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

Abstract

BACKGROUND

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with immune-related adverse events, including ICIs hepatitis. Mycophenolate mofetil (MMF) is often used as a second-line immunosuppressive agent for steroid-refractory cases. However, there is no standardized approach to MMF tapering, leading to uncertainties regarding relapse risk, optimal tapering strategies, and long-term outcomes.

AIM

To evaluate current evidence on MMF tapering in ICI hepatitis, focusing on strategies, clinical outcomes, and the risk of hepatitis recurrence. Additionally, we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.

METHODS

A comprehensive literature search was conducted in PubMed, EMBASE, and clinical trial registries to identify studies reporting MMF use and tapering strategies in ICI hepatitis. We extracted data from manuscripts including patient characteristics, MMF dosing regimens, tapering duration, relapse rates, and oncologic outcomes. Risk factors for recurrence and successful tapering were analyzed.

RESULTS

There was significant heterogeneity in the duration of MMF taper, which ranged from 4 weeks to greater than 6 months. The tapering schedules presented were individualized based on the severity of liver injury, patient response to treatment, and risk factors for relapse. We summarize current tapering approaches, including rapid vs slow withdrawal, predictors of successful tapering, and alternative immunosuppressive strategies. The impact of MMF duration on liver recovery, relapse risk, and cancer prognosis will be discussed. Evidence on ICI rechallenge post-taper will also be reviewed.

CONCLUSION

While MMF is effective in managing ICI hepatitis, tapering remains a clinical challenge with potential risks of hepatitis flare and disease progression. Standardized tapering protocols are needed to optimize immunosuppression while preserving anticancer efficacy. Future studies should focus on biomarker-driven tapering strategies and prospective trials to establish best practices.

Key Words: Immune checkpoint inhibitor hepatitis; Mycophenolate mofetil; Tapering; immunosuppression; Hepatotoxicity; Immune-related adverse events; Cancer immunotherapy

Core Tip: This systematic review describes immune checkpoint inhibitor hepatitis (ICI) hepatitis and explores the different treatment strategies for this condition, with a focus on the data behind one of the second line agents used for treatment, mycophenolate mofetil (MMF). We review the evidence behind use of MMF for ICI hepatitis, including pathophysiology, clinical outcomes, risk of relapse, tapering strategies, and challenges with restarting immunotherapy in these patients. Future directions and unmet needs within this evolving field are also briefly discussed.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) are a mainstay of oncologic therapy for a variety of cancers and are being utilized increasingly since their inception[1]. One cross-sectional study among patients diagnosed with cancer in the United States reported that the proportion of patients with cancer eligible for ICIs increased from 1.5% to 43.6% from 2011 to 2018, respectively[1]. This study also reported that the percentage of patients estimated to have partial or complete response to ICI therapy improved from 0.1% in 2011 to 12.5% in 2018[1]. However, these drugs have unwanted toxicities, including immune related adverse events (irAEs), one of which is ICI hepatitis. ICI hepatitis is generally treated by withholding ICI doses and/or prescribing corticosteroids. Mycophenolate mofetil (MMF) is often used as a second-line immunosuppressive agent for steroid-refractory cases. However, there is no standardized approach to MMF tapering, leading to uncertainties regarding relapse risk, optimal tapering strategies, and long-term outcomes. This systematic review aims to evaluate current evidence on MMF tapering in ICI hepatitis, focusing on strategies, clinical outcomes, and the risk of hepatitis recurrence. Additionally, we explore the feasibility of reintroducing ICI therapy after immunosuppression withdrawal.

MATERIALS AND METHODS

A comprehensive literature search was conducted to identify relevant studies evaluating ICI hepatitis and MMF use. The search included articles from 2015 up to March 2025 across PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library. The search strategy combined Medical Subject Headings and keywords related to ICI hepatitis and MMF use. Relevant key words such as “immune checkpoint inhibitor hepatitis” or “mycophenolate mofetil use in immune checkpoint inhibitor hepatitis” were used to find relevant sources. Additionally, the reference lists of included studies and relevant reviews were manually screened to identify any additional eligible studies. Studies were included based on the following criteria: Adult patients (≥ 18 years) with ICI hepatitis. We excluded literature related to non-human subjects, pediatric populations and articles not published in English. The authors independently screened titles and abstracts for eligibility, and articles were then retrieved for further evaluation of meeting eligibility criteria. Discrepancies were resolved through discussion by the authors to reach consensus (Figure 1).

