Immunotherapy and immune-related adverse events
Recognition is the first step to successful treatment
Recommended management of ir-AEs
Organ-specific recommendations for ir-AEs
Grading | Management | |
---|---|---|
1. Skin toxicities
|
According to CTCAE is a challenge for skin. Severity is based on BSA, tolerability, morbidity and duration
| |
1.1. Rash/inflammatory dermatitis
Erythema multiforme minor, lichenoid, eczematous
| G3: as G2 but with failure to respond to indicated interventions for G2 dermatitis | Holding ICI & weekly monitoring and treat with topical emollients, antihistamines & high-potency topical corticosteroids + initiate 1–2 mg/kg corticosteroida + tapering over at least 4 weeks |
G4: all severe rashes unmanageable with prior interventions | Systemic corticosteroids IV a 1–2 mg/kg with slow tapering when toxicity resolves. Consult with dermatology. Consider alternative antineoplastic therapy, if ICIs are the patient’s only option, consider restarting once these adverse effects have resolved to a G1 level | |
1.2. Bullous dermatoses
including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction
| G3: skin sloughing covering >30% BSA with associated pain and limiting self-care ADL | Hold ICI & consult with dermatology; administer IV corticosteroidsa 1–2 mg/kg, tapering over at least 4 weeks, if bullous pemphigoid is diagnosed, it may be possible to avoid long term use of systemic corticosteroids and start with rituximab as an alternative approach to treat ir-AEs. Seek infectious disease consultation if patient have secondary cellulitis or other infection risk factors like neutropenia etc. |
G4: blisters covering >30% BSA with associated fluid or electrolyte abnormalities | Permanently discontinue ICIs, place patient under supervision of a dermatologist, administer IV corticosteroidsa 1–2 mg/kg & treat with rituximab as an alternative approach + seek infectious disease consultation if patient have secondary cellulitis or other infection risk factors like neutropenia etc. | |
1.3. SCARs (including SJS, TEN, acute generalized exanthematous pustulosis, DRESS/DIHS)
severe changes in either structure or function of skin, the appendages or the mucous membranes due to a drug
| G3: skin sloughing covering <10% BSA with mucosal involvement associated signs (e.g., erythema, purpura, epidermal detachment, mucous membrane detachment) | Hold ICI & consult with dermatology; treat skin with topical emollients & other petrolatum emollients; administer IV corticosteroidsa 0.5-1 mg/kg & convert to oral on response, wean over at least 4 weeks; add additional immunosuppressive agent (cyclosporine) in corticosteroid unresponsive cases |
G4:skin erythema & blistering/ sloughing covering ≥10 to >30% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, mucous membrane detachment) and/or systemic symptoms and concerning associated blood work abnormalities (e.g., liver function test elevations in the setting of DRESS/DIHS) | Permanently discontinue ICIs; admit patient immediately to a burn unit or ICU with consulted dermatology & wound care services. Initiate IV corticosteroidsa 1–2 mg/kg and tapering when toxicity resolves to normal; IVIG or cyclosporine may also be considered in corticosteroid unresponsive cases | |
Additional considerations: the usual prohibition of corticosteroids for SJS is not relevant here, as the underlying mechanism is a T-cell immunodirected toxicity. Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of DRESS/DIHS
| ||
2. Enterocolitis
|
Work up of blood; testing of lactoferrin (to determine who needs more urgent endoscopy) & calprotectin (to follow-up on disease activity); screening laboratories (HIV
, hepatitis A & B, blood quantiferon for tuberculosis) to prepare patients for infliximab treatment & should be routinely determined in patients at high risk; imaging (e.g., CT scan of abdomen & pelvis & GI endoscopy with biopsy) for early detection of ulceration in the colon that can predict a corticosteroid-refractory course that may require early infliximab treatment
| |
