How is ir-hepatitis presented and reported in melanoma ICPI-treated patients?

Usually, ir-hepatitis is developed asymptomatically with mild elevation of aminotransferases on routine blood testing or with non-specific symptoms (eg, fever, fatigue) and is expressed as a mixed hepatocellular and cholestatic injury.17 However, in a few cases, if immune-mediated hepatotoxicity remains undiagnosed, untreated or becomes treatment-resistant, it can be worsened with highly increased aminotransferases, obstructive enzymes and serum bilirubin, progressing even to fulminant hepatic failure.17 18 The severity of immune-related hepatotoxicity is mainly driven by the elevation of ALT and AST, and do not necessarily require the co-increase of serum bilirubin or obstructive enzymes (eg, alkaline phosphatase (ALP) and GGT).16 Table 1 summarizes all the phase III trials investigating immunotherapy on patients with melanoma, and presents the rate and the level of AST/ALT increases as well as the reported ir-hepatitis. In view of these results, hepatotoxicity of any grade (1.2%–32.4% vs 1.8%–6.2%) and of grade ≥3 (0.0%–8.0% vs 0.4%–1.8%) occurs at higher rates in patients treated with ipilimumab compared with anti-PD-1 agents.8 In confirmation, the large open-label, multicohort, phase Ib KEYNOTE-001 that recruited 655 patients with metastatic melanoma and treated them with pembrolizumab, identified a similar low rate of both grade 1–2 (n=4, 0.6%) and grade 3–4 (n=2, 0.3%) ir-hepatitis with no effect of prior ipilimumab exposure.19

A meta-analysis synthesized the hepatotoxic risk of ICPIs among 17 phase II and III trials and reported an OR for any grade liver toxicity, 5.01 (95% CI 4.06 to 6.2) for anti-CTLA-4 inhibitors (ipilimumab and tremelimumab), compared with 1.94 (95% CI 1.28 to 2.94) for PD-1 inhibitors (nivolumab and pembrolizumab) and a respective OR for high-grade hepatotoxicity 4.67 (95% CI 3.42 to 6.39) and 1.58 (95% CI 0.66 to 3.78).20 In the same study, a subgroup analysis, according to the type of underlying malignancy, showed statistically significant differences between melanoma and other types of cancer (OR=5.66, 95% CI 4.39 to 7.29 vs OR=2.71, 95% CI 2.04 to 3.29). Ipilimumab-induced hepatitis, identified by liver enzyme disturbances, seems to be dose dependent (reaching a rate of 32.4% at 10 mg/kg vs 18.6% at 3 mg/kg for any grade hepatotoxicity and to 20.7% vs 3.1% for grade ≥3) and to affect more frequently patients receiving it in adjuvant versus metastatic setting (any grade: 13.2%–32.4% vs 0.8%–3.9% and grade ≥3: 3.1%–8.0% vs 0%–1.6%, respectively).

As expected, the two highest rates of hepatic enzymes elevations were observed in the studies where ipilimumab was combined with conventional chemotherapy with dacarbazine (grade 3–4 increase of AST: 17.4% and ALT: 20.7%)21 and with nivolumab (grade 3–4 increase of AST: 6.1% and ALT: 8.3%).9 10 The high rates of ir-hepatic AEs reported for the nivolumab/ipilimumab combination in the phase III CheckMate067 trial9 10 are in agreement with the findings of CheckMate069 phase II trial, where grade 3–4 elevation of transaminases occurred in 11% of patients treated with both ICPIs and in none of those treated with ipilimumab alone.22 However, no hepatitis-related death was recorded and severe hepatotoxicity was resolved in almost all cases, after initiation of immunosuppression and discontinuation of immunotherapy. In patients with melanoma treated with nivolumab, prior ipilimumab exposure may influence the expected hepatotoxicity risk. In CheckMate037 (phase III) and in CheckMate172 (phase II) trials, patients with relapsed melanoma on or after ipilimumab were treated with nivolumab, regardless of BRAF status and experienced grade 3–4 hepatic AEs in 0.7% and 2.8%, respectively.10 23 In addition to the different histological pattern of induced liver injury, which will be thoroughly discussed in the section of liver biopsy findings, De Martin et al also recognized that patients with CTLA-4-associated hepatitis had a longer time to hepatotoxicity onset (14 vs 3 weeks), were significantly older (69 vs 52 years), compared with those with PD-1/programmed death ligand 1 (PD-L1)-associated hepatitis, but with no gender disparity.24

