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Crisantaspase L Asparaginase

Crisantaspase (L-Asparaginase): A Cornerstone in Acute Lymphoblastic Leukemia Therapy

Introduction

Crisantaspase, a purified form of L-asparaginase derived from Erwinia chrysanthemi, is an essential chemotherapeutic enzyme used in the treatment of acute lymphoblastic leukemia (ALL), particularly in pediatric populations. L-asparaginase exploits the metabolic vulnerability of leukemic cells that lack the ability to synthesize asparagine, an amino acid crucial for their proliferation and survival. By depleting extracellular asparagine, crisantaspase induces selective leukemic cell apoptosis while sparing normal cells.

Overview and Historical Context

L-asparaginase has been a cornerstone of ALL treatment since the 1960s. Initially sourced from Escherichia coli, the enzyme was later derived from Erwinia chrysanthemi to address hypersensitivity reactions in some patients. Crisantaspase is the recombinant or purified Erwinia-based formulation, developed for patients who cannot tolerate E. coli-derived asparaginase due to allergic reactions or silent inactivation.

Mechanism of Action

Crisantaspase catalyzes the hydrolysis of L-asparagine into L-aspartic acid and ammonia. Normal cells can synthesize asparagine via asparagine synthetase, but leukemic lymphoblasts often lack sufficient activity of this enzyme. Consequently, the depletion of circulating asparagine leads to leukemic cell death through apoptosis.

  • Substrate: L-asparagine

  • Products: L-aspartic acid + Ammonia

  • Selectivity: Targets leukemic cells due to their asparagine-dependence

Pharmacokinetics and Pharmacodynamics

  • Absorption: Given parenterally (IV or IM); oral bioavailability is negligible

  • Distribution: Widely distributed but does not cross the blood-brain barrier effectively

  • Half-life: Shorter than E. coli-derived preparations (approx. 0.5 to 1.5 days)

  • Metabolism: Broken down by proteolytic enzymes

  • Elimination: Primarily renal

Therapeutic Uses

  1. Acute Lymphoblastic Leukemia (ALL):

    • Standard part of induction and consolidation phases

    • Especially in pediatric ALL protocols

    • Used in patients with hypersensitivity to E. coli L-asparaginase

  2. Acute Myeloid Leukemia (AML):

    • Rarely used but under investigation in specific subtypes

  3. Lymphoblastic Lymphoma:

    • Occasionally incorporated into regimens for lymphoid malignancies

Formulations and Dosage

Crisantaspase is administered either intramuscularly or intravenously. Dosing depends on the patient’s weight and treatment protocol.

  • Typical Dose: 25,000 IU/m^2 IM or IV every 48 hours for up to 6 doses following allergic reactions to pegylated asparaginase

Comparison with Other Asparaginase Preparations

Feature E. coli Asparaginase Pegaspargase (PEG) Crisantaspase
Source E. coli PEGylated E. coli Erwinia chrysanthemi
Half-life ~1.3 days ~5.5 days ~0.6 days
Hypersensitivity Moderate Lower than native Low if switched after E. coli allergy
Dosing Frequency Daily or QOD Every 2-3 weeks Every 48 hours

Side Effects and Toxicity

Crisantaspase can cause a range of side effects, some of which are serious and require close monitoring.

  1. Hypersensitivity Reactions

    • Rash, urticaria, bronchospasm, or anaphylaxis

    • Prevalence lower than with E. coli-derived L-asparaginase

  2. Hepatotoxicity

    • Elevated transaminases, hyperbilirubinemia, hepatic steatosis

  3. Pancreatitis

    • May present as abdominal pain and elevated serum amylase/lipase

    • Can necessitate permanent discontinuation

  4. Thrombosis and Coagulopathy

    • Due to decreased synthesis of coagulation factors

    • Increased risk of venous thromboembolism (VTE)

  5. Hyperglycemia

    • Particularly in combination with corticosteroids

  6. Neurotoxicity

    • Rare; may present as confusion or encephalopathy

Monitoring Parameters

  • Serum asparaginase activity (to assess efficacy)

  • Liver function tests (AST, ALT, bilirubin)

  • Amylase/lipase (for pancreatitis)

  • Coagulation profile (PT, aPTT, fibrinogen)

  • Blood glucose levels

  • Signs of hypersensitivity

Immunogenicity and Resistance

A major challenge in L-asparaginase therapy is immune-mediated inactivation. This can be:

  • Clinical hypersensitivity: Visible allergic reaction

  • Silent inactivation: Antibodies neutralize the enzyme without overt symptoms, leading to therapeutic failure

Crisantaspase is particularly valuable in managing patients with such complications and restoring enzyme activity.

Role in Pediatric Oncology

Crisantaspase is a staple in pediatric oncology, where treatment protocols like ALL-BFM, COG, and UKALL include it as part of combination chemotherapy. Children generally tolerate asparaginase better than adults, though they are still at risk for side effects.

Combination Therapy

L-asparaginase is not used in isolation but as part of multi-drug regimens with agents like:

  • Vincristine

  • Dexamethasone or prednisone

  • Anthracyclines (e.g., daunorubicin)

  • Methotrexate

These combinations improve remission rates and overall survival.

Guidelines and Recommendations

  • NCCN Guidelines: Recommend crisantaspase as an alternative in patients with hypersensitivity to pegylated L-asparaginase

  • FDA & EMA Approvals: Approved for use in relapsed or refractory ALL, especially following allergy to E. coli-derived preparations

Research and Future Directions

  1. Recombinant Technologies

    • Efforts underway to develop recombinant crisantaspase with reduced immunogenicity

  2. Pegylated Crisantaspase

    • PEGylation of Erwinia-derived asparaginase may extend half-life and reduce injection frequency

  3. Alternative Delivery Systems

    • Liposomal encapsulation to improve pharmacokinetics

    • Nanoparticle carriers under development

  4. Biomarker Development

    • Studies exploring predictive markers of asparaginase sensitivity

Case Studies

  • Case 1: A 9-year-old patient with standard-risk ALL developed an anaphylactic reaction to PEG-asparaginase. Switched to crisantaspase, achieving full remission with no further hypersensitivity.

  • Case 2: A 15-year-old with relapsed ALL experienced silent inactivation of native L-asparaginase. Serum asparaginase activity confirmed low levels, prompting a switch to crisantaspase with restoration of therapeutic enzyme activity.

Patient Counseling Points

  • Educate patients and caregivers on recognizing hypersensitivity symptoms

  • Stress the importance of adherence to dosing schedule

  • Maintain hydration and monitor for abdominal symptoms

  • Discuss possible lab monitoring during treatment

Conclusion

Crisantaspase has solidified its place as a vital alternative in the treatment of acute lymphoblastic leukemia, particularly for patients who cannot tolerate E. coli-derived asparaginases. Its unique mechanism of action, selective cytotoxicity toward leukemic cells, and adaptability in hypersensitivity scenarios make it an indispensable agent in modern oncology. Continued research into improving its pharmacokinetic profile and reducing immunogenicity may enhance its efficacy and convenience, ensuring its sustained relevance in leukemia management.

References

  • Avramis VI, Panosyan EH. Pharmacokinetic and pharmacodynamic studies of asparaginase in leukemia. Clinical Pharmacokinetics.

  • Silverman LB. Treatment of childhood ALL: Current perspectives. Hematology Am Soc Hematol Educ Program.

  • National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.

  • EMA and FDA drug labeling and safety information for crisantaspase.