Management of Immune-Related Adverse Events - ASCO Guideline Save

The American Society of Clinical Oncology, Inc (ASCO) has updated its guidelines and recommendations for the management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy.

A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process on evidence published from 2017 through 2021. This included a total of 175 studies meeting eligibility criteria.  Below are select statements from this guideline - please see the full journal citation for full text and complete details.

Key Recommendations

All recommendations in this guideline are consensus based with benefits outweighing harms. The following are general recommendations that should be followed irrespective of affected organ

• Patient and family caregivers should receive up-to-date education about immunotherapies, their mechanism of action, and possible irAEs before initiating therapy
• There should be a high level of suspicion of irAE, as new symptoms may be treatment-related
• In general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities.
• Consider holding ICPis for most grade 2 toxicities and resume when symptoms and/or laboratory values revert ≤ grade 1. Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be administered.
• Hold ICPis for grade 3 toxicities and initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or equivalent). Corticosteroids should be tapered over the course of at least 4-6 weeks. If symptoms do not improve with 48-72 hours of high-dose steroid, infliximab may be offered for some toxicities.
• When symptoms and/or laboratory values revert ≤ grade 1, rechallenging with ICPis may be offered; however, caution is advised, especially in those patients with early-onset irAEs. Dose adjustments are not recommended. Rechallenge with PD-1/PD-L1 monotherapy may be offered in patients with toxicity from combined therapy with a CTLA-4 antagonist once recovered to ≤ grade 1.
• In general, grade 4 toxicities warrant permanent discontinuation of ICPis, except for endocrinopathies that have been controlled by hormone replacement.

