delay institution of therapy 

Symptomatic treatment e.g. fluid and electrolyte replacement

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 1 to 2 mg/kg/day for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent

DO NOT administer corticosteroids if GI perforation is present
If symptoms worsen or persist treat as Grade 2 or Grade 3 to 4 If symptoms worsen or persist for >2 to 3 days despite oral steroids escalate to treat as per Grade 3 to 4 

If symptoms persist >3 days or recur after improvement, or if pancolitis observed on imaging or severe ulceration on endoscopy, consider additional non-corticosteroid immunosuppressive therapy e.g. IV infliximab 5 mg/kg (NOTE: not TGA approved)

Infliximab or other agents should only be considered in discussion with a gastroenterologist. Infliximab is contraindicated if GI perforation or sepsis is suspected, if liver dysfunction is present or patient is a hepatitis B chronic carrier

Perform pre-commencement workup prior to initiation of infliximab including quantiferon gold assay, chest x-ray, hepatitis B (if not already known), etc. as per local/institutional guidelines

IV vedolizumab 300 mg (NOTE: not TGA approved), in consultation with a gastroenterologist, may be a suitable alternative

May consider faecal microbiota transplant, in consultation with a gastroenterologist if refractory to previous immunosuppressants
Follow-up

Monitor patient closely for worsening symptoms

Educate patient to report worsening symptoms immediately

If symptoms resolve to Grade 1, or baseline consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

Resume treatment at next scheduled dose after completion of steroid taper and/or if there is evidence of endoscopic and histological remission (may consider faecal calprotectin as a surrogate). Consider permanent discontinuation of anti-CTLA-4)

If symptoms resolve to Grade 1, or baseline consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound. Steroid may be tapered over <4 weeks if non-corticosteroid immunosuppressive agents have been used

Grade 3: single agent anti-PD-1 or anti-PD-L1 ONLY: after management with corticosteroids is complete, may resume treatment at next scheduled dose after careful discussion of risks/benefits with the treating team
  • Management of haematological toxicities greater than Grade 1 should be immediately referred to and managed by a haematologist.
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents, and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid refractory irAEs, consider use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF), IVIG, anti-thymocyte globulin (ATG) or rituximab after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients

Testing for haematological toxicity

Essential:

  • FBC and film to examine for spherocytes or RBC fragments
  • Haemolysis screen – direct and indirect bilirubin, haptoglobins, LDH, reticulocytes, Coombs, DAT
  • Coagulation profile – to exclude DIC or look for factor inhibition

Consider (in consultation with haematologist):

  • Screening for alternative causes of AIHA/ITP/cytopenias – ANA, hepatitis and other viral serology, protein electrophoresis/serum free light chains, peripheral blood lymphocyte flow cytometry, haematinic screen (iron studies/B12/folate), bone marrow biopsy
  • ADAMTS13 if TTP suspected
  • Factor and inhibitor levels, if coagulation profile suggests factor inhibitor
  • C3/C4 if HUS suspected

 

Autoimmune haemolytic anaemia (AIHA) Grade 1 Grade 2 Grade 3 to 4
  Hb < LLN to 100 g/L Hb <100 to 80 g/L

Grade 3: Hb <80 g/L; transfusion indication 

Grade 4: life-threatening; urgent intervention needed
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Continue treatment Withhold treatment Permanently discontinue treatment
Tests

Refer to Testing for haematological toxicity 

Evaluation of medication history with special consideration of any new drugs
Management Close clinical follow-up As per haematologist
Follow-up Check Hb prior to each cycle  As per haematologist
Acquired thrombotic thrombocytopenic purpura (TTP) Grade 1 Grade 2 Grade 3 to 4
  RBC destruction (schistocytosis) without anaemia, renal insufficiency or thrombocytopenia RBC destruction (schistocytosis) without clinical consequence with Grade 2 anaemia and thrombocytopenia

Grade 3: thrombocytopenia, anaemia and renal insufficiency

Grade 4: life-threatening consequences
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Withhold treatment Permanently discontinue treatment
Tests

Refer to Testing for haematological toxicity

Nutritional assessment

Work-up for infectious causes
Management Haematology referral As per haematologist
Follow-up Consider restarting treatment, although currently lack of data to recommend restarting  As per haematologist
Aplastic anaemia (AA) Grade 1 Grade 2 Grade 3 to 4
 

Non-severe

ANC >0.5 x109/L

Hypocellular marrow (marrow cellularity <25%) 

Platelet count >20,000 

Reticulocyte count >20,000

Severe

Hypocellular marrow <25% and two of the following:

ANC <0.5x109/L 

Platelet count <20,000 

Reticulocyte count <20,000

Very severe

ANC <0.2 x 109/L 

Hypocellular marrow <25%

Platelet count <20,000 

Reticulocyte count <20,000
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Withhold treatment
Tests

Refer to Testing for haematological toxicity

Nutritional assessment

Renal function

Work-up for infectious causes
Management

Haematology referral

Blood product support

Supportive transfusions as per local guidelines 

As per haematologist
Follow-up

Close clinical follow-up

Consider restarting treatment in discussion with a haematologist

As per haematologist
Immune thrombocytopenia (ITP) Grade 1 Grade 2 Grade 3 to 4
  Platelet count 75 to 100 x109/L Platelet count 50 to 75 x109/L

Grade 3: Platelet count 25 to 50 x109/L

Grade 4: Platelet count <25 x109/L
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Continue treatment
Tests

Refer to Testing for haematological toxicity

H.pylori 

Direct antigen test for Evan syndrome
Management Continue treatment As per haematologist
Follow-up Close clinical follow-up As per haematologist
Acquired haemophilia (AH) Grade 1 Grade 2 Grade 3 to 4
 

