The ex vivo production of ammonia predicts l-asparaginase biological activity in children with acute lymphoblastic leukemia

Abstract

Patients with acute lymphoblastic leukemia (ALL), who develop antiasparaginase antibodies without clinical allergic reactions ("silent inactivation") during L: -asparaginase (L: -Asp) treatment, have poor outcomes. Ammonia is produced by hydrolysis of asparagine by L: -Asp. We postulated that plasma ammonia level might reflect the biological activity of L: -Asp. Five children with ALL treated according to the Tokyo Children's Cancer Study Group (TCCSG) protocol were enrolled. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature and "ex vivo ammonia production" was defined as increase in ammonia concentration. Ex vivo ammonia production well correlated with L: -Asp activity (r = 0.882, P < 0.01, n = 23). It always exceeded 170 microg/dL (170-345 microg/dL) in induction therapy. We found 3 patients whose ammonia production was negligible during later phases of therapy. Antiasparaginase antibody was detected and L: -Asp activity decreased in these patients. Ex vivo ammonia production is a surrogate marker of L: -Asp biological activity.

Plasma ammonia concentration after L‐asparaginase therapy in 27 dogs with high‐grade lymphoma or leukemia

“…14,35 One report found significant increases in plasma ammonia concentrations 1 day after intravenous L-asp, with plasma ammonia concentration reaching up to 7 times normal, although no signs of hyperammonemia were reported. 36 Another study found clinical signs of hyperammonemia including mild neurologic symptoms and vomiting in 7% of patients receiving asparaginase therapy over a 5-year period. 13 Plasma ammonia concentration in affected patients ranged from 260-700 mol/L (442-1192 g/dL), and affected patients all recovered after receiving acute detoxification therapy.…”

“…Clinical signs of hyperammonemia in people are reported to occur at plasma concentrations >58.7 μmol/L (>100 μg/dL) and include anorexia, irritability, lethargy, and vomiting . One report found significant increases in plasma ammonia concentrations 1 day after intravenous L‐asp, with plasma ammonia concentration reaching up to 7 times normal, although no signs of hyperammonemia were reported . Another study found clinical signs of hyperammonemia including mild neurologic symptoms and vomiting in 7% of patients receiving asparaginase therapy over a 5‐year period .…”

Clinical Utility of Ammonia Concentration as a Diagnostic Test in Monitoring of the Treatment with L-Asparaginase in Children with Acute Lymphoblastic Leukemia

“…Steiner et al described ammonia fluctuations in 10 patients treated with ASP, up to sevenfold above the normal values 1 day after ASP administration and slow returning to the normal level within 2 consecutive days, but the authors did not monitor ASP activity [16]. Watanabe et al found that ex vivo ammonia production well correlated with ASP activity, but only 5 patients were enrolled to the study and 23 samples were tested [17]. To the authors' knowledge, till now, there has been no publication describing a correlation between plasma ammonia level and ASP activity in larger cohort.…”

“…There are few studies concerning the ammonia concentration during a treatment with ASP [13–17]. A significant increase of ammonia levels after an intravenous ASP administration was described [13, 14, 16].…”

Hypoglycemia associated with L-asparaginase in acute lymphoblastic leukemia treatment: a case report

“…L-Asp activity was 0.709 U/mL on day 10, 0.674 U/mL on day 11, and 1.78 U/mL on day 12, where 25000 U/m 2 of L-Asp was administered on days 6 and 11. L-Asp activity was measured using the enzyme coupling methods described by Tsurusawa et al [13,14]. L-Asp activity above 0.1 U/mL was generally considered therapeutic.…”