Balancing act: Tapering mycophenolate mofetil in immune checkpoint inhibitor hepatitis-strategies, outcomes, and risks

Table 1 Comparing common prognostic indices for drug-induced liver injury, highlighting key differences in purpose, application, interpretation, and application

Metric	Purpose	Key parameters	Interpretation	Application
CTCAE (ICI hepatitis)	Grading severity for oncologic toxicity	ALT, AST, bilirubin, symptoms (e.g., jaundice)	Grade 1-5 (mild to death)-determines ICI holding/resuming, steroid initiation	Oncology (especially in immunotherapy)
MELD score	Predict liver-related mortality	Bilirubin, INR, Creatinine (± Na, albumin)	Numerical score → mortality prediction, transplant priority	Cirrhosis, acute liver failure, transplant prioritization
Hy’s law	Identify serious DILI risk	ALT or AST > 3 × ULN AND total bilirubin > 2 × ULN without obstruction	Signals risk of serious hepatotoxicity in idiosyncratic DILI. Predicts about 10% risk of death or transplant in DILI cases	Drug safety (clinical trials, post-market surveillance)
Modified Hy’s law	Improve prediction of DILI-related outcomes	Similar to Hy’s but may use ALP and stricter temporal linkage	More clinically specific/refined for assessing hepatotoxicity risk	Adaptation for real-world/Lab data

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CTCAE: Common terminology criteria for adverse events; DILI: Drug-induced liver injury; INR: International normalized ratio; ICI: Immune checkpoint inhibitor; MELD: Model for end-stage liver disease; ULN: Upper limit of normal.

Table 2 Summary of studies providing guidance on mycophenolate mofetil tapering strategies

Study name	Study type	Type of cancer, ICI regimen, and grade of ICI hepatitis at peak LFT elevation	Initial MMF dosing and tapering protocol	Recurrence of ICI hepatitis after MMF taper?	Limitations
Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer[39]	Case report	Bladder cancer. Nivolumab and Ipilimumab combination therapy. Grade 3 ICI Hepatitis	Initial dose: MMF 2 g daily. Taper: MMF tapering started once prednisolone tapered to 10 mg daily. MMF total daily dose was reduced by 0.5 g every 3 days until off	No	Small sample size (n = 1). Patient did not undergo liver biopsy to rule out other causes of liver injury, although serologic and radiographic workup was negative and had good response to treatment of ICI hepatitis
Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab[55]	Case report	Stage IV melanoma. Nivolumab, followed by ipilimumab (sequential, not combination therapy). Grade 4 ICI hepatitis	Initial dose: MMF 2 g daily. Taper: MMF tapering started once prednisolone tapered to 0.5 mg/kg/d and LFTs improved to Grade 1 hepatitis. MMF initially reduced to 1 g daily, continued for 1 week, then stopped	No	Small sample size (n = 1). Patient did not undergo liver biopsy to rule out other causes of liver injury, although serologic and radiographic workup was negative and had good response to treatment of ICI hepatitis
Immune-mediated liver injury from checkpoint inhibitors: Best practices in 2024[56]	Review article	NA; recommendations provided based upon expert opinion	Initial dose: MMF 500-1500 mg BID. Taper: Begin MMF taper once LFTs normalize. Total daily dose of MMF can be decreased each week by 250-500 mg BID over a span of 6-8 weeks until off	NA; recommendations per expert opinion	Recommendations based upon expert opinion. No specific citations listed relevant to MMF tapering recommendations
Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors[53]	Review article	NA; recommendations provided based upon expert opinion	Initial dose: MMF 1 g BID. Taper: Timing of when to begin taper is not specified. Recommended to taper over 10-12 weeks and can consider resuming ICI once LFTs are normal and both steroids and MMF have been discontinued	NA; recommendations per expert opinion	Recommendations based upon expert opinion. No specific citations listed relevant to MMF tapering recommendation. No recommendation provided on when to begin MMF taper

BID: Twice daily; ICI: Immune checkpoint inhibitor; LFTs: Liver function tests; MMF: Mycophenolate mofetil; NA: Not applicable.

Table 3 Summary of studies reporting rechallenge outcomes in immune checkpoint inhibitor hepatitis

Ref.	Cancer type	Immunotherapy type	Risk of recurrent ICI with rechallenge
Li et al[63]	Melanoma	Anti-CTLA-4, Anti-PD-1, Anti-PD-L1, Combination (CTLA-4 + PD-1)	12.9% (4/31) developed recurrent ICI hepatitis; higher recurrence when rechallenged with same ICI class
Riveiro-Barciela et al[64]	Multiple (not specified)	Mostly Anti-PD-1 or Anti-PD-L1 monotherapy	34.8% (8/23) recurrence of ICI hepatitis, including 1 case of grade 4 hepatitis with liver failure
Hwang et al[20]	Mixed	Mixed	About 22% recurrence rate among those rechallenged (of about 40% who were rechallenged out of 1856 patients)
Haanen et al[60]	Not specified	Rechallenge strategy with concurrent immunosuppression (e.g., Tocilizumab)	No direct recurrence data; prophylactic strategy proposed, limited evidence for efficacy in ICI hepatitis
Pollack et al[66]	Metastatic melanoma	Anti-CTLA-4 + Anti-PD-1 initially; Anti-PD-1 monotherapy on rechallenge	16% recurrence in patients previously on MMF vs 22% in steroid-only group; higher risk if still on steroids

CTLA-4: Cytotoxic T-lymphocyte associated antigen 4; ICI: Immune checkpoint inhibitor; MMF: Mycophenolate mofetil; PD-1: Programmed cell death protein 1; PDL-1: Programmed death-ligand 1.