Mild

5 to 40% of normal factor activity in blood

Moderate

1 to 5% of normal factor activity in blood

Severe

<1% of normal factor activity in blood
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Withhold treatment Permanently discontinue treatment
Tests

Refer to Testing for haematological toxicity

Bethesda unit level of inhibitor  
Management

Haematology referral

Administer oral prednisolone 0.5 to 1 mg/kg/day

Transfusion support as required 

 As per haematologist
Follow-up As per haematologist
Haemolytic uraemic syndrome (HUS) Grade 1 Grade 2 Grade 3 to 4
  RBC destruction (schistocytosis) without anaemia, renal insufficiency or thrombocytopenia RBC destruction (schistocytosis) without clinical consequence with Grade 2 anaemia and thrombocytopenia

Grade 3: thrombocytopenia, anaemia and renal insufficiency

Grade 4: life-threatening consequences
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Withhold treatment Permanently discontinue treatment
Tests

Refer to Testing for haematological toxicity

Nutritional assessment

Work-up for infectious causes
Management Supportive care As per haematologist
Follow-up Close clinical follow-up As per haematologist
Lymphopenia Grade 1 Grade 2 Grade 3 to 4
 

500 to 1,000 peripheral blood (PB) lymphocyte count

500 to 1,000 PB lymphocyte count

Grade 3: 250 to 499 PB lymphocyte count

Grade 4: <250 PB lymphocyte count
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Continue treatment

Grade 3: continue treatment

Grade 4: consider withholding treatment  
Tests

Refer to Testing for haematological toxicity

Nutritional assessment

Work-up for infectious causes
Management Continue treatment As per haematologist
Follow-up Check PB lymphocyte count prior to each cycle As per haematologist
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF) after specialist consultation.
  • Anti-thymocyte globulin (ATG) has been used for life-threatening immune-related hepatic failure but carries a mortality risk and should only be used after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Hepatotoxicity Grade 1 Grade 2 Grade 3 to 4

Signs and symptoms:

  • transaminase elevation
  • total bilirubin elevation
  • jaundice
  • severe nausea or vomiting
  • pain on the right side of the abdomen
  • drowsiness
  • dark urine
  • bleeding or bruising more easily than normal
  • anorexia

Asymptomatic 

AST or ALT >1 to 3 x ULN 
and/or
Total bilirubin >1 to 1.5 x ULN

Asymptomatic

AST or ALT >3 to <5 x ULN
and/or
Total bilirubin >1.5 to <3 x ULN

Grade 3: symptomatic liver dysfunction, fibrosis on biopsy, compensated cirrhosis, reactivation of chronic hepatitis

AST or ALT >5 to 20 x ULN
and/or
Total bilirubin >3 to 10 x ULN

Grade 4: decompensated liver function (e.g. ascites, coagulopathy, encephalopathy, coma)

AST or ALT >20 x ULN
and/or
Total bilirubin >10 x ULN
Treatment with anti-PD-1 or anti-PD-L1 Continue treatment Withhold treatment Permanently discontinue treatment
Treatment with anti-CTLA-4 or anti-CTLA-4 and anti-PD-1 Continue treatment; consider deferring in select patients Withhold treatment Permanently discontinue treatment
Tests/monitoring

Monitor LFTs more closely e.g. weekly and prior to treatment (more or less frequent monitoring may be considered depending on degree of elevation and rate of change)

Evaluate to exclude other causes of hepatic injury, including infections, disease progression or medication

Monitor LFTs more frequently
e.g. every 3 days

Evaluate to exclude other causes of hepatic injury, including infections, disease progression or medication

Monitor LFTs more frequently
e.g. every 1 to 2 days

Evaluate to exclude other causes of hepatic injury, including infections, disease progression or medication

Consider liver biopsy 
Management No treatment recommended for Grade 1 

Symptomatic treatment

Consider referral to a gastroenterologist

Consider corticosteroid therapy for patients who are symptomatic or have worsening LFTs. e.g. oral prednisolone 0.5 to 1 mg/kg/day or equivalent

Hospitalise patient if unwell

Referral to a gastroenterologist

Symptomatic treatment

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 1 to 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent
If Grade 1 hepatitis persists or worsens then consider treatment as for Grade 2  If AST or ALT >5 x ULN and/or total bilirubin >3 x ULN treat as Grade 3 to 4 If elevations persist for >3 to 5 days, worsen or rebound after improvement and despite optimal steroids consider urgent referral to a gastroenterologist to prescribe other steroid-sparing agents
Follow-up Monitor LFTs more closely

If improved to Grade 1 (Grade 0 for anti-CTLA-4 containing regimen), or baseline (without corticosteroid therapy) resume treatment at next scheduled dose

If corticosteroid therapy has been administered, consider initiating corticosteroid taper.

Tapering over at least 4 weeks is recommended to avoid rebound

Elevations in LFTs during taper may be managed with an increased corticosteroid dose and slow taper

After management with corticosteroids is complete, resume treatment at next scheduled dose

If improvement of AST and ALT to Grade 1 or less, consider initiating corticosteroid taper

Tapering over at least 4 weeks is recommended to avoid rebound

Elevations in LFTs during taper may be managed with an increased corticosteroid dose and slow taper
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF), disease modifying anti-rheumatic drugs (DMARDs), IVIG after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy.
    Trimethoprim/ sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Inflammatory arthritis Grade 1 Grade 2 Grade 3 to 4 
Signs and symptoms: 
​Joint pain or swelling, morning stiffness or after inactivity		 Mild pain with erythema or joint swelling  Moderate pain with associated joint swelling or erythema, limiting instrumental ADL Severe pain associated with signs of inflammation; irreversible joint damage; disabling; limiting instrumental ADL
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4 		 Continue treatment Withhold treatment
Tests

Thorough rheumatological examination of all joints/spine, consider imaging e.g. XRAY to exclude metastases and to evaluate for joint erosions

