What are the guideline sources, guidelines and references for Immune checkpoint inhibitor toxicity ?
Guideline sources The following summarized guidelines for the management of immune checkpoint inhibitor toxicity (ICI) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2022; 2020; 2017), the European Society of Cardiology (ESC/ESTRO/EHA/IC-OS 2022), the American Gastroenterological Association (AGA 2021), the European Association for the Study of the Liver (EASL 2019), and the American Society of Clinical Oncology (ASCO 2018). 1 2 3 4 5 6 7 8 8 8 9 Definition Cancer immunotherapy toxicity is an immune activation and inflammatory response resulting from the use of cancer immunotherapies such as CTLA-4 and PDL-1 inhibitors. 8 Epidemiology Cancer immunotherapy toxicity is caused by therapy-induced activation of the immune system and inflammatory response against the host's healthy tissues. 8 Disease course Clinical manifestations include skin toxicity (dermal hypersensitivity, dermatomyositis, pyoderma gangrenosum, bullous disorders, Stevens-Johnson syndrome/toxic epidermal necrolysis), colitis, hepatitis, endocrinopathies (hyperthyroidism, hypothyroidism, hypophysitis, adrenal insufficiency), pneumonitis, rheumatologic toxicity (polyarthritis, uveitis, sarcoidosis, lupus), neurologic toxicity (myasthenia gravis), renal toxicity (nephritis), ocular toxicity, cardiovascular toxicity (myocarditis, https://web.pathway.md/diseases/recYcyShC1LUv8QBP 1/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway acute cardiovascular collapse), and hematologic toxicity (anemia, myelodysplasia, neutropenia, thrombocytopenia). 8 Prognosis and risk of recurrence Immune-related myocarditis has a mortality rate of approximately 50%. 9 Guidelines 1. Medical management Management of infusion reactions: Discontinue or slow the infusion rate and administer symptomatic treatment in patients with grade 1/2 infusion reactions to atezolizumab, nivolumab, pembrolizumab, or ipilimumab administration. Restart ipilimumab infusion with close monitoring. B Discontinue the infusion and administer aggressive symptomatic treatment in patients with grade 3/4 infusion reactions to atezolizumab, nivolumab, pembrolizumab, or ipilimumab administration. B Management of skin toxicity: evaluate and confirm the relationship between immune checkpoint inhibitor therapy and the skin adverse events, if possible, since the patient is usually on several medications. B Show 3 more Management of gastrointestinal toxicity, evaluation: As per ESMO 2022 guidelines: Perform flexible sigmoidoscopy or colonoscopy and biopsies in patients treated with immune checkpoint inhibitor experiencing grade > 1 diarrhea. B Do not obtain CT to diagnose immune-related enterocolitis. D As per AGA 2021 guidelines, exclude infectious causes of diarrhea before initiating treatment for suspected immune checkpoint inhibitor colitis. B Show 4 more Management of gastrointestinal toxicity, treatment: As per ESMO 2022 guidelines, offer low-fiber diet and loperamide in patients with grade 1 diarrhea or colitis. Consider continuing immune checkpoint inhibitor therapy under close medical supervision. B Show 3 more As per AGA 2021 guidelines, consider initiating high-dose systemic corticosteroids (0.5-2 mg/kg/day of prednisone equivalent, with a taper of 4-6 weeks) in patients with immune checkpoint inhibitor colitis. C Show 3 more Management of hepatotoxicity, evaluation: https://web.pathway.md/diseases/recYcyShC1LUv8QBP 2/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway As per ESMO 2022 guidelines, obtain measurements of serum transaminases, ALP, and bilirubin before every cycle of immune checkpoint inhibitor therapy. B As per AGA 2021 guidelines, obtain baseline liver tests (TBIL, ALP, AST, and ALT) and pretreatment screening for HBV (HBsAg, HBcAb, and HBsAb) in all patients undergoing immune checkpoint inhibitor therapy. Repeat liver tests before each immune checkpoint inhibitor treatment cycle, with management based on the CTCAE version 5 grade. B Show 2 more As per EASL 2019 guidelines, recognize that immune checkpoint inhibitors can induce immune- related hepatotoxicity in a substantial proportion of patients, with CTLA-4 inhibitors (ipilimumab) being more hepatotoxic than PD-L1 agents (nivolumab) and combination treatments carrying greater risk. A Management of hepatotoxicity, treatment: As per ESMO 2022 guidelines, monitor liver enzymes every 1-2 weeks without holding immune checkpoint inhibitor therapy in patients with grade 1 immune-related liver injury. B Show 2 more As per AGA 2021 guidelines, repeat liver monitoring 1-2 times weekly in patients