Immune Checkpoint Inhibitor–Related Hepatitis: Evaluation, Management, and Rechallenge

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Initiate a gradual corticosteroid taper only in patients who actually received systemic corticosteroids and have demonstrated sustained clinical and biochemical improvement. The taper should be individualized according to initial hepatitis severity, duration of treatment, current liver biochemical tests, and risk of recurrence. Before starting the taper Confirm: Improvement of AST and ALT to Grade 1 or baseline, or an appropriate specialist-defined threshold. Improvement or stabilization of bilirubin. No new evidence of hepatic synthetic dysfunction. Clinical stability. Resolution or improvement of relevant hepatic symptoms. No unresolved competing cause requiring further management. Corticosteroid taper Gradually reduce the prescribed corticosteroid dose over approximately 4–6 weeks or longer when clinically indicated. Patients with severe, prolonged, or recurrent hepatitis may require a more extended taper. There is no universally appropriate fixed dose-reduction schedule. Document the corticosteroid agent, current daily dose, planned dose reductions, and dates for reassessment. Biochemical monitoring Monitor: AST and ALT. ALP and GGT when relevant. Total and direct bilirubin. INR when clinically indicated. Trends relative to baseline. New symptoms or evidence of recurrent hepatic injury. Arrange frequent laboratory monitoring during tapering, especially in patients recovering from Grade 3–4 disease. Continue monitoring after corticosteroid discontinuation because hepatitis can recur. Corticosteroid safety Assess: Hyperglycemia and hypertension. Infection risk. Mood, sleep, and neuropsychiatric symptoms. Muscle weakness and bone health. Gastrointestinal and metabolic complications. Need for Pneumocystis jirovecii pneumonia prophylaxis during prolonged high-dose therapy according to institutional guidance. Avoid abrupt corticosteroid discontinuation after prolonged exposure. Recurrence during taper If liver tests rise again: Reassess biochemical grade and clinical severity. Evaluate adherence and recent changes in corticosteroid dose. Reconsider infection, hepatotoxic drugs, tumor progression, and other liver disorders. Pause further tapering pending evaluation. Consider corticosteroid re-escalation or specialist-directed additional immunosuppression when clinically indicated. Do not automatically label every biochemical rebound as steroid-refractory hepatitis. Continued improvement After sustained recovery, proceed to "Confirm biochemical and clinical recovery". ICI resumption or permanent discontinuation must be determined separately according to previous toxicity severity, current treatment status, guideline recommendations, and product labeling. Important distinction Patients whose hepatitis improved without corticosteroid treatment require continued biochemical follow-up, not a corticosteroid taper.

Continue active hepatology-directed management in patients with persistent, worsening, or steroid-refractory suspected ICI-related hepatitis. This pathway represents ongoing treatment and diagnostic reassessment, not observation alone or automatic progression to recovery. Confirm inadequate treatment response Review: Initial hepatitis grade and clinical severity. Current AST, ALT, ALP, GGT, and bilirubin. PT/INR and evidence of impaired hepatic synthetic function. Corticosteroid agent, dose, route, and treatment duration. Actual treatment exposure and adherence. Biochemical trajectory after treatment initiation. Presence of jaundice, encephalopathy, coagulopathy, or other clinical deterioration. Patients with suspected acute liver failure require immediate specialized care regardless of the duration of corticosteroid treatment. Reassess competing diagnoses Consider: Viral hepatitis or viral reactivation. CMV, HSV, or other opportunistic infections when clinically relevant. Other hepatotoxic medications and supplements. Hepatic metastases or malignant infiltration. Ischemic or vascular liver injury. Biliary obstruction or immune-mediated cholangitis. Underlying autoimmune or metabolic liver disease. Repeat liver imaging when indicated. Consider liver biopsy, particularly in atypical presentations, persistent steroid nonresponse, or before further immunosuppressive escalation when the diagnosis remains uncertain. Biopsy must be performed only when clinically appropriate and safe. Second-line immunosuppression For severe immune-mediated hepatitis without adequate improvement after approximately 3–5 days of appropriate systemic corticosteroid treatment, consider specialist-directed second-line immunosuppression. Earlier escalation