1993-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.

Introduction

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: Management of Immunotherapy-Related Toxicities^r
Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up^r
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update^r
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events^r

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

Cardiac toxicity

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.
Abatacept with ruxolitinib has been used in concomitant myositis and myocarditis cases.^r ^r
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 or pericardial effusion fatigue nausea may be associated with a general myositis or other irAEs	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, CK Additional testing to be guided by cardiologist and may include viral titres, 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

Endocrinopathies

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 and hyperthyroidism Signs and symptoms: Hypothyroidism fatigue lethargy cold intolerance possible constipation Hyperthyroidism palpitations heat intolerance restlessness, anxiety and insomnia frequent bowel movements weight loss despite normal or increased appetite tremors increased perspiration	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
Signs and symptoms: nausea loss of appetite weight loss fatigue light-headedness hypoglycaemia hypotension	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 (0.05-0.1 mg/day)	Refer to an endocrinologist Administer stress corticosteroid therapy (e.g. hydrocortisone 30-50 mg daily or prednisone 20 mg daily). Initiate fludrocortisone (0.05-0.1 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
Signs and symptoms: severe dehydration hypotension/hypotension vasodilatory shock haemodynamic instability severe dehydration decreased consciousness lethargy unexplained hypoglycaemia hyponatremia seizure coma	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
Acute signs and symptoms: dizziness headache nausea anorexia severe fatigue confusion lethargy, and/or low blood pressure	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. 1 mg/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
Signs and symptoms: excessive thirst frequent urination general weakness vomiting confusion abdominal pain dry skin dry mouth increased heart rate fruity breath odour	If T1DM is suspected, treatment should be withheld during work-up for diabetic ketoacidosis (DKA) Patients with new-onset T1DM should be tested for haemoglobin 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

Gastrointestinal toxicity

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: watery diarrhoea or more bowel movements than usual nocturnal bowel movements blood or mucous in stools dark, tarry, sticky stools abdominal pain, cramping, tenderness or urgency systemic symptoms eg fever, hypotension, nausea and vomiting	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 more then 24 hours, or unable to transition to oral steroids 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

Gastrointestinal toxicity

Grade 1

Grade 2

Grade 3 to 4

Signs and symptoms:

watery diarrhoea or more bowel movements than usual
nocturnal bowel movements
blood or mucous in stools
dark, tarry, sticky stools
abdominal pain, cramping, tenderness or urgency
systemic symptoms eg fever, hypotension, nausea and vomiting

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 more then 24 hours, or unable to transition to oral steroids 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

Haematological toxicity

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 x 10⁹/L Hypocellular marrow (marrow cellularity <25%) Platelet count >20,000/mm³ (>20 x 10⁹/L) Reticulocyte count >20,000/mm³ (>20 x 10⁹/L)	Severe Hypocellular marrow <25% and two of the following: ANC <0.5 x 10⁹/L Platelet count <20,000/mm³ (<20 x 10⁹/L) Reticulocyte count <20,000/mm³ (<20 x 10⁹/L)	Very severe ANC <0.2 x 10⁹/L Hypocellular marrow <25% Platelet count <20,000/mm³ (<20 x 10⁹/L) Reticulocyte count <20,000/mm³ (<20 x 10⁹/L)
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/mm³ (0.5 to 1.0 x 10⁹/L) peripheral blood (PB) lymphocyte count	500 to 1,000/mm³ (0.5 to 1.0 x 10⁹/L) PB lymphocyte count	Grade 3: 250 to 499/mm³ (0.25 to 0.499 x 10⁹/L) PB lymphocyte count Grade 4: <250/mm³ (<0.25 x 10⁹/L) 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

Hepatotoxicity

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.
For patients with concomitant diarrhoea or leukopenia, tacrolimus can be considered over MMF. Tacrolimus can be added to MMF in refractory cases. Tacrolimus should only be used after specialist consultation. Renal function should be monitored when tacrolimus is used.^r
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 Monitor INR /PT periodically Evaluate to exclude other causes of hepatic injury, including infections, disease progression or medication Check CPK to rule out myositis	Monitor LFTs more frequently e.g. every 1 to 2 days Monitor INR /PT periodically 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
Management	If Grade 1 hepatitis persists or worsens then consider treatment as for Grade 2	If elevations persist for >3 to 7 days or worsen treat as Grade 3 to 4 If AST or ALT >5 x ULN and/or total bilirubin >3 x ULN treat as Grade 3 to 4	If elevations persist for >1 to 2 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

Musculoskeletal toxicity

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.
Abatacept with ruxolitinib has been used in concomitant myositis and myocarditis cases.^r ^r
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 Commence oral prednisolone 10 to 20 mg/day or equivalent. If no response after 2 weeks increase prednisolone dose to 30 mg/day If no improvement on prednisone 30 mg for 2 weeks, refer to a rheumatologist to consider DMARDs or biologic therapy	Urgent referral to a rheumatologist Commence oral prednisolone 0.5 to 1 mg/kg/day or equivalent
Management	If no response to NSAIDs, consider prednisone 10 to 20 mg daily for 2 to 4 weeks; if not improving or unable to taper prednisone to ≤10 mg/day, consider referring to a rheumatologist to consider disease modifying anti-rheumatic drugs (DMARDs)	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 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 If unable to lower prednisolone to <10 mg/day after 2-4 weeks or no response, addition of TNF inhibitors or IL-6 inhibitors can be considered
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	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, troponin, CMP 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 If no response to corticosteroids, consider re-evaluating for myasthenia gravis and myocarditis, and treat as per Grade 3	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

