S2913 Tocilizumab As an Effective Steroid-Sparing Agent for the Treatment of Recurrent and Steroid-Dependent Immune Checkpoint Inhibitor-Mediated Hepatotoxicity: A Case Study and Insight into Pathophysiology

Introduction: Immunotherapy-mediated hepatotoxicity (IMH) is a well-recognized immune-mediated adverse event (irAE) in patients who undergo treatment with immune checkpoint inhibitors. An effective pathway for addressing steroid-resistant or steroid-dependent cases of IMH remains an area of ongoing investigation. Limited published experience has introduced tocilizumab, an IL-6 receptor antagonist, as a viable steroid-sparing agent to manage challenging cases of IMH. We describe a successful case of utilizing tocilizumab in both subcutaneous (SC) and intravenous (IV) forms, without concurrent steroids, to treat a case of recurrent and steroid-dependent IMH. Case Description/Methods: A 32-year-old woman with a history of Hodgkin lymphoma and no underlying liver disease was evaluated for elevated liver enzymes. Her lymphoma was managed with autologous stem cell transplant (SCT) (2011), allogenic SCT (2012), nivolumab (2016), and lenalidomide (2019). She started pembrolizumab in 3/2020; the dose was increased by 12/2020. Due to CTCAE grade 3 liver toxicity in 1/2021, pembrolizumab was held. A liver biopsy performed in 2/2021 confirmed IMH (instead of hepatic graft-vs-host disease). Initial treatment with prednisone (total of 66 days) yielded biochemical remission. By the end of 4/2021, she was re-challenged with one dose of pembrolizumab but soon developed grade 4 liver enzyme elevations, so prednisone was reintroduced (induction dose 60 mg/d), but liver enzymes exhibited only partial improvement after 70 days of steroids. Liver enzymes increased again after stopping steroids. Repeat liver biopsy reaffirmed IMH. To avoid prolonged exposure to systemic corticosteroids, SC tocilizumab 162 mg was given, leading to subsequent improvement in liver enzymes. She developed a brief episode of shingles that was treated. IV tocilizumab 4 mg/kg was given about 2 months later to bring her to biochemical remission that was achieved 1.5 months thereafter, without need for steroids. (Figure) Discussion: IL-6 plays an important role in liver biology. Limited reports feature tocilizumab as a feasible and effective option to treat select cases of IMH, including cholangiohepatitis phenotypes and steroid-refractory cases. In this case, both SC and IV tocilizumab conferred efficacy in treating IMH without concurrent systemic steroids. Our example further highlights the unmet clinical need to study steroid-sparing strategies in order avert a protracted course of steroids and to allow patients to engage sooner in additional cancer treatment.Figure 1.: (A) and (B): Histologic evaluation (hematoxylin & eosin) from the second liver biopsy, which was performed before initial tocilizumab administration. The key features include panlobular hepatitis with bridging/centrilobular necrosis. The portal tracts show slight expansion with a mixed inflammatory infiltrate, comprised mostly of lymphocytes and occasional neutrophils and plasma cells, interface activity, bile duct injury, and bile ductular proliferation, without bile ductopenia, and no florid duct lesions are identified. No granulomas are seen. (C): Timeline of liver biochemical tests and associated treatments. Although induction steroids with prednisone 60 mg/d was able to yield improvement in liver enzymes, subsequent elevation of liver enzymes after completion of steroid taper suggests she was steroid-dependent. Subcutaneous tocilizumab was administered, yielding significant response but not yet ALT normalization before a second dose of tocilizumab (now intravenous route) was administered to eventually attain biochemical remission. No additional corticosteroids were prescribed. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; SC, subcutaneous; IV, intravenous; d, day. Table 1. - Chronological biochemical lab trends referenced from the time of initial tocilizumab (subcutaneous) administration Lab (Reference range) Day 0 (SC toci given) Day 1 Day 14 Day 21 Day 30 Day 85 Day 93 (IV toci given) Day 130 ALT (N ≤ 33 U/L) 360 349 344 297 274 80 107 30 AST (N ≤ 32 U/L) 449 417 400 347 290 120 138 35 ALP (N = 35 – 104 U/L) 163 162 165 116 133 102 145 90 GGT (N = 5 – 36 U/L) 133 137 203 - - - 62 - IL-6 (N = 0 – 5 pg/mL) 102 89 - - - - 222 - No systemic corticosteroids were administered in the time frame displayed. Intravenous tocilizumab (4 mg/kg) was administered at 2.8 months from the initial tocilizumab dose, at which time there was already significant improvement in the transaminase levels, and biochemical remission (normalization of ALT) was achieved an additional 1.5 months thereafter. There was no correlation of liver biochemical response with the serum IL-6 level. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; IL-6, interleukin-6; SC, subcutaneous; IV, intravenous; toci, tocilizumab.