Pharmacology
Mechanism of Action
In leukemic cells, asparaginase hydrolyzes L-asparagine to ammonia and L-aspartic acid, leading to depletion of asparagine. Leukemia cells, especially lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. Asparagine depletion in leukemic cells leads to inhibition of protein synthesis and apoptosis. Asparaginase is cycle-specific for the G1 phase.
Pharmacokinetics/Pharmacodynamics
Distribution
IV: Slightly higher than plasma volume; <1% CSF penetration
Metabolism
Systemically degraded
Time to Peak
IM: 14 to 24 hours
Half-Life Elimination
IM: 34 to 49 hours; IV: 8 to 30 hours
Use: Labeled Indications
Acute lymphoblastic leukemia: Treatment of acute lymphoblastic leukemia (ALL) (in combination with other chemotherapy)
Use: Off Label
Lymphoblastic lymphomab
Data from small study supports the use of asparaginase (E. coli) (as part of a combination chemotherapy regimen) in the treatment of lymphoblastic lymphoma Thomas 2004.
Contraindications
Known hypersensitivity to asparaginase (E. coli-derived) or any component of the formulation; severe hepatic impairment, pancreatitis (current), history of severe pancreatitis associated with asparaginase, recent yellow fever vaccination, concurrent use with phenytoin.
Dosage and Administration
Dosing: Adult
Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase.
Acute lymphoblastic leukemia (ALL):
Daily administration: Induction: IM, IV: 200 to 1,000 units/kg/day for 28 consecutive days; continue induction therapy for an additional 14 days if not in remission or begin maintenance therapy if in remission (Canadian labeling)
Intermittent administration: Induction: IM, IV: 400 units/kg on Monday and Wednesday and 600 units/kg on Friday; repeat weekly for 4 weeks; continue induction therapy for an additional 2 weeks if not in remission or begin maintenance therapy if in remission (Canadian labeling)
CALGB-8811 regimen (off-label dosing): SubQ: 6,000 units/m2/dose on days 5, 8, 11, 15, 18, and 22 (induction phase) and on days 15, 18, 22, and 25 (early intensification phase) (Larson 1995)
Hyper-CVAD regimen (off-label dosing): IV: 20,000 units weekly for 4 doses (starting on day 2) during either months 7 and 19 or months 7 and 11 of intensification phase (Thomas 2010)
Linker regimen (off-label dosing): IM:
Remission induction: 6,000 units/m2/dose on days 17 to 28; if bone marrow on day 28 is positive for residual leukemia: 6,000 units/m2/dose on days 29 to 35 (Linker 1991)
Consolidation (Treatment A; cycles 1, 3, 5, and 7): 12,000 units/m2/dose on days 2, 4, 7, 9, 11, and 14 (Linker 1991)
Lymphoblastic lymphoma (off-label use): Hyper-CVAD regimen: IV: 20,000 units weekly for 4 doses (starting on day 2) for 2 cycles (months 7 and 11) during maintenance phase (Thomas 2004)
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase.
Acute lymphoblastic leukemia (ALL): Children and Adolescents: Refer to adult dosing.
CCG 1922 protocol (off-label dosing): IM: 6,000 units/m2/dose 3 times weekly for 9 doses beginning either on day 2, 3, or 4 (induction phase) and 6,000 units/m2/dose on Monday, Wednesday, and Friday for 6 doses beginning day 3 (delayed intensification phase) (Bostrom 2004)
DFCI-ALL Consortium protocol 00-01 (off-label dosing): IM: 25,000 units/m2 for 1 dose (induction phase) and 25,000 units/m2/dose weekly for 30 weeks (intensification phase) (Vrooman 2013)
DFCI-ALL Consortium protocol 95-01 (off-label dosing): IM: 25,000 units/m2 for 1 dose on day 4 (induction phase) and 25,000 units/m2/dose weekly for 20 weeks (intensification phase) (Moghrabi 2007)
Hyper-CVAD regimen (off-label dosing): Adolescents ≥13 years: Refer to adult dosing.
