Mycophenolate mofetil for immune checkpoint inhibitor-related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review.

Immune checkpoint inhibitors (ICIs) sometimes cause immune-related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high-dose corticosteroids are usually effective in treatment of ICI-related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI-related liver injury that relapses under corticosteroid therapy after temporary remission. Here we report two cases of ICI-related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74-year-old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI-related liver injury (mixed pattern) developed. In the second case, a 46-year-old man with stage IVB lung cancer received pembrolizumab-containing chemotherapy. After the first cycle, grade 2 ICI-related hepatitis developed. In the both cases, liver injury improved with high-dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI-related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone. MMF appears to be an appropriate treatment option for ICI-related liver injury that respond to high-dose corticosteroids but relapse during steroid tapering.

Ueno M ，Takabatake H ，Hata A ，Kayahara T ，Morimoto Y ，Notohara K ，Mizuno M ... -  《Cancer Reports》

Effectiveness of tacrolimus in a case of immune checkpoint inhibitor-induced hepatotoxicity that was refractory to steroids and mycophenolate mofetil.

Immune checkpoint inhibitors (ICIs) sometimes induce immune-mediated hepatotoxicity (IMH), and corticosteroids and mycophenolate mofetil (MMF) are recommended for the treatment of IMH. However, there is no consensus on the treatment of IMH refractory to these drugs. Here, we report a case of refractory IMH that was successfully treated with tacrolimus. A 69-year-old man presented with liver injury after receiving durvalumab, an ICI, for lung cancer. He was diagnosed with IMH and received corticosteroids including methylprednisolone pulses and MMF, but his liver damage did not improve. Liver histology showed infiltration of inflammatory cells, mainly CD8 + T cells, in the portal area. Tacrolimus was added to corticosteroid and MMF to suppress mainly T cells. After the tacrolimus administration, the liver damage promptly improved. Since IMH is thought to be caused by activated CD8 + T-cell infiltration, T-cell suppression may be an effective treatment. This case suggests that tacrolimus may be an effective option for IMH refractory to corticosteroids or MMF if CD8 + T-cell infiltration is confirmed in the liver tissue.

Sato K ，Inoue J ，Ninomiya M ，Iwata T ，Sano A ，Tsuruoka M ，Onuki M ，Sawahashi S ，Ouchi K ，Masamune A ... -  《-》

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

Suzuki Y ，Ishiguro S ，Shimada H ，Ohgami M ，Suzuki M ... -  《-》

Steroid-refractory immune checkpoint inhibitor (ICI) hepatitis and ICI rechallenge: A systematic review and meta-analysis.

Hwang SY ，Hsieh P ，Zhang W 《Hepatology Communications》

Effect of corticosteroid dosing on outcomes in high-grade immune checkpoint inhibitor hepatitis.

Consensus guidelines recommend high-dose corticosteroids (1-2 mg/kg/day methylprednisolone equivalents) for treating grade ≥3 immune checkpoint inhibitor (ICI) hepatitis. We examined the effect of corticosteroid dosing on time to alanine aminotransferase (ALT) normalization, need for additional immunosuppression, and steroid-related complications. We conducted a retrospective cohort study of 215 ICI-treated patients from 2010 to 2020 who developed grade ≥3 (ALT > 200 U/L) ICI hepatitis. Patients were grouped by initial corticosteroid dose (≥1.5 mg/kg or <1.5 mg/kg methylprednisolone equivalents). Propensity scores were calculated predicting the risk of receiving the higher steroid dose and used in inverse probability of treatment weighted (IPTW) logistic or Cox regression. The 87 patients in the ≥1.5 mg/kg group received higher initial (2.0 vs. 0.8 mg/kg/day, p < 0.001) and maximum (2.0 vs. 1.0 mg/kg/day, p < 0.001) steroid doses than the 128 patients in the <1.5 mg/kg group. There was no difference between the higher versus lower-dose groups in development of steroid-refractory hepatitis (OR 1.22, 95% CI 0.79-1.89, p = 0.365) on IPTW-logistic regression. In patients with steroid-responsive disease, there was no difference between the two groups in time to ALT normalization using either standard Cox regression (HR 1.02, 95% CI 0.72-1.45, p = 0.903) or IPTW-Cox regression (HR 1.09, 95% CI 0.78-1.51, p = 0.610). The ≥1.5 mg/kg group had longer exposure to corticosteroids (median 60 vs. 44 days, p = 0.005) and higher incidences of infection (18.4% vs. 7.0%, relative risk [RR] 2.6, 95% CI 1.2-5.6, p = 0.011) and hyperglycemia requiring treatment (23.3% vs. 7.8%, RR 3.0, 95% CI 1.5-6.0, p = 0.001). In patients with high-grade ICI hepatitis, initial treatment with 1 mg/kg/day methylprednisolone equivalents provides similar hepatitis outcomes with reduced risk of steroid-related complications when compared with higher-dose regimens.

Li M ，Wong D ，Vogel AS ，Sack JS ，Rahma OE ，Hodi FS ，Zucker SD ，Grover S ... -  《-》