Significance of Immune-related Lipase Increase Induced by Antiprogrammed Death-1 or Death Ligand-1 Antibodies: A Brief Communication

Abstract

Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4-11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment.

Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury

“…The clinical presentation of ICIPI was similar to the clinical picture of traditional acute pancreatitis, including epigastric pain, nausea and vomiting, fever, and diarrhea. Our findings are consistent with those of a case series of 21 patients with ICI-induced serum lipase elevation, in which 14% of patients developed symptoms of pancreatitis and 86% of patients were asymptomatic [21]. No statistically significant differences were found in that study regarding the presence of clinical symptoms in patients who received anti-CTLA-4–based therapy compared with those who received anti-PD-1/L1 therapy.…”

“…This finding suggests that patients with asymptomatic ICIPI could have been undertreated owing to underestimation of the degree of ICIPI. This contradicts a previous recommendation to treat asymptomatic lipase elevation as an insignificant finding [21]. Our findings indicate that IV fluid administration should be considered, even in asymptomatic patients, for lipase elevation of grade 3 or higher, especially within 48 h of onset, to minimize long-term adverse outcomes.…”

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

“…Previous studies have hypothesized that autoimmune T1DM is a combined endocrine–exocrine disease wherein loss of functional β-cell mass is most clinically apparent ( 122 ), and non-specific elevations in amylase and lipase occur in 16–25% of cases with DKA in ‘classic’ T1DM ( 123 ). In the context of ICI therapy, asymptomatic elevations in lipase and/or amylase have also been reported in the absence of new-onset DM ( 124 , 125 ). Several authors have also described radiographic changes in pancreatic volume during immunotherapy, notably pancreatic enlargement before DM onset followed by a decrease in volume ( 121 , 126 ).…”

“…Several authors have also described radiographic changes in pancreatic volume during immunotherapy, notably pancreatic enlargement before DM onset followed by a decrease in volume ( 121 , 126 ). In the study by Michot et al , 3 of 21 patients (14%) developed clinical or radiologic immune-related pancreatitis that led to permanent treatment discontinuation in 15 of 21 (71%) patients, while the increase in lipase was not considered clinically significant, and treatment was continued ( 125 ). Ongoing pancreatic inflammation has been hypothesized to be a factor in the precipitation of DM; however, this is an additional question that should be addressed in prospective studies ( 109 , 127 ).…”

Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?

“…Some authors recently demonstrated that high lipase level was not associated with pancreatic disease in most cases and should not be automatically associated with treatment cessation [72].…”