with CTCAE grade 1 hepatitis (AST/ALT 1-3 the ULN or TBIL 1-1.5 the ULN). Hold immune checkpoint inhibitor therapy until resolution to grade 1 in patients with CTCAE grade 2 hepatitis (AST/ALT > 3-5 the ULN or TBIL > 1.5-3 the ULN). Consider administering prednisone 0.5-1.0 mg/kg/day or equivalent in patients with clinical symptoms of liver toxicity. B Show 2 more As per EASL 2019 guidelines, decide on corticosteroid treatment in patients with immune- mediated hepatitis associated with immune checkpoint inhibitors by a multidisciplinary team involving hepatologists if DILI is sufficiently severe based on clinical and histological assessment. B Management of pancreatobiliary toxicity: Excude differential diagnoses of immune-related pancreatic toxicity, including pancreatic metastases and pancreatic injury due to other causes (such as alcohol, hypertriglyceridemia, bile stones or sludge, and drugs other than immune checkpoint inhibitors). Conduct differential diagnosis based on medical history, biochemical analyses, and imaging (ultrasound, CT, MRI, and EUS with biopsies if needed). B Initiate UDCA and prednisone/budesonide in patients with immune-related cholangitis. B Management of pulmonary toxicity: obtain a full clinical work-up, including excluding infectious pneumonia, tumor progression, pulmonary embolism, cardiac events (including HF, myocarditis, acute myocardial infarction, and arrhythmias), and pleural carcinomatosis or effusion, in patients with dyspnea. B Show 6 more Management of endocrine toxicity: initiate HRT (levothyroxine 50-100 g/day) in symptomatic patients with grade > 2 immune-related hypothyroidism and increase the dose over several weeks https://web.pathway.md/diseases/recYcyShC1LUv8QBP 3/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway until TSH levels normalize. Interrupt immune checkpoint inhibitor therapy only if symptoms are severe (grade 3). B Show 4 more Management of renal toxicity: exclude other causes of renal failure in cases of suspected immune-related nephritis. B Show 4 more Management of cardiovascular toxicity, evaluation: As per ESMO 2022 guidelines, admit patients with suspected immune-related myocarditis to level 2 or 3 care with ECG monitoring and resuscitation facilities. B Show 3 more As per IC-OS/ESTRO/EHA/ESC 2022 guidelines, obtain ECG, natriuretic peptides, and cardiac troponin measurements in all patients before initiating immune checkpoint inhibitor therapy. B Show 4 more As per ESMO 2020 guidelines: Obtain further appropriate work-up (ECG, troponin, BNP or N-terminal pro-BNP, CRP, viral titer, echocardiogram with global longitudinal strain, cardiac MRI) for immune checkpoint inhibitor-associated cardiovascular toxicity, particularly myocarditis and other common differential diagnoses, in patients developing new cardiovascular symptoms or with incidentally detected arrhythmia, conduction abnormality on ECG, or LV systolic dysfunction on echocardiogram, while undergoing (or after recent completion) of immune checkpoint inhibitor therapy. B Consider performing an endomyocardial biopsy for diagnostic confirmation if the diagnosis is highly suspected with otherwise negative work-up. C Management of cardiovascular toxicity, treatment: As per ESMO 2022 guidelines, interrupt immune checkpoint inhibitor therapy in patients with immune-related cardiovascular toxicities and discontinue permanently in most cases of confirmed immune-related myocarditis. B Show 6 more As per IC-OS/ESTRO/EHA/ESC 2022 guidelines, obtain cardiac troponin, ECG, and cardiovascular imaging (echocardiography and cardiac MRI) to diagnose immune checkpoint inhibitor-associated myocarditis. B Show 10 more As per ESMO 2020 guidelines, withhold further therapy with immune checkpoint inhibitors and initiate high-dose corticosteroids (methylprednisolone 1,000 mg/day, followed by oral prednisone 1 mg/kg/day) promptly in patients with either suspected or confirmed immune checkpoint inhibitor-associated myocarditis. Continue corticosteroids until resolution of symptoms and normalization of troponin, LV systolic function, and conduction abnormalities. B Show 4 more Management of neurological toxicity: consider referring patients with mild (or more severe) symptoms of Guillaine-Barr syndrome, leukoencephalopathy, myasthenia gravis, myopathy, or https://web.pathway.md/diseases/recYcyShC1LUv8QBP 4/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway peripheral neuropathy to a neurologist. Decide on the type and frequency of assessments according to the grade of symptoms. C Show 4 more Management of hematological toxicity: As per ESMO 2022 guidelines, involve a hematologist