Immune Checkpoint Inhibitor-Related Adverse Events

Publication Date: February 24, 2023
Last Updated: July 18, 2024

General panel recommendations

  • Patients should receive dedicated education on irAEs by a medical professional and may receive additional materials such as informational booklets or reference cards.

  • Patients should be encouraged to use contraception while receiving immunotherapy. Fertility should be discussed prior to treatment.

  • The following tests should be performed prior to beginning ICI therapy: complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), free thyroxine (fT4). Urinalysis should be considered to evaluate for baseline kidney disease.

  • Consider performing a baseline electrocardiogram (EKG) on patients deemed at a higher risk for myocarditis (eg, cardiac comorbidities, diabetes mellitus, anti-PD-(L)1 with anti-CTLA-4 ICI combination therapy, etc). Baseline troponin testing may also be considered to provide information for evaluating potential future cardiac toxicity.

  • When beginning corticosteroid therapy, patients should be specifically counseled about potential toxicities, including hyperglycemia, mood disturbances, insomnia, gastritis, weight gain, and opportunistic infections (eg, Pneumocystis pneumonia) (LE: 140 41).

  • CBC with differential, CMP, TSH, and fT4 tests should be performed intermittently throughout the course of treatment in patients receiving ICI therapy.

  • Patients should be referred to a specialist when they experience toxicities of grade ≥3, if toxicities of any grade do not respond to steroid treatment, if toxicities require hospitalization or for selected lower-grade toxicities in which diagnosis or management advice is needed, such as neurological and rheumatological toxicities (eg, inflammatory arthritis not interfering with instrumental activities of daily living, mild pain with erythema, or joint swelling).

  • Diagnostic evaluation for all irAEs should attempt to rule out other possible etiologies (eg, diarrhea/colitis associated with Clostridium difficile infection), but treatment for irAEs should be initiated as is deemed clinically appropriate.

  • For patients with life-threatening autoimmune disorders, the decision to initiate ICI therapy should only be considered after a careful risk-benefit discussion between patient and provider, and consideration of alternative therapies. Consideration should include risks of autoimmune flares against the survival benefits of ICI therapies, especially in cancers with high expected rates of durable responses (LE: 112).

  • Patients with a history of non-life-threatening autoimmune disease should only receive ICIs after counseling on the possibility of exacerbation or flare-ups. These patients should be monitored closely for exacerbations of their existing autoimmunity while being treated with ICIs, and concurrent monitoring and treatment by an appropriate specialist should be considered (LE: 112).

  • Unless otherwise specified, patients experiencing grade 1 irAEs should be monitored for worsening symptoms, but may continue ICI therapy.

  • Unless otherwise specified, patients experiencing grade 2 irAEs should have ICI therapy temporarily withheld and be treated with corticosteroids depending on the toxicity in question.

  • The decision to re-challenge patients with ICIs may be complex. Factors that may cause clinicians to lean away from re-challenge include severe or life-threatening irAEs, requirement for prolonged or multiple immunosuppressants, and a history of long-term ICI therapy and/or patients with complete responses or prolonged clinical benefit.

  • Unless otherwise specified, patients who have experienced grade 2 irAEs may be re-challenged with ICI therapy if their signs and symptoms have resolved or are controlled with ≤10 mg of prednisone (or equivalent) per day (LE: 344 45).

  • The decision to re-challenge a patient who has experienced grade 3 or 4 irAEs should be risk-adjusted based on anticipated benefit with therapy versus the potential for toxicity (LE: 344 45).

  • Patients experiencing any grade of myositis, myocarditis, or neurological symptoms (such as myasthenia gravis):

    1. Should be referred to a specialist.

    2. Should be tested with a shared set of diagnostics, due to the possibility of overlapping symptoms and high risk to the patient.

    3. Should have testing including erythrocyte sedimentation rate (ESR), C reactive protein (CRP), creatine kinase (CK), antibody tests (acetylcholine, muscle-specific kinase (MusK), striational), aldolase, troponin, EKG, nerve conduction, and electromyography (EMG).

    4. Should receive frequent pulmonary assessment in addition to typical irAE treatment (ie, corticosteroids).

GI toxicity panel recommendations

Nausea

  • Patients who develop ICI-related nausea and vomiting of grade ≥2 should receive antiemetics (LE: 150 51). If no response to these therapies is observed within 5–7 days, esophagogastroduodenoscopy should be considered. Corticosteroids are not recommended for ICI-related nausea and vomiting.

Diarrhea and colitis

  • Diagnostic workup for grade 1 diarrhea or colitis symptoms should include CBC, CMP, and fecal lactoferrin.

  • Additional workup should be performed for patients with diarrhea or colitis symptoms of grade ≥2, and these additional tests should include fecal calprotectin, and stool infectious analysis (stool ova and parasite, C. difficile and cytomegalovirus (CMV) testing via polymerase chain reaction (PCR) if available or if high index of suspicion is present, among other infectious studies (eg, COVID-19)). Serum TSH and celiac serologies (antitransglutaminase antibodies with total IgA level) may also be considered, if clinical suspicion of ICI-induced celiac disease is present.

  • Abdominal CT scan should be obtained in patients with signs and symptoms of colitis complications, such as bowel perforation or toxic megacolon. Flexible sigmoidoscopy and/or colonoscopy with biopsy should be performed for patients with diarrhea or colitis symptoms of grade ≥3 or with persistent (≥5 days) diarrhea or colitis symptoms of grade 2 (LE: 472–74).

