High Incidence of Symptomatic Hyperammonemia in Children with Acute Lymphoblastic Leukemia Receiving Pegylated Asparaginase

Abstract

Asparaginase is a mainstay of treatment of childhood acute lymphoblastic leukemia. Pegylation of asparaginase extends its biological half-life and has been introduced in the newest treatment protocols aiming to further increase treatment success. Hyperammonemia is a recognized side effect of asparaginase treatment, but little is known about its incidence and clinical relevance. Alerted by a patient with severe hyperammonemia after introduction of the new acute lymphoblastic leukemia protocol, we analyzed blood samples and clinical data of eight consecutive patients receiving pegylated asparaginase (PEG-asparaginase) during their treatment of acute lymphoblastic leukemia. All patients showed hyperammonemia (>50 mmol/L) and seven patients (88 %) showed ammonia concentrations > 100 mmol/L. Maximum ammonia concentrations ranged from 89 to 400 mmol/L. Symptoms varied from mild anorexia and nausea to headache, vomiting, dizziness, and lethargy and led to early interruption of PEG-asparaginase in three patients. No evidence of urea cycle malfunction was found, so overproduction of ammonia through hydrolysis of plasma asparagine and glutamine seems to be the main cause. Interestingly, ammonia concentrations correlated with triglyceride values (r ¼ 0.68, p < 0.0001), suggesting increased overall toxicity.The prolonged half-life of PEG-asparaginase may be responsible for the high incidence of hyperammonemia and warrants future studies to define optimal dosing schedules based on ammonia concentrations and individual asparagine and asparaginase measurements.

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

“…[82] Asparaginase therapy has also been associated with nonantibody-mediated infusion reactions that may result from spikes in serum ammonia levels. [83][84][85][86] Ammonia accumulation occurs as asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid and glutamic acid, with ammonia as the shared by-product of both reactions. [10] Symptoms of hyperammonemia are often transient in nature and can include nausea, vomiting, headache, dizziness, and rash.…”

“…[10] Symptoms of hyperammonemia are often transient in nature and can include nausea, vomiting, headache, dizziness, and rash. [83,87,88] In patients receiving IV asparaginase, serum levels of ammonia have been shown to rise sharply following drug administration. Steiner et al [89] reported a significant elevation in ammonia levels in 10 patients 1 day after IV administration of native E. coli asparaginase (5000 IU/m 2 every 3 days), with recorded peak ammonia levels up to sevenfold the normal value.…”

IV Administration of Erwinia-Derived Asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia: Single-Centre Case Series

“…9 Furthermore, it is possible that the nausea experienced by patients in the current series was a result of increased serum ammonia secondary to asparagine breakdown, as described by other investigators. 15,16 None of the current patients experienced lethargy or alteration in mental status suggestive of severe hyperammonemia, but systematic comparison of these results to symptoms seems justified. Finally, a direct comparison of the adverse effects experienced by patients with IM versus IV administration of EA should be performed.…”

Non-cirrhotic Hyperammonemia—When High Ammonia Is not Always from Cirrhosis

“…On the other hand, high dose steroids can lead to hyperammonemia by their catabolic action on skeletal muscle. Several other medications have been associated with increased ammonia (Table 2) [25][26][27][28].…”