Routine Premedication For Pegylated Asparaginase

What Is Asparaginase Therapy?

• Since the 1970s, there has been a significant improvement in the long-term prognosis for acute lymphoblastic leukemia (ALL) due to efficient therapies and thoughtfully constructed treatment regimens.

• Acute lymphoblastic leukemia (ALL) in children has a better outcome due to a higher percentage of favorable genetics and more efficacious treatment.

• Asparaginase microbes enzymes are among the drugs used to treat ALL.

• L-asparagine is an amino acid that leukemic cells cannot synthesize on their own in the plasma.

• The antileukemic effect of asparaginase is due to the depletion of plasma L-asparagine.

• This makes it an essential therapy for pediatric acute lymphoblastic leukemia (ALL).

What Are the Types of Asparaginase Therapy?

The most common asparaginase therapies are:

1. Asparaginase derived from Escherichia coli.

2. A pegylated version (PEG-asparaginase).

3. Erwinia asparaginase, an enzyme isolated from Erwinia chrysanthemi.

4. E. coli recombinant asparaginase preparation.

PEG-asparaginase is the most widely used form of asparaginase.

How to Monitor Asparaginase Levels?

• Asparaginase therapy helps to reduce the amount of asparagine in blood, but its effectiveness has not yet reached a critical minimum level.

• It is difficult to accurately measure asparagine levels in the blood because the enzyme can continue to degrade asparagine.

• As a result, monitoring asparaginase levels are more reliable than measuring asparagine itself.

• A serum level of asparagine depletion corresponds to greater than 100 IU/L and is possibly more significant than 50 IU/L.

• With enzyme concentrations below this level, complete asparagine depletion occurs less frequently.

• Clinical testing to measure asparagine depletion, on the other hand, is not routinely performed, though therapeutic drug monitoring is available.

What Is the Difference Between Peg-Asparaginase and Erwinia?

Continued PEG asparaginase therapy is advantageous for several reasons, which include:

Premedication before PEG asparaginase is less expensive and results in fewer shifts to Erwinia.

Furthermore, global shortages have resulted in limited Erwinia supplies, which can lead to the lag or depletion of this medication.

What Are the Benefits of Using Premedication Before Peg-Asparaginase?

Premedication has several advantages that include:

• Low cost.

• Widespread availability.

• Tolerability in general.

What Are the Disadvantages of Premedications?

• Routine premedication does have some drawbacks.

• Asparaginase neutralization- antihistamines and corticosteroids may conceal disease manifestations.

• As a result, when premedication is used, it is recommended that serum asparaginase levels be monitored to detect silent inactivation.

• Fatigue or a paradoxical stimulant effect.

• Time-consuming premedication use increases the time required for asparaginase administration marginally because premedications are typically administered 30 to 60 minutes before asparaginase to achieve the best effect.

What Is the Justification for Using Premedications?

• Several researchers have advocated for the use of premedication before PEG-asparaginase.

• However, due to the infrequent development of all reactions with the initial dose, they discovered that premedication is only indicated in patients receiving more than two doses of PEG-asparaginase.

• As a result, premedication before all PEG-asparaginase doses is reasonable and cost-effective.

• According to a recent survey of pediatric hemato-oncology, 65 percent of practitioners used premedication for the first and subsequent doses of PEG-asparaginase.

• Because of the importance of PEG-asparaginase in acute lymphoblastic leukemia (ALL), the routine use of premedication before all doses should be considered.

What Are the Side Effects of Peg-Asparaginase?

• Milder hypersensitivity reactions in 20 % of patients experience drug reactions, ranging in severity from mild dermal reactions to dangerous systemic responses such as anaphylaxis.

• Adverse reactions necessitate transitioning from PEG-asparaginase to the less immunogenic Erwinia chrysanthemi asparaginase.

• The development of anti-asparaginase antibodies may also warrant a change in medication.

• As a result of these antibodies, asparaginase activity and efficacy are reduced, contributing to poor results due to low-dose asparaginase activity.

• Although successful PEG-asparaginase substitution with Erwinia maintains disease-free preservation in the event of clinical hypersensitivity or silent inactivation, Erwinia decreased half-life necessitates a more frequent regime.

What Are the Strategies For Reducing Peg-Asparaginase Therapy Complications?

• Therapeutic drug monitoring of serum asparaginase activity levels to detect silent inactivation is one strategy for identifying and reducing complications associated with PEG-asparaginase therapy.

• Pretreatment to avoid clinical hypersensitivity reactions.

• Although premedication before PEG-asparaginase effectively reduces the incidence of hypersensitivity reactions that lead to PEG-asparaginase discontinuation, it has not yet become standard practice.

• The commonly used premedication regimens include Acetaminophen, Diphenhydramine, Antihistamines, and Corticosteroids.

What Is Recommended Premedication Dosage To Prevent The Side Effects?

Hypersensitivity Response-

• The prevention of hypersensitivity response by giving premedications intravenously (I.V.): These include:

  1. Acetaminophen.

  2. Hydrocortisone.

  3. Diphenhydramine.

• Grade III severe hypersensitivity reaction: discontinuation of PEG-asparaginase and substitution with Erwinase (Erwinia chrysanthemi).

Hepatotoxicity-

Baseline and weekly monitoring for at least four weeks after each PEG-asparaginase dose:

1. The enzyme aspartate aminotransferase (AST).

2. Alanine aminotransferase enzyme (ALT).

3. Total bilirubin.

4. Direct bilirubin.

If direct bilirubin is greater than 3 mg/dL -

• Vitamin B complex, one tablet twice daily.
• L-carnitine 50 mg/kg/day IV in six divided doses.

Patients with PEG-asparaginase-induced hyperbilirubinemia could receive PEG-asparaginase in subsequent treatment phases if their elevated serum levels return to normal.

Pancreatitis -

• Amylase and lipase levels should be monitored at baseline, two to three days after PEG-asparaginase administration, and then weekly for at least four weeks after each dose.

• In patients who develop clinical pancreatitis with amylase or lipase incline is greater than 3 ULN for more than three days and develop a hepatocellular cyst, discontinue PEG-asparaginase permanently.

• These patients should not be given asparaginase products.

Hemorrhage -

• Fibrinogen levels should be monitored at baseline three times per week for at least four weeks following the first dose of PEG-asparaginase.

• If fibrinogen is 80 to 150 mg/dL and thrombin time (TT) is more significant than 1.5 ULN- replete with 1 unit of cryoprecipitate.

• Grade 2 hemorrhage in conjunction with hypofibrinogenemia- withhold subsequent PEG-asparaginase doses until toxicity is grade 1.

Thromboprophylaxis -

• Enoxaparin should be given to all patients for at least four weeks after each pegaspargase dose. Patients must meet the following criteria:

1. They must not be on therapeutic anticoagulation.

2. Platelet serum levels of 30 K/mL.

3. No substantial bleeding.

4. Serum creatinine clearance of 30 mL/min.

• Monitor antithrombin III levels at baseline and twice weekly for at least four weeks following each pegaspargase dose.

Conclusion

Reexposure to PEG-asparaginase after hypersensitivity reactions has been successful with premedication and intensive care monitoring. This approach remains unsuccessful in a subset of patients. On the other hand, a primarily preventive approach with premedication is inexpensive, uses readily available medications, and has few side effects.

Even though premedication has yet to be deemed a mainstay of treatment, several practitioners have published their favorable experiences with premedication before PEG-asparaginase.