Immunosuppressant mycophenolate mofetil for patients with steroid-refractory immune-related hepatitis induced by checkpoint inhibitors in oncology.

Immune-checkpoint inhibitor (ICI) hepatitis, which does not improve with steroids and requires additional immunosuppressant, is defined as steroid-refractory ICI hepatitis. The outcome of patients with steroid-refractory ICI hepatitis remains poorly determined. Herein, we investigated the incidence, clinical features, and outcome of patients treated with second-line immunosuppressant for steroid-refractory ICI hepatitis. This is a retrospective analysis of patients who presented ICI hepatitis from 1st June 2016 to 30th September 2022. Steroid-refractory ICI hepatitis was defined as no clinical and biological improvement after systemic steroid therapy ≥1 mg/kg/d. Main objectives were to assess the frequency and risk factors associated with steroid-refractory ICI hepatitis and to evaluate the efficacy of second-line immunosuppressants. In total, 130 patients with grade ≥3 ICI hepatitis were screened, of them 60 (46.2%) were treated with systemic steroids. In total, 11/130 (8.5%) had steroid-refractory hepatitis. Statistically significant factors associated with steroid-refractory hepatitis included previous liver comorbidities (54.5% versus 11.6%; p < 0.01), hyperbilirubinemia (p < 0.001), and general symptoms (fever, jaundice, ascites, and/or encephalopathy) associated with hepatitis (72.7% versus 30.8%; p = 0.015). The 11 patients with steroid-refractory hepatitis were treated with mycophenolate mofetil. In total, resolution or return to grade ≤1 for hepatitis was observed in 81.8% (9/11) of patients. Steroid-refractory ICI hepatitis accounted for 8.5% of patients with grade ≥3 immune-related hepatitis and was statistically associated with previous liver comorbidities, hyperbilirubinemia, and general symptoms. Mycophenolate mofetil was a suitable option of therapy for steroid-refractory ICI hepatitis.

Alouani E ，Laparra A ，Perret A ，Sakkal M ，Messayke S ，Danlos FX ，Ouali K ，Hollebecque A ，Even C ，Ammari S ，Baldini C ，Champiat S ，Besse B ，Robert C ，Guettier C ，Samuel D ，Lambotte O ，De Martin E ，Michot JM ... -  《-》

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

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

Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.

Ruf T ，Kramer R ，Forschner A ，Leiter U ，Meier F ，Reinhardt L ，Dücker P ，Ertl C ，Tomsitz D ，Tietze JK ，Gutzmer R ，Dabrowski E ，Zimmer L ，Gesierich A ，Zierold S ，French LE ，Eigentler T ，Amaral T ，Heinzerling L ... -  《-》

Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events.

The optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the basis of case reports and expert opinion. We evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes. Among 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure). Steroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.

Luo J ，Beattie JA ，Fuentes P ，Rizvi H ，Egger JV ，Kern JA ，Leung DYM ，Lacouture ME ，Kris MG ，Gambarin M ，Santomasso BD ，Faleck DM ，Hellmann MD ... -  《-》

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》