Management guidelines for hepatic irAEs1,2,6
Common hepatic irAE symptom
BMS-recommended management guidelines for hepatic irAEs1,2,6
For suspected irAEs, first exclude other causes. Do not give infliximab because of hepatotoxicity risk
| Nivolumab monotherapy | Nivolumab + Ipilimumab | |
|---|---|---|
| Hepatitis with no tumour involvement of the liver | If AST/ALT increases to >3.0x and ≤8.0x ULNor
Total bilirubin increases to >1.5x and ≤3.0x ULN: Withholda If AST/ALT increases to >8.0x ULN or Total bilirubin increases to >3.0x ULN: Permanently discontinue |
– |
| Hepatitis with tumour involvement of the liverb | If baseline AST/ALT is >1.0x and ≤3.0x ULN and increases to >5.0x and ≤10.0x ULN
or Baseline AST/ALT is >3.0x and ≤5.0x ULN and increases to >8.0x and ≤10.0x ULN: Withholda If AST/ALT increases to >10.0x ULN or Total bilirubin increases to >3.0x ULN: Permanently discontinue |
– |
| Hepatitis with no tumour involvement of the liver
or Hepatitis with tumour involvement of the liver/non-HCC |
– | If AST/ALT increases to >3.0x ULN and ≤5.0x ULN
or Total bilirubin increases to ≥1.5x and ≤3.0x ULN: Withholda If AST or ALT >5.0x ULN or Total bilirubin >3.0x ULN: Permanently discontinue |
| Hepatitis with tumour involvement of the liverc/HCC | – | If baseline AST/ALT is >1.0x and ≤3.0x ULN and increases to >5.0x and ≤10.0x ULN
or Baseline AST/ALT is >3.0x and ≤5.0x ULN and increases to >8.0x and ≤10.0x ULN: Withholda If AST/ALT increases to >10.0x ULN or Total bilirubin increases to >3.0x ULN: Permanently discontinue |
aResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
bIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue nivolumab based on recommendations for hepatitis with no liver involvement.
cIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue nivolumab in combination with ipilimumab based on recommendations for hepatitis with no liver involvement.
| Grade 1 | Grade 2 | Grade 3–4 | |
| Definition | AST or ALT >ULN to 3.0x ULN
and/or total bilirubin to 1.5x ULN |
AST or ALT >3.0x to ≤5.0x ULN
and/or total bilirubin >1.5x to ≤3.0x ULN |
AST or ALT >5.0x ULN
and/or total bilirubin >3.0x ULN |
| Monitoring | Monitor LFT before and periodically during treatment | Every 3 days | Every 1–2 days |
| Consultations | – | – | Gastroenterology |
| Medication | – | 0.5–1 mg/kg/day methylprednisolone equivalent* | 1–2 mg/kg/day methylprednisolone equivalent** |
| Follow-up | Continue monitoring LFTs
If worsens or persists: Treat as Grade 2 or 3–4 |
If improved to Grade 1 or baseline:
Resume treatment If steroids have been administered, taper steroids over ≥1 month before resuming treatment Resume routine LFT monitoring If AST/ALT >5.0× and/or total bilirubin >3.0× ULN: Treat as Grade 3–4 |
If improved to Grade <2:
Taper steroids over ≥1 month** If persists for >3–5 days, worsens or rebounds: Add non-corticosteroid immunosuppressive medication (e.g. MMF 1 g BID)2 If no response within an additional 3–5 days, consider other immunosuppressants per local guidelines |
*Consider prophylactic antibiotics for opportunistic infections; **Add prophylactic antibiotics
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; irAE, immune-related adverse event; HCC, hepatocellular carcinoma; IPI, ipilimumab; LFT, liver function test; MMF, mycophenolate mofetil; ULN, upper limit of normal
International guideline (ASCO, ESMO and NCCN) recommendations for hepatic irAEs3–5^
^ For detailed guidelines, please refer to original publication
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Immunotherapy | Continue3,6
or Consider holding4 |
Hold3–5 | Hold4
or Consider (permanently)3 discontinuing if asymptomatic;(permanently)3 discontinue if symptomatic3,5 |
Consider3 (permanently)3,4 discontinuing if asymptomatic; (permanently)3,4 discontinue if symptomatic3–5 |
| Monitoring/transaminases and bilirubin assessment | Assess with increased frequency4
or Repeat one5 to two3 times weekly |
Monitor every 33,5 to 5 days4
and Unnecessary medications and any known hepatotoxic drugs should be avoided5 |
Monitor every 15 to 2 days3
or Every 1–5 days depending upon magnitude and rate of change4 |
Monitor liver enzymes/laboratories daily3–5 or every other day3 |
| Consultation | – | Consider hepatology consultation3 | Consider early hepatology consultation3–5*
Consider GI consultation4 |
|
| Liver biopsy | – | – | Consider liver biopsy3,5 | |
| Medication** | – | Consider4 starting oral prednisone if rising ALT/AST; if liver enzymes do not improve after 3 days, treat as Grade 34 | Start prednisone or (methyl)prednisolone3–5 | Administer prednisone4 or (methyl)prednisolone3–5 |
| Please see additional recommendations for steroid-refractory patients | ||||
| Inpatient care | – | – | Consider inpatient care4,5 or transfer to tertiary care3 | Inpatient care4,5 or consider transfer to tertiary care3 |
*If no improvement is achieved with corticosteroids or for patients on combination therapy with a novel agent, with standard chemotherapy, or with targeted therapy
