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Erwinia asparaginase
Erwinia asparaginase is an enzyme purified from Erwinia chrysanthemi. It hydrolyzes extracellular L-asparagine, an amino acid that appears to be essential for protein synthesis by some tumour cells, which are unable to synthesize asparagine. Erwinia asparaginase is serologically distinct from asparaginase derived from E. coli, although their antineoplastic activity and toxicity are similar.
Mostly confined to blood compartment.
| Cross blood brain barrier? | Minimal |
The metabolism pathway for asparaginase is unknown; it may occur via degradation within the reticuloendothelial system and by serum proteases.
| Active metabolites | None known |
| Inactive metabolites | Yes |
Erwinia asparaginase is absent from blood 7 days after a single 25000 u/m2 IM dose.
| Half-life | IM: 16 hours |
- Acute lymphoblastic leukemia (ALL); primarily in combination with other antineoplastic agents to induce remission
- For patients who developed hypersensitivity (not anaphylaxis) to E-coli derived L-asparaginase
Emetogenic Potential:
Extravasation Potential: None
The adverse effects in the following table were mainly observed in 2 pediatric ALL Erwinia asparaginase clinical trials. The list also includes severe or life-threatening events reported with other asparaginase formulations.
^ Incidences reported in Erwinia asparaginase
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial/venous thromboembolism (2%) (including CNS)^ | E | |||
| Gastrointestinal | Abdominal pain (1%) ^ | E | |||
| Anorexia, weight loss (>20% weight loss: 1%)^ | E | ||||
| Diarrhea (3%) ^ | E | ||||
| GI perforation (rare) | E | ||||
| Nausea, vomiting (5%) (usually mild, rarely severe)^ | I E | ||||
| General | Fever (3%) (drug or disease-related; may be severe)^ | I | |||
| Hematological | Fibrinogen decreased (1%) (also ↑ PT, aPTT ± bleeding; may be severe)^ | E | |||
| Hemorrhage (3%) (including CNS)^ | E | ||||
| Myelosuppression (rare, usually mild ± infection) | E | ||||
| Hepatobiliary | ↑ LFTs (1%) (may be severe)^ | E D | |||
| Pancreatitis (2%) ^ | E D | ||||
| Hypersensitivity | Hypersensitivity (14%) (anaphylaxis <1%)^ | I | |||
| Immune | Antibody response | E D | |||
| Metabolic / Endocrine | Hyperglycemia (diabetes <1%; may be severe)^ | E | |||
| Hyperuricemia (during periods of active cell lysis) | I | ||||
| Other ( ↑ or ↓ in lipids) | E | ||||
| Nervous System | Cognitive disturbance (2%) (coma ± seizures)^ | E D | |||
| Headache (usually mild) | E | ||||
| RPLS / PRES (rare) | E | ||||
| Tremor (rare) | E | ||||
| Renal | Nephrotoxicity (rare) | E | |||
| Reproductive and breast disorders | Infertility | E D L | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
Hyperuricemia during periods of active cell lysis can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
Hepatotoxicity is frequent, usually mild but may be severe especially in debilitated patients or when used in combination with other hepatotoxic drugs. Asparaginase treatment may increase pre-existing liver impairment from underlying liver disease or caused by prior therapy. Liver abnormalities usually resolve after the end of therapy and some reversal may occur during the course of treatment.
Asparaginase or hepatic impairment may produce decreased levels of factors V, VII, VIII, IX, X and fibrinogen, and possibly contribute to coagulation disorders. Replacement therapy should be given if fibrinogen is less than 1g/L or ATIII less than 60%. Increased fibrinolytic activity has also been observed
Hemorrhagic and thrombotic cardiovascular or neurologic events occur in approximately 1-2% of patients receiving asparaginase. These events generally occur after a few weeks of l-asparaginase therapy, and may occur after therapy is completed.
Cognitive dysfunction may include mild to severe lethargy, drowsiness, depression, confusion, hallucination, agitation, seizures or personality changes. They are seen during the first day of therapy and resolve within a few days to a week after drug discontinuation. Rare cases of posterior reversible encephalopathy syndrome (PRES / RPLS) have been reported.
Pancreatitis can occur during or after therapy, and can be fatal. It may be present despite normal serum amylase concentrations.
Hyperglycemia has been observed, which appears to be potentiated by prednisone. Transient diabetes mellitus may develop. Insulin may be required for severe hyperglycemia, but it is usually reversible when the drug is discontinued. Glucose intolerance may be irreversible.
