L-Asparaginase-Induced Pancreatic Injury is Associated with an Imbalance in Plasma Amino Acid Levels

BACKGROUND: The use of L-asparaginase (ASNase) to modify amino acid metabolism is one of the most effective chemotherapeutic means of inducing remission in acute lymphoblastic leukemia (ALL). However, severe pancreatitis sometimes occurs in patients receiving ASNase, because of an unknown mechanism. OBJECTIVE: The purpose of the present study was to evaluate the relationship between ASNase-induced pancreatic injury and plasma amino acid levels in patients undergoing ASNase therapy. METHODS: A total of 29 children aged 1–13.25 years (median age 4 years; male:female ratio 19:10) with ALL, who received induction therapy according to the Tokyo Children’s Cancer Study Group L04–16 protocol, were studied. Levels of plasma amino acids and serum rapid turnover proteins (RTPs), pancreatic enzymes, and pancreatic protease inhibitors were measured before and 1, 2, 3, 4, 5, and 7 weeks after the first administration of ASNase. RESULTS: Plasma asparagine levels were significantly lower after the first injection of ASNase (p<0.01) and had almost recovered 2 weeks after the last ASNase injection. At 4 weeks after the first ASNase injection, serum aspartic acid, trypsin, and pancreatic secretory trypsin inhibitor (PSTI) levels remained significantly higher than those before the first ASNase injection (p<0.01), and serum levels of prealbumin and transferrin remained significantly lower than those before the first ASNase injection (p<0.01). Plasma amino acid and serum RTP levels gradually normalized after the last ASNase injection. CONCLUSIONS: Levels of serum trypsin and PSTI were elevated during the 2 weeks after administration of ASNase, which suggested the presence of subclinical pancreatitis. This period is similar to the time period in the present study when the levels of plasma amino acids changed, thus suggesting that ASNase-induced pancreatic injury could be caused by the imbalance of plasma amino acid levels.