Asparaginase is an enzyme that hydrolyzes asparagine to aspartic acid and ammonia. E. coli asparaginase is one of the most widely studied forms of this enzyme and has been used as an antileukemic agent, especially in the treatment of acute lymphoblastic leukemia (ALL).

Onconase (E. coli Asparaginase) is a chemotherapeutic drug that is used to treat patients with acute lymphoblastic leukemia and acute lymphoblastic lymphoma. It is used in combination with other chemotherapeutic drugs as a part of a multi-drug regimen and has little bone marrow toxic effects.

Onconase (E. coli Asparaginase) Uses:

• Acute lymphoblastic leukemia:
  • Used in the treatment of acute lymphoblastic leukemia (ALL) (in combination with other chemotherapy)
• Off Label Use of E. coli asparaginase in Adults:
  • Used in lymphoblastic lymphoma

Onconase (E. coli Asparaginase) Dose in Adults

Note: Frequency, number of doses,Dose and start date may vary by protocol and treatment phase.

Onconase (E. coli Asparaginase) Dose in the treatment of Acute lymphoblastic leukemia (ALL):

Daily Method:

• Given every day.
• During the starting phase, give an injection (IM or IV) with a dose of 200 to 1,000 units for each kilogram of patient's weight. This is done for 28 straight days.
• If the patient hasn’t recovered after those 28 days, continue this for another 14 days. If the patient has recovered, move to the maintenance phase.

Three Times a Week Method:

• Given on Monday, Wednesday, and Friday.
• On Monday and Wednesday, give an injection (IM or IV) of 400 units for each kilogram of patient's weight.
• On Friday, the dose is a bit higher: 600 units for each kilogram of patient's weight.
• This is done for 4 weeks.
• If the patient hasn’t recovered after the 4 weeks, continue for another 2 weeks. If the patient has recovered, move to the maintenance phase.

Special Methods (not the usual way but sometimes used):

• CALGB-8811: Given under the skin (SubQ). The dose is 6,000 units for each square meter of patient's body surface area. This is given on certain days during the first two phases of treatment.
• Hyper-CVAD: Given through IV. The dose is a total of 20,000 units. This is given once a week for 4 weeks. It's given during specific months of the treatment phase.

Linker Regimen:

• Remission induction: Given as an injection (IM). The dose is 6,000 units for each square meter of patient's body surface area. This is given on specific days based on the bone marrow test results.
• Consolidation: This is another phase. Here, the dose is 12,000 units for each square meter of patient's body surface area. This is given on certain days across multiple cycles.

Onconase (E. coli Asparaginase) Dose in the treatment of Lymphoblastic lymphoma (off-label):

Hyper-CVAD Regimen:

• The medicine is given through an IV (a drip into the vein).
• The dose is 20,000 units.
• It's given once a week.
• The patient will receive this dose 4 times (so, for 4 weeks).
• Start giving this dose on the 2nd day.
• This process is repeated during 2 specific periods (or cycles) of the maintenance phase: in the 7th month and then in the 11th month.

Onconase (E. coli Asparaginase) Dose in Children:

Note: frequency, number of doses, dose, and start date may vary by protocol and treatment phase.

Onconase (E. coli Asparaginase) Dose in the treatment of Acute lymphoblastic leukemia (ALL):

General Recommendation:

• For children and adolescents, use the same dosage as you would for adults.
• CCG 1922 Protocol (Based on Bostrom 2004):
  • Given through an injection into the muscle (IM).
  • Dose: 6,000 units for each square meter of body surface area.
  • Frequency: 3 times a week.
  • Duration: 3 weeks, totaling 9 doses. Start on day 2, 3, or 4 for the first phase (induction).
  • For the delayed intensification phase: Use the same dose but only on Monday, Wednesday, and Friday for 2 weeks, starting on day 3.
• DFCI-ALL Consortium Protocol 00-01 (Based on Vrooman 2013):
  • Given through an IM injection.
  • Dose: 25,000 units for each square meter of body surface area.
  • For the induction phase: Give only one dose.
  • For the intensification phase: Give the same dose once a week for 30 weeks.
• DFCI-ALL Consortium Protocol 95-01 (Based on Moghrabi 2007):
  • Given through an IM injection.
  • Dose: 25,000 units for each square meter of body surface area.
  • For the induction phase: Give only one dose, specifically on day 4.
  • For the intensification phase: Give the same dose once a week for 20 weeks.
• Hyper-CVAD Regimen:
  • For adolescents who are 13 years or older: Follow the same dosage recommendations as adults.

