Hypersensitivity to E. coli-derived asparaginase

Asparaginase therapy has been a core component of multiagent treatment regimens for patients with acute lymphoblastic leukemia and lymphoblastic lymphoma for more than 45 years.

Asparaginase is an enzyme that targets and mediates hydrolysis of asparagine, an amino acid that leukemia cells—as well as healthy cells—require for growth.

Asparaginase converts serum asparagine into aspartic acid and ammonia, depriving leukemia cells of asparagine.

The depletion of asparagine prohibits protein synthesis, leading to leukemia cells being unable to proliferate and survive.

Asparaginase-containing treatment regimens for ALL and LBL most commonly utilize long-acting E. coli-derived asparaginase.

Exposure to asparaginase treatment can trigger an immune response in the body that results in the proliferation of antibodies from plasma B cells, which can lead to hypersensitivity.

Immunoglobulin E, or IgE, antibodies can activate immune cells called mast cells, which are central to the physiology that underlies clinical hypersensitivity.

IgE antibodies attach their fragment crystallizable, or Fc region, to the mast cell, exposing their fragment antigen binding region, known as Fab, to encounter an antigen.

If a patient is re-exposed to the antigen, the Fab region of the IgE antibody crosslinks to the antigen.

When IgE antibodies are bound to mast cells in the presence of asparaginase, mast-cell degranulation is triggered, leading to the release of immune mediators of chemical substances, such as histamines, prostaglandins, leukotrienes, and cytokines, which trigger activation of other immune cells.

In this manner, these IgE antibodies can cause hypersensitivity.

Hypersensitivity can affect a range of organ systems.

Severe hypersensitivity reactions can include anaphylaxis and even lead to death.

Immunoglobulin G, or IgG, is another type of antibody.

IgG antibodies can bind and create immune complexes with asparaginase in the blood, leading to phagocytosis, which neutralizes asparaginase in the blood. This leads to the rapid clearance of asparaginase, and significant reduction in asparaginase activity.

IgG antibodies can compromise asparaginase efficacy by shortening asparaginase half-life, causing subtherapeutic asparaginase levels, and reduced depletion of asparagine.

To help maintain asparaginase activity and optimal asparagine depletion, patients experiencing hypersensitivity to E. coli-derived asparaginase should switch to an immunologically distinct asparaginase.

The switch should occur as soon as clinically possible, ideally within 48 to 72 hours, to ensure that asparaginase activity is maintained and patients do not miss a scheduled dose.

Patients who develop hypersensitivity to asparaginase therapy are at increased risk of experiencing another reaction if treated again with asparaginase derived from the same source.

Switching to recombinant Erwinia chrysanthemi-derived asparaginase—which has minimal immunologic cross-reactivity to E. coli-derived asparaginase—can help prevent missed doses and provide sustained asparaginase activity.