Which is the diagnostic algorithm of immune-related hepatotoxicity?

Prior to any consideration of immunotherapy, a complete patient medical history is essential, including details on alcohol consumption, concomitant medications and chronic liver conditions, such hepatitis infections, non-alcoholic fatty liver or autoimmune disease. Based on data from immunotherapy on advanced/metastatic hepatocellular carcinoma, treatment with ICPIs is not contraindicated in patients with pre-existing chronic liver diseases and does not offer to them an increased risk for ir-hepatitis.25–27 However, before starting any ICPI, all patients with cancer should be physically examined for any clinical sign of advanced liver disease and baseline assessment with imaging and blood testing is also needed to recognize any hepatic disorder and to evaluate cancer burden and functional liver status. At the onset of immunotherapy, blood testing should be more extensive and should include complete blood count (CBC), liver biochemistries (eg, ALT, AST, ALP, GGT and bilirubin), metabolic and lipid profile, thyroid panel13 and serum screening for tuberculosis,28 for viral hepatitis (eg, surface antigen, surface antigen and core antibodies for hepatitis B virus; antibodies against hepatitis C and E viruses, against HIV and cytomegalovirus)29, as well as assessment for autoimmune liver damage, including antibodies of ANA, SMA, AMA, LKM and SLA.30 Before every immunotherapy cycle, main LFTs and CBC should be also repeated. Whenever aminotransferases rise, with or without a concurrent bilirubin elevation, all contributory reasons of liver injury including viral reactivation, autoimmune reaction or alcohol/drug abuse should be reconsidered and the above-mentioned specific diagnostic workup should be repeated. Patients with underlying liver diseases should be monitored more closely and be earlier referred for hepatology consultancy, even as early as the initiation of immunotherapy.

Is liver biopsy mandatory in the era of modern imaging modalities?

According to the recommendations of the European Association for the Study of the Liver, liver biopsy should be considered in cases with severe drug-induced liver injury or refractory hepatotoxicity to standard immunosuppression with corticosteroids, but the decision should be made by a multidisciplinary team.31 Given its invasive nature, its significant risks, and its relatively low clinical benefits, this diagnostic procedure should be performed in carefully selected patients.2 Indeed, ir-hepatitis does not offer pathognomonic histological findings and liver biopsy may assist only to exclude other causes of liver disease (eg, metastatic involvement or cirrhosis), to identify the type of liver injury, as well as to evaluate the severity of immune-mediated reaction.

In an effort to better characterize the liver injury induced by immunotherapy, De Martin et al analyzed 16 liver biopsies of cases with severe ir-hepatitis and noticed that the histological pattern in patients receiving anti-PD-1/PD-L1 agents alone was more heterogeneous compared with patients who received anti-CTLA-4 therapy.24 Histology related to anti-PD-1/PD-L1 inhibitors is characterized by lobular (mostly pan-lobular) inflammation with infiltrating CD4+/CD8+ T cells (in different proportions) and milder portal tract inflammation while it is usually indistinguishable from autoimmune hepatitis.24 On the other hand, histology related to anti-CTLA-4 inhibitors could be separately identified, more often with non-necrotizing granulomas17 24 and in some cases with additional sinusoidal histiocytosis and central vein endothelitis.24 Doherty et al described three histopathologically distinct cases with steroid-resistant, anti-PD-1-induced hepatotoxicity driven by biliary injury.32 None of these three cases demonstrated the above-mentioned histological characteristics of ir-hepatitis, nor was any significant lymphocytic infiltration evident while variable degrees of duct damage, including vanishing bile duct syndrome, was revealed at the time of liver biopsy. Despite the prolonged and severe course of hepatotoxicity, all three cases showed gradual improvement in LFTs after commencing steroids, and as a matter of fact, one did not require additional immunosuppression to recover ALT/ALP/bilirubin derangements.32