Onconase (E. coli Asparaginase) Lymphoblastic lymphoma (off-label):

• Adolescents >15 years:
  • Refer to adult dosing.

Dosing adjustment for toxicity:

E. coli asparaginase for toxicity in children and adolescents:

Manufacturer's Guidelines:

• Allergic Reaction/Hypersensitivity: Stop treatment if severe reactions occur.
• Neurotoxicity (PRES): Pause the therapy if PRES is suspected, manage blood pressure, and monitor for seizures.
• Pancreatitis: Stop treatment forever.
• Thrombotic Event: Stop treatment for severe reactions.

Adjustments Based on Stock 2011 (For Older Adolescents):

• Hyperammonemia-related Fatigue:
  • Grade 2: Continue treatment.
  • Grade 3: Reduce dose by 25%. Go back to the full dose when toxicity decreases to grade 2.
  • Grade 4: Reduce dose by 50%. Resume full dose when toxicity is at or below grade 2.
• Hyperglycemia:
  • If it requires insulin: Pause asparaginase until glucose is managed. Resume at previous dose level.
  • Life-threatening hyperglycemia: Pause asparaginase until managed with insulin, then resume but don't account for missed doses.
• Hypersensitivity Reactions:
  • Minor reactions: Continue treatment.
  • Severe reactions: Stop the treatment.
• Hypertriglyceridemia:
  • If <1,000 mg/dL: Continue but monitor for pancreatitis.
  • If >1,000 mg/dL: Pause treatment until levels return to normal, then resume.
• Pancreatitis:
  • Mild symptoms or only test findings: Continue and monitor.
  • Moderate symptoms: Pause until enzyme levels stabilize or decrease.
  • Severe symptoms or confirmed pancreatitis: Stop treatment forever.
• CNS Thrombosis and Bleeding:
  • Thrombosis: For severe symptoms, adjust or stop treatment based on symptom grade.
  • Hemorrhage: Adjust or stop treatment based on symptom grade.
• Non-CNS Thrombosis and Bleeding:
  • Thrombosis: Continue for minor lab findings. Adjust for severe symptoms.
  • Hemorrhage: Adjust or stop treatment based on severity.

Onconase (E. coli Asparaginase) Pregnancy Risk Category: C

• Data from studies with animals suggest that exposure to asparaginase derived from E.
• coli during pregnancy might be harmful to the developing fetus.
• The manufacturer advises that females who could become pregnant should avoid getting pregnant while receiving chemotherapy with this drug.
• Similarly, males who are undergoing chemotherapy with this drug should avoid fathering a child during treatment and for some time after their last dose of the drug.
• This caution is based on the possibility of potential risks to the unborn child.
• It's important to follow these recommendations to ensure the safety of both the potential mother and the developing fetus.

Use of E.coli asparaginase during breastfeeding

• The company that makes the drug advises against breastfeeding while using it.
• This is usually due to concerns about the drug passing into breast milk and potentially affecting the baby.

Onconase (E. coli Asparaginase) Dose in Kidney Disease:

The manufacturer’s labeling doesn't provide any dosage adjustments.

Onconase (E. coli Asparaginase) Dose in Liver disease:

Firstly, people with serious liver problems shouldn't use this drug.