Figure 1 PRISMA flow diagram on selection of studies. Included records were those that were published in English, on adult populations (> 18 years old), and were relevant to our systematic review. ¹Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers); ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

RESULTS

A total of 68 articles were reviewed by the authors for inclusion in this systematic review. Of the resources included, there were four national guidelines identified that provided recommendations relevant to this paper’s topic. These four guidelines were published by the American Gastroenterological Association (AGA), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN). Although these guidelines provide broad recommendations on ICI hepatitis, other data on MMF use, tapering strategies, and re-introduction of ICI primarily derived from case reports given the relatively low incidence of the disease. Once all of the data from our literature search was collected, it was synthesized and organized into the following sections of the manuscript: Pathophysiology and immune mechanisms of ICI-related liver injury, clinical grading and severity classification, current standard of care for ICI hepatitis, evidence on MMF use in ICI hepatitis, challenges in MMF tapering, restarting immunotherapy after MMF tapering, and future directions and unmet needs. Furthermore, given the nature of this systematic review, the results and discussion sections were grouped together as both raw data from sources and our interpretation or summary of those results are outlined under each individual section of this paper.

DISCUSSION

Pathophysiology and immune mechanisms of ICI-related liver injury

ICI hepatitis occurs in less than 5% of patients on one ICI and up to a quarter of patients on multiple ICIs[2]. To understand how these agents cause inflammation in the liver, one must first consider their mechanism of action. In normal physiology, immune checkpoints are important to prevent uncontrolled immune activation or autoimmune disease. Normal antigen responsive T-cells require a two-step process for activation. The first step involves an antigen presenting cell (APC) showing an antigen via major histocompatibility complex class 2, which is then recognized by the T-cell receptor on any given T-cell previously programmed to recognize the presented antigen. After this first antigen-receptor interaction, the second interaction that takes place occurs between CD80 or CD86 on the APC and the CD28 receptor on the T-cell. Once both interactions occur, this prompts T-cell activation to perform its intended function to combat foreign cells (e.g., infectious or tumor cells). As a regulatory mechanism, T-cells also have receptors that promote downregulation or apoptosis. For example, the CTLA-4 receptor on T-cells can compete with the CD28 receptor for binding to CD80 or CD86; however, instead of T-cell activation, CTLA-4 binding downregulates T-cell activity. Similarly, the PD-1 receptor on T-cells also prevents immune over-activation when bound, ultimately leading to T-cell inactivity and apoptosis. Unfortunately, tumor cells take advantage of this mechanism by expressing PD-L1, which binds and activates the PD-1 receptor, allowing tumor cells to evade T-cell mediated destruction. Consequently, these pathways are the focus of ICI therapies such as anti-CTLA-4 (e.g., ipilimumab, tremelimumab), anti-programmed cell death protein 1 (anti-PD-1) (e.g., pembrolizumab, nivolumab), and anti-PD-L1 antibodies (e.g., durvalumab, atezolizumab)[3].

Although different ICIs have different targets within the immune system, they all can cause liver injury. The mechanism by which this occurs is multifactorial and not fully understood. Some patients develop ICI hepatitis while others do not-the incidence seems to vary given certain risk factors including type and dose of ICI, combination therapy, genetic predisposition, pharmacotherapy, and exposure to potentially hepatotoxic medications like statins and acetaminophen[4]. The presence of other autoimmune conditions, especially autoimmune hepatitis, can increase the risk[4]. The liver is constantly exposed to foreign pathogens and their antigens; therefore it is less reactive to immune reactions locally. However, when ICI mechanisms block the CTLA-4, PD-1 or PD-L1 pathways, this disrupts the self-tolerance within the liver. This loss of self-tolerance results in an exaggerated immune response from the CD8+ cytotoxic T lymphocytes (CTLs), causing them to attack certain antigens that are normally present in the body. Multiple theories exist regarding the pathophysiology of liver injury in ICI hepatitis. One theory suggests that it is related to the overreactive CTLs, directly leading to hepatocyte cell death[5]. Others suggest a more indirect immune effect resulting in inflammation by the activation of the innate immune system or the effect on T-helper and regulatory cells causing increased cytokine release[6], and/or that ICIs disrupt hepatic immune tolerance[7].