Encompassing the modern radiological modalities, alternative diagnoses such as progressive hepatic metastasis, cirrhosis, obstruction or cholestasis with elevated bilirubin, GGT and ALP can be sufficiently explored with the help of baseline and subsequent liver imaging, from a simple ultrasound up to MR cholangiopancreatography. Even on CT scans, commonly used to evaluate tumor burden in the liver, severe ir-hepatitis may be depicted with hepatomegaly, peri-portal edema and peri-portal lymphadenopathy while mild ir-hepatitis usually has normal appearance.33 If abdominal imaging is indicative of underlying cirrhosis, hepatic elastography (in patients without hepatic metastases) could further confirm cirrhotic liver without biopsy.

In general, liver biopsy is unlikely to affect hepatotoxicity management and should be suggested only in cases with significant diagnostic uncertainty. In support of this claim, the large recent retrospective study by Cheung et al identified 21 cases with ir-hepatitis among 453 immunotherapy-treated patients with cancer (incidence: 4%), all of whom were diagnosed and managed empirically without liver biopsy.34

When to discontinue and when to resume immunotherapy?

Given that ICPI-treated patients usually have metastatic cancer without many treatment options, the decision to temporarily withhold or permanently discontinue immunotherapy is a reasonable clinical dilemma. For patients with grade 1 hepatotoxicity, ICPIs can be uninterruptedly continued, but ALT/AST, ALP/GGT and bilirubin should be monitored before every cycle to promptly detect further elevation. For patients with grade 2 hepatotoxicity, ICPIs should be temporarily withheld and LFTs should be tracked closely (eg, every 3–5 days). In this moderate ir-hepatitis, steroids (usually prednisolone at a dose of 0.5–1 mg/kg/day) should be considered, if LFTs remain persistently raised on rechecking. Immunotherapy could be resumed when transaminases are improved to grade 1 or less and after a tapering of steroids. For patients with grade 3 or 4 elevation of liver enzymes, with or without concurrent bilirubin increase, ICPIs should be permanently discontinued.13 14 According to the summarized product information, pembrolizumab-induced hepatitis requires permanent immunotherapy discontinuation in only 0.3% of cases while 9% of patients with nivolumab/ipilimumab-induced hepatitis cannot continue their ICPIs combination.

Despite the general assumption that patients who discontinued CTLA-4/PD-1 blockade for severe irAEs will have relatively high rates of recurrent toxicities on immunotherapy resumption, there are many reported cases that resume immunotherapy without hepatotoxicity recurrence.5 24 34–36 For instance, De Martin et al reintroduced immunotherapy in 3 of 16 patients with ir-hepatitis without recurrence of liver dysfunction24 while Ziemer et al reported two cases with metastatic melanoma and ICPI-induced severe liver toxicity, in which immunotherapy was safely and effectively re-introduced with the concomitant administration of budesonide.37 Based on its topical liver-targeted immunosuppressive effect, the authors propose that budesonide could be a potential way to continue ICPIs even in cases where permanent withholding is recommended. Likewise, another recent study reported safe resuming of anti-PD-1 in 21 out of 29 patients (14 out of 19 cases for grade 3–4) with ir-hepatitis during combined anti-CTLA-4 and anti-PD-1 treatment of their metastatic melanoma.5 Switching between ICPIs, from a CTLA-4 inhibitor, with high susceptibility to recurrence, toward a PD-1/PD-L1 inhibitor should also be considered. In the study by Cheung et al,34 four patients who developed ir-hepatitis after double checkpoint inhibition underwent a rechallenge with immunotherapy when liver function abnormalities had resolved, two patients continued on nivolumab maintenance and another two changed to pembrolizumab with no sign of hepatotoxicity recurrence up to the date of publication.