ANA, RF, anti-CCP, CRP, ESR, consider HLA-B27 

As for Grade 1 

In addition, consider US +/- MRI of affected joints

Consider arthrocentesis if suspicious of septic/crystal-induced arthritis

As for Grade 2 
Management

Paracetamol and NSAIDS 

Consider referral to a rheumatologist

If not adequately controlled with escalated doses of NSAIDs commence oral prednisolone 10 to 20 mg/day or equivalent

Urgent referral to a rheumatologist 

Commence oral prednisolone 0.5 to 1 mg/kg/day or equivalent
 

If worsens or no improvement after initial 4 weeks treat as Grade 3 to 4 

If unable to lower prednisolone to <10 mg/day after 6-8 weeks, refer to a rheumatologist to consider disease modifying anti-rheumatic drugs (DMARDs) or intra-articular corticosteroid injections for large joints (may be only treatment required for oligoarthritis)

 If no improvement after 2 weeks or worsening symptoms start a DMARD as advised by a rheumatologist
Follow-up  

If improvement on oral prednisolone 10 to 20 mg/day then slowly taper over 4 to 6 weeks

Withhold treatment until symptom control and on prednisolone <10 mg/day

Resume in consultation with a rheumatologist once recovered to Grade 1 and after careful discussion of risks/benefits with the treating team

Patients should be monitored with serial rheumatological examinations including CRP/ESR every 4 to 6 weeks once treatment has resumed
Polymyalgia-like syndrome Grade 1 Grade 2 Grade 3 to 4
Signs and symptoms:
Pain and stiffness in proximal upper or lower extremities		 Mild stiffness and pain  Moderate stiffness and pain, limiting instrumental ADL Severe stiffness and pain, limiting self-care ADL
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4		 Continue treatment Consider withholding treatment Withhold treatment
Tests

Examine for signs of temporal arteritis, temporal artery biopsy if present  

ANA, RF, anti-CCP, CK, CRP, ESR 
Management

Paracetamol and NSAIDs

Urgent referral to ophthalmologist if symptoms of temporal arteritis present

Commence oral prednisolone 10 to 20 mg/day or equivalent

If no improvement, or need for higher doses after 4 weeks, treat as Grade 3

Consider referral to a rheumatologist

Consider hospitalisation if severe symptoms present 

Referral to a rheumatologist 

Commence oral prednisolone 20 to 40 mg/day or equivalent

If no improvement or need for higher doses consider non-corticosteroid immunosuppressive therapy 
Follow-up  

Consider withholding treatment until symptom control or on prednisolone <10 mg/day 

Taper prednisolone after 3 to 4 weeks 

Limited evidence to guide steroid weaning in cases of polymyalgia-like syndrome

 Resume treatment in consultation with a rheumatologist once recovered to Grade 2 or less and after careful discussion of risks/benefits with the treating team (cases of toxicity have been reported upon re-challenge)
Myositis Grade 1 Grade 2 Grade 3 to 4

Signs and symptoms: 
Muscle inflammation and weakness

 Mild weakness with or without pain  Moderate weakness with or without pain, limiting instrumental ADL Severe weakness with or without pain, limiting self-care ADL
Treatment with anti-PD-1 or
anti-PD-L1		 Continue treatment Withhold treatment
Treatment with anti-CTLA-4 or anti-CTLA-4 and anti-PD-1

Withhold treatment

Withhold treatment

Consider permanently discontinuing treatment if objective findings of severe muscle involvement present

Withhold treatment

Permanently discontinue treatment if myocardial involvement
Tests

Complete rheumatological and neurological examination 

CK, transaminases (ALT, AST), LDH, CRP, ESR 

If myositis likely then consider troponin, ECG to evaluate for cardiac involvement, consider antibody testing to evaluate concomitant myasthenia gravis, consider EMG and muscle biopsy 

Consider evaluation for paraneoplastic syndromes

Urinalysis for rhabdomyolysis
Management

Consider referral to a rheumatologist or a neurologist 

Paracetamol or NSAIDs

If CK is elevated and muscle weakness present, consider treatment as for Grade 2 

Consider withholding statins

There have been cases reported of concurrent immune mediated myositis, myasthenia gravis and myocarditis

Referral to a rheumatologist or a neurologist 

NSAIDS 

If CK ≥3 x ULN commence oral prednisolone 0.5 to 1 mg/kg/day or equivalent 

Hospitalise patient

Urgent referral to a rheumatologist or a neurologist 

Commence oral prednisolone 1 mg/kg/day or equivalent 

If severe weakness/ dysphagia/ cardiac or respiratory involvement commence IV methylprednisolone 1 to 2 mg/kg/day or equivalent

If symptoms and CK levels do not improve consider non-corticosteroid immunosuppressive therapy in consultation with a rheumatologist e.g. IVIG or plasmapheresis
Follow-up  

Resume treatment upon symptom control, normal CK and on oral prednisolone <10 mg/day, however caution is required when re-challenging

If symptoms worsens treat as per Grade 3

Withhold treatment until Grade 1, however caution is advised for re-challenging (limited evidence as majority of documented cases did not re-challenge)

Permanently discontinue treatment if myocardial involvement
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • Neurological conditions may rapidly lead to respiratory compromise. Consider transferring patient care to hospitals with access to ICU-level facilities
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents e.g. IVIG after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy.
  • Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis-Pneumocystis jiroveci (carinii) in cancer patients
Neurological toxicity Grade 1  Grade 2 Grade 3 to 4

Conditions/syndromes:

  • aseptic meningitis
  • myasthenia gravis
  • Guillain-Barré syndrome (GBS)
  • encephalitis
  • meningeal symptoms
  • neuropathy (including mononeuritis)
  • acute inflammatory demyelinating polyneuropathy (AIDP) (including multiple sclerosis, transverse myelitis, acute-disseminated encephalomyelitis, optic neuritis, and neuromyelitis optic)
 Asymptomatic or mild symptoms New onset moderate symptoms (motor or sensory neuropathy, muscle weakness); limiting instrumental ADL New onset severe symptoms; limiting self-care ADL; life-threatening
Treatment with anti-PD-1 or anti-PD-L1

Withhold treatment

Permanently discontinue treatment
Treatment with anti-CTLA-4 or
anti-CTLA-4 and anti-PD-1

Withhold treatment

Withhold treatment

Consider permanently discontinuing anti-CTLA-4

Permanently discontinue treatment
Tests

E.g. lumbar puncture, nerve conduction studies, MRI brain, EEG, respiratory function assessment, antibody testing, paraneoplastic panel, thyroid panel

Monitor patient closely

Evaluate to exclude other causes such as disease progression, infection, metabolic syndromes or medications
Management

Consider referral to a neurologist

Consider corticosteroid therapy
e.g. oral prednisolone 1 mg/kg/day or equivalent

Referral to a neurologist

Corticosteroid therapy e.g. oral prednisolone 1 mg/kg/day or equivalent

Myasthenia gravis/GBS/AIDP:
All grades require intervention given the risk to lead to respiratory compromise

Myasthenia gravis: oral prednisolone 0.5 mg/kg/day or equivalent may be administered

GBS: discontinue treatment

Hospitalise patient

Urgent referral to a neurologist

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent

Myasthenia gravis: continue steroids. Initiate non-corticosteroid immunosuppressive therapy e.g. IVIG or plasmapheresis

GBS and peripheral neuropathy: Initiate non-corticosteroid immunosuppressive therapy e.g. IVIG or plasmapheresis. IV methylprednisolone 2 to 4 mg/kg/day, or pulse 1 g/day for 5 days may be considered

AIDP: commence methylprednisolone pulse dosing 1 g/day

If symptoms worsen treat as Grade 2 or Grade 3 to 4

If symptoms do not improve, consider additional non-corticosteroid immunosuppressive therapy in consultation with a neurologist e.g. IVIG

If worsens or no improvement treat as Grade 3 to 4

If symptoms do not improve or atypical presentation, a neurologist may suggest other non-corticosteroid immunosuppressive therapy e.g. IVIG or plasmapheresis
Follow-up

Monitor patient for worsening symptoms

Educate patient to report worsening symptoms immediately

If corticosteroid therapy has not been administered, once improved to baseline, resume treatment at next scheduled dose

If corticosteroid therapy has been administered, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

After management with corticosteroids is complete, resume treatment at next scheduled dose

Avoid medication that can worsen myasthenia gravis

If improved to baseline, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

After management with corticosteroids is complete, careful consideration should be used before resuming treatment at next scheduled dose

If improved to Grade 2 or less, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence.
  • The recommendations made on eviQ are intended as a guide only and are generally conservative.
  • This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about PJP prophylaxis Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Ocular toxicity Grade 1 Grade 2 Grade 3 to 4
Uveitis/iritis:
Inflammation of the middle layer of the eye		 Anterior uveitis with trace cells Anterior uveitis with 1+ or 2+ cells 

Grade 3: anterior uveitis with 3+ or greater cells, intermediate posterior or panuveitis

Grade 4: vision 20/200 or worse 
Episcleritis:
Inflammation of the episcleral tissue between the conjunctiva and sclera		 Asymptomatic Vision 20/40 or better

Grade 3: symptomatic and vision worse than 20/40

Grade 4: vision 20/200 or worse 
Blepharitis:
Inflammation of the eyelid that affects tear production		 No formal grading system 
Treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 Uveitis/iritis, episcleritis: continue treatment Uveitis/iritis, episcleritis: withhold treatment Uveitis/iritis: permanently discontinue treatment 
Blepharitis: continue treatment
Tests

Ophthalmology assessment of visual acuity, colour vision, red reflex, pupils, fundoscopy, optical coherence tomography (OCT)
Management

Uveitis/iritis, episcleritis:

Prompt referral to an ophthalmologist (within a week)

Artificial tears 

Uveitis/iritis, episcleritis: 

Urgent referral to an ophthalmologist

Withhold immunotherapy until after ophthalmology review

Commence topical corticosteroids (e.g. 1% prednisolone acetate suspension), cycloplegic agents (e.g. atropine), and systemic corticosteroids (prednisone 1 mg/kg/day or equivalent) as per ophthalmologist

Uveitis/iritis, episcleritis: 

Urgent referral to an ophthalmologist

Consider hospitalisation

Commence systemic corticosteroids e.g. oral prednisolone 1 to 2 mg/kg/day or IV methylprednisolone 1 to 2 mg/kg/day and intravitreal/periocular/topical corticosteroids as per ophthalmologist 

Consider additional immunosuppressive therapy

Blepharitis:

Warm compresses and lubrication drops 

Continue therapy unless persistent and serious

Blepharitis: 

As per Grade 1

Blepharitis:

As per Grade 1
Follow-up  

Uveitis/iritis, episcleritis:

Taper corticosteroids over at least 4 to 6 weeks in discussion with an ophthalmologist 

Treatment may be resumed once improved to ≤ Grade 1 and off systemic corticosteroids which are purely indicated for ocular adverse effects or once corticosteroids for other concurrent systemic irAEs are reduced to ≤10 mg/day; continued topical/ocular corticosteroids are permitted when resuming therapy to manage and minimise local toxicity 

Uveitis/iritis, episcleritis:

Taper corticosteroids over at least 4 to 6 weeks in discussion with an ophthalmologist 
  • The immune related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF), IVIG, cyclophosphamide or infliximab after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Pulmonary toxicity Grade 1 Grade 2 Grade 3 to 4