Clinical grading and severity classification

Diagnosis of ICI hepatitis is made clinically in patients on ICIs with elevation of liver function tests (LFTs), inclusive of aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, and albumin. It is important to rule out other causes of elevated liver enzymes such as intrahepatic metastases, biliary obstruction, viral hepatitis, alcohol use, autoimmune hepatitis, and drug induced liver injury from another medication. In cases where the diagnosis is not clear, when the liver injury is grade 2 or higher, or refractory to steroid therapy, liver biopsy can be obtained for a definitive diagnosis. Pathology from liver biopsy classically shows focal necrosis, CD8+ T cell-rich mononuclear infiltration, but can also show granulomatous foci with lymphocytes and histiocytes[5]; however, the specific pattern seen on biopsy can vary based on which ICI is implicated. Clinically, patients may be asymptomatic or may have nonspecific symptoms such as fever, malaise, and jaundice[8]. The presence of jaundice and hepatic decompensation is hypothesized to be a much greater predictor of mortality than the degree of elevation of the AST or ALT.

Once the diagnosis is made, grading the severity of liver injury is important to determine next steps from a management perspective. Grading of ICI hepatitis is based on the degree of AST, ALT and total bilirubin elevation as well as the patient’s symptom(s). The grading system commonly used in oncology clinical trials to classify this is the Common Terminology Criteria for AE (CTCAE), or The Common Terminology Criteria for Adverse Events, which is used to guide immunotherapy and treatment decisions. In Grade 1 ICI hepatitis, the patient is asymptomatic with AST and/or ALT 1-3 × greater than the upper limit of normal (ULN), and T. bili 1-1.5 × greater than the ULN. In Grade 2 hepatitis, the patient is also asymptomatic with AST and/or ALT elevation 3-5 × greater than ULN, and T. bili 1.5-3 × greater than the ULN. If the patient develops symptoms of liver dysfunction, fibrosis on biopsy, compensated cirrhosis and/or reactivation of chronic hepatitis along with AST and/or ALT elevation 5-20 × greater than the ULN and T. bili 3-10 × greater than ULN, this classifies as Grade 3 hepatitis. Patients with grade 4 ICI hepatitis have symptoms of decompensated liver dysfunction including ascites, coagulopathy, or encephalopathy with AST and/or ALT elevation greater than 20 × the ULN and T. bili greater than 10 × the ULN. Grade 5 is classified as death attributed to ICI-related hepatotoxicity[9].

In contrast, the model for end-stage liver disease score is a prognostic model designed for chronic liver failure, not specific to ICI hepatitis but is useful if liver failure develops. Hy’s Law and modified Hy’s Law are safety tools to predict severe outcomes (like death or transplant) in idiosyncratic drug induced liver injury. However, the underlying mechanisms of ICI hepatitis (immune-mediated) differ from idiosyncratic drug-induced liver injury (often metabolic or unpredictable), so a different framework is needed to evaluate and manage ICI hepatitis. A further comparison of these common prognostic indices can be found in Table 1.

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.

Data is conflicting on the oncologic prognosis in patients who have ICI hepatitis. Some literature associates ICI hepatitis with improved oncologic outcomes[10,11], whereas other studies suggest that ICI hepatitis is associated with worse oncologic outcomes[12].

Current standard of care for ICI hepatitis

Broadly, first-line therapy for ICI hepatitis includes holding the ICI and treating the patient with corticosteroids. Corticosteroids decrease hepatocellular damage by suppressing excessive immune activation[13]. Systemic corticosteroids are the first-line treatment for ICI hepatitis due to their well-documented effectiveness in achieving remission and preventing serious complications. This treatment aims to manage inflammation while minimizing long-term immunosuppressive side effects. Early initiation of corticosteroid therapy in cases of high-grade ICI hepatitis is associated with improved control and reduced hepatic failure rates[14]. It is unclear if steroids are improving survival or if developing ICI hepatitis is a marker of a more robust immune response, resulting in reduced disease progression and improves survival[15]. However, prolonged corticosteroid use increases the risk of opportunistic infections, osteoporosis, and metabolic complications, making close monitoring and gradual tapering essential to mitigate these adverse effects[15]. More importantly, there is a theoretical risk that prolonged, high dose immunosuppression will counteract the bodies immunological response to malignancy and worsen oncologic outcomes. Although accepted recommendations are provided in current guidelines for the use of corticosteroids, the ideal dose, duration, and tapering regimens are still uncertain. New evidence suggests that in some cases, using lower doses of corticosteroids provides similar effectiveness while reducing the risk of adverse outcomes[16].