Are corticosteroids needed in first-line treatment for ir-hepatitis?

As with the majority of other AEs induced by ICPIs, systemic corticosteroids should be considered for first-line treatment of ir-hepatitis.13–15 After ruling out other causes, persistent grade 2 liver enzymes elevation for >1 week should be treated with 1 mg/kg/day prednisolone or equivalents, with at least 1 month tapering. In cases with more severe hepatotoxicity (grade ≥3), methylprednisolone should be immediately initiated at a dose 1–2 mg/kg/day or an equivalent and on resolution of hepatotoxicity to less than grade 2, a slow tapering should follow. On receiving systemic corticosteroids, most patients with persistent grade 2 or worse ir-hepatitis will resolve their liver toxicity, with no long-term effects on their prognosis.

Interestingly, two recent reports challenge the necessity of corticosteroids in the management of ir-hepatitis. First, De Martin et al noticed the benign course of acute liver injury (grade ≥3) induced by immunotherapy in 16 patients with cancer treated with anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies, in monotherapy or in combination regimens.24 Without receiving any corticosteroid therapy, six of these patients (38%) experienced a spontaneous improvement in LFTs and no severe ir-hepatitis was observed after an immunotherapy rechallenge in two of them. In parallel, Gauci et al presented 10 patients with melanoma that experienced ir-hepatitis during their PD-1 and/or CTLA-4 inhibition.35 Hepatotoxicity recovered in all cases but in half of them no steroids were administered and no second-line immunosuppressive treatment was needed for any ir-hepatic AE. It is worth noting that resolution of ir-hepatitis was achieved in 4.7 weeks (median, range 2.0–20.6) for patients who did not receive any additional steroids (n=6, including one patient who was already under steroid treatment for cerebral metastasis) vs 8.6 weeks (median, range 4.3–55.1) in patients who received corticosteroids (n=4).35 No significant difference was observed due to the small number of patients. Both reports by De Martin et al and Gauci et al concluded that a more patient-oriented management is needed and systemic corticosteroid therapy could be eventually avoided. In accordance, a previous study coming from the Mount Sinai Medical Center reported a spontaneous resolution of ir-hepatitis in six patients (three of them with hepatotoxicity grade 3) after ipilimumab had been temporarily withheld, without administration of any additional immunosuppressive medication, including corticosteroids.38 Moving from the research findings to the market approval of nivolumab/ipilimumab combination, the pharmaceutical summary recognizes that only 46% of patients with melanoma will require high-dose corticosteroid (eg, at least 40 mg prednisone daily or equivalents) to resolve their PD-1/CTLA-4-associated hepatitis. The data above call into question the necessity of steroids in the frontline management of ir-hepatitis and, in any case, suggest that the administration of steroids should be guided by a multidisciplinary decision that takes into account the severity of liver injury. Regarding the exact dose regimen, no trials have directly addressed this issue and the commonly used corticosteroid dose of 1 mg/kg/day prednisolone (or equivalents) is borrowed from the management of other irAEs or from the treatment of autoimmune hepatitis. Recently, Cheung et al retrospectively compared two patient cohorts with ir-hepatitis that had been treated either with standard 50–60 mg prednisolone daily or with a higher steroid dose of 1 mg/kg/day.34 The higher prednisolone dose did not shorten the time of ALT recovery despite the fact that the group receiving this dosing regimen had a lower baseline ALT level than the group receiving the standard steroid dose.34 Looking through the studies on steroid-resistant ir-hepatitis (table 2), high-dose pulse steroids were also tested39–41 as a fast-acting immunosuppressive therapy but do not offer any significant benefit in the resolution of hepatotoxicity. It is interesting that in the case described by Nakano et al, the other immune-mediated toxicities (eg, skin rash and diarrhea) were rapidly improved by high-dose pulse steroids but not the patient’s hepatotoxicity.41