For liver toxicity during treatment (based on Stock 2011):

• ALT/AST Levels (these are liver enzymes):
  • If they're between 3 to 5 times the upper normal limit (ULN): Keep going with the treatment.
  • If they're between 5 to 20 times the ULN: Pause the treatment until these enzymes drop to less than 3 times the ULN.
  • If they're more than 20 times the ULN: Stop the treatment if, in over a week, these enzymes don't drop below 3 times the ULN.
• Direct Bilirubin Levels (another measure of liver function):
  • If it's less than 3 mg/dL: Continue the treatment.
  • If it's between 3.1 to 5 mg/dL: Pause the treatment until bilirubin drops below 2 mg/dL. Think about switching to a different asparaginase product.
  • If it's more than 5 mg/dL: Stop using asparaginase. Don't switch to other asparaginase products and don't account for missed doses.

Onconase (E. coli Asparaginase) Side effects:

• Cardiovascular:
  • Cerebrovascular accident (hemorrhagic stroke and thrombotic stroke, thrombosis (including cerebral thrombosis)
• Central Nervous System:
  • Cerebral hemorrhage
  • Cerebrovascular hemorrhage
  • Central nervous system disease (disorientation, mild depression, delusion,  Parkinsonian-like syndrome, personality disorder, and seizure)
• Endocrine & metabolic:
  • Amenorrhea
  • Hyperglycemia
  • Hypertriglyceridemia
  • Hypoalbuminemia
  • Hypocholesterolemia
  • Increased uric acid
  • Decreased glucose tolerance
  • Hyperammonemia (with clinical signs of metabolic encephalopathy such as impaired consciousness with confusion, coma, and stupor])
  • Hypercholesterolemia
  • Weight loss
• Gastrointestinal:
  • Cholestatic injury
  • Diarrhea (infrequent)
  • Intestinal perforation (rare)
  • Nausea (frequent, but rarely severe; nauses may be due to increased blood urea nitrogen and increased uric acid)
  • Abdominal pain (infrequent)
  • Acute pancreatitis (may be fatal)
  • Vomiting (frequent, but rarely severe; may be due to increased blood urea nitrogen and increased uric acid)
• Genitourinary:
  • Azoospermia
• Hematologic:
  • Antithrombin III deficiency
  • Prolonged partial thromboplastin time
  • Blood coagulation disorder (change in hemostatic function)
  • Bone marrow depression
  • Decreased clotting factors (factors VII, VIII, IX, and X)
  • Decreased plasminogen
  • Hypofibrinogenemia
  • Prolonged prothrombin time
• Hepatic:
  • Hyperbilirubinemia
  • Increased serum alkaline phosphatase
  • Increased serum ALT
  • Increased serum AST (mild)
  • Jaundice
  • Hepatic injury
  • Hepatotoxicity (usually mild and regressive, but may be fatal rarely)
  • Liver steatosis
• Hypersensitivity:
  • Allergic reactions (includes  bronchospasm, edema, hypotension, laryngeal edema, skin rash, urticaria, anaphylactic shock, and anaphylaxis;
    • allergic reactions usually occur within one hour of administration and the risk increases with the increasing number of exposures)
• Immunologic:
  • Increased serum globulins (beta and gamma)
• Infection:
  • Septicemia (during bone marrow depression)
• Renal:
  • Renal failure
  • Increased blood urea nitrogen
• Respiratory:
  • Respiratory distress (with retrosternal pressure)
• Miscellaneous:
  • Fever

Contraindications to Onconase (E. coli Asparaginase):

People should not use asparaginase (E. coli-derived) if they:

• Have had an allergic reaction to it before or to any ingredient in the medication.
• Have serious liver problems.
• Currently have pancreatitis (an inflamed pancreas).
• Have had severe pancreatitis in the past because of asparaginase.
• Recently received the yellow fever vaccine.
• Are currently taking phenytoin (a medication mainly used for seizures).

Warnings and precautions

Allergic Reactions Warning:

• Allergic reactions can happen while using this treatment, especially in patients who are already allergic to other forms of asparaginase.
• Watch for reactions after taking the medication. Reactions usually show up between 30 to 60 minutes after taking it, although they might appear later too.
• It's important to be prepared to treat allergic reactions immediately during the administration of the medication.
• If a severe allergic reaction occurs, the treatment should be stopped.
• People who have been exposed to asparaginase before are at a higher risk of having allergic reactions.
• Administering the drug through intravenous (IV) injection (compared to injections into muscles or under the skin) and being younger might also increase the chances of allergic reactions.
• Important Note:
  • If someone has an allergic reaction to E. coli asparaginase, they might also react to other types of asparaginase treatments or pegaspargase.