Guidelines from leading oncology and immunotherapy societies, including ASCO (2021), NCCN (2022), SITC (2022), and ESMO (2023), and the AGA (2020) provide a structured approach to managing ICI hepatitis. The initial management of ICI hepatotoxicity is based upon the severity of the liver injury, as defined by the CTCAE v5.0[8,17,18]. For patients with grade 1 hepatitis, any potential hepatotoxic medications should be held and the patient should be advised to stop any use of alcohol, if present. These cases warrant close monitoring without immediate corticosteroid intervention unless the disease progresses[8,16-18]. Postponing or stopping ICI treatment is the first step in managing grade 2 ICI hepatitis. Prednisone or methylprednisolone at 0.5-1 mg/kg/day is recommended, with LFTs monitored at least twice weekly. Once LFTs improve to Grade ≤ 1, corticosteroid tapering should proceed gradually over 4-6 weeks to minimize the risk of relapse[8,13,16,18]. For patients with grade 3 hepatitis, high-dose intravenous (IV) methylprednisolone (1-2 mg/kg/day) is recommended. Close monitoring and consideration of second-line agents are warranted if there is no improvement after 3 days[13,16,18,19]. Lastly, patients with grade 4 ICI hepatitis require hospitalization and aggressive immunosuppressive management with IV methylprednisolone at 2 mg/kg/day. In steroid-refractory patients, escalation to second-line immunosuppressive agents should be considered to prevent irreversible liver damage and hepatic failure[13,18-20]. Second-line agents can also be used when patients have a flare of their ICI hepatitis after being transitioned from IV to PO corticosteroids.

The tapering phase of corticosteroid therapy represents a critical juncture in ICI hepatitis management. Premature tapering may trigger rebound inflammation. Evidence suggests that gradual tapering over 4-6 weeks, particularly in high-grade hepatitis, reduces relapse rates and enhances long-term outcomes[16,20,21].

Budesonide has emerged as a potential alternative in select cases of steroid-refractory ICI hepatitis due to its high hepatic first-pass metabolism[15,22]. Kankaria et al[23] reported successful use of budesonide in patients with steroid-refractory ICI hepatitis, demonstrating its efficacy in achieving remission with fewer systemic side effects. Budesonide’s favorable safety profile may make it an attractive option for ICI rechallenge in patients with a history of steroid-refractory hepatitis[23]. Despite the availability of established guidelines, important gaps persist in corticosteroid tapering regimens and the management of steroid-refractory cases. Hercun et al[13] emphasized the critical need for prospective studies to refine individualized tapering regimens and explore alternative immunosuppressive strategies to minimize prolonged steroid use.

When steroids fail to improve ICI hepatitis after 3-5 days of therapy or if patients have a flare of ICI hepatitis when transitioning from IV to PO corticosteroids, providers should utilize one of the second-line agents to treat ICI hepatitis[8]. These include MMF, azathioprine, tacrolimus, tofacitinib, infliximab, and antithymocyte globulin (ATG)[24,25]. Providers should also consider the need for liver biopsy in this scenario.

MMF and mychophenolic acid

In patients with glucocorticoid-refractory ICI hepatotoxicity, MMF (initial dose 500 mg twice daily up to a maximum of 1.5 g twice daily) is recommended to be administered concurrently with glucocorticoids. MMF is generally preferred to other immunosuppressive agents due to a better tolerability profile and faster onset of action, with improvement in LFT beginning to be observed within 2 weeks of the commencement of this drug[26,27]. Close monitoring of complete blood counts is recommended to monitor for potential myelosuppression, as MMF can suppress bone marrow and reduce circulating blood cell counts. MMF may cause gastrointestinal (GI) side effects, in which case mycophenolic acid can be utilized instead as it is an enterically coated formulation of mycophenolate that may be associated with less GI side effects. Additional details regarding MMF use are discussed below.

Azathioprine

Traditionally, azathioprine has served as the first-line steroid-sparing agent for autoimmune hepatitis. However, it is not largely used compared with MMF in the therapy of ICI-related hepatotoxicity because of its inferior time-to-therapy response. The highest therapeutic response is also usually observed 30 days or later after initiation of treatment. Still, clinical guidelines advocate for the uses of azathioprine in patients who are having glucocorticoid-refractory ICI hepatitis[8,28]. Despite these concerns, azathioprine has been demonstrated to be effective in treating patients with ICI steroid-refractory hepatitis in several studies and case reports[20,29].

