S4 Autoimmune Pancreatitis Secondary to Immune Checkpoint Inhibitor Therapy (Type 3 AIP): Insights into a New Disease from Clinical Review and Serial Pancreatic Imaging

Abstract

Introduction: Autoimmune pancreatitis (AIP), types 1 and 2, are well described. While type 1 AIP is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD) and type 2 AIP is a duct-centric pancreatic injury sometimes associated with inflammatory bowel disease. A third form of AIP (type 3) is caused by increased immune activity by immune checkpoint inhibitor therapy (ICI-℞) for advanced malignancies. We describe the clinico-radiological spectrum and short-term natural history of type 3 AIP. Methods: We performed a detailed clinical record review of the 248/11,165 (2.2%) adult patients receiving ICI-℞ who developed type 3 AIP (>3-fold serum lipase elevation + pain, absent other etiologies). A radiologist reviewed 379 abdominal computerized tomography scans (CT) and measured pancreas volume in a subset of CTs done before, during and after pancreatitis. Results: At onset, type 3 AIP was painful in 96 (38%) and asymptomatic in 154 (62%); none had jaundice or local/systemic complications. CT showed normal pancreas (43%), peri-pancreatic edema (27%), loss of feathery pattern (21%) or diffuse/focal pancreatic enlargement (10%). A minority achieved complete and persistent biochemical resolution, more often when ICI-℞ was held (32/89) vs no intervention (13/84, P = 0.003) or vs steroid treatment alone (2/23, P = 0.01). Early or late relapses occurred equally frequently regardless of intervention. Compared to pancreas volume before ICI-℞, >20% volume loss occurred in 55% 1 year post-pancreatitis, more so with dual ICI-Rx, regardless of pain or steroid therapy at presentation. 18% had new diabetes within 2 years of pancreatitis. No patient developed calcifications or duct dilation. Conclusion: Type 3 AIP is a novel drug-induced chronic inflammatory disease of the pancreas. Predominantly asymptomatic and mild in severity, it causes rapid pancreatic atrophy and functional endocrine failure despite steroid therapy or ICI-℞ withdrawal. Table 1. - Clinical profile of all type 3 and subjects in imaging cohorts Type 3 AIP* (n=248) Imaging cohort (n=93) Symptomatic (n=94) Asymptomatic (n=154) ≥3x lipase elevation cohort (n=48) 2x lipase elevation cohort (n=24) Normal lipase cohort (n=21) Median Age in years (IQR) 61 (50-68) 62 (54-69) 58 (49-67) 63 (54-69) 59 (55-67) Male N (%) 37 (39%) 72 (47%) 17 (35%) 18 (75%) 13 (62%) Cancer type (%) Genitourinary 27 (29%) 63 (41%) 20 (42%) 14 (58%) 10 (48%) Melanoma 26 (28%) 28 (18%) 16 (33%) 3 (13%) 5 (24%) Other 41 (44%) 63 (41%) 12 (25%) 7 (29%) 6 (29%) ICI Agent (%) CTLA-4 8 (9%) 10 (6%) 5 (10%) 2 (8%) 4 (19%) PD-1 62 (66%) 95 (62%) 28 (58%) 14 (58%) 10 (48%) Combined 24 (26%) 49 (32%) 15 (31%) 8 (33%) 7 (33%) ICI doses prior to elevated lipase (IQR) 4 (2-6) 3 (2-8) 5.5 (3-10) 4.5 (3-13) 3 (2-5, to normal lipase) Median days from ICI to pancreatitis (IQR) 114 (69-264) 113 (52-230) 124 (83-261) 175 (63-348) 95 (47-167, to normal lipase) ICI discontinued (%) 67 (71%) 74 (48%) 28 (58%) 14 (58%) 11 (52%) Risk factors (%) Alcohol consumption 40 (43%) 69 (45%) 22 (46%) 13 (54%) 12 (57%) Smoking history 52 (55%) 77 (50%) 24 (50%) 17 (71%) 7 (33%) Diabetes prior to pancreatitis 16 (17%) 44 (29%) 15 (31%) 6 (25%) 4 (19%) Drug allergy 56 (60%) 81 (53%) 22 (46%) 10 (42%) 10 (48%) Prior history of pancreatitis 5 (5%) 6 (4%) 2 (4%) 1 (4%) 0 *Autoimmune pancreatitis, IQR= interquartile range, ICI= immune checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death receptor-1) and PD-L1 (programmed cell death ligand-1) Figure 1.: a: Serial pancreatic volume in normal lipase, 2x and 3x groups (median, cm3), b: Serial Pancreatic Volume: Single Agent vs Combination in 3x group (median, cm3), c: Percentage of patients with >20% pancreas volume loss in each group.