Signs and symptoms:

  • radiographic changes
  • dyspnoea
  • new or worsening cough
  • hypoxia
  • tachycardia
  • chest pain
  • fever 

Asymptomatic

Radiographic changes only

 Mild to moderate new symptoms (e.g. new onset cough or shortness of breath); symptoms worsen from baseline, limiting instrumental ADL

Grade 3: severe symptoms; new or worsening hypoxia requiring oxygen, limiting self-care ADL

Grade 4: life-threatening
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4

Consider withholding treatment until radiographic improvement  

If continuing treatment monitor regularly for symptoms

Withhold treatment

For recurrent Grade 2: permanently discontinue treatment

Permanently discontinue treatment
Tests

Monitor for symptoms every 2 to 3 days 

CT Chest 

Consider PFTs to identify potential functional deficit if CT is negative for pneumonitis

Evaluate to exclude other causes such as disease progression, infections, metabolic syndromes or medications

Monitor symptoms daily

As for Grade 1, and consider bronchoscopy and lung biopsy 

 As for Grade 2
Management Consider referral to respiratory and infectious disease physicians

Consider hospitalisation

Referral to respiratory and infectious disease physicians

Consider empirical antibiotics in consultation with respiratory and/or infectious disease physicians 

Administer corticosteroid therapy e.g. oral prednisolone 1 to 2 mg/kg/day or equivalent

Hospitalise patient 

Urgent referral to respiratory and infectious disease physicians

Consider empirical antibiotics in consultation with respiratory and/or infectious disease physicians 

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 1 to 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent
  Grade 1 often resolves by withholding treatment, however if symptoms worsen, treat as Grade 2 or Grade 3 to 4 If there is no improvement within 2 to 3 days of treatment with prednisolone then treat as Grade 3 to 4 If symptoms worsen or persist after 2 days consider additional non-corticosteroid immunosuppressive therapy e.g. infliximab, mycophenolate mofetil (MMF), IVIG or cyclophosphamide in consultation with a respiratory physician 
Follow-up

Monitor patient closely for worsening symptoms

Educate patient to report worsening symptoms immediately

Repeat CT in 3 to 4 weeks

If treatment has been withheld, once radiographic improvement to baseline, resume treatment at next scheduled dose

If improved to baseline taper prednisolone by 5 to 10 mg/week over at least 4 to 6 weeks

After management with corticosteroids is complete, consider resuming treatment at next scheduled dose

Re-image prior to resuming treatment

If improved to baseline taper prednisolone by 5 to 10 mg/week over at least 4 to 6 weeks
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, consider use of other steroid-sparing agents e.g. mycophenolate mofetil (MMF) after specialist consultation.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis-Pneumocystis jiroveci (carinii) in cancer patients
Renal toxicity Grade 1 Grade 2 Grade 3 to 4

Signs and symptoms

  • increase in serum creatinine
  • oliguria
  • haematuria
  • swelling in the ankles
  • anorexia
 Creatinine >1 to 1.5 x ULN
or >1.0 to 1.5 x baseline		 Creatinine >1.5 to 3.0 x ULN
or >1.5 to 3.0 x baseline

Grade 3: 
Creatinine >3.0 to 6.0 x ULN
or >3.0 x baseline

Grade 4:
Creatinine >6.0 x ULN;
life-threatening; dialysis required 
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4 		 Continue treatment Withhold treatment Permanently discontinue treatment
Tests

Monitor creatinine, sodium, potassium, phosphate and urea weekly

Urinalysis for casts and protein

Evaluate to exclude other causes of renal injury, including hypovolaemia, urinary retention, infection, disease progression or medications, including IV contrast

Monitor creatinine, sodium, potassium, phosphate and urea more frequently
e.g. every 2 to 3 days 

Urinalysis for casts and protein

Evaluate as per Grade 1

Consider renal biopsy

Monitor creatinine, sodium, potassium, phosphate and urea daily

Urinalysis for casts and protein

Close fluid balance is necessary to monitor for oliguria/anuria

Evaluate as per Grade 2

Consider renal biopsy
Management

Corticosteroid therapy not indicated

Promote hydration and cease nephrotoxic drugs

Referral to a nephrologist

Administer corticosteroid therapy
e.g. oral prednisolone 1 mg/kg/day or equivalent

Hospitalise patient

Urgent referral to a nephrologist

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 1 to 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent

If worsens treat as Grade 2 or Grade 3 to 4

If creatinine elevations persist for >7 days or worsen treat as Grade 3 to 4

If creatinine elevations persist >2 to 3 days or worsen, consider additional immunosuppressive therapy in consultation with a nephrologist
Follow-up

If creatinine returns to baseline, resume routine creatinine monitoring

If improved to Grade 1, taper corticosteroids over at least 4 to 6 weeks with regular creatinine and clinical monitoring to avoid rebound

After management with corticosteroids is complete, resume treatment at next scheduled dose

If improved to Grade 1, taper corticosteroids over at least 4 to 6 weeks with regular creatinine and clinical monitoring to avoid rebound
  • The immune-related adverse events (irAEs) management guidelines below are based on a low level of evidence. The recommendations made on eviQ are intended as a guide only and are generally conservative. This document should be used in conjunction with expert clinical judgement (by specialist physicians experienced in the treatment of cancer using immunological agents), and individual institutional guidelines or policies.
  • irAEs can escalate quickly, close monitoring of patients is required.
  • irAEs should improve promptly after introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice.
  • CTCAE grading may not be the best reflection of the severity of skin toxicity.
  • If multiple medium-grade irAEs occur concurrently on combination anti-CTLA-4 and anti-PD-1 therapy, the clinician should consider permanent discontinuation of anti-CTLA-4 therapy.
  • For some high-grade toxicities that resolve quickly, re-challenge with anti-PD-1 or anti-PD-L1 therapy may be considered in consultation with an experienced specialist (anti-CTLA-4 therapy recommencement is not advised).
  • Prednisolone and methylprednisolone dosing are not equivalent: 1 mg prednisolone = 0.8 mg methylprednisolone.
  • For steroid-refractory irAEs, ensure dermatology consultation and skin biopsy; consider use of other steroid-sparing agents in discussion with dermatologist.
  • Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term immunosuppressive therapy. Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for Pneumocystis jiroveci (carinii) (PJP) prevention in adults. Read more about Prophylaxis - Pneumocystis jiroveci (carinii) in cancer patients
Skin toxicity Grade 1 to 2 Grade 3 Grade 4