may be needed if hepatic function deteriorates. Mycophenolate mofetil (MMF) is commonly used as the preferred second-line agent. A commonly used starting regimen is 500–1,000 mg orally twice daily, with specialist-directed adjustment according to response, tolerance, and institutional guidance. Selected patients may require titration up to 1,500 mg twice daily under specialist supervision. MMF dosing is individualized and is not a mandatory fixed-dose sequence. Monitoring during MMF treatment Monitor: AST, ALT, ALP, and bilirubin. PT/INR when clinically indicated. Complete blood count for cytopenias. Renal function and medication tolerance. Infectious complications. Biochemical response and corticosteroid requirements. Coordinate the frequency of monitoring with hepatology according to severity. If response remains inadequate Reassess the diagnosis and consider liver biopsy if not previously performed. Evaluate the possibility of concomitant infection, cholangitic injury, or another liver disorder. Additional treatment options, such as tacrolimus, may be considered in selected refractory cases under expert hepatology supervision. There is no universally established third-line treatment sequence. Critical safety messages Do not use infliximab for immune-mediated hepatitis. Do not continue escalating immunosuppression without reassessing the diagnosis and infectious risk. Do not route patients with persistent severe hepatitis or worsening hepatic synthetic function directly to clinical recovery. When improvement occurs Continue treatment and appropriate biochemical monitoring. If corticosteroids were administered, begin or continue a gradual individualized taper once liver tests have improved sufficiently. Proceed to biochemical and clinical recovery assessment only after documented improvement or resolution.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Initiate a gradual corticosteroid taper only in patients who actually received systemic corticosteroids and have demonstrated sustained clinical and biochemical improvement. The taper should be individualized according to initial hepatitis severity, duration of treatment, current liver biochemical tests, and risk of recurrence. Before starting the taper Confirm: Improvement of AST and ALT to Grade 1 or baseline, or an appropriate specialist-defined threshold. Improvement or stabilization of bilirubin. No new evidence of hepatic synthetic dysfunction. Clinical stability. Resolution or improvement of relevant hepatic symptoms. No unresolved competing cause requiring further management. Corticosteroid taper Gradually reduce the prescribed corticosteroid dose over approximately 4–6 weeks or longer when clinically indicated. Patients with severe, prolonged, or recurrent hepatitis may require a more extended taper. There is no universally appropriate fixed dose-reduction schedule. Document the corticosteroid agent, current daily dose, planned dose reductions, and dates for reassessment. Biochemical monitoring Monitor: AST and ALT. ALP and GGT when relevant. Total and direct bilirubin. INR when clinically indicated. Trends relative to baseline. New symptoms or evidence of recurrent hepatic injury. Arrange frequent laboratory monitoring during tapering, especially in patients recovering from Grade 3–4 disease. Continue monitoring after corticosteroid discontinuation because hepatitis can recur. Corticosteroid safety Assess: Hyperglycemia and hypertension. Infection risk. Mood, sleep, and neuropsychiatric symptoms. Muscle weakness and bone health. Gastrointestinal and metabolic complications. Need for Pneumocystis jirovecii pneumonia prophylaxis during prolonged high-dose therapy according to institutional guidance. Avoid abrupt corticosteroid discontinuation after prolonged exposure. Recurrence during taper If liver tests rise again: Reassess biochemical grade and clinical severity. Evaluate adherence and recent changes in corticosteroid dose. Reconsider infection, hepatotoxic drugs, tumor progression, and other liver disorders. Pause further tapering pending evaluation. Consider corticosteroid re-escalation or specialist-directed additional immunosuppression when clinically indicated. Do not automatically label every biochemical rebound as steroid-refractory hepatitis. Continued improvement After sustained recovery, proceed to "Confirm biochemical and clinical recovery". ICI resumption or permanent discontinuation must be determined separately according to previous toxicity severity, current treatment status, guideline recommendations, and product labeling. Important distinction Patients whose hepatitis improved without corticosteroid treatment require continued biochemical follow-up, not a corticosteroid taper.

