Treatment and outcomes of symptomatic hyperammonemia following asparaginase therapy in children with acute lymphoblastic leukemia

Mol Genet Metab. 2023 Jul;139(3):107627. doi: 10.1016/j.ymgme.2023.107627. Epub 2023 Jun 7.


Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.

Keywords: Erwinia; Phenylacetate; RC-P; Rylaze; Sodium benzoate.

MeSH terms

  • Ammonia
  • Antineoplastic Agents* / adverse effects
  • Asparaginase / adverse effects
  • Child
  • Glutamine / adverse effects
  • Humans
  • Hyperammonemia* / chemically induced
  • Hyperammonemia* / drug therapy
  • Phenylbutyrates / therapeutic use
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / chemically induced
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / complications
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Sodium Benzoate / adverse effects
  • Treatment Outcome


  • Asparaginase
  • 4-phenylbutyric acid
  • Phenylbutyrates
  • Sodium Benzoate
  • Glutamine
  • Ammonia
  • Antineoplastic Agents