Neurological toxicity

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) demyelinating diseases (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
Management	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

Ocular toxicity

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: withhold treatment episcleritis: continue treatment	Uveitis/iritis, episcleritis: withhold treatment	Uveitis/iritis: permanently discontinue treatment
Treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4	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
Management	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

Pulmonary toxicity

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

Renal toxicity

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 levels oliguria haematuria or proteinuria Fluid retention causing sudden weight gain, oedema, shortness of breath anorexia dark urine abdominal or pelvic pain nausea or vomiting high blood pressure, and/or change in mental status, such as confusion or drowsiness	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 or obstruction, 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 limit/discontinue nephrotoxic drugs Avoid proton-pump inhibitors (use H2 blockers for gastrointestinal prophylaxis if initiating corticosteroids)	Referral to a nephrologist Administer corticosteroid therapy e.g. oral prednisolone 0.5 to 1 mg/kg/day or equivalent Promote hydration and limit/discontinue nephrotoxic drugs Avoid proton-pump inhibitors (use H2 blockers for gastrointestinal prophylaxis if initiating corticosteroids)	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 Promote hydration and limit/discontinue nephrotoxic drugs Avoid proton-pump inhibitors (use H2 blockers for gastrointestinal prophylaxis if initiating corticosteroids)
Management	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

Skin toxicity

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 new or worsening skin lesions hand-foot syndrome loss of skin pigmentation	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. topical emollients, 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. topical emollients, 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 no improvement after 3 days, consider use of other steroid-sparing agents in discussion with dermatologist
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

Skin toxicity

Grade 1 to 2

Grade 3

Grade 4

Signs and symptoms:

rash
skin blisters
pruritus
new or worsening skin lesions
hand-foot syndrome
loss of skin pigmentation

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. topical emollients, 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. topical emollients, 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 no improvement after 3 days, consider use of other steroid-sparing agents in discussion with dermatologist

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

References References

[%id%]: [%title%]

Read abstract

[%abstract%]
: Bristol-Myers Squibb Pty Ltd. Opdivo (nivolumab) Immune-Mediated Adverse Reactions Management Guide: Amended June 2020.

Read abstract
: Bristol-Myers Squibb Pty Ltd. Opdivo (nivolumab) Product Information. Date of Most Recent Amendment: 15 April 2020

Read abstract
: Bristol-Myers Squibb Pty Ltd. Yervoy (ipilimumab) Product Information. Date of Most Recent Amendment: 7 February 2020.

Read abstract
: Merck Sharp & Dohme (Australia) Pty Ltd. Keytruda (pembrolizumab) Product Information. Date of Most Recent Amendment: 12 June 2020.

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: Common Terminology Criteria for Adverse Events (CTCAE). V5.0: 27 November 2017.

Read abstract
: 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.

Read abstract

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.

Read abstract

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.

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: 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.

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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.

Read abstract

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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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.

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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).

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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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History

Version 5

Date	Summary of changes
19/04/2024	Document reviewed at immunotherapy and skin reference committee meeting on 23/02/2024. Approved for publication with the following changes made: Cardiac, gastrointestinal, hepatic, musculoskeletal, ocular, renal and skin toxicity sections updated to align with current best practice recommendations and NCCN 2024 and ESMO 2022 updates. More detailed symptoms added to different toxicity categories. Version number increased to V.5. Next review in 2 years.
18/06/2024	Neurological conditions/syndromes 'acute inflammatory demyelinating polyneuropathy (AIDP)' updated to 'demyelinating diseases'.
14/08/2024	Units added for platelet count, reticulocyte count and lymphocyte count in haematological toxicity section.

Date

Summary of changes

19/04/2024

Document reviewed at immunotherapy and skin reference committee meeting on 23/02/2024. Approved for publication with the following changes made:

Cardiac, gastrointestinal, hepatic, musculoskeletal, ocular, renal and skin toxicity sections updated to align with current best practice recommendations and NCCN 2024 and ESMO 2022 updates.
More detailed symptoms added to different toxicity categories.

Version number increased to V.5. Next review in 2 years.

18/06/2024

Neurological conditions/syndromes 'acute inflammatory demyelinating polyneuropathy (AIDP)' updated to 'demyelinating diseases'.

14/08/2024

Units added for platelet count, reticulocyte count and lymphocyte count in haematological toxicity section.

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.

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.

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.

This document reflects what is currently regarded as safe practice. While every effort has been made to ensure the accuracy of the content at the time of publication, the Cancer Institute NSW does not accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work. Any reference throughout the document to specific pharmaceuticals and/or medical products as examples does not imply endorsement of any of these products. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information source. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 6 December 2016
Last reviewed:: 19 April 2024
Review due:: 30 June 2026

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1993

11 Oct 2024

Management of immune-related adverse events (irAEs)

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

References References

Bibliography

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