Tacrolimus

In cases where ICI related hepatotoxicity is unresponsive to both glucocorticoids and MMF, or when MMF is poorly tolerated, tacrolimus, a calcineurin inhibitor, is recommended to be an alternative immunosuppressive agent[2,8]. Several case reports have described patients with severe immunotherapy-induced hepatitis that required prolonged immunosuppressive therapy. In these cases, resolution was achieved through combination regimens that included tacrolimus, MMF, and corticosteroid[30,31]. The typical dosing regimen for tacrolimus in this context starts at a dose of 0.05-0.1 mg/kg/day, with adjustments based on therapeutic drug monitoring to achieve target trough levels of 5-10 ng/mL. While trough levels are used for toxicity monitoring, dose modifications are generally guided by clinical response in LFT. Close monitoring for adverse effects, including hypertension, nephrotoxicity, neurotoxicity, and hyperglycemia, is essential during tacrolimus therapy. Hypertensive side-effects are particularly relevant since many ICI combinations include bevacizumab which also increases the risk of hypertension.

Tofacitinib

Tofacitinib, an oral Janus kinase 1 and 3 inhibitor, should be considered for ICI related hepatotoxicity unresponsive to glucocorticoids, MMF, or tacrolimus[32]. In a multi-center study of 35 patients treated for irAEs, including 22 with ICI-induced hepatitis, 96.7% achieved clinical remission with tofacitinib, indicating strong efficacy in steroid-resistant cases[33]. Tofacitinib is given at 10 mg twice daily and reserved for patients with rapidly worsening liver enzymes or those who have failed triple immunosuppressive therapy. However, due to the potential interference with antitumor immunity, tofacitinib should be avoided when other effective therapies are available[25].

Infliximab

A study by Burri et al[34] evaluated 10 patients with grade 3 or higher steroid resistant hepatitis. Among these patients, 70% demonstrated a positive response to infliximab, characterized by stabilization of liver enzyme levels and control of hepatitis without the need for additional immunosuppressive therapy. The treatment was not associated with hepatotoxicity and resulted in sustained clinical benefit in 9 out of 10 cases, with a median follow-up duration of 487 days[34]. However, the AGA recommend that infliximab be used with caution or avoided in ICI hepatitis due to the potential for idiosyncratic liver injury[8]. Furthermore, recent consensus guidelines recommend infliximab as a first-line agent for steroid-resistant immune-mediated colitis but advise against its use in ICI-related hepatitis due to concerns regarding hepatotoxicity and infectious complications[35,36].

ATG

ATG has been reported as an effective treatment option for fulminant hepatitis induced by anti-PD-1 therapy[37]. However, its use is generally limited to severe and refractory cases that do not respond to corticosteroids or other second-line immunosuppressive agents. This cautious approach is due to the increased risk of infection and the potential for ATG to compromise antitumor immune responses.

Evidence on MMF (CellCept) use in ICI hepatitis

Of the second-line agents discussed above, MMF is most utilized for steroid-refractory ICI hepatitis[38]. MMF blocks de novo purine synthesis by reversibly and noncompetitively inhibiting inosinate dehydrogenase, which is integral for lymphocyte proliferation. Furthermore, this disrupts antibody development, proinflammatory cytokine cascades, and cellular immunity. MMF also promotes T regulatory cell activity, leading to increased activated T-cell apoptosis. These mechanisms also explain MMF’s success in treating patients with autoimmune hepatitis[39,40].

The highest level of evidence for MMF, or any other second line agents, for treating ICI hepatitis is from retrospective cohort studies due to the overall low incidence of steroid refractory ICI hepatitis[38]. Nonetheless, the data supports MMF as a worthy second-line agent. As shown by Chen et al[41], MMF achieved a 93% (95%CI: 0.79-1.0) response rate for the treatment of ICI hepatitis. Luo et al[42] examined patients with lung cancer who were treated with immune checkpoint blockade who experienced irAEs and the efficacy of second-line immunomodulators, finding that 5 out of 6 patients (83%) who received MMF for 3 months had improvement of their hepatitis. In another study by Miller et al[43], 67 of 100 patients with significant hepatoxicity were initiated on steroids, 3 of which needed MMF due to worsening ALT levels. After MMF initiation, ALT improved to grade 1 ICI hepatitis or lower within 10 days for one patient and within 20 days for two patients. In a retrospective study by Alouani et al[44], 11 of 130 patients had steroid refractory ICI hepatitis. Those 11 patients were treated with MMF, and 9 out of 11 of the patients had resolved or returned to grade 1 ICI hepatitis.

Early use of MMF, in addition to steroids, should be considered for optimal results[45]. However, much of the literature supporting this statement was found in studies that analyzed autoimmune hepatitis and not specifically ICI hepatitis. In one study by Snijders et al[46], they found that in patients with autoimmune hepatitis, the combination of MMF and prednisolone revealed a higher rate of biochemical remission at 24 weeks in comparison with azathioprine combined with prednisolone.

