Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers
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ORIGINAL ARTICLE – CLINICAL ONCOLOGY
Clinical features of immune‑mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers Atsushi Yamamoto1 · Yoshihiko Yano1 · Yoshihide Ueda1 · Eiichiro Yasutomi1 · Yuri Hatazawa1 · Hiroki Hayashi1 · Ryutaro Yoshida1 · Naoki Asaji1 · Yuuki Shiomi1 · Kazutoshi Tobimatsu1 · Arata Sakai1 · Yuzo Kodama1 Received: 2 October 2020 / Accepted: 29 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose The risk factors and clinical characteristics of ICI-induced immune-mediated hepatotoxicity (IMH) are not fully understood. Thus, the present study sought to clarify the clinical features of IMH. Methods All patients treated with ICIs between September 2014 and April 2019 at our institution were included. Clinical data were retrospectively collected from medical records. The frequency of grade ≥ 2 liver damage, clinical characteristics, and risk factors for developing IMH were examined. Results Overall, 250 patients (median age 71 years; range 30–87 years; 202 males and 48 females) were included in the analyses. Forty-five patients had elevated transaminase levels (> threefold the upper limit of normal). Of these, 21 were considered to have IMH. The remaining 24 patients had other causes of elevated transaminase levels. Steroids were administered to 13/21 patients with IMH. Although all patients exhibited improvement, IMH was not associated with the anticancer efficacy of the ICIs or OS. A multivariable analysis revealed that IMH was significantly associated with malignant melanoma (odds ratio [OR] 11.6; 95% confidence interval [CI] 3.5–38.0; P = 0.0002) and ipilimumab–nivolumab combination therapy (OR 61.2; 95% CI 7.9–1275.3; P threefold the upper limit of the institutional normal (ULN). In this study, IMH was defined as patients with grade ≥ 2 elevations in AST or ALT who could be excluded liver injury due to other causes. Patients with AST or ALT elevation > threefold the ULN at the start of ICI treatment were excluded from the analyses. Patients with known causes of liver injury other than ICI, such as biliary obstruction, other drugs, circulatory disorder, or cancer progression, were also excluded. The response and progression were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) at 3–6 months after starting ICI administration.
Statistical analysis We performed a χ2 test to assess the association between IMH and the anticancer effect or the prognosis of ICI therapy. Fisher’s exact test was used to identify possible risk factors for IMH. The factors were then entered into a stepwise logistic regression analysis using IMH as the dependent variable. A P value threefold the ULN at the start of ICI therapy. Among the 245 eligible patients, 45 (18.4%) had elevated AST or ALT levels > threefold the ULN during the observation period. Among them, 24 patients were excluded from further analysis because the cause of liver injury was biliary obstruction (n = 6), other drugs (n = 11
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