How Genes Influence Asparaginase Allergy?

What is Asparaginase?

Asparaginase is a bacterial enzyme used in the pharmaceutical industry to treat Acute Lymphoblastic Leukemia (ALL).

This chemotherapy drug prevents the cancer cells from growing and reproducing.

There are three kinds of asparaginase available in the market:

Made from a kind of bacteria called Escherichia coli.
Made from a kind of bacteria called Erwinia chrysanthemi.
A pegylated version of the enzyme is called pegaspargase.

Pegylation is a process that helps improve drug stability and solubility. It also helps the drug stay in the body for a longer period of time.

This drug is available as intramuscular or intravenous injections.

What is Asparaginase Used For?

Asparaginase is used in treating a type of cancer called Acute Lymphoblastic Leukemia (ALL).

ALL is cancer in the bones and bone marrow, and the disease progresses very quickly and needs targeted drug therapy and chemotherapy from the early stages.

This type of cancer majorly affects children.

Since the introduction of asparaginase for treating ALL, the survival rates in children have increased by 90%.

What Type of Chemotherapy Drug Is Asparaginase?

Asparaginase is an antineoplastic chemotherapy drug classified under the category ‘enzyme.’

How Does Asparaginase Work?

Asparaginase works primarily by breaking down a non-essential amino acid called asparagine.

This substance is needed for making new cells in the body.

Normal cells in the body make their asparagine, while cancer cells cannot.

Asparaginase breaks down asparagine in the body and prevents the cancer cells from using them to grow and multiply.

How Fast Does L-Asparaginase Work?

L-asparaginase is a fast-acting drug.

The half-life of asparaginase with intramuscular injection is between 0.65-5.73 days, depending on the type of asparaginase chosen.

Similarly, the half-life of intravenous injections can be between 0.27 and 0.76 days.

Side Effects Of Asparaginase

The common side effects of asparaginase:

Increased risk of developing infections
Diarrhea
Abdomen pain
Loss of appetite
Increased risk of high blood sugar levels
Risk of skin rashes, itching, redness in the skin
Tiredness

The severe side effects of asparaginase:

Risk of liver damage
Abnormally low platelet counts
Mouth sores and ulcers
Seizures
Mood swings
Hallucinations

Asparaginase: Interactions With Other Drugs

Asparaginase may interact with other drugs and lead to changes in drug efficacy or cause severe side effects. So talk to your doctor if you are prescribed any of the following drugs along with asparaginase.

Immunosuppressants - Both immunosuppressants and asparaginase can suppress the immune system and lead to a severe risk of developing infections.
Vaccines - Asparaginase suppresses the immune system and should not be used while receiving any live vaccine.
Lomitapide - Lomitapide is a cholesterol-lowering medication. Lomitapide and asparaginase can both cause hepatotoxicity (liver damage) and should not be administered at the same time.

Can You Be Allergic To Asparaginase?

The allergic reaction to asparaginase may vary depending on the specific formulation of the drug.

According to a 2021 article, the allergic reaction rate could be anywhere from 3% to 45% in patients.

What Foods Contain Asparaginase?

Many baked foods contain heat-stable asparaginase to bring down the levels of acrylamide in them.

Acrylamide is a natural substance found in many plant-based foods, and high levels of acrylamide have been proven to cause cancer in animals and may affect human health.

Heat-stable asparaginase is found in

Corn-based foods like tortillas, tortilla chips, and nachos
Potato chips and other potato-based snacks
Crackers and biscuits
Bread
Rye-based products

Genetics of Asparaginase Allergy

HLA-DRB1 Gene and Asparaginase Allergy

The HLA-DRB1 gene (histocompatibility complex, class II, DR beta 1 gene) plays a major role in controlling the immune system.

This gene makes the HLA complex, which the body uses to differentiate between the body’s proteins and foreign substances.

rs17885382 is a Single Nucleotide Polymorphism (SNP) in this gene.

The risk allele, T, is associated with a higher risk of developing asparaginase hypersensitivity when compared to the major allele, C.

Allele	Implications
T	Higher risk of developing asparaginase hypersensitivity
C	Regular risk of developing asparaginase hypersensitivity

GRIA1 Gene and Asparaginase Allergy

The GRIA1 gene (Glutamate receptor 1 gene) helps produce the GRIA1 protein.