Coagulopathy Warning:

• The medication can lead to changes in blood clotting tests. Specifically, there can be an increase in the time it takes for blood to clot when tested (prothrombin time and partial thromboplastin time), and a decrease in fibrinogen, a protein necessary for blood clotting.
• There have been cases of blood clots in the brain and bleeding reported in patients using this medication.
• It's crucial to check blood clotting at the beginning of treatment and then periodically while on the medication.
• Important Recommendations:
  • Be extra careful when using this drug in patients who already have issues with blood clotting.
  • If the fibrinogen level drops below 1g/L or another clotting factor, antithrombin III (ATIII), drops below 60%, consider giving replacement therapy.
  • If this therapy doesn't help, it's recommended to stop the asparaginase treatment. Only restart it once the blood clotting tests have returned to normal levels.

Hepatotoxicity Warning:

• The medication can lead to negative effects on liver function. This is especially important for people who already have liver issues due to previous treatments or other health conditions.
• Doctors should carefully weigh the benefits of the treatment against the risks of liver damage.
• The drug can lead to changes in liver function tests, like increased levels of enzymes (AST, ALT, alkaline phosphatase), bilirubin, and reduced levels of albumin and plasma fibrinogen.
• Rare cases of severe liver failure have occurred.
• Fatty liver might be observed on a biopsy (a sample of liver tissue).
• Recommended Actions:
  • Use the medication cautiously, especially in patients with existing liver problems.
  • Monitor liver function tests at least once a week during the course of treatment.
  • If there are significant changes in the liver function tests, stop the therapy.

Hyperammonemia Warning:

• The medication can lead to high levels of ammonia in the blood.
• Watch out for symptoms of a brain condition called metabolic encephalopathy, which can be caused by this high ammonia.
• Symptoms include confusion, a dazed feeling, and in severe cases, coma.

Hyperglycemia Warning:

• The medication might raise blood sugar levels or cause the body to have difficulty using sugar properly. This condition can sometimes be permanent.
• There have been cases where patients developed diabetic ketoacidosis, a severe diabetes complication where the body starts breaking down fats too quickly.
• It's important to regularly check blood sugar levels when on this medication, as advised by a doctor.

Neurotoxicity Warning:

• There's a brain condition called Posterior Reversible Encephalopathy Syndrome (PRES) that some patients have developed when treated with asparaginase, especially when combined with other chemotherapy drugs.
• Look out for signs of PRES. These include changes in thinking or awareness, headaches, high blood pressure, seizures, or issues with vision.
• If PRES is suspected, stop the asparaginase treatment temporarily.
• It's important to manage blood pressure and watch closely for signs of seizures during this time.

Pancreatitis Warning:

• The medication can lead to a serious, possibly severe or even deadly, inflammation of the pancreas called pancreatitis.
• If patients experience abdominal pain, they should be checked immediately.
• If patients have high levels of certain enzymes (amylase or lipase) which are more than 3 times the normal limit, but don't show symptoms, the treatment might still continue. However, these enzyme levels should be watched closely to ensure they don't keep rising.
• If a patient has symptoms of pancreatitis like vomiting or intense abdominal pain, and their enzyme levels are high for more than 3 days, or if they develop a fluid-filled sac in the pancreas (pancreatic pseudocyst), the treatment should be stopped forever.
• Avoid drinking alcohol while on this treatment.

Thrombotic Events Warning:

• There's a risk of severe blood clots when using this medication, including a specific type of clot that can occur in the brain called sagittal sinus thrombosis.
• If a patient experiences a serious clotting event, the treatment should be stopped.
• Some patients might benefit from medicines that prevent clotting (anticoagulation prophylaxis) while they are on this medication.
• Adults may have a higher risk of getting these blood clots compared to younger patients.