The response to steroids should be assessed in the first 48–72 hours and if further deterioration of liver function or no improvement is seen, then additional immunosuppressive therapy should be considered. In an effort to reconsider the need and response to steroids, Horvat et al estimated that in a cohort of 298 patients with melanoma treated with ipilimumab, 85% experienced an irAE of any type and grade, approximately one-third of them required systemic corticosteroids and almost a third of the latter required further immunosuppression.42 It is noteworthy that overall survival and time to ICPI failure were not affected by the occurrence of irAEs or the addition of steroids.42

Which is the optimal management of steroids-refractory ir-hepatitis?

In the rare cases of refractoriness on steroids, many agents have been studied and appear to be effective for treating resistant ir-hepatitis, including MMF (500–1000 mg twice daily),24 32 34 39–41 43–48 azathioprine (AZA) (1–2 mg/kg/day),49 50 6-mercaptopurine (6-MP) (1 mg/kg/day),17 ciclosporin (100 mg twice daily),50 antithymocyte globulin (ATG) (doses of 1.5 mg/kg),39 43–45 infliximab (5 mg/kg/dose),34 46 tacrolimus (targeting blood levels 8–10 ng/mL)34 46 and tocilizumab (4 mg/kg/dose)51 and plasmapheresis.47 These therapies, which specifically target T cell subpopulations, are preferred since hepatic infiltration by CD8+ T lymphocytes is the main histopathology finding in ir-hepatitis.

The American Association for the Study of Liver Diseases guidelines recommend AZA as the first-line choice for the treatment of autoimmune hepatitis, and MMF is considered as an alternative therapeutic option for patients who did not previously tolerate or failed to respond to AZA.52 Before using AZA or its active metabolite 6-MP, the FDA suggests testing for thiopurine S-methyltransferase (TMPT) genotype or enzyme activity in order to identify patients with decreased TPMT function that are at high risk for developing life-threatening bone marrow suppression. Based on their efficacy against autoimmune hepatitis, both AZA and 6-MP have been used in previous case reports to manage steroid-refractory ir-hepatitis.17 49 50 For example, Iwamoto et al successfully used AZA in the case of a Japanese man aged 75 years with metastatic melanoma who developed hepatotoxicity after 10 cycles of nivolumab.49 No clear evidence exists that AZA is superior to MMF in steroid-refractory ir-hepatitis.53 MMF is a purine antagonist that acts by inhibiting the proliferation of lymphocytes infiltrating the liver.54 Many studies have tested the addition of MMF to steroids after there was no response of hepatotoxicity to the initial immunosuppression and have successfully treated some of these cases.32 40 41 Therefore, without randomized evidence, MMF was added to the clinical guidelines as a second-line option for the treatment of steroid-resistant ir-hepatitis,15 55 and AZA is considered a legitimate alternative to MMF.