This protein plays a role in inflammation of the Central Nervous System (CNS).

rs4958351 is an SNP in the GRIA1 gene.

According to a study, people with the AA and AG genotypes had a higher chance of developing asparaginase hypersensitivity (74% and 44%) than those with the GG genotype (32%).

Genotype	Implications
AA	74% higher chance of developing asparaginase hypersensitivity
AG	44% higher chance of developing asparaginase hypersensitivity
GG	32% higher chance of developing asparaginase hypersensitivity

CNOT3 Gene and Asparaginase Allergy

The CNOT3 gene (CCR4-NOT transcription complex subunit 3 gene) helps produce the CNOT3 protein.

This protein may be involved in metabolism regulation.

rs73062673 is an SNP in this gene, and the minor C allele of this SNP is associated with a higher risk of PEG-asparaginase allergy.

PEG-asparaginase is used to treat acute lymphoblastic leukemia in adults and children.

Allele	Implication
C	Higher risk of developing PEG-asparaginase allergy
T	Normal risk of developing PEG-asparaginase allergy

Analyze Your Genetic Response to Asparaginase

Recommendations To Use Asparaginase

Risk Of Hypersensitivity

One of the most common risks of using asparaginase is developing allergic reactions to it.

Symptoms include swelling, tenderness, skin rashes, high sugar levels, hypotension (low blood pressure), and angioedema (swelling under the skin).

It is recommended to stay aware of hypersensitivity symptoms and contact your doctor right away if you experience anything unpleasant after using the drug.

Risk Of Thrombosis

Another common complication of asparaginase is thrombosis.

Thrombosis is the development of blood clots in the vessels.

Upper central venous thrombosis is the most common type of thrombosis in people using asparaginase.

In a study that analyzed the risk of thrombosis in people using asparaginase, experts concluded that adults were more at risk than pediatric patients.

It is recommended to check antithrombin and fibrinogen levels before treating with asparaginase and supplement these if they are low.

Risk Of Other Asparaginase Toxicity Symptoms

Apart from developing hypersensitivity to the drug and thrombosis, patients may develop other toxicity symptoms, which may cause severe side effects when left unidentified. Some of the conditions that can develop because of asparaginase toxicity are:

Pancreatitis (inflammation of the pancreas)
Hepatotoxicity (injury to the liver)
Neurotoxicity (toxic damage to the nervous system)
Hemorrhage (internal bleeding from a damaged blood vessel)
Avascular necrosis (death of bone tissue due to lack of blood)
Bone fracture

Asparaginase-Inactivating Antibodies Leading To Drug Resistance

Even without developing hypersensitivity or toxic symptoms, up to one-third of the individuals may develop asparaginase-inactivating antibodies upon using the drug.

These inactivating antibodies cause a decrease in the concentration of asparaginase in the body and may lead to drug resistance.

Such individuals may have to be treated with appropriately high doses upon the suggestion of a qualified medical practitioner.

The Need To Identify Optimal Doses

The goal of asparaginase is to reduce serum levels of asparagine.

The drug's half-life varies depending on the type of bacteria or enzyme used in preparing it.

According to experts, an asparaginase activity level of 0.1 IU/mL should be the target to reduce serum asparagine levels effectively.

Doctors will need to identify optimal drug doses for each patient to ensure the drug performs effectively.

Summary

Asparaginase is a bacterial enzyme used to treat Acute Lymphoblastic Leukemia (ALL). Asparaginase breaks down an amino acid called asparagine, which the cancer cells need to grow and divide.
Some side effects of asparaginase are increased risk of infections, diarrhea, loss of appetite, low platelet counts, liver damage, and mood swings.
Changes in the HLA-DRB1, GRIA1, and CNOT3 genes can increase the risk of developing hypersensitivity towards asparaginase drugs.
Asparaginase toxicity may lead to thrombosis, pancreatitis, hepatotoxicity, neurotoxicity, and avascular necrosis. It is important to monitor a patient on asparaginase to identify and treat these conditions early.
Some people may develop Asparaginase-Inactivating Antibodies, which can reduce the asparaginase content in the body and cause drug resistance. Such people may have to be treated with higher doses.