Hypersensitivity reactions to l-asparaginase have occurred in the absence of a positive skin test. A lower incidence of anaphylaxis has been reported with IM use, although there was a higher incidence of mild hypersensitivity than with the IV route. Risk of anaphylaxis to Erwinia l-asparaginase may be greater in patients who have reacted to E. coli l-asparaginase (or pegaspargase) and is related to the number of doses given.
Anti-drug antibodies were detected in up to 13% of patients in 2 clinical trials. Patients with hypersensitivity reactions to asparaginase were more likely to have antibodies than those who did not have reactions. Hypersensitivity reactions are associated with increased asparaginase clearance, and higher antibody levels may lead to decreased asparaginase activity.
Patients who are rechallenged after prior hypersensitivity reactions should be pretreated with steroids.
When substituting one asparaginase formulation for the other, modifications in dose and schedule are required. Refer to specific regimen for details.
May be given either by intramuscular (preferable), subcutaneous or IV (bolus) injection.
Numerous dosing schedules exist. Refer to protocol by which patient is being treated. Usually used in combination with other cytotoxic drugs.
Example: Induction, in combination: 10000 u/m2 SC 3 times weekly starting on week 4 for 4 weeks
Dosage with Myelosuppression: No dose adjustment required.
- Myelosuppression is not increased when used with other antileukemic drugs.
Dosage with Other Toxicity
| Toxicity | Action |
| Thrombotic or hemorrhagic events | Hold; restart when resolved if appropriate |
| Suspected pancreatitis | Hold, investigate and if confirmed, discontinue. |
| Grade 2 bilirubin ± grade 3 AST/ALT | Hold; restart if resolved to ≤ grade 1 within 7 days; otherwise discontinue |
| Severe hypersensitivity reactions, anaphylaxis | Discontinue |
| RPLS / PRES | |
| Grade ≥3 bilirubin ± grade 4 AST/ALT | |
| Other grade 4 organ/ non-hematologic |
May increase pre-existing liver impairment. The following recommendations are based on literature.
| Hepatic Impairment | LFTs | Action |
| Mild | Use with caution; no information found. | |
| Moderate | ||
| Severe | Grade ≥3 bilirubin ± AST/ALT > 10 x ULN | Do not use |
No adjustment required.
Limited data are available in patients ≥ 65 years.
Refer to protocol being used. Asparaginase toxicity is reported to be greater in adults than in children.
Risk of medication error: The 3 asparaginase formulations (pegaspargase, E. coli asparaginase, Erwinia asparaginase) are not Interchangeable. Confirm the formulation carefully against the regimen used before prescribing, dispensing and administration.
- Reconstitute with Normal Saline. Do not use Sterile Water for injection as the reconstituted product is not isotonic and may cause painful injections.
- Minimize drug contact with the rubber stopper of the vial as it may denature the reconstituted drug and form transiently insoluble filaments.
- Avoid vigorous shaking as a loss of enzymatic potency may result.
- IM or SC administration routes are recommended due to lower incidence of anaphylaxis than other routes (e.g. IV).
- Use multiple injection sites if an IM/SC dose greater than 2 mL is to be given.
- Refrigerate unopened vials (2 to 8ºC).
- patients who a history of hypersensitivity reactions to Erwinia asparaginase or any of its components
- patients who have or had pancreatitis (including hemorrhagic)
- patients with known serious thrombosis or serious hemorrhagic events with previous l-asparaginase therapy
- patients who have recently been vaccinated against yellow fever
Other Warnings/Precautions:
- Avoid live and attenuated live vaccines.
- L-asparaginase may worsen pre-existing liver impairment
- Use with caution in diabetic patients
- Risk of severe hypersensitivity reactions is higher in patients with known hypersensitivity to other forms of asparaginase.
Other Drug Properties:
- Carcinogenicity: Unknown
Pregnancy and Lactation:
- Mutagenicity: Unknown
- Embryotoxicity: Yes
- Teratogenicity: Yes
L-asparaginase is contraindicated in pregnancy. Adequate contraception should be used by both sexes, during asparaginase treatment and for at least 6 months after treatment cessation.
- Breastfeeding: Contraindicated
- Fertility effects:
Azoospermia and amenorrhea have been reported in l-asparaginase.