In the literature, only few cases required further immunosuppression due to failure of corticosteroids and MMF, all of which are summarized in table 2. In a large study, this year, including 5762 patients with cancer who received ICPIs (either as single agents or in combination regimens), among 433 cases (8%) experiencing hepatotoxicity of any grade, 67 required steroids, 10 had hepatitis recurrence after steroid tapering and only 2 patients had progressive hepatic injury and required MMF.48 Based on that both MMF and tacrolimus (a calcineurin inhibitor) are used as immunosuppressants in liver transplant recipients, the latter also having been tested in steroid-refractory cases with ir-hepatotoxicity.34 Among 21 patients with ir-hepatitis detected by Cheung et al, only 3 required a third-line immunosuppressant beyond steroids and MMF and responded after the addition of tacrolimus (one case) and infliximab (two cases).34 In general, infliximab should be avoided for the treatment of ir-hepatitis due to concerns about a rare autoimmune hepatocellular reaction induced by this medication.2 14 Last year, Zhang et al described a case with prostate adenocarcinoma, treated with ipilimumab and nivolumab combination, which developed hepatotoxicity after exposure to infliximab prescribed to treat ir-colitis.56 However, in extraordinary cases where patients co-develop ir-colitis non-responsive to steroids,57 or present side effects to other immunosuppressive agents,46 infliximab should be considered as an option. More specifically, Corrigan et al required to use four of these immunosuppressants (methyloprednisolone, MMF, infliximab, tacrolimus) to manage a grade 4 ir-hepatitis after 3 cycles of nivolumab/ipilimumab combination in a woman aged 53 years with metastatic BRAF-mutated melanoma.46 In this case, methylprednisolone 200 mg was given once daily for 5 days and then, treatment was escalated with MMF 1 g twice daily, as per recommended guidelines. MMF was discontinued after 7 days due to severe neutropenia while 2 cycles of infliximab were administered 2 weeks apart, with a rapid improvement in bilirubin and ALT.46 It is worth mentioning that the patient underwent three percutaneous liver biopsies during her hepatotoxicity management: 1) the initial one (at her diagnosis) showed severe acute lobular hepatitis with absence of fibrosis and predominance of CD3+CD8+ lymphocytes throughout; 2) the second one (after the intolerance to MMF and persistence of high LFTs) showed severe lobular CD3+CD8+ T cells predominant hepatitis with confluent/bridging necrosis and evolving mild peri-portal fibrosis, while 3) the last biopsy (8 weeks after infliximab treatment when ALT and bilirubin were increased yet again) revealed significant improvements in lobular inflammation, but progressive liver fibrosis with bridging and early nodule formation. Even the observed improvement of lobular inflammation, tacrolimus was initiated in order to keep immunosuppression and to gradually taper prednisolone, avoiding an immune flare. Eleven weeks after initial presentation of ir-hepatitis, LFTs recovered completely and despite intensive immunosuppression, 14 months after the last ICPI delivery, she had sustained radiological response, without further immunotherapy.

Ten years ago, when facing the clinical scenario of a patient with melanoma with resistant T cell-mediated fulminant hepatitis after adjuvant ipilimumab treatment for the first time, Chmiel et al 39 administered ATG (1.5 mg/kg) in order to overcome refractoriness to steroids and MMF. Within 24 hours, liver enzymes were normalized, followed by a suppression of total lymphocyte count and consistent symptoms of cytokine release (eg, fever and rigors). Subsequent ATG infusions over the next couple of weeks maintained lymphocytes at low levels, MMF was ceased over a period of 1 week while prednisolone dose was gradually weaned over the next 6 weeks, with marked improvement in his psychiatric background.39 The addition of ATG as a third-line option had shown similar efficacy in three other patients with melanoma with ir-hepatotoxicity.43–45 Spänkuch et al reported a metastatic melanoma patient with severe, fulminant nivolumab/ipilimumab-induced hepatitis in whom liver parameters were improved after 5 days of co-administration of ATG and high steroid doses (1 g/day) while previous therapies with prednisolone (2 mg/kg) and MMF had already failed.44 Being on steroid tapering, subsequent restaging revealed melanoma progression and immunotherapy with pembrolizumab was decided again with no new hepatic deterioration.44 Ahmed et al reported the co-administration of three immunosuppressants (MMF, methyloprednisolone and ATG) in an Australian woman with metastatic melanoma and ipilimumab-induced hepatitis after initial recurrence on steroids.43 Interestingly, in this case, equine antithymocyte globulin was used instead of rabbit thymoglobulin ATG as the latter was not available on site at that time.43 Finally, McGuire et al reported an unusually severe case of hepatitis arising in a patient with cutaneous melanoma after >6 months of uncomplicated adjuvant treatment with an anti-PD-1 agent.45 The rapidly developed resistance to the standard dose of methylprednisone and to steroid pulsing together with MMF forced the addition of ATG to control liver enzymes elevation. Mass cytometry analysis of the patient’s blood before melanoma onset revealed multiple abnormalities in CD4+ T cell phenotype, including a subpopulation of CCR4−CCR6− effector/memory CD4+ T cells, expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multidrug resistance type 1 transporter (MDR1) activity.45 The expression of MDR1 has been implicated in steroid resistance and may have contributed to the lack of a sustained steroid response.58 Circulating CD4+ T cells were profoundly depleted by ATG while CD8+ T cells, B cells, natural killer cells and monocytes were relatively spared.45