Continue active hepatology-directed management in patients with persistent, worsening, or steroid-refractory suspected ICI-related hepatitis. This pathway represents ongoing treatment and diagnostic reassessment, not observation alone or automatic progression to recovery. Confirm inadequate treatment response Review: Initial hepatitis grade and clinical severity. Current AST, ALT, ALP, GGT, and bilirubin. PT/INR and evidence of impaired hepatic synthetic function. Corticosteroid agent, dose, route, and treatment duration. Actual treatment exposure and adherence. Biochemical trajectory after treatment initiation. Presence of jaundice, encephalopathy, coagulopathy, or other clinical deterioration. Patients with suspected acute liver failure require immediate specialized care regardless of the duration of corticosteroid treatment. Reassess competing diagnoses Consider: Viral hepatitis or viral reactivation. CMV, HSV, or other opportunistic infections when clinically relevant. Other hepatotoxic medications and supplements. Hepatic metastases or malignant infiltration. Ischemic or vascular liver injury. Biliary obstruction or immune-mediated cholangitis. Underlying autoimmune or metabolic liver disease. Repeat liver imaging when indicated. Consider liver biopsy, particularly in atypical presentations, persistent steroid nonresponse, or before further immunosuppressive escalation when the diagnosis remains uncertain. Biopsy must be performed only when clinically appropriate and safe. Second-line immunosuppression For severe immune-mediated hepatitis without adequate improvement after approximately 3–5 days of appropriate systemic corticosteroid treatment, consider specialist-directed second-line immunosuppression. Earlier escalation may be needed if hepatic function deteriorates. Mycophenolate mofetil (MMF) is commonly used as the preferred second-line agent. A commonly used starting regimen is 500–1,000 mg orally twice daily, with specialist-directed adjustment according to response, tolerance, and institutional guidance. Selected patients may require titration up to 1,500 mg twice daily under specialist supervision. MMF dosing is individualized and is not a mandatory fixed-dose sequence. Monitoring during MMF treatment Monitor: AST, ALT, ALP, and bilirubin. PT/INR when clinically indicated. Complete blood count for cytopenias. Renal function and medication tolerance. Infectious complications. Biochemical response and corticosteroid requirements. Coordinate the frequency of monitoring with hepatology according to severity. If response remains inadequate Reassess the diagnosis and consider liver biopsy if not previously performed. Evaluate the possibility of concomitant infection, cholangitic injury, or another liver disorder. Additional treatment options, such as tacrolimus, may be considered in selected refractory cases under expert hepatology supervision. There is no universally established third-line treatment sequence. Critical safety messages Do not use infliximab for immune-mediated hepatitis. Do not continue escalating immunosuppression without reassessing the diagnosis and infectious risk. Do not route patients with persistent severe hepatitis or worsening hepatic synthetic function directly to clinical recovery. When improvement occurs Continue treatment and appropriate biochemical monitoring. If corticosteroids were administered, begin or continue a gradual individualized taper once liver tests have improved sufficiently. Proceed to biochemical and clinical recovery assessment only after documented improvement or resolution.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

Confirm sustained clinical and biochemical recovery following treatment or monitoring of suspected ICI-related hepatitis. Recovery assessment is necessary regardless of whether immunotherapy will be resumed or permanently discontinued. Biochemical recovery Confirm improvement or resolution of relevant abnormalities: AST and ALT return to Grade 1 or baseline. Bilirubin improves or returns to baseline. ALP and GGT improve when a cholestatic or mixed pattern was present. PT/INR is stable or normalized when previously abnormal. No new evidence of impaired hepatic synthetic function. Interpret results relative to pre-treatment liver tests and underlying hepatic disease. Clinical recovery Document: Resolution of clinically significant jaundice. Improvement in fatigue, nausea, abdominal discomfort, and other hepatic symptoms. Absence of encephalopathy or progressive hepatic dysfunction. Clinical stability and improvement in functional status. Resolution