Specific Toxicities

• Cutaneous: Immune-related cutaneous AEs may include inflammatory dermatoses, bullous dermatoses, and severe cutaneous adverse reactions (SCARs - including Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis). The median time to onset of skin toxicities is 4 weeks (range: 2 to 150 weeks). Rash or inflammatory irAEs encompass erythema multiforme, lichenoid, eczematous, psoriasiform, morbilliform, and palmoplantar erythrodysesthesia, or hand-foot syndrome. 
• Gastrointestinal: GI toxicities include colitis, hepatitis, gastritis, and enterocolitis. The median time to onset of GI toxicities is 6 weeks (range of 1-107 weeks). Presenting symptoms may include abdominal pain, nausea, diarrhea, blood and mucous in the stool, fever, jaundice, anorexia, RUQ pain, dark urine (tea-colored), bleeding, or bruising.
• Pulmonary: Pneumonitis is best defined computed tomography imaging and symptoms may include new or worsening cough, shortness of breath, increased oxygen requirement, chest pain, and/or fever. The median time to onset of pneumonitis is 34 weeks (range 1.5 to 127 weeks).
• Endocrine: irAE may include primary hypothyroidism, thyrotoxicosis, primary adrenal insufficiency, hypophysitis, and diabetes. The median time to onset of endocrine toxicities is 14.5 weeks (range of 1.5-130 weeks).
• Musculoskeletal: irAEs may include inflammatory arthritis (IA), myositis, and polymyalgia-like syndrome. The median time to onset is 38 weeks (range: 1 to 127 weeks). Improvement of symptoms with NSAIDs or corticosteroids, but not with opioids or other pain medications, may also be suggestive of Inflammatory arthritis. Patients with myositis can also develop myasthenia gravis–like syndrome and/or myocarditis (see cardiovascular and neurologic sections for further details), which can be life-threatening if respiratory muscles or myocardium are involved.
• Renal: irAEs may include nephritis or acute kidney injury (AKI). The median time to onset of renal toxicities is 14 weeks (range 6.5 to 21 weeks). 
• Neurologic: The broad range of neurologic syndromes includes myasthenia gravis or myasthenic syndrome, myasthenia gravis with myositis overlap, aseptic meningitis, encephalitis, Guillain-Barré–like syndrome, peripheral neuropathy, and demyelinating disorders. The median time to onset of nervous system toxicities is 4 weeks (range:1 to 68 weeks. Aseptic meningitis may present with headache, photophobia, neck stiffness, nausea or vomiting, and occasionally fever. Mental status should be normal, in contrast to encephalitis. Encephalitis symptoms may include confusion, altered mental status, altered behavior, headaches, seizures, weakness, and gait instability. Other potentially immune-related demyelinating diseases include multiple sclerosis, transverse myelitis, acute-disseminated encephalomyelitis, optic neuritis, and neuromyelitis optica.
• Hematologic: these may include hemolytic anemia, acquired thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, aplastic anemia, lymphopenia, immune thrombocytopenia (ITP), and acquired hemophilia A. The median time to onset of hematologic toxicities in general is 5.7 weeks (range: from 1 to 84 weeks). 
• Cardiovascular:  CV toxicities from ICPis nat include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism. The median time to onset of cardiovascular toxicities is 6 weeks (range: 2 to 54 weeks).  Presenting symptoms could include progressive fatigue, myalgia or weakness, palpitations, chest pain, presyncope or syncope, shortness of breath, and peripheral edema. Severe cases can present with cardiogenic shock or sudden death. Symptoms can be associated with other irAEs (eg, myositis, pneumonitis, and hypothyroidism) or pulmonary symptoms related to malignancy or comorbid conditions. 
• Ocular: irAEs include uveitis, iritis, and episcleritis. The median onset is 5 weeks (range from 1 to 72 weeks).
• Steroid Use: Steroids are often used in the management of irAEs. Higher steroid doses may be necessary and if prolonged, there may be significant risk for steroid-related toxicities. Prophylactic agents to prevent certain opportunistic infections along with preemptive measures to mitigate various toxicities are necessary for patients needing longer-term steroid use. Use the lowest possible dose of steroids. A multidisciplinary approach may be used in management of certain steroid-related complications and institutional guidelines should be considered in decision making.
• Autoimmune Disease (AD) Patients:  Patients with pre-existing ADs are often not offered therapy with ICPis out of concern for exacerbation of symptoms (also typically excluded from clinical trials). Yet data suggest that they may be safely treated with ICPi therapy. 2016 systematic review of patients with pre-existing ADs treated with ICPis found that only 41% of patients experienced an exacerbation of their pre-existing AD, despite 46% having active disease upon ICPi initiation. In another study of 112 patients with pre-existing ADs, 70 patients (71%) experienced AD and/or other irAE(s), with pre-existing AD flare occurring in 53 patients (47%) and/or other irAE(s) in 47 patients (42%). There was a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICPi in 24 patients (21%). There are two strategies for immunosuppressive use with ICPi: (1) Rotation phase: discontinuation of all nonselective immunosuppressants and replacement with the most appropriate selective immunosuppression and assess for the stability of AD 2-4 weeks before the start of concomitant ICPi treatment, if timing allows based on the pace of cancer growth and urgency of treatment; 2. Maintenance phase: simultaneous selective immunosuppression and ICPis during the entire immunotherapy period.
• Rechallenge: Whether to resume ICPi therapy after resolution of toxicity is challenging, with many factors to consider, such as previous tumor response, duration of treatment, type and severity of the toxicity, time to toxicity resolution, availability of alternate therapies, and patient performance status. In addition, the optimal duration of ICPi therapy is not defined.  A patient's tumor response status is an important factor in deciding whether to resume ICPi. If a patient has achieved an objective response to initial ICPi, there is a reasonable likelihood that the response will be durable and that resumption of therapy (with attendant risk of recurrence of toxicity) may not be advisable. Conversely, for patients who have not yet responded or whose response is deemed inadequate, consideration of resumption of ICPi therapy after resolution of toxicity is reasonable. For some patients with a rapid resolution of certain moderate to severe irAEs after corticosteroid use, resumption of ICPi may be less precarious.

The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read.