L-spar

Approved Indications:

• Acute Lymphoblastic Leukemia (ALL):
  Used as part of combination chemotherapy protocols (e.g., BFM, COG, Hyper-CVAD) during induction and consolidation phases in both pediatric and adult patients.
• Lymphoblastic Lymphoma (LBL):
  Treatment in patients with lymphoblastic lymphoma, particularly those with leukemic transformation.

Clinically Accepted Off-Label Uses:

• NK/T-cell lymphoma: Especially for relapsed or refractory cases that are sensitive to asparagine depletion.
• Refractory or relapsed ALL: In patients who are intolerant to or have developed resistance to other formulations.

Route: Intravenous (IV) or intramuscular (IM) injection

Standard Dosing (Native L-Asparaginase):

• Children and Adults: 5,000–10,000 IU/m² IM or IV 3 times per week (every 48 hours) for up to 9–10 doses per induction cycle.
• Doses and duration depend on chemotherapy protocol.

Special Populations:

• Renal Impairment: Use cautiously; monitor renal function.
• Hepatic Impairment: Use with caution; monitor liver enzymes and bilirubin.
• Elderly: No specific adjustments, but monitor for toxicities more frequently.

Premedication (if history of hypersensitivity):

• Antihistamines, corticosteroids, or antipyretics may be used.

L-Asparaginase is an enzyme that catalyzes the hydrolysis of circulating L-asparagine into L-aspartic acid and ammonia. Many leukemic cells, particularly in acute lymphoblastic leukemia, lack the ability to synthesize asparagine and depend on exogenous sources. Depletion of L-asparagine starves these malignant lymphoblasts, leading to inhibition of protein synthesis, cell cycle arrest, and apoptosis, while sparing most normal cells that can synthesize asparagine.

• Absorption: Not applicable (parenteral only)
• Onset: Rapid asparagine depletion within hours of administration
• Distribution: Primarily intravascular; does not cross the blood-brain barrier significantly
• Half-life:
• Native form: ~1.2–1.5 days
• Pegylated form: ~5.5 days
• Metabolism: Proteolytic degradation (non-CYP dependent)
• Elimination: Renal and reticuloendothelial clearance

Pregnancy:

• FDA Category C
  Animal studies show fetal harm; no adequate human data. Use only if potential benefit outweighs the risk.

Lactation:

• Unknown if excreted in breast milk. Due to potential for serious adverse effects in infants, breastfeeding is not recommended during treatment.

• Primary Class: Antineoplastic agent
• Subclass: Enzymatic antimetabolite (asparagine depleting agent)

• Known hypersensitivity to L-asparaginase or E. coli–derived proteins
• History of severe pancreatitis related to prior asparaginase therapy
• Severe hepatic impairment
• Active hemorrhage or thromboembolic events
• Uncontrolled bleeding or coagulation disorders

• Hypersensitivity reactions: May include rash, urticaria, or anaphylaxis—monitor closely during and after administration.
• Pancreatitis: Can be life-threatening; discontinue permanently if confirmed.
• Hepatotoxicity: Monitor liver enzymes, bilirubin, and coagulation parameters.
• Coagulopathy and bleeding: Due to decreased synthesis of clotting factors; monitor PT, aPTT, fibrinogen.
• Hyperglycemia: May induce glucose intolerance or transient diabetes, especially with concurrent steroids.
• Thrombosis: Increased risk, especially with central venous lines and corticosteroids.
• Neurotoxicity: Rare; may include seizures or altered mental status.
• Immunosuppression: Avoid live vaccines during and shortly after therapy.

Common:

• Nausea, vomiting
• Fever, fatigue
• Elevated liver enzymes
• Hypoalbuminemia
• Injection site pain or inflammation

Serious/Rare:

• Anaphylaxis
• Acute pancreatitis
• Hepatic failure
• Deep vein thrombosis or pulmonary embolism
• CNS effects (confusion, seizures)
• Severe coagulopathy with bleeding

Timing:
Adverse effects like hypersensitivity and thrombosis may appear within the first few doses; others like hepatotoxicity or pancreatitis may occur later in the treatment course.

• Methotrexate: Concurrent use reduces methotrexate efficacy; sequence therapy properly.
• Vincristine: Risk of increased neurotoxicity
• Corticosteroids (e.g., dexamethasone): Increased risk of hyperglycemia, thrombosis
• Anticoagulants and antiplatelets: Increased bleeding risk due to clotting factor suppression
• Live vaccines: Contraindicated during immunosuppressive therapy

Enzyme Involvement:
Not metabolized by cytochrome P450 enzymes; minimal enzyme-based drug interactions.

• NCCN and WHO guidelines confirm L-asparaginase as essential in pediatric ALL protocols.
• Pegaspargase is increasingly preferred in newly diagnosed ALL due to less frequent dosing and fewer allergic reactions.
• Erwinia-derived asparaginase is now standard for patients who develop hypersensitivity to E. coli–based L-asparaginase.
• Therapeutic drug monitoring (TDM) is recommended in some protocols to optimize efficacy and minimize toxicity.

• Vial (Lyophilized powder):
• Store at 2°C to 8°C (refrigerated)
• Do not freeze
• Protect from light and moisture
• Reconstitute with sterile water as directed (e.g., 1–2 mL)
• Use immediately after reconstitution or within time limits specified in product insert
• Handling:
• Do not shake after reconstitution
• Inspect for particulate matter or discoloration before use
• Discard if precipitate forms or solution is cloudy