It is important to avoid delaying MMF therapy in patients without improvement in LFTs after 3-5 days. Eight patients at a single center who underwent ICI treatment developed steroid refractory ICI hepatitis treated with MMF[40]. Four of the eight patients were deemed “good responders”, based upon return of LFTs to grade 1 or less during MMF treatment, while the other four patients were deemed “poor responders”, as they did not meet this target on MMF therapy. Data was collected on several factors between these two groups including demographic data, type of malignancy, type of ICI, duration of ICI therapy, time from start of ICI therapy to onset of hepatitis, grade of ICI hepatitis, starting dose of MMF therapy, duration of MMF therapy, and duration from onset of ICI hepatitis to initial MMF administration. Of these many variables, the only one that reached statistical significance was duration from onset of ICI hepatitis to initial MMF administration. The median time from discovery of ICI hepatitis to initial MMF dose was 3 days in the “good responder” group compared to 25.5 days in the “poor responder” group. These data support the various society recommendations previously referenced that recommend starting MMF (or another second line agent) within 3-5 days if no adequate response to corticosteroids[40]. Even with prompt treatment with MMF when indicated, about 10%-30% of patients will require alternative or additional immunosuppression[27,41,42]. Some of these extremely refractory cases seem to involve more biliary injury and cholestasis[5].

There do not appear to be any prospective or randomized-controlled trials comparing one second-line agent for ICI hepatitis to another. One retrospective study comparing efficacy and safety of MMF and tacrolimus as second-line therapy for patients with autoimmune hepatitis showed no significant difference in proportion of patients with a complete response, with a slightly higher percentage of patients on tacrolimus developing side effects from the medication[47]. Overall, a favorable aspect of MMF over other immunomodulators, such as azathioprine or infliximab, is its lower incidence of hepatotoxicity and faster time-to-therapeutic effect. Side effect profiles and patient comorbid conditions should be considered when choosing a second line agent to use.

Challenges in MMF tapering

While the use of MMF has widely been accepted as an ideal second-line therapy for ICI hepatitis, there is minimal literature regarding the tapering of MMF. Per the NCCN guidelines, once MMF is used in steroid-refractory cases, the maximum dose is 1.5 g every 12 hours[45]. In the ESMO guidelines for managing toxicities of immunotherapy, resolution of ICI hepatitis should be expected within 4-6 weeks with appropriate treatment; however, other etiologies should be considered if improvement does not occur, and the initial workup should be repeated[25].

While patients are receiving MMF therapy, patients should have a complete blood count done weekly for monitoring, as MMF can cause myelotoxicity. Once liver biochemistries improve, MMF can be decreased by 250-500 mg twice daily/weekly over 6 to 8 weeks. The patient should have weekly monitoring of liver biochemistries to ensure that the patient has not had rebound hepatitis. Sanjeevaiah et al[48] recommend that once LFTs respond, steroids should be tapered for no less than 4 weeks. They also note that ICI hepatitis can recur after discontinuation of ICI, and patients may require multiple courses of steroids. Prompt initiation of MMF has been shown to result in a prompt biochemical response with up to a 50% improvement in ALT after 11 days for one study that included 7 patients[49]. Additional failure of MMF therapy reported is between 10%-30% who receive a combination of high-dose steroids and MMF[49,50].

In one case study, MMF was tapered down by 0.5 g daily every 3 days from a total daily dose of 2 g until off the medication. In this study, the MMF taper did not begin until the steroid dose was down to 10 mg daily. There was no noted recurrence of ICI hepatitis based on this taper strategy[39]. In a different case report, MMF was reduced from 2 to 1 g daily once LFTs returned to grade 1 Levels, which also coincided with when steroids were tapered down to 0.5 mg/kg/d. MMF was then stopped a week after the initial reduction in dose with no re-elevation of LFTs seen[51-55]. De Martin et al[53] propose that in patients with ICI grade 3 or greater hepatitis that patients who have improvement on MMF should be tapered over 10-12 weeks with resumption of ICI therapy when LFTs are normalized and after MMF and steroids have been discontinued[53]. These tapering strategies are crucial in the management of immune-related hepatitis and any irAEs in immunotherapy especially, as these immunosuppressive therapies may interfere and compromise cancer response. Targeting various inflammatory pathways and tailoring immunosuppressants is key in ensuring appropriate response and prevention of relapses[54].