G3: increase of 7 or more stools per day over baseline, incontinence, hospitalization indicated, severe increase in ostomy output compared with baseline, limited self-care ADL | Consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to G1 or less., administer corticosteroidsa 1–2 mg/kg; if symptoms persist ≥3–5 days or recur after improvement, consider administering IV corticosteroidsa or infliximab; consider colonoscopy in cases where patients have been on immunosuppression & may be at risk for opportunistic infections (i.e., CMV colitis) & for those who are anti-TNF or corticosteroid refractory | |
G4: life-threatening situation; urgent intervention indicated | Permanently discontinue treatment; administer 1–2 mg/kg corticosteroidsa until symptoms improve to G1 & then start taper over 4–6 weeks; if symptoms are refractory to corticosteroids administer infliximab 5–10 mg/kg within 2–3 days. If there is concern of new infection or symptoms remain refractory to treatment consider lower GI endoscopy and consider vedolizumab in patients refractory to infliximab and/or contraindicated to TNF-alpha blockade.b | |
3. Hepatitis
| G3: symptomatic liver dysfunction, fibrosis by biopsy, compensated cirrhosis, reactivation of chronic hepatitis (AST or ALT 5–20 × ULN and/or total bilirubin 3–10 × ULN) | Permanently discontinue ICIs, immediately start corticosteroida 1–2 mg/kg; if no improvement assessed after 3 days or if corticosteroid refractory, consider mycophenolate mofetil or azathioprine, daily laboratories & close monitoring for patients with AST/ALT > 8 × ULN and or elevated TB 3 × ULN (infliximab should not be used—potential risk of liver failure); corticosteroid taper can be attempted around 4–6 weeks; re-escalate if needed, optimal duration is unclear |
G4: decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma; AST or ALT > 20 × ULN and/or total bilirubin >10 ULN) | Permanently discontinue ICIs, immediately start corticosteroida 2 mg/kg, if no improvement assessed after 3 days or if corticosteroid refractory the same management as in the case of G3 | |
4. Pneumonitis
focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging)
| G3: severe symptoms, hospitalization required, involves all lung lobes or >50% of lung parenchyma, limiting self-care ADL, oxygen indicated | Permanently discontinue ICI, empirical antibiotics; administer corticosteroida 1–2 mg/kg, no improvement after 48 h, add infliximab 5 mg/kg or mycophenolate mofetil IV 1 g twice a day or IVIG for 5 days or cyclophosphamide; taper corticosteroids over 4–6 weeks. Pulmonary & infectious disease consults if necessary, BAL ± transbronchial biopsy offered |
G4: life threatening respiratory compromise, urgent intervention indicated (intubation) | ||
5. Endocrinopathies
| ||
5.1. Primary hypothyroidism
| G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL | Hold ICI until symptoms resolve to baseline with appropriate supplementation; endocrine consultation, add IV therapy if signs of myxedema (bradycardia, hypothermia); thyroid supplementation and reassessment as in G2 |
5.2. Hyperthyroidism
| G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL | Hold ICIs until symptoms resolve to baseline, endocrine consultation, beta blocker for symptomatic relief, for severe symptoms administer corticosteroidsa 1–2 mg/kg and taper over 1–2 weeks & consider also use of SSKI or thionamide (methimazole or PTU) |
5.3. Primary adrenal insufficiency
| G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL | Hold ICIs until patient is stable on replacement hormone, endocrine consultation, IV stress dose corticosteroids on presentation (hydrocortisone 100 mg or dexamethasone 4 mg—if diagnosis is not clear & stimulation testing will be needed). Taper stress dose corticosteroids down to maintenance doses over 7–14 days after discharge, continue maintenance therapy as in G1 and titrate down as symptoms dictate |
5.4. Hypophysitis
Low ACTH with low cortisol; low or normal TSH with a low FT4; hypernatremia and volume depletion with diabetes insipidus; low testosterone or estradiol with low LH & FSH
| Consider MRI of the brain with or without contrast with pituitary/sellar cuts in patients with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes | |
G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL | Hold ICIs until patient is stable on replacement hormone; hormonal replacement as in G1; consider initial pulse therapy with corticosteroida 1–2 mg/kg oral daily with subsequent tapering over at least 1–2 weeks | |