**Consult steroid and immunosuppression dosing information below for recommendations. Do not give infliximab because of hepatotoxicity risk
ALT, alanine transaminase; AST, aspartate aminotransferase
Liver blood test monitoring AST, ALT and bilirubin. For Grade ≥2 symptoms3,4 or elevated transaminitis,4 work-up for other causes of elevated liver enzyme is advised,† and LFT should be carried out every 3 days.5
| ASCO3 | ESMO5 | NCCN4 | |
|---|---|---|---|
| Grade 1
(Asymptomatic3 or mild4) |
AST or ALT >ULN–3.0× ULN and/or total bilirubin >ULN–1.5× ULN | AST or ALT >ULN–3.0× ULN | AST and ALT <3.0× ULN |
| Grade 2
(Asymptomatic3 or moderate4) |
AST or ALT >3.0–≤5.0× ULN and/or total bilirubin >1.5–≤3.0× ULN | AST or ALT 3.0–5.0× ULN | AST and ALT 3.0–5.0× ULN |
| Grade 3
(Symptomatic liver dysfunction, fibrosis by biopsy, compensated cirrhosis and reactivation of chronic hepatitis3 or severe4) |
AST or ALT 5.0–20.0× ULN and/or total bilirubin 3.0–10.0× ULN | AST or ALT 5.0–20.0× ULN | AST and ALT >5.0–20.0× ULN |
| Grade 4
(Decompensated liver function [e.g. ascites, coagulopathy, encephalopathy and coma]3 or life-threatening4) |
AST or ALT >20.0× ULN and/or total bilirubin >10.0× ULN | AST or ALT >20.0× ULN | AST and ALT >20.0× ULN |
†Including viral hepatitis, alcohol history, iron study, thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from primary malignancy. If suspicion for primary autoimmune hepatitis is high, can consider antinuclear antibodies, anti-smooth muscle antibodies, antineutrophil cytoplasmic antibodies. If patients have elevated alkaline phosphatase alone, γ-glutamyl transferase should be tested. For isolated elevation of transaminases, consider checking creatine kinase for other aetiologies3
ALT, alanine transaminase; ASCO, American Society of Clinical Oncology; AST, aspartate aminotransferase; ESMO, European Society for Medical Oncology; LFT, liver function test; NCCN, National Comprehensive Cancer Network; ULN, upper limit of normal
|
ASCO, ESMO, NCCN |
|
|---|---|
| Grade 2 | Consider prednisone 0.5–1 mg/kg/day or equivalent.3–5 If improved to Grade ≤1 and patients are receiving corticosteroid ≤10 mg/day,3 wean over 2–4 weeks.3–5 Re-escalate if worsening4,5 |
| Grade 3 | 1–2 mg/kg/day prednisone or methylprednisolone or equivalent,3,4 taper around 4–6 weeks.3 If AST/ALT <400 U/L and normal bilirubin/INR/albumin, start corticosteroid 1–2 mg/kg.5 If AST/ALT >400 U/L or raised bilirubin/INR/low albumin, start IV (methyl)prednisolone 2 mg/kg.5 Once improved to Grade 2, change to oral prednisolone and wean over 4 weeks.5 Rechallenge only at consultant direction5 |
| Grade 4 | Start 1–2 mg/kg/day prednisone or methylprednisolone4 or equivalent3 or IV (methyl)prednisolone 2 mg/kg.5 Treat until symptoms improve to Grade ≤1 then taper over 44 to 6 weeks.3 Once improved to Grade 2, change to oral prednisolone and wean over 4 weeks5 |
ALT, alanine transaminase; ASCO, American Society of Clinical Oncology; AST, aspartate aminotransferase; ESMO, European Society for Medical Oncology; INR, international normalized ratio of prothrombin time; IV, intravenous; NCCN, National Comprehensive Cancer Network
ESMO: For worsening despite steroids, change from oral to IV (methyl)prednisolone. If on IV, consider MMF 1000 mg twice daily, tocilizumab 8 mg/kg, tacrolimus, azathioprine, cyclosporine or anti-thymocyteglobulin (100 mg divided over 2 days). Infliximab should not be used in patients with ICI-induced liver toxicity.5
For Grade ≥2 transaminitis with bilirubin levels above 1.5 ULN (excluding patients with Gilbert’s syndrome), management is similar to that for high-grade hepatitis without bilirubin elevation. Permanently discontinue immunotherapy and initiate prednisone at 2 mg/kg/day. Mycophenolate can be considered in addition to steroid for refractory cases after 3 days.4
For Grade ≥3 symptoms, in case of no improvement or steroid refractory after 1–2 days, consider adding mycophenolate. If no improvement, consider ATG.4 Azathioprine can be also considered if infectious cause is ruled out (if using azathioprine should test for thiopurine methyltransferase deficiency).3 MMF treatment (0.5–1 g every 12 hours) can be considered in patients who have persistent severe hepatitis despite high-dose corticosteroids.4,5 Consider discontinuation of mycophenolate when LFTs improved to Grade ≤1 and after completion of steroid taper.4 Infliximab should not be used for hepatitis.3–5
ATG, anti-thymocyte globulin; ESMO, European Society for Medical Oncology; ICI, immune checkpoint inhibitor; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; TNF, tumour necrosis factor; ULN, upper limit of normal
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- Schneider BJ, et, al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2022. Available: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 2023.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
