Risk factors and long-term prognostic impact of immunerelated pancreatic injury in patients receiving immune checkpoint inhibitors

Yu AkazawaTakuto NosakaYosuke MurataTomoko TanakaKazuto TakahashiTatsushi NaitoMasahiro OhtaniYasunari Nakamoto^*

• Department of Second Internal Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan

Background: With the widespread use of immune checkpoint inhibitors (ICIs), the management of immune-related adverse events (irAEs) has become increasingly important. ICI-induced pancreatic injury (ICI-PI) is rare, and its clinical characteristics remain unclear. This study aimed to clarify the risk factors for the development of ICI-PI and prognostic impact of ICI-PI. Methods: A total of 1039 patients with malignant tumors who received ICI therapy were recruited from September 2014 to December 2024 for this retrospective study. The clinical and pathological characteristics of ICI-PI, including risk factors and prognostic impact, were analyzed. The onset of ICI-PI and irAEs of other organs were defined according to CTCAE ver5.0. The pathological characteristics were evaluated using pancreatic tissue specimens obtained by endoscopic ultrasound-guided fine-needle biopsy. Results: Of the 982 patients (703 males, 279 females; median age, 71.1 years) included in the study, 48 (4.9%) developed ICI-PI (Grades 2, 3, and 4 in 41, 3, and 4 cases, respectively), and 6 patients (0.6%) developed pancreatitis. Multivariate analysis revealed that the high serum amylase levels before ICI administration (odds ratio, 6.10; 95%CI, 2.55-14.6; P < 0.001) and the onset of irAE in other organs (odds ratio, 3.49; 95%CI, 1.88-6.49; P < 0.001) were independent risk factors for ICI-PI development. The incidence of other organ irAEs was significantly higher in the ICI-PI onset group than in the ICI-PI non-onset group (P < 0.001). Additionally, there was significantly better overall survival in the ICI-PI onset group than in the ICI-PI non-onset group (P < 0.001), which was corroborated by a landmark analysis. Also, pathological examination of ICI-related pancreatitis using multiplex fluorescence immunohistochemistry demonstrated infiltration of predominantly CD8 positive T lymphocytes contained abundant granzyme B into the pancreatic parenchyma. Conclusions: High serum amylase levels before ICI administration and development of other organ irAEs were identified as novel risk factors for ICI-PI onset, and the long-term prognosis was better in patients with ICI-PI. This finding suggests that thorough systemic management, including proactive evaluation of serum amylase levels and comprehensive monitoring for various irAEs, can contribute to early detection of ICI-PI, potentially leading to improved patient outcomes.