  • ICIs may be temporarily withheld (instead of discontinued) in patients experiencing grade ≥3 diarrhea or colitis symptoms. These patients may be re-challenged with ICIs if their symptoms are stable (grade ≤1 or baseline) with <10 mg/day of prednisone (or equivalent) (LE: 463).

  • Close monitoring for recurrence of diarrhea or colitis symptoms is recommended after re-challenging patients with ICI therapy.

  • Corticosteroids should be started in patients experiencing diarrhea or colitis symptoms of grade ≥2. The initial dose of prednisone should be 1 mg/kg/day (or equivalent) for grade 2 diarrhea or colitis and 1–2 mg/kg/day for grades 3 and 4. Grade 4 diarrhea or colitis should initially be treated with IV corticosteroids. Corticosteroids should be tapered within 4 weeks after improvement of diarrhea or colitis symptoms to grade ≤1 (LE: 161).

  • Prior to administration of infliximab or vedolizumab, patients should be tested for HBV, HIV, and TB. Administration of infliximab or vedolizumab should not be delayed if test results are pending.

  • If diarrhea or colitis symptoms do not respond to corticosteroid therapy within 3–5 days, if diarrhea or colitis symptoms recur after tapering corticosteroids, or if there is severe ulcerative presentation on colonoscopy, 3 doses of infliximab (5 mg/kg) should be administered at 0, 2, and 6 weeks (LE: 165) to reduce the risk of colitis recurrence.

  • If diarrhea or colitis symptoms persist after the second dose of infliximab treatment, the third dose should be held and 3 doses of vedolizumab (300 mg) should be administered at 0, 2, and 6 weeks (LE: 197).

  • If no clinical improvement is observed following immunosuppressive therapy in patients with grade ≥3 diarrhea or colitis, a repeat endoscopy with infectious workup (C. difficile and CMV) should be performed. Repeat endoscopy should be performed prior to resuming ICI therapy.

  • If diarrhea or colitis symptoms recur following corticosteroid taper, they should be evaluated and treated in the same manner as the first episode.

Hepatitis

  • Liver biochemical tests (aka liver function tests (LFTs)) should be checked prior to each ICI infusion. Diagnostic workup for grade ≥2 liver toxicity should include ALT, AST, alkaline phosphatase, prothrombin time/international normalized ratio (PT/INR) serum bilirubin, iron studies, autoimmune hepatitis panel (antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), antimitochondrial antibody (AMA), peripheral ANCA (p-ANCA), and antismooth muscle antibody (ASMA)), and viral hepatitis panel.

  • For patients experiencing liver toxicity of grade ≥3, abdominal imaging (eg, CT, magnetic resonance imaging (MRI), etc) should be considered if the patient has pre-existing liver disease or if there is concern of disease progression/liver metastases.

  • LFTs should be rechecked weekly for patients experiencing grade 1–2 liver toxicities, and should be rechecked every 1–2 days for patients with liver toxicities of grade ≥3.

  • Corticosteroids should be administered to patients experiencing liver toxicity of grade ≥2. Grade 2 liver toxicity should be treated initially with prednisone 0.5–1 mg/kg/day (or equivalent), and grades 3 and 4 should be treated initially with methylprednisolone 1–2 mg/kg/day (or equivalent). Corticosteroids should be tapered over a period of 4–6 weeks after LFTs revert to grade ≤1 (LE: 186).

  • If ALT or AST results do not improve to grade ≤1 within 10–14 days of corticosteroid initiation, or if liver toxicity recurs after steroid taper, mycophenolate mofetil (1–2 g divided two times per day) may be given (LE: 498). Infliximab should not be used in patients with liver toxicity, given the risk for hepatotoxicity (LE: 186 99). Other agents that could be considered include tacrolimus and antithymocyte globulin (ATG).

  • If ALT or AST results do not improve to grade ≤1 within 10–14 days of administration of mycophenolate mofetil, liver biopsy should be considered and possible CMV infection should be ruled out by PCR, if available.

Cholecystitis and cholangitis

  • Patients who develop ICI-related acute cholecystitis or cholangitis should not receive steroids and should instead receive typical treatments for these diseases. Diagnosis of these conditions should result in a patient being referred to a GI specialist and/or surgeon.

Pancreatitis

  • In patients with clinical symptoms of pancreatitis, workup for acute pancreatitis should include amylase, lipase, CBC, CMP, triglycerides, and abdominal CT scan. ICI therapy should be held if acute pancreatitis is confirmed until resolution of symptoms and CT findings.

  • Patients with persistent (>4 weeks) or recurrent symptoms of acute pancreatitis should receive repeat abdominal CT with contrast to evaluate for possible consequences of acute pancreatitis. These patients should also be evaluated for non-pancreatic etiologies of lipase or amylase elevation.

  • Patients with elevated lipase or amylase but no other symptoms of acute pancreatitis should be monitored closely for the development of acute pancreatitis but should continue on immunotherapy.

  • Prednisone (0.5–1 mg/kg/day) or equivalent may be considered in patients with acute pancreatitis if no improvement of symptoms occurs within 3–5 days of supportive treatment (IV fluids and analgesics). These patients should also be referred to a GI specialist.

Overview

Title

Immune Checkpoint Inhibitor-Related Adverse Events

Authoring Organization

Society for Immunotherapy of Cancer