General takeaways from these and other studies seem to support that starting to taper MMF once LFTs reflect grade 1 hepatitis or have normalized is an effective strategy. Unlike the slow and methodical nature of steroid tapers, it also appears safe to taper MMF more rapidly, even over the span of 1-2 weeks, however, some review articles recommend longer tapers over the span of 6-12 weeks to reduce risk of recurrent hepatotoxicity. The decision on duration of MMF taper should involve consideration of the grade of patient’s ICI hepatitis, the severity of clinical presentation, the dose and duration of corticosteroids, and the decision on whether the patient will eventually be re-challenged with ICI therapy. Admittedly, these recommendations are based on case reports and review articles, which introduces the possibility of type I and II statistical errors due to low power, confounding bias, publication heterogeneity, and lack of generalizability. However, given the relatively low incidence of ICI hepatitis, for now, these studies provide the only guidance on how to manage these patients (Table 2). Ultimately, additional studies need to be conducted to refine guidelines regarding MMF tapering and ICI hepatitis.

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.

No studies to date have evaluated the risk of recurrent ICI hepatitis with re-challenge of immunotherapy treatment after patients were successfully treated with a combination of high-dose corticosteroids and MMF. Most of the studies that evaluated the response of MMF as an alternative therapy for ICI hepatitis showed its efficacy in steroid refractory disease, but in all of these studies, there were post recovery complications that resulted in death from non-ICI hepatitis-related causes once initial treatment was completed[26,55-58].

In a retrospective study previously referenced in this paper by Kadokawa et al[40], the patients were classified into two primary groups, the “good responders” and “poor responders”[40]. They studied the response of steroid refractory immune related hepatitis to MMF therapy with the utilization of total bilirubin, AST, ALT, and alkaline phosphatase as laboratory markers for disease improvement. The “poor responder” group had a worsening clinical status, leading to the progression of primary disease or the need for alternative immunosuppression[40]. Another study by Almousawi et al[59] in 36 patients with CTCAE grade 3 ICI hepatotoxicity, 5 patients with relapse with steroid taper needed re-escalation of steroids, with 8 patients needing additional treatment with MMF. This study also noted that combination ICI therapy was noted to confer a higher risk of relapse than monotherapy and also, interestingly, delayed steroid taper initiation reduced risk for relapse. ESMO guidelines recommend a quicker steroid taper of 2 weeks for milder (grade 2) immune-related hepatitis as compared to a more gradual taper of 4-6 weeks for severe (grade 3 or 4) hepatitis until there is improvement in the grade of liver injury. There are no available guidelines in terms of a combination of MMF or additional immunosuppressive medications in conjunction with a specific steroid taper, especially with steroid-resistant disease where these additional therapies are required[25]. Should this paragraph and the one prior be in the section on MMF tapering strategies or the next section on restarting immunotherapy?/do these paragraphs add much or do you think we should delete them? One point to consider highlighting is in the Kadokawa et al[40] they were trying to show that it’s important to start MMF early in patients who aren’t responding to steroids—the median time to starting MMF was much shorter in the “good responder” group compared to the “poor responder” group. I think that was the main takeaway from that study-not sure it really fits under this theme/paragraph that seems to focus on ICI rechallenge/relapse but will defer to you.

Restarting immunotherapy after MMF tapering

After MMF tapering, the next consideration for these patients is feasibility of re-introducing ICI therapy, especially if it was effective compared to other anticancer therapy in controlling the patient’s primary malignancy and related metastases. There are no universally accepted guidelines currently that address reinitiation of immune therapy after an episode of ICI-induced hepatitis and data on the safety and feasibility of reintroducing ICIs therapy after tapering MMF. The NCCN, ASCO and ESMO guidelines all agree that it may be reasonable to resume immunotherapy after ALT and AST improve following a Grade 2 ICI-associated hepatitis if corticosteroid use is no greater than the equivalent of 10 mg daily of prednisone when applicable[25,28,45]. After clinical and biochemical resolution of initial liver injury, the estimated recurrence rate of ICI hepatitis is approximately 20% to 40%; however, studies assessing the feasibility rechallenging patients with prior or ongoing MMF use for treatment of ICI hepatitis remains sparse.

The NCCN recommends permanent discontinuation of ICIs therapy for Grade 4 AEs with synthetic liver dysfunction and/or development of biliary strictures necessitating endoscopic retrograde cholangiopancreatography[45]. The ASCO suggests permanent discontinuation of ICI therapy in symptomatic patients and consideration of permanent discontinuation in asymptomatic patients with Grade 3 and Grade 4 ICI hepatitis[28]. Similarly, ESMO recommends discontinuation of ICI therapy for Grade 3 and 4 Liver injuries[31].

