Introduction ⬇
AHFS Class:
- Antineoplastic Agents 10:00
Generic Name(s):
Calaspargase pegol, an Escherichia coli -derived asparaginase enzyme that is conjugated with monomethoxy polyethylene glycol (mPEG), is an antineoplastic agent.1
Uses ⬆ ⬇
Acute Lymphocytic Leukemia
Calaspargase pegol-mknl is used as a component of combination chemotherapy for the treatment of childhood and young adult acute lymphocytic (lymphoblastic) leukemia (ALL).1 Asparaginase preparations are used as a component of induction and/or intensification (consolidation) regimens administered prior to initiation of maintenance therapy; CNS-directed therapy (for prophylaxis of CNS involvement) also is required in patients with ALL.8,9,10 For additional information on other asparaginase preparations and the treatment of ALL, see Pegaspargase 10:00.
The current indication for calaspargase pegol-mknl is based on achievement and maintenance of serum trough asparaginase activity of at least 0.1 units/mL,1,4,7 which has been demonstrated to correlate with depletion of asparagine in both CSF and serum and has been established as a surrogate pharmacodynamic end point of asparaginase efficacy.3 The combined results of 2 randomized open-label studies in pediatric patients and young adults (DFCI 11-001 and AALL07P4) indicate that 99% of 124 patients with B-cell lineage ALL receiving calaspargase pegol-mknl as a component of combination chemotherapy would maintain steady-state serum trough asparaginase activity of at least 0.1 units/mL at 6, 12, 18, 24, and 30 weeks during the postinduction phase when treated with a dosage of 2500 units/m2 IV every 3 weeks.1,3,7 DFCI 11-001 alone was insufficient for determination of calaspargase pegol-mknl efficacy because of a low number of patients with evaluable pharmacokinetic data.3 Evaluable pharmacokinetic data were available for patients in AALL07P4; however, because the 2 studies evaluated different dosages of calaspargase pegol-mknl (2500 units/m2 every 3 weeks in DFCI 11-001; 2100 or 2500 units/m2 every 2 weeks in AALL07P43,7 ), pharmacokinetic modeling and simulation were used in AALL07P4 to evaluate asparaginase activity at a dosage of 2500 units/m2 IV every 3 weeks.3 The pharmacokinetic analysis indicated comparable steady-state serum trough asparaginase activity for calaspargase pegol-mknl 2500 units/m2 every 3 weeks and pegaspargase 2500 units/m2 every 2 weeks.5
Although DFCI 11-001 was not designed to assess clinical outcomes, no detrimental effect on survival was apparent in patients receiving calaspargase pegol-mknl; in the subgroup of patients with Philadelphia chromosome-negative, B-cell lineage ALL, 98% of those receiving calaspargase pegol-mknl achieved complete remission compared with 99% of those receiving pegaspargase, and estimates of overall survival were comparable in both treatment groups.1,3
Dosage and Administration ⬆ ⬇
General 
Calaspargase pegol should be administered in a setting where resuscitation equipment and other agents necessary to treat anaphylaxis are available.1 Patients should be monitored for hypersensitivity reactions for 1 hour after administration of calaspargase pegol.1 (See Hypersensitivity under Warnings/Precautions: Sensitivity Reactions, in Cautions.)
Bilirubin, aminotransferase, and glucose concentrations should be monitored and clinical examinations should be performed at least weekly until patients have recovered from the cycle of therapy.1
Administration
Calaspargase pegol-mknl is administered by IV infusion over 1 hour.1
Calaspargase pegol-mknl injection concentrate must be diluted prior to IV administration.1 Prior to administration, calaspargase pegol-mknl injection concentrate should be inspected visually for particulate matter, cloudiness, and discoloration.1
The concentrate should be clear and colorless; the concentrate should not be used if it is cloudy or discolored or if particulate matter is present.1 The concentrate also should not be used if it has been shaken or vigorously agitated, frozen, or stored at room temperature for longer than 48 hours.1
To prepare the calaspargase pegol-mknl dilution, the calculated dose of injection concentrate must be withdrawn from the vial(s) and diluted in 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.1
Following dilution, calaspargase pegol-mknl should be administered immediately into a running infusion of the same solution (0.9% sodium chloride injection or 5% dextrose injection) that was used for dilution.1 Diluted solutions of the drug may be stored for up to 4 hours at room temperature (15-25°C) or up to 24 hours under refrigeration (2-8°C).1 Diluted solutions of the drug should be protected from light and should not be shaken or frozen.1
Unopened vials of calaspargase pegol-mknl injection should be stored at 2-8°C but may be stored at room temperature (15-25°C) for up to 48 hours.1 Vials should be stored in the original carton to protect the drug from light.1
Calaspargase pegol-mknl injection contains no preservatives and is intended for single use only; any unused portion in the vial should be discarded.1
Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering asparaginase preparations.41
Dosage
Dosage of calaspargase pegol-mknl is expressed in units and must be individualized according to body surface area.1
Acute Lymphocytic Leukemia
For use as a component of combination chemotherapy for the treatment of acute lymphocytic leukemia (ALL) in pediatric patients and young adults 1 month to 21 years of age, the recommended dosage of calaspargase pegol-mknl is 2500 units/m2 administered no more frequently than every 21 days.1 Clinicians should consult published protocols for the dosage of calaspargase pegol and other chemotherapeutic agents and the method and sequence of administration.