Signs and symptoms:

  • rash
  • skin blisters
  • pruritus

Grade 1: Rash covering  <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness; symptoms do not affect instrumental ADL or controlled with topical regimen

Grade 2: Rash covering 10% to 30% BSA with or without symptoms (e.g. pruritus, burning and tightness); limiting instrumental ADL; rash covering >30% BSA with or without mild symptoms

Rash covering >30% of  BSA with moderate or severe symptoms; limiting self-care ADL

Rash – Severe consequences requiring hospitalisation or urgent intervention
indicated or life threatening

Stevens-Johnson syndrome, toxic epidermal necrolysis; or rash complicated by full thickness dermal ulceration, or necrotic, bullous, haemorrhagic manifestations
Treatment with anti-PD-1,
anti-PD-L1 or anti-CTLA-4

Grade 1: continue treatment

Grade 2: continue treatment with weekly monitoring

Withhold treatment

Permanently discontinue treatment
Tests

Evaluate to exclude other causes

FBC to exclude possibility of bacterial infection

Skin scrapings if fungal or unusual parasitic infections suspected

Evaluate to exclude other causes

Consider skin biopsy 

Evaluate to exclude other causes

Consider skin biopsy and use of serial clinical photography 
Management

Administer symptomatic treatment
e.g. antihistamines and topical steroids

For problematic grade 2, consider corticosteroid therapy e.g. oral prednisolone 0.5 to 1 mg/kg/day or equivalent

Consider referral to a dermatologist if refractory to corticosteroid treatment

Referral to a dermatologist

Administer symptomatic treatment
e.g. antihistamines and topical steroids

May consider phototherapy for severe pruritus

Administer corticosteroid therapy e.g. oral prednisolone 0.5 to 1 mg/kg/day or equivalent, or IV methylprednisolone 1 to 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent 

Hospitalise patient

Urgent referral to a dermatologist

Urgent administration of corticosteroid therapy e.g. IV methylprednisolone 1 to 2 mg/kg/day (up to 1 g/day) for 3 days, followed by high dose oral prednisolone 1 to 2 mg/kg/day or equivalent

If mild to moderate symptoms persist for 1 to 2 weeks or recur, withhold treatment and consider skin biopsy

If symptoms worsen treat as Grade 3 or 4

If symptoms worsen treat as Grade 4

  
Follow-up

If symptoms improving, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

After management with corticosteroids is complete, resume treatment at next scheduled dose

Monitor patient 

Educate patient to report worsening symptoms immediately

If symptoms resolve to Grade 1 or less, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

After management with corticosteroids is complete, can resume treatment with careful monitoring at next scheduled dose

If symptoms resolve to Grade 1 or less, consider initiating corticosteroid taper

Tapering over at least 4 to 6 weeks is recommended to avoid rebound

After management with corticosteroids is complete and after careful discussion of risks/benefits with the treating team, can resume treatment with careful monitoring at next scheduled dose 

Consider alternative anti-cancer therapy if symptoms do not resolve to Grade 1
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Bibliography

Bristol-Myers Squibb Pty Ltd. Opdivo (nivolumab) Immune-Mediated Adverse Reactions Management Guide: Amended June 2020.
Bristol-Myers Squibb Pty Ltd. Opdivo (nivolumab) Product Information. Date of Most Recent Amendment: 15 April 2020
Bristol-Myers Squibb Pty Ltd. Yervoy (ipilimumab) Product Information. Date of Most Recent Amendment: 7 February 2020.
Merck Sharp & Dohme (Australia) Pty Ltd. Keytruda (pembrolizumab) Product Information. Date of Most Recent Amendment: 12 June 2020.
Common Terminology Criteria for Adverse Events (CTCAE). V5.0: 27 November 2017.
Champiat, S., O. Lambotte, E. Barreau, et al. 2016. "Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper." Ann Oncol 27(4):559-574.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare ( approximately 10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

Spain, L., S. Diem, J. Larkin. (2016). "Management of toxicities of immune checkpoint inhibitors." Cancer Treat Rev 44: 51-60.

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Supplement to: Robert, C., G. V. Long, B. Brady, et al. 2015. "Nivolumab in previously untreated melanoma without BRAF mutation." N Engl J Med 372(4):320-330.
Ball, S., R. K. Ghosh, S. Wongsaengsak, et al. 2019. "Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week." J Am Coll Cardiol 74(13): 1714-1727.

Immune checkpoint inhibitors (ICIs) have been an important therapeutic advance in the field of cancer medicine, resulting in a significant improvement in survival of patients with advanced malignancies. Recent reports provided greater insights into the incidence of cardiovascular adverse events (CVAEs) with ICI use. Myocarditis is the most common CVAE associated with ICI. Pericardial diseases, Takotsubo syndrome, arrhythmias, and vasculitis constitute other significant AEs. Physicians should be aware of these infrequent, but potentially fatal toxicities associated with ICIs as their therapeutic use becomes widespread with a myriad of approvals by the U.S. Food and Drug Administration. Management involves prompt administration of high-dose corticosteroids and discontinuation of ICIs in severe myocarditis. This review summarizes the most updated evidence on epidemiology, pathophysiological mechanisms, and management strategies of various CVAEs associated with ICIs. Highlights from recent guidelines published by National Comprehensive Cancer Network on ICI-related CV toxicities have also been incorporated.

