Kazuyuki Mizuno1, Takanori Ito2, Masatoshi Ishigami1, Yoji Ishizu1, Teiji Kuzuya1, Takashi Honda1, Hiroki Kawashima3, Yosuke Inukai4, Hidenori Toyoda4, Kenji Yokota5, Tetsunari Hase6, Osamu Maeda7, Hitoshi Kiyoi8, Masato Nagino9, Hideharu Hibi10, Yasuhiro Kodera11, Yasushi Fujimoto12, Michihiko Sone12, Momokazu Gotoh13, Yuichi Ando7, Masashi Akiyama5, Yoshinori Hasegawa6,14, Mitsuhiro Fujishiro1. 1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. 2. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. tahkun56@med.nagoya-u.ac.jp. 3. Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan. 4. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan. 5. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 6. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. 7. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan. 8. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 9. Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 10. Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 11. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. 12. Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 13. Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 14. National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.
Abstract
BACKGROUND: Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. METHODS: A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. RESULTS: Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001). CONCLUSIONS: We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.
BACKGROUND:Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. METHODS: A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. RESULTS: Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001). CONCLUSIONS: We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.
Authors: Johanna Winter; Max M Lenders; Maximilian Gassenmaier; Andrea Forschner; Ulrike Leiter; Benjamin Weide; Mette-Triin Purde; Lukas Flatz; Antonio Cozzio; Martin Röcken; Claus Garbe; Thomas K Eigentler; Nikolaus B Wagner Journal: Cancer Immunol Immunother Date: 2020-10-28 Impact factor: 6.968