Therapy Interruption for Toxicity
If adverse reactions occur, treatment should be modified accordingly, as described in Table 1.1
Table 1. Therapy Interruption for Calaspargase Pegol Toxicity
Adverse Reaction and Severity | Modification |
|---|
Infusion Reaction or Hypersensitivity Reaction | |
Grade 1 | Reduce infusion rate by 50% |
Grade 2 | Interrupt therapy and treat symptoms; when symptoms resolve, resume infusion at reduced rate of 50% |
Grade 3 or 4 | Permanently discontinue therapy |
Hemorrhage | |
Grade 3 or 4 | Withhold therapy and evaluate for presence of coagulopathy; consider whether clotting factor replacement is needed; if bleeding is controlled, resume therapy with next scheduled dose |
Pancreatitis | |
Grade 3 or 4 | For lipase or amylase concentrations >3 times the upper limit of normal (ULN), withhold therapy until enzyme concentrations stabilize or decline; permanently discontinue therapy if pancreatitis is confirmed |
Thromboembolism | |
Uncomplicated deep-vein thrombosis (DVT) | Withhold therapy and initiate appropriate antithrombotic therapy; when symptoms resolve, may consider resuming therapy while continuing antithrombotic therapy |
Severe or life-threatening thrombosis | Permanently discontinue therapy and initiate appropriate antithrombotic therapy |
Hepatotoxicity | |
Total bilirubin concentration >3 times to ≤10 times the ULN | Withhold therapy until total bilirubin concentrations ≤1.5 times the ULN |
Total bilirubin concentration >10 times the ULN | Discontinue therapy; do not make up for missed doses |
Special Populations
The manufacturer makes no specific dosage recommendations for patients with hepatic or renal impairment.1 The drug is contraindicated in patients with severe hepatic impairment.1 (See Specific Populations under Cautions: Warnings/Precautions.)
Cautions ⬆ ⬇
Contraindications
Calaspargase pegol is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis, to pegylated asparaginase or a history of serious thrombosis, pancreatitis, or hemorrhagic events during previous therapy with asparaginase.1 (See Hypersensitivity under Warnings/Precautions: Sensitivity Reactions, in Cautions.) The drug also is contraindicated in patients with severe hepatic impairment.1
Warnings/Precautions
Sensitivity Reactions
Hypersensitivity
In clinical trials of calaspargase pegol-mknl, grade 3 or 4 hypersensitivity reactions, including anaphylaxis, occurred in 7-21% of patients receiving the drug.1 Hypersensitivity reactions observed with other asparaginase preparations include angioedema, lip or eye swelling, erythema, hypotension, bronchospasm, dyspnea, pruritus, and rash.1
Calaspargase pegol should be administered in a setting where resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, IV corticosteroids, antihistamines) are available, and patients should be observed for 1 hour following infusion.1 If a serious hypersensitivity reaction occurs, calaspargase pegol therapy should be discontinued and appropriate therapy initiated.1 (See Therapy Interruption for Toxicity under Dosage and Administration: Dosage.)
Pancreatitis
In clinical trials of calaspargase pegol-mknl, pancreatitis occurred in 12-16% of patients receiving the drug.1 In a safety study evaluating calaspargase pegol-mknl and pegaspargase, one patient receiving calaspargase pegol-mknl experienced fatal multiorgan failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.1,3 Hemorrhagic or necrotizing pancreatitis also has occurred in patients receiving other asparaginase preparations.1
Serum amylase and/or lipase concentrations should be measured to identify early signs of pancreatic inflammation.1 If pancreatitis is suspected, calaspargase pegol therapy should be withheld; if confirmed, therapy should be discontinued permanently.1 (See Therapy Interruption for Toxicity under Dosage and Administration: Dosage.)
Thrombosis
In clinical trials of calaspargase pegol-mknl, serious thrombotic events (e.g., sagittal sinus thrombosis) occurred in 9-12% of patients receiving the drug.1
Calaspargase pegol therapy should be discontinued in patients experiencing serious thrombotic events.1 (See Therapy Interruption for Toxicity under Dosage and Administration: Dosage.)
Hemorrhage
Hemorrhagic events associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia have occurred in patients receiving calaspargase pegol-mknl.1
Coagulation parameters (e.g., PT, PTT, fibrinogen) should be evaluated in patients experiencing signs and symptoms of hemorrhage.1 The need for appropriate clotting factor replacement therapy should be considered in patients with