Despite current societal recommendations that advocate against reinitiation of ICI therapy after a severe AEs, several studies have evaluated the feasibility of rechallenging patients with Grade 3 and 4 ICI hepatitis on ICI therapy[15]. There are three main strategies for reintroduction of ICI therapy after the development of an immune-related AEs[60]: (1) Switch ICI class from an anti-CTLA-4 to anti-PD-(L) agent or vice versa; (2) Rechallenge with an agent from the same class [anti-CTLA-4 or anti-PD-(L)]; and (3) Rechallenge with an agent from the same class [anti-CTLA-4 or anti-PD-(L)] with concurrent immunosuppressive use.

Since the two main classes of ICI agents [anti-CTLA-4 and anti-PD-(L)1] have distinct mechanisms of action, it is reasonable to consider a reintroduction of ICI therapy with the alternative agent class. Notably, anti CTLA-4 based regimens and combination therapy both have an increased risk of ICI hepatitis compared to anti-PD-(L)1 and monotherapy regimens[61,62]. Table 3 summarizes key studies that have investigated the safety and outcomes of ICI rechallenge in patients with a history of ICI hepatitis, with specific attention to cancer type, type of immunotherapy, and observed risk of hepatitis recurrence. This provides context for evaluating the potential risks and benefits of ICI resumption in this patient population (Table 3).

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.

While NCCN, ASCO and ESMO recommend close monitoring of LFT, there are no clear recommendations regarding frequency or duration of monitoring post ICI rechallenge or discussion on the role of continued mycophenolate use during the rechallenge period[25,28,45]. They acknowledge that this recommendation is based on experience and review of the literature though that management should be guided by an interdisciplinary discussion[53].

Ultimately, the decision to restart immunotherapy must be individualized with careful consideration to the severity of initial liver injury, initial response to treatment, the patient’s performance status, the patient’s goals of care, as well as the availability of alternate treatment. Further studies are needed to further elucidate the safety and efficacy of ICI rechallenge, particularly in the context of prior MMF use.

Future directions and unmet needs

As detailed throughout this review article, there are plenty of targets for future research and unmet needs in the treatment of ICI hepatitis. These include, but are not limited to: (1) Prediction of cancer response to ICIs; (2) Prediction of risk of ICI hepatitis; (3) Optimal initial workup of ICI hepatitis, including the role for liver biopsy; (4) Optimal initial treatment of ICI hepatitis; (5) Role and comparative effectiveness of second line agents; (6) Tapering strategies of corticosteroids and second line therapies; and (7) Risk and benefits of rechallenge with ICIs.

Another area of future investigation is the role of biomarkers including cytokines for both predicting patients at higher risk for ICI hepatitis and to help guide treatment strategies and tapering decisions[61-67]. Autoantibodies have also been studied to determine whether they can predict development of ICI-induced hepatitis and therefore may be useful in a tailored approach to tapering mycophenolate. However, a study that looked at autoantibodies including perinuclear antineutrophil cytoplasmic antibodies, Anti-actin, anti-smooth muscle antibody, anti-mitochondrial antibody, liver kidney microsomal antibody, and antinuclear antibody, as well as HLA subtyping, found no significant association between presence of autoantibodies and development of ICI-induced hepatitis[68].

For now, national guidelines, review articles, and ongoing collaboration between providers at the intersection of hepato-oncology will serve as the basis for our treatment of patients with ICI hepatitis, including those with steroid-refractory disease.

CONCLUSION

This review highlights the critical knowledge gaps and clinical variability surrounding MMF tapering in the management of ICI hepatitis. Despite its widespread use as a second-line agent for steroid-refractory cases, MMF tapering strategies remain highly individualized, with durations ranging from a few weeks to over six months. Current evidence suggests that tapering approaches—whether rapid or prolonged—are influenced by the severity of hepatic injury, initial response to immunosuppression, and underlying risk factors for relapse. However, the lack of standardized tapering protocols contributes to uncertainty in predicting recurrence and balancing hepatotoxicity control with the need to preserve oncologic benefit. Notably, successful tapering without flare appears feasible in selected patients, and emerging data support cautious ICI rechallenge following MMF withdrawal. Moving forward, the development of biomarker-guided tapering strategies and prospective clinical trials will be essential to refine treatment algorithms, reduce relapse risk, and support safe resumption of immunotherapy.