Lymphoblastic lymphoma (off-label use): Adolescents >15 years: Refer to adult dosing.
Dosing adjustment for toxicity:
Manufacturer labeling: Children and Adolescents:
Allergic reaction/hypersensitivity: Discontinue for severe reactions.
Neurotoxicity (posterior reversible encephalopathy syndrome [PRES]): Interrupt therapy for suspected PRES; control blood pressure and closely monitor for seizure activity.
Pancreatitis: Discontinue permanently.
Thrombotic event: Discontinue for serious reactions.
The following adjustments have also been recommended (Stock 2011): Older Adolescents:
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
Hypersensitivity reactions: May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, and/or life-threatening hypersensitivity reactions occur, discontinue asparaginase.
Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
Pancreatitis:
Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue asparaginase and monitor levels closely.
Symptomatic amylase or lipase >3 times ULN: Hold asparaginase until enzyme levels stabilize or are declining.
Symptomatic pancreatitis or clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue asparaginase.
Thrombosis and bleeding, CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Hemorrhage: Discontinue therapy; do not withhold therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Thrombosis and bleeding, non-CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 or 4 toxicity occurs, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold therapy for abnormal laboratory findings without clinical correlate.
Hemorrhage: If grade 2 bleeding in conjunction with hypofibrinogenemia occurs, withhold therapy until bleeding ≤ grade 1. Do not withhold therapy for abnormal laboratory findings without clinical correlate. For grade 3 or 4 bleeding, withhold therapy until bleeding ≤ grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.
Dosing: Adjustment for Toxicity
Allergic reaction/hypersensitivity: Discontinue for severe reactions.
Neurotoxicity (posterior reversible encephalopathy syndrome; PRES): Interrupt therapy for suspected PRES; control blood pressure and closely monitor for seizure activity.
Pancreatitis: Discontinue permanently (per manufacturer).
Thrombotic event: Discontinue for serious reactions.
The following adjustments have also been recommended (Stock 2011):
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
Hypersensitivity reactions: May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, and/or life-threatening hypersensitivity reactions occur, discontinue asparaginase.
Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
Pancreatitis:
Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue asparaginase and monitor levels closely.
Symptomatic amylase or lipase >3 times ULN: Hold asparaginase until enzyme levels stabilize or are declining.
Symptomatic pancreatitis or clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue asparaginase.
Thrombosis and bleeding, CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Hemorrhage: Discontinue therapy; do not withhold therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Thrombosis and bleeding, non-CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 or 4 toxicity occurs, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold therapy for abnormal laboratory findings without clinical correlate.
Hemorrhage: If grade 2 bleeding in conjunction with hypofibrinogenemia occurs, withhold therapy until bleeding ≤ grade 1. Do not withhold therapy for abnormal laboratory findings without clinical correlate. For grade 3 or 4 bleeding, withhold therapy until bleeding ≤ grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.
Reconstitution
Reconstitute each vial with 4 mL sterile water for injection; rotate gently, do not shake. For IM administration, the US manufacturer recommended reconstitution of the lyophilized powder with 2 mL NS to a concentration of 5000 units/mL; however, some institutions reconstitute with 1 mL NS for IM use, resulting in a concentration of 10,000 units/mL. Shake well, but not too vigorously. A 5 micron filter may be used to remove fiber-like particles in the solution (do not use a 0.2 micron filter; has been associated with loss of potency).
Standard IM dilution: 5,000 units/mL (10,000 units/mL has been used by some institutions)
Standard IV dilution: Dilute in 50 to 250 mL NS or D5W
Administration
May be administered IM (preferred for intermittent administration) or IV; has been administered SubQ (off-label route; Larson 1995) in specific protocols. May administer corticosteroids 1 to 2 days prior to initiating reinduction therapy (to prevent hypersensitivity reaction). Observe patients for 1 hour after administration; have epinephrine, diphenhydramine, and hydrocortisone at the bedside. A physician should be readily accessible.