or adequate management of relevant alternative causes. Review ongoing treatment Document: Whether corticosteroids were administered. Current corticosteroid agent and dose. Completion or ongoing status of the steroid taper. Any additional immunosuppressive therapy, including MMF. Treatment-related adverse effects. The plan for subsequent biochemical monitoring. Persistent abnormalities If liver biochemical tests remain clinically abnormal, reassess the underlying injury pattern and the need for continued hepatology care. Persistent cholestatic abnormalities may require additional evaluation for immune-mediated cholangitis or other bile duct injury. Do not assume that normalization of AST and ALT alone establishes complete hepatic recovery. Assess eligibility for ICI resumption Clinical and biochemical recovery does not automatically establish eligibility for ICI rechallenge. For selected patients with previous Grade 1–2 hepatitis, consider individualized evaluation after recovery. ASCO guidance allows consideration of ICI resumption after recovery to Grade 1 or baseline, with prednisone 10 mg/day or less when corticosteroids were administered, provided there are no other contraindications. For previous Grade 3 hepatitis, apply hepatitis-specific ASCO recommendations, patient symptoms, product labeling, and multidisciplinary assessment. Patients with previous Grade 4 hepatitis should not enter routine rechallenge. Longitudinal follow-up Continue appropriate liver biochemical surveillance after corticosteroid discontinuation or other immunosuppressive treatment. Monitor for recurrent hepatitis, persistent cholestasis, and delayed hepatic complications.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

ICI rechallenge following immune-mediated hepatitis requires an individualized multidisciplinary risk–benefit assessment. Recovery of liver biochemical tests alone does not guarantee that further immunotherapy is safe or appropriate. Potential eligibility Consider ICI rechallenge primarily in appropriately selected patients recovering from Grade 1–2 immune-mediated hepatitis. Confirm: AST and ALT have returned to Grade 1 or baseline. Bilirubin has improved or returned to baseline. No clinically significant ongoing hepatic dysfunction. No active encephalopathy or coagulopathy attributable to liver injury. Clinical recovery is adequate. Corticosteroids, when used, have been tapered to an acceptable dose. The proposed ICI regimen and product labeling permit resumption. ASCO guidance permits considering resumption when prednisone is 10 mg/day or less, provided the other clinical requirements are satisfied. Previous Grade 3 hepatitis Follow ASCO hepatitis-specific guidance. Consider permanent ICI discontinuation after asymptomatic Grade 3 hepatitis. Permanently discontinue ICI after symptomatic Grade 3 hepatitis. Product-specific restrictions and multidisciplinary specialist assessment must be incorporated. Rechallenge after Grade 3 hepatitis must not be treated as an automatic standard pathway. Previous Grade 4 hepatitis Permanently discontinue ICI. Do not routinely rechallenge after Grade 4 immune-mediated hepatitis. Hepatic risk assessment Review: Previous hepatitis grade and clinical severity. Presence of jaundice, coagulopathy, or impaired synthetic function. Time required for biochemical recovery. Corticosteroid requirements and duration. Previous steroid-refractory disease. Need for additional immunosuppression. Recurrence during steroid taper. Baseline liver disease and hepatic metastases. Previous cholestatic or mixed liver injury. Planned ICI class and treatment combination. Oncologic risk–benefit assessment Consider: Current cancer status. Previous oncologic benefit from ICI. Expected benefit of further immunotherapy. Availability of effective alternative treatments. Patient preferences and treatment goals. Risk of recurrence Discuss the possibility of recurrent immune-mediated hepatitis or another immune-related adverse event. Explain that recurrence may require additional corticosteroids, immunosuppression, or permanent ICI discontinuation. Shared decision-making Document the multidisciplinary assessment, anticipated oncologic benefit, hepatic risks, and patient-informed treatment decision. Decision Yes — Rechallenge appropriate: Proceed to "Resume ICI with close monitoring". No — Rechallenge inappropriate: Proceed to "Discontinue ICI or plan alternative cancer treatment". Critical safety message Never use biochemical recovery alone as justification for ICI rechallenge.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.