5.5. Diabetes
T1DM (autoimmune) results from islet destruction and is often acute onset, with ketosis and an insulin requirement
| G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL G3: >250–500 mg/dl | Hold ICIs until glucose control is obtained on therapy with reduction of toxicity to G1 or less, urgent endocrine consultation for all patients, admit for inpatient management: possibility of developing DKA |
G4: >500 mg/dl | ||
6. Nervous system toxicities
| ||
6.1. Myastenia gravis
| G3–4: limiting self-care and aids warranted, weakness limiting walking, any dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms | Permanently discontinue ICIs; admit patient, may need ICU level monitoring, neurology consult, continue corticosteroidsa 1–2 mg/kg and initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) or plasmapheresis for 5 days, frequent pulmonary function assessment, daily neurologic review. Pyridostigmine starting at 30 mg orally three times a day and gradually increase based on symptoms |
6.2. Guillain-Barré syndrome
Corticosteroids are usually not recommended for idiopathic Guillain-Barré syndrome, however, in ICIs related forms a treatment is reasonable
| G3–4: severe, limiting self-care and aids warranted, weakness limiting walking, any dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms | Rapid transfer to ICU-level monitoring, start IVIG (0.4 g/kg/day for 5 days) or plasmapheresis; administer corticosteroidsa 2–4 mg/kg/day followed by slow taper, frequent pulmonary function assessment, daily neurologic review; nonopioid management of neuropathic pain |
6.3. Peripheral neuropathy
| G3–4: severe, limiting self-care and aids warranted, weakness limiting walking; severe may be Guillain-Barré syndrome | Proceed as per Guillain-Barré syndrome |
6.4. Autonomic neuropathy
| G3–4: severe limiting self-care and aids warranted | Permanently discontinue ICIs; admit patient; initiate corticosteroida 1 g daily for 3 days followed by taper, neurologic consultation |
6.5. Aseptic meningitis
| G3–4: severe, limiting self-care and aids warranted | Hold ICI and discuss resumption with patient only after taking into account the risks and benefits. Consider empirical antiviral (IV acyclovir) and antibacterial therapy until CSF results—once bacterial & viral infection are negative, may closely monitor off corticosteroidsa or consider oral corticosteroidsa 0.5 –1 mg/kg/day if moderate/severe symptoms |
6.6. Encephalitis
| G3–4: severe, limiting self-care and aids warranted | Proceed as per aseptic meningitis, consider administration of corticosteroida 1–2 mg/kg if severe: pulse corticosteroida 1 g IV for 3–5 days plus IVIG 2 g/kg over 5 days; if positive for autoimmune encephalopathy antibody and limited or no improvement, consider rituximab or plasmapheresis in consultation with neurology |
6.7. Transverse myelitis
| G3–4: severe, limiting self-care and aids warranted | Permanently discontinue ICIs; administer corticosteroida 2 mg/kg; strongly consider higher doses of 2 g/day for 3–5 days; strongly consider IVIG |
7. Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis
| G3: moderately abnormal testing or symptoms with mild activity | Hold ICIs and permanently discontinue after G1 |
G4: moderate or severe decompensation; IV medication or intervention required, life-threatening conditions | High dose corticosteroidsa 1–2 mg/kg initiated rapidly (oral or IV depending on symptoms), admit patient, cardiology consultation; in patients without immediate response to high dose corticosteroidsa, increase to 1 g every day of corticosteroids and consider the addition of either mycophenolate, infliximab or antithymocyte globulin | |
Statement: Holding of checkpoint inhibitor therapies recommended for all grades of cardiovascular complications
| ||
8. Nephritis
| G3: creatinine > 3 × baseline or > 4.0 mg/dl; hospitalization indicated | Permanently discontinue ICIs; administer corticosteroidsa 0.5–1 mg/kg, if worsening or no improvement increase to 1–2 mg/kg/day and taper over 4–6 weeks |
G4: life threatening consequences; dialysis indicated | Consult nephrology, evaluate for other causes; administer corticosteroidsa 1–2 mg/kg/day |