Guo, C. W., M. Alexander, Y. Dib, et al. (2020). "A closer look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies." Eur J Cancer 124: 15-24.

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.

Lyon, A. R., N. Yousaf, N. M. L. Battisti, et al. 2018. "Immune checkpoint inhibitors and cardiovascular toxicity." Lancet Oncol 19(9): e447-e458.

Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.

Mahmood, S. S., M. G. Fradley, J. V. Cohen, et al. (2018). "Myocarditis in Patients Treated With Immune Checkpoint Inhibitors." J Am Coll Cardiol 71(16): 1755-1764.

BACKGROUND: Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized. OBJECTIVES: The authors sought to understand the presentation and clinical course of ICI-associated myocarditis. METHODS: After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block. RESULTS: The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 +/- 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of >/=1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates. CONCLUSIONS: Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

 

Higham, C. E., A. Olsson-Brown, P. Carroll, et al. 2018. "SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Acute management of the endocrine complications of checkpoint inhibitor therapy." Endocr Connect 7(7): G1-G7.

Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3-4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1-2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.

Powell, N., H. Ibraheim, T. Raine, et al. 2020. "British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis." Lancet Gastroenterol Hepatol 5(7): 679-697.

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.

Michot, J. M., J. Lazarovici, A. Tieu, et al. 2019. "Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage?" Eur J Cancer 122: 72-90.

Immune checkpoint inhibitors (ICIs) are changing the treatments of many patients with cancer. These immunotherapies are generally better tolerated than chemotherapy, and their adverse events are immune-related mimicking autoimmune or inflammatory conditions. Although these immune-related adverse events mainly affect the skin, endocrine glands, digestive tract, joints, liver or lungs, all the organs can be theoretically affected, and the haematopoietic system is not spared. This review of the literature will focus on the haematological immune-related adverse events (Haem-irAEs). By reviewing the largest clinical trials of ICIs, we estimate the frequency of Haem-irAEs at 3.6% for all grades and 0.7% for grades III-IV. Frequency of Haem-irAEs of all grades was found to be higher with anti-programmed cell death 1 (4.1%) or anti-programmed cell death ligand 1 (4.7%) than with anti-cytotoxic T-lymphocyte-associated protein 4 (0.5%) (p < 0.0001). From the 63 cases with Haem-irAEs reported in the literature, the mean time to the onset was found to be 10 weeks after ICI initiation, and the large range for occurrence (1-84 weeks) and the regular incidence suggest that Haem-irAEs could occur at any time after ICI therapy. Among the 63 reported cases with Haem-irAEs, the distribution was immune thrombocytopenia (n = 18, 29%), pancytopenia or immune aplastic anaemia (n = 12, 19%), neutropenia (n = 11, 17%), haemolytic anaemia (n = 10, 16%), cytokine release syndrome with haemophagocytic syndrome (n = 7, 11%) and other Haem-irAEs including bicytopenia or pure red cell aplasia (n = 5, 8%). Haem-irAEs are generally highly severe adverse reactions with a mortality rate of Haem-irAEs reported to be 14% (9 deaths among the 63 cases reported). The more severe and life-threatening Haem-irAEs were both cytokine release syndrome with haemophagocytic syndrome and pancytopenia or aplastic anaemia. Haem-irAEs induced by ICIs are potentially life-threatening. By discussing their pathophysiological aspects and clinical picture, we propose in this review clinical guidelines for management.

Jennings, J. J., R. Mandaliya, A. Nakshabandi, et al. 2019. "Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies." Expert Opin Drug Metab Toxicol 15(3): 231-244.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury. Areas covered: A comprehensive review was performed to define the clinicopathologic forms of liver injury associated with ICIs, comparing the various ICI classes as well as comparing this form of IMH with idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. Liver biopsy has proven very useful in selected patients. A specific form of fibrin ring granulomatous hepatitis appears to be associated with IMH. The current societal treatment algorithms and emerging data were reviewed to determine when to utilize corticosteroids. Expert opinion: Monitoring for severe ICI-IMH is recommended although acute liver failure remains rare. Most patients with grade 3-4 hepatotoxicity respond to corticosteroids, but a subset of patients with mild hepatitis on liver biopsy resolve without steroids and need to be carefully selected in concert with the consultation of a hepatologist.

Gediz, F. and S. Kobak,. 2019. "Immune Checkpoint Inhibitors-related Rheumatic Diseases: What Rheumatologist Should Know?" Curr Rheumatol Rev 15(3): 201-208.

Immune checkpoint inhibitors are revolutionized drugs for cancer immunotherapy in the last years. The mechanism of action of CPIs including the limitation of the activation of Tcells, and thus enhancing the self-immune response against tumour cells. Checkpointinhibitors( CPIs) may dysregulate the immune system, resulting in some toxicities. These toxicities or side effects are called Immune-related Adverse Events (IRAEs) that can potentially affect any organ and tissue. Rheumatic diseases due to checkpoint inhibitors are also reported in the literature. The spectrum of rheumatic manifestations are quite wide; the most common are arthralgia/arthritis, myalgia/myositis, polimyalgia rheumatica, lupus, rheumatoid arthritis, Sjogren's syndrome. At the same time, these drugs can also cause an exacerbation of known rheumatologic disease. Treatment approaches for developing rheumatic findings due to checkpoint inhibitors should be multidisciplinary. There should be a close relationship between oncologists who follow-up these patients and rheumatologists. The rheumatic manifestations should be defined and treated early. In general, the musculoskeletal side effects are transient and may regress after stopping CPIs. The most commonly used medications are corticosteroids. Immunosuppressive drugs (HQ, MTX, anti-TNF-alpha, anti-IL-6) should be preferred when treatment is unresponsive or as steroid-sparing agents. The aim of this review was to evaluate the checkpoint inhibitors-related rheumatologic findings and therapeutic strategies in light of recent literature data.