The following also includes interactions reported in other formulations of asparaginase.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Hepatotoxic drugs | ↑ hepatotoxicity | Additive | Monitor liver function; use with caution |
| Drugs requiring hepatic enzyme metabolism | May ↑ toxicity of these agents | Asparaginase may interfere with enzymatic detoxification | Caution |
| Methotrexate | ↓ effect of both drugs when asparaginase given immediately before or concurrently with methotrexate; Enhanced effect of both drugs when asparaginase given after methotrexate | Suppression of asparagine concentrations or cell replication | Refer to protocol by which patient is treated |
| Cytarabine | ↓ effect of asparaginase when asparaginase given immediately before or concurrently with cytarabine; Enhanced effect of asparaginase when asparaginase given after cytarabine | Suppression of asparagine concentrations or cell replication | Refer to protocol by which patient is treated |
| Immunosuppressants (i.e., cyclosporine, tacrolimus, sirolimus) | ↑immunosuppression, risk of lymphoproliferation | Additive | Caution |
| Phenytoin | ↑ risk of seizures | ↓ phenytoin uptake; risk of ↑ toxicity or ↓ efficacy of cytotoxics due to metabolism induction | Use other anticonvulsant alternatives |
| Prednisone | ↑hyperglycemia | Additive | Monitor |
| Vincristine and/or prednisone | ↑ vincristine toxicity when vincristine given concurrently or immediately after asparaginase | Unknown | Refer to protocol by which patient is treated |
| Anticoagulants, including NSAIDs, ASA | ↑ risk of bleeding | Changes in coagulation by asparaginase | Use with caution |
| Serum thyroxine-binding globulin | ↓ total serum thyroxine-binding globulin concentration | ↓ synthesis of thyroxine-binding globulin in liver | Delay measurement until 4 weeks after end of asparaginase therapy |
| Live and attenuated live vaccines | ↑ risk of severe infections | immunosuppressive activity of asparaginase | Avoid. Vaccinations with live vaccines should be given at least 3 months after the end of the entire treatment protocol |
| Oral contraceptives | May ↓ efficacy of oral contraceptives (reported with pegaspargase) | May impair hepatic clearance of oral contraceptives due to asparaginase's hepatotoxic effects | Use alternative contraception method |
| Glucocorticoids | ↑ effects on fibrinogen and ATIII decreases (reported with pegaspargase) | Unknown | refer to protocol by which patient is treated |
| Highly protein-bound drugs | ↑ toxicity of these drugs (reported with pegaspargase) | Decreased serum proteins | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests and serum amylase levels | Baseline and as clinically indicated |
Clotting profile (aPTT, fibrinogen, AT III, KPTT) | Baseline and before each dose |
Blood glucose especially in patients known to be diabetic | Baseline and as clinically indicated |
Clinical toxicity assessment for tumour lysis syndrome, pancreatitis, GI, infection, hypersensitivity reactions, thromboembolism/bleeding, neurologic effects | At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Cholesterol and triglycerides | As clinically indicated |
Albumin levels | As clinically indicated |
Urinary glucose | Baseline and as clinically indicated |
CBC | Baseline and as clinically indicated |
New Drug Funding Program (NDFP Website )
- Erwinia Asparaginase - Newly Diagnosed Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Erwinia Asparaginase - Relapsed or Refractory Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations. Clin Pharmacokinet 2005; 44(4): 367-93.
Feinberg WM and Swensen FR. Cerebrovascular complications of l-asparaginase therapy. Neurology 1988; 38: 127-33.
Ho DH, Yap HY, Brown N, et al. Clinical pharmacology of intramuscularly administered L-asparaginase. J Clin Pharmacol 1981 Feb-Mar;21(2):72-8.
Kingsley CD. Hypersensitivity reactions. In: Perry MC, editor. The Chemotherapy Source Book. 4th ed. Philadelphia: Lippincourt Williams & Wilkins; 2008. p. 153.
L-asparaginase drug monograph, Cancer Care Ontario. September 2019.
McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists.
Product Monograph: Kidrolase® (asparaginase). Jazz Pharmaceuticals, December 2017.
Product Monograph: Erwinase® (Erwinia asparaginase). Jazz Pharmaceuticals. July 2016.
Product Monograph: Oncaspar® (pegaspargase) . Shire Pharma Canada Corp. April 20, 2018.
Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011;52(12):2237-53.
January 2020 Added NDFP forms
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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