IM: Doses should be given as a deep intramuscular injection into a large muscle; volumes >2 mL should be divided and administered in 2 separate sites.
IV: Infuse over at least 30 minutes through the side arm of a NS or D5W infusion.
Storage
Intact vials of powder should be refrigerated at 2°C to 8°C (36°F to 48°F). Reconstituted solution should be used immediately after preparation, although is stable for 3 hours at room temperature or 72 hours refrigerated.
Drug Interactions
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. Monitor therapy
Adverse Reactions
Frequency not defined:
Cardiovascular: Acute myocardial infarction, arterial thrombosis, cerebral thrombosis, cerebrovascular accident (Morgan 2011), embolism, facial edema, flushing, hypertension, hypotension, peripheral edema, thrombosis, venous thrombosis
Dermatologic: Erythema of skin, pruritus, urticaria
Endocrine & metabolic: Amenorrhea, decreased glucose tolerance, diabetic ketoacidosis, hyperammonemia (with clinical signs of metabolic encephalopathy), hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hypoalbuminemia, hypocholesterolemia, increased serum amylase, increased uric acid, weight loss
Gastrointestinal: Abdominal pain, acute pancreatitis, cholestasis, diarrhea, hemorrhagic pancreatitis, intestinal perforation (rare), nausea (frequent, but rarely severe; may be secondary to increased blood urea nitrogen and increased uric acid), necrotizing pancreatitis, swelling of lips, vomiting (frequent, but rarely severe; may be secondary to increased blood urea nitrogen and increased uric acid)
Genitourinary: Azoospermia
Hematologic & oncologic: Anemia, antithrombin III deficiency, bone marrow depression, decreased clotting factors (factors VII, VIII, IX, and X), disorder of hemostatic components of blood (change in hemostatic function; decrease in plasminogen), febrile neutropenia, hemorrhage, hypofibrinogenemia, leukopenia, neutropenia, prolonged partial thromboplastin time, prolonged prothrombin time, thrombocytopenia
Hepatic: Cholestatic hepatitis, hepatic failure, hepatic injury, hepatitis, hepatomegaly, hepatotoxicity, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin, jaundice, liver steatosis
Hypersensitivity: Anaphylactic shock, anaphylaxis, hypersensitivity reaction, type I hypersensitivity reaction
Immunologic: Antibody development (including neutralizing), increased serum globulins (beta and gamma)
Infection: Bacterial infection, fungal infection, opportunistic infection, sepsis, viral infection
Local: Injection site reaction
Nervous system: Cerebrovascular hemorrhage (Morgan 2011), chills, confusion, delusion, disorientation, fatigue, malaise, mild depression, pain, parkinsonism, personality disorder, reversible posterior leukoencephalopathy syndrome, seizure
Renal: Increased blood urea nitrogen, renal failure syndrome
Respiratory: Bronchospasm, dyspnea, laryngeal edema, respiratory distress (with retrosternal pressure)
Miscellaneous: Fever
Warnings/Precautions
Concerns related to adverse effects:
- Allergic reactions: [Canadian Boxed Warning]: Allergic reactions may occur during therapy, particularly in patients with known hypersensitivity to other forms of L-asparaginase. Observe for reactions following administration; reactions generally occur 30 to 60 minutes following administration (although may also occur beyond that time). Immediate treatment for hypersensitivity reactions should be available during administration. Discontinue if serious allergic reaction occurs. Prior exposure to asparaginase is a risk factor for allergic reactions; IV administration (compared to IM or SubQ administration) and younger age also may be associated with hypersensitivity reactions (Stock 2011; Woo 2000). Patients who have an allergic reaction to E. coli asparaginase may also react to asparaginase (Erwinia) or to pegaspargase.
- Coagulopathy: Increased prothrombin time, partial thromboplastin time, and hypofibrinogenemia may occur; cerebrovascular thrombosis and hemorrhage have been reported; monitor coagulation parameters at baseline and periodically during and after therapy. Use with caution in patients with an underlying coagulopathy. Replacement therapy should be instituted if fibrinogen <1g/L or ATIII <60%; if ineffective, treatment should preferably be suspended and resumed only when the laboratory parameters have normalized.