More revolutionary strategies have also been proposed recently, including plasma exchange for patients with acute liver failure due to ICPI-induced hepatitis.47 In this report, the authors describe a case of a woman aged 76 years with metastatic wild-type BRAF vulvar melanoma who initially developed a grade 2 ir-hepatitis due to nivolumab and in the next line of treatment, a grade 4 ipilimumab-induced hepatitis. Steroids were initiated at 2 mg/kg/day, and 48 hours later MMF (1.5 g/day) was added, but with further deterioration and hepatic encephalopathy. Thus, plasma exchange was tried in a course of five treatments with the patient experiencing a gradual clinical and analytical improvement. In another interesting study, tocilizumab, an anti-interleukin-6 antibody was tested for the management of steroid-refractory irAEs, including hepatitis, showing an overall clinical improvement in nearly 80% of the patients, with half of them requiring just a single dose.51 In a theoretical context, acetylcysteine may have a role in the recovery of hepatic damage while ursodeoxycholic acid may have a role in immune-mediated cholestasis.59

In order to sort the above-mentioned immunosuppressive options, a proposed therapeutic algorithm for severe (≥grade 3) ir-hepatitis, resistant to steroids, is presented in figure 2, including the differences among oncology experts’ societies. Large immunotherapy trials are not designed to respond with details about how the ICPIs-induced toxicities are treated, keeping precise records of administered immunosuppressants (eg, dose, sequence, etc). In addition, the treatment of developed ir-AEs, including ir-hepatitis, is not usually described when the original trial is published. Thus, the main information for the management of immune-mediated toxicities comes from retrospective studies and case reports. Regarding ir-hepatitis, current data presented in table 2 are limited to establishing the use of any immunosuppressive agent in the treatment of steroid-resistant and MMF-resistant ir-hepatitis and in each case, the decision should be completely personalized. In this respect, we could only highlight the requirements that should be satisfied by the selected agent: i) it should be administered with feasibility and safety for prolonged duration (>6 weeks), ii) it should keep stable immunosuppression without additional corticosteroids and iii) it should allow for the weaning of steroids and of MMF, as soon as possible, without an immune flare. Based on the experience from the era of organ transplantation and autoimmune hepatitis, tacrolimus seems to surpass the other immunosuppressive agents in the management of immunotherapy-associated hepatotoxicity. It is an oral macrolide antibiotic with a powerful immunosuppressive activity (100–1000 more potent calcineurin inhibitor than ciclosporin),60 measurable serum levels and well-tolerated toxicities. At the molecular level, tacrolimus binds to intracellular immunophilins and this complex inhibits the enzyme of calcineurin, which is needed for the cytokine production.60 This loss-of-function of the enzyme results in a net inhibitory effect on both B and T cells, making tacrolimus a potential therapeutic option for any immune-mediated reaction. Finally, monitoring serum levels of tacrolimus will allow its prolonged administration and reduce the risk of major dose-dependent AEs (eg, nephrotoxicity and neurotoxicity).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

A suggested algorithm for the addition of further immunosuppressive options after steroid failure in ir-hepatitis and the differentiations between oncology societies. ASCO, American Society of Oncology; ESMO, European Society of Oncology; LFTs, liver function tests; MMF, mycophenolate mofetil; NCCN, National Comprehensive Cancer Network; SITC, Society of Immunotherapy of Cancer.