Spain, L., Z. Tippu, J. M. Larkin, et al. 2019. "How we treat neurological toxicity from immune checkpoint inhibitors." ESMO Open 4(Suppl 4): e000540.

Neurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies.

Fang, T., D. A. Maberley and M. Etminan,. 2019. "Ocular adverse events with immune checkpoint inhibitors." J Curr Ophthalmol 31(3): 319-322.

Purpose: To quantify the risk of ocular adverse events with immune checkpoint inhibitors (ICIs) as reported to the Food and Drug Administration (FDA). Methods: Disproportionality analysis using data from U.S. FDA's Adverse Events Reporting System (FAERS) database 2003 to 2018. Data from pharmaceutical manufacturers, healthcare providers, consumers in the U.S., and post-marketing clinical trial reports from U.S. and non-U.S. studies. All cases of uveitis, dry eye syndrome, ocular myasthenia and eye inflammation with use of the following ICIs: atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab and pembrolizumab. Reported odds ratios (RORs) and corresponding 95% confidence intervals (CIs) were computed for all drugs as a group or as individual agents. Results: We identified 113 ocular adverse events for all ICIs of interest including uveitis, dry eye, ocular myasthenia and eye inflammation. Nivolumab had the highest number of adverse events (N = 68) associated with use of the ICI. Nivolumab had the highest association with ocular myasthenia [ROR = 22.82, 95% CI (7.18-72.50)] followed by pembrolizumab [ROR = 20.17, 95% CI (2.80-145.20)]. Among all ICIs approved in North America, atezolizumab had the highest association with eye inflammation [ROR = 18.89, 95% CI (6.07-58.81)] and ipilmumab had the highest association with uveitis [ROR = 10.54, 95% CI (7.30-15.22)]. Conclusion: The results of this disproportionality analysis suggest use of ICIs is associated with an increase risk for ocular adverse reactions. Future epidemiologic studies are needed to better quantify these adverse events.

Delaunay, M., G. Prevot, S. Collot, et al. 2019. "Management of pulmonary toxicity associated with immune checkpoint inhibitors." Eur Respir Rev 28(154).

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

Kalisz, K. R., N. H. Ramaiya, K. R. Laukamp, et al. 2019. "Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management." Radiographics 39(7): 1923-1937.

In recent years, the use of immune checkpoint inhibitor (ICI) therapy has rapidly grown, with increasing U.S. Food and Drug Administration approvals of a variety of agents used as first- and second-line treatments of various malignancies. ICIs act through a unique mechanism of action when compared with those of conventional chemotherapeutic agents. ICIs target the cell surface receptors cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, or programmed cell death ligand 1, which result in immune system-mediated destruction of tumor cells. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. ICI therapy-related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. Several distinct radiographic patterns of pneumonitis have been observed: (a) organizing pneumonia, (b) nonspecific interstitial pneumonia, (c) hypersensitivity pneumonitis, (d) acute interstitial pneumonia-acute respiratory distress syndrome, (e) bronchiolitis, and (f) radiation recall pneumonitis. Published guidelines outline the treatment of ICI therapy-related pneumonitis based on the severity of symptoms. Treatment is often effective, although recurrence is possible. This article reviews the mechanism of ICIs and ICI therapy complications, with subsequent management techniques and illustrations of the various radiologic patterns of ICI-therapy related pneumonitis.((c))RSNA, 2019.

Zhong, L., M. Altan, V. R. Shannon, et al. 2020. "Immune-Related Adverse Events: Pneumonitis." Adv Exp Med Biol 1244: 255-269.

Checkpoint inhibitors are part of the family of immunotherapies and are increasingly being used in a wide variety of cancers. Immune-related adverse events pose a major challenge in the treatment of cancer patients. Pneumonitis is a rare immune-related adverse event that presents in distinct patterns. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.

Ellis, S. R., A. T. Vierra, J. W. Millsop, et al. 2020. "Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features." J Am Acad Dermatol.

Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.

Haanen, J., M. Ernstoff, Y. Wang, et al. 2020. "Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy." J Immunother Cancer 8(1).

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

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Version 4

Date Summary of changes
19/04/2022

Document reviewed at immunotherapy reference committee meeting on 04/03/2022. Approved for publication with the following changes made:

  • Cardiac, endocrinopathies, gastrointestinal, musculoskeletal, neurological, ocular, pulmonary and skin toxicity sections updated to align with current best practice recommendations and ASCO and SITC 2021 updates. 
  • Formatting and minor wording changes. 

Version number increased to V.4. Next review in 2 years.

Version 3

Date Summary of changes
07/09/2020

Document reviewed electronically by eviQ immunotherapy reference committee. Approved for publication with the following changes made:

  • All sections updated to align with current best practice recommendations
  • Cardiac, haematological, ocular and musculoskeletal toxicity sections added and order of sections changed to alphabetical
  • Formatting and minor wording changes 

Version number increased to V.3. Next review due in 2 years.

Version 2

Date Summary of changes
31/05/2017 Transferred to new eviQ website. Version number changed to V.2.
04/07/2018 Reviewed at Medical Oncology Reference Committee meeting on 15 June 2018. Wording changed 'medical oncologist' to 'treating clinician' to incorporate immunotherapy use in haematology. Next review in 2 years

Version 1

Date Summary of changes
06/12/2016 Developed in consultation with eviQ Medical Oncology Reference Committees and Melanoma Institute Australia. Published on eviQ. Review in 1 year. 

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