Resume ICI only when an individualized risk–benefit assessment confirms that rechallenge is clinically appropriate and permitted by applicable product labeling. Establish a documented liver monitoring and safety plan before the first subsequent ICI administration. Before restarting ICI Document: ICI agent and proposed regimen. Initial hepatitis grade and clinical severity. AST, ALT, ALP, and bilirubin at recovery. Baseline liver abnormalities. Current corticosteroid dose. Any ongoing additional immunosuppression. Hepatology assessment when appropriate. Expected oncologic benefit. Patient-informed decision. Laboratory monitoring Obtain liver biochemical tests before restarting ICI and before subsequent infusions. Consider additional early testing between treatment cycles for patients at increased risk of recurrence. Monitor: AST and ALT. ALP and GGT when indicated. Total and direct bilirubin. PT/INR when hepatic dysfunction is suspected. Monitoring frequency should be individualized according to initial hepatitis severity, treatment regimen, residual liver abnormalities, and specialist recommendations. Clinical monitoring Assess: Fatigue and general clinical condition. Nausea, vomiting, or anorexia. Right upper quadrant discomfort. Jaundice or scleral icterus. Dark urine or pale stools. Pruritus. Confusion, abnormal bleeding, or other manifestations of hepatic dysfunction. Patient education Provide clear instructions to report new hepatic symptoms promptly. Explain that recurrent immune-mediated hepatitis may initially be asymptomatic and detected through laboratory monitoring. Ensure the patient understands when to contact the oncology team and when urgent assessment is required. If hepatitis recurs Hold ICI and repeat diagnostic evaluation and CTCAE grading. Reassess competing causes, biochemical severity, and hepatic synthetic function. Determine the need for corticosteroids or additional specialist-directed treatment. Reevaluate whether further ICI treatment remains appropriate. Important treatment principle ICI dose reduction is not an established strategy for preventing recurrent immune-mediated hepatitis. Do not empirically reduce the ICI dose as an alternative to appropriate interruption or discontinuation. Ongoing follow-up Maintain communication between oncology and hepatology. Continue surveillance for recurrent liver injury and delayed treatment-related complications.

Permanently discontinue ICI when required by the severity of immune-mediated hepatitis, applicable guidelines, product labeling, or an unfavorable individualized risk–benefit assessment. Continue appropriate liver-directed treatment, monitoring, and oncology care. Reasons for permanent discontinuation These may include: Grade 4 immune-mediated hepatitis. Symptomatic Grade 3 hepatitis under ASCO recommendations. Other Grade 3 cases when permanent discontinuation is indicated by guidelines, product labeling, or specialist assessment. Severe or recurrent immune-mediated liver injury. Clinically significant hepatic dysfunction. Persistent steroid-refractory disease. Recurrent hepatitis requiring additional immunosuppression. An unfavorable oncologic risk–benefit assessment. Document the decision Record: Initial hepatitis grade. Presence or absence of clinical hepatic dysfunction. Treatments administered. Response to corticosteroids and any additional immunosuppression. Biochemical recovery status. Reason for permanent ICI discontinuation or for avoiding rechallenge. Any relevant product-label restrictions. Continue liver-directed care Permanent ICI discontinuation does not mean stopping treatment of immune-mediated hepatitis. Continue: Appropriate corticosteroid treatment and tapering. MMF or other specialist-directed therapy when indicated. Biochemical monitoring. Evaluation for recurrent hepatitis. Monitoring for infection and immunosuppression complications. Hepatology follow-up. Management of residual cholestatic or other hepatic abnormalities. For unresolved steroid-refractory disease, continue active specialist-directed care. Alternative oncologic treatment planning Review: Current cancer stage and disease status. Previous systemic treatment exposure. Available non-ICI anticancer therapies. Expected treatment benefit and risks. Performance status and hepatic function. Patient preferences and treatment goals. Coordinate treatment selection with the relevant oncology team. Communication and continuity Document the immune-mediated liver injury and ICI disposition clearly in the medical record. Communicate relevant treatment restrictions to all clinicians involved in subsequent anticancer care. Provide the patient with clear guidance regarding ongoing monitoring and follow-up. Key safety message Stopping ICI does not stop care. Permanent ICI discontinuation must be accompanied by continued appropriate hepatic management and individualized oncologic treatment planning.