early and interrupt immune checkpoint inhibitor therapy in patients with suspected immune-related hematological toxicity. Set a low threshold for obtaining a bone marrow aspirate and trephine to assist in the diagnosis. B Show 3 more As per ASCO 2018 guidelines, obtain the following diagnostic workup for acquired TTP: history with specific questions related to drug exposure (such as chemotherapy, sirolimus, tacrolimus, oxymorphone ER, antibiotics, quinine) physical examination peripheral smear ADAMTS13 activity level and inhibitor titer LDH, haptoglobin, reticulocyte count, bilirubin proTT, aPTT, fibrinogen blood group and antibody screen, direct antiglobulin test CMV serology, viral studies consider obtaining CT, MRI of the brain, echocardiogram, and ECG. Show 6 more Management of rheumatological toxicity: consider referring patients with insufficient response to acceptable doses of corticosteroids and patients requiring corticosteroids-sparing regimens to a rheumatologist early (grade 2 symptoms) before initiating corticosteroids. C Show 7 more Management of ocular toxicity: involve an ophthalmologist for both the diagnosis and treatment of patients with suspected immune-related ocular toxicity. B 2. Preventative measures Prevention of infusion reactions: Consider administering premedication with antipyretics and antihistamines before nivolumab, pembrolizumab, and ipilimumab infusion. Consider observing patients for a short period after ipilimumab infusion. C Do not administer premedication before atezolizumab infusion. D References 1. Michael Dougan, Yinghong Wang, Alberto Rubio-Tapia et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. https://web.pathway.md/diseases/recYcyShC1LUv8QBP 5/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway 2021 Mar;160 4 1384 1393. Open 2. G Curigliano, D Lenihan, M Fradley et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020 Feb;31 2 171 190. Open 3. J Haanen, M Obeid, L Spain et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Dec;33 12 1217 1238. Open 4. Alexander R Lyon, Teresa L pez-Fern ndez, Liam S Couch et al. 2022 ESC Guidelines on cardio- oncology developed in collaboration with the European Hematology Association EHA , the European Society for Therapeutic Radiology and Oncology ESTRO and the International Cardio-Oncology Society IC OS . Eur Heart J Cardiovasc Imaging. 2022 Sep 10;23 10):e333-e465. Open 5. S Rosell , I Blasco, L Garc a Fabregat et al. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017 Jul 1;28(suppl_4):iv100-iv118. Open 6. Julie R Brahmer, Christina Lacchetti, Bryan J Schneider et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018 Jun 10;36 17 1714 1768. Open 7. European Association for the Study of the Liver, Clinical Practice Guideline Panel: Chair, Panel members et al. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019 Jun;70 6 1222 1261. Open 8. Lucy Boyce Kennedy, April K S Salama. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020 Mar;70 2 86 104.2020 Mar;70 2 86 104. Open 9. K. Esfahani, L. Roudaia, N. Buhlaiga et al. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol. 2020 Apr; 27 Suppl 2 S87 S97. Open 10. Haanen JBAG, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv119-iv142. Open 11. Bryan J Schneider, Jarushka Naidoo, Bianca D Santomasso et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021 Dec 20;39 36 4073 4126. Open 12. Lucy Boyce Kennedy, April K S Salama. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020 Mar;70 2 86 104. Open 13. A. Kartolo, J. Sattar, V. Sahai et al. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol. 2018 Oct; 25 5 e403 e410. Open 14. K Esfahani, L Roudaia, N Buhlaiga et al. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol. 2020 Apr;27 Suppl 2 S87 S97.2020 Apr;27 Suppl 2 S87 S97. Open 15. Bianca D Santomasso, Loretta J Nastoupil, Sherry Adkins et al. Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. J Clin Oncol. 2021 Dec 10;39 35 3978 3992. Open 16. C E Higham, A Olsson-Brown, P Carroll et al. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE Acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr Connect. 2018 Jul;7 7 G1 G7. Open https://web.pathway.md/diseases/recYcyShC1LUv8QBP 6/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway 17. Julie R Brahmer, Hamzah Abu-Sbeih, Paolo Antonio Ascierto et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021 Jun;9 6):e002435. Open 18. F Castinetti, F Albarel, F Archambeaud et al. French Endocrine Society Guidance on endocrine side effects of immunotherapy. Endocr Relat Cancer. 2019 Feb;26 2 G1 G18. Open https://web.pathway.md/diseases/recYcyShC1LUv8QBP 7/7