Tumor Lysis Syndrome Warning:

• Tumor lysis syndrome is a condition where a large number of tumor cells die at once, releasing their contents into the bloodstream. This can lead to complications such as high uric acid levels, which might damage the kidneys.
• It's essential to take steps to prevent this from happening when using asparaginase.
• Regularly check patients for signs of this syndrome.
• Consider treatments to reduce uric acid levels in the blood, ensure the patient is well-hydrated, and possibly adjust the pH of their urine to make it more alkaline.

E. coli Asparaginase: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
DexAMETHasone (Systemic)	Asparaginase (E. coli) may increase the serum concentration of DexAMETHasone (Systemic). This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism.

Monitoring parameters:

Blood Tests:

• Complete Blood Count (CBC) with details about different blood cells.
• Digestive Enzymes:
  • Amylase
  • Lipase
• Blood Fats: Triglycerides
• Liver Function: Checked before starting and then weekly.
• Blood Clotting: Checked before each injection.
• Blood Sugar Levels: Glucose
• Uric Acid Levels: To detect potential kidney problems.

Observations:

• Allergic Reactions: Watch for signs like itching, rash, or breathing problems.
• Abdominal Pain: Be alert for any stomach pain which can indicate pancreatitis.
• Mental Status: Check for confusion or changes in behavior, indicating possible brain issues.

Vital Signs:

• Regularly measure blood pressure, heart rate, breathing rate, and temperature during medication administration.

How to administer Onconase (E. coli Asparaginase)?

Methods:

• IM (Intramuscular): This is the preferred method for intermittent administration. The medication is injected deep into a large muscle.
• IV (Intravenous): The medication is infused directly into the bloodstream.
• SubQ (Subcutaneous): An off-label method where medication is injected under the skin. It's used in specific treatment plans.

Precautions Before Starting:

• Consider giving corticosteroids 1 to 2 days before re-starting the treatment. This helps prevent allergic reactions.

Observation After Giving the Drug:

• Watch patients for 1 hour after they get the medication.
• Always have emergency medications like epinephrine, diphenhydramine, and hydrocortisone ready nearby.
• A doctor should be available quickly if needed.

Specific Instructions:

• IM: If you're giving more than 2 mL, split the dose. Inject in two different large muscles.
• IV: Infuse the medication over at least 30 minutes. You can use a side arm of an IV line already delivering Normal Saline (NS) or D5W (dextrose 5% in water).

Mechanism of action of Onconase (E. coli Asparaginase):

How Asparaginase Works in Leukemic Cells

Step 1: Leukemic cells (like those in leukemia) contain an enzyme called asparaginase.

Step 2: Asparaginase does something important: it breaks down a specific amino acid called L-asparagine into two things: ammonia and L-aspartic acid.

Step 3: This process causes a reduction of asparagine in the leukemic cells.

Step 4: Now, here's the interesting part: Leukemia cells, especially those known as lymphoblasts, really need this asparagine from outside their own cells. This is because they can't make it themselves.

Step 5: On the other hand, regular cells can produce their own asparagine.

Step 6: When asparagine is in short supply in leukemic cells, things start to happen:

• Protein synthesis (the process of making proteins) gets slowed down.
• Apoptosis takes place. This is a process of programmed cell death that helps to get rid of unhealthy cells.

Step 7: Asparaginase is most effective during a specific phase of the cell cycle called the "G phase".

Distribution:

• IV (Intravenous): It spreads a bit more than the volume of the blood plasma.
• Very little (less than 1%) of the drug reaches the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.

Metabolism:

• The body breaks down asparaginase throughout the system.

Half-life Elimination (the time it takes for half of the drug to be eliminated from the body):

• IM (Intramuscular): 34 to 49 hours.
• IV: 8 to 30 hours.

Time to Peak, Plasma (how long it takes to reach the highest concentration in the blood):

• IM: 14 to 24 hours.

International Brands of E. coli asparaginase:

• Kidrolase
• Asparaginase medac
• Colaspase
• Crasnitin
• Elspar
• Kidrolase
• L-aspase
• Laspar
• Leucoginase
• Leunase
• Oncaspar
• Onconase
• Paronal
• Spectrila

E. coli asparaginase Brands Names in Pakistan:

Not available.