- Hepatotoxicity: [Canadian Boxed Warning]: Adverse effects on liver function may be observed including exacerbation of preexisting liver impairment (due to prior therapy or underlying disease). Physicians should carefully consider therapeutic benefits versus toxicity risks. Altered liver function tests (eg, increased AST, ALT, alkaline phosphatase, bilirubin, and decreased serum albumin, plasma fibrinogen) may occur; fulminant hepatic failure has also occurred. Fatty liver may be observed on biopsy. Use with caution and monitor liver function tests at least weekly during therapy; discontinue therapy for any significant changes.
- Hyperammonemia: May induce excessive ammonia production; monitor for signs of metabolic encephalopathy (confusion, stupor, coma).
- Hyperglycemia: May cause hyperglycemia/glucose intolerance (may be irreversible); cases of diabetic ketoacidosis have been observed. Monitor blood glucose as clinically necessary.
- Neurotoxicity: Posterior reversible encephalopathy syndrome (PRES) has been observed in patients treated with asparaginase (in combination with other chemotherapy agents). Monitor for signs/symptoms of PRES (eg, altered mental status, headache, hypertension, seizures, visual disturbances); interrupt therapy for suspected PRES. Control blood pressure and closely monitor for seizure activity.
- Pancreatitis: [Canadian Boxed Warning]: May cause serious and possibly fulminant or fatal pancreatitis; promptly evaluate patients with abdominal pain. May consider continuing therapy for asymptomatic chemical pancreatitis (amylase or lipase >3 times ULN) or only radiologic abnormalities; monitor closely for rising amylase and/or lipase levels (Stock 2011). Discontinue permanently for clinical pancreatitis (eg, vomiting, severe abdominal pain) with amylase/lipase elevation >3 times ULN for >3 days and/or development of a pancreatic pseudocyst. Avoid alcohol use (Stock 2011).
- Thrombotic events: Serious thrombosis, including sagittal sinus thrombosis may occur; discontinue with serious thrombotic events. Anticoagulation prophylaxis during therapy may be considered in some patients (Farge 2013). The risk for thrombosis may be higher in adult patients (Stock 2011).
- Tumor lysis syndrome: Appropriate measures must be taken to prevent tumor lysis syndrome and subsequent hyperuricemia and uric acid nephropathy; monitor, consider antihyperuricemic therapy, hydration and urinary alkalization.
Other warnings/precautions:
- Antibody formation: Development of neutralizing antibodies has been reported with repeated dosing and is associated with reduced L-asparaginase activity. Monitor L-asparaginase activity levels in serum or plasma; consider switching to another asparaginase preparation.
- Experienced physician: [Canadian Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician in a setting where full resuscitative facilities are immediately available.
- Medication error prevention: Do not interchange E. coli asparaginase for Erwinia asparaginase, calaspargase pegol, or pegaspargase; ensure the proper formulation, route of administration, and dose prior to administration. The E. coli and the Erwinia strains of asparaginase differ slightly in their gene sequencing and have slight differences in their enzyme characteristics. Both are highly specific for asparagine and have <10% activity for the D-isomer.
Monitoring Parameters
CBC with differential, amylase, lipase, triglycerides, liver function prior to and weekly during therapy, coagulation parameters (baseline and prior to each injection), blood glucose, uric acid. Monitor for allergic reaction; monitor for onset of abdominal pain and mental status changes. Monitor vital signs during administration.
Pregnancy
Pregnancy Considerations
Based on data from animal reproduction studies, in utero exposure to asparaginase (E. coli-derived) may cause fetal harm.
Per the manufacturer, females of reproductive potential should avoid pregnancy during chemotherapy, and males should not father a child during chemotherapy and for a period of time after the last dose of asparaginase (E. coli-derived).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea or vomiting. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of infection, severe loss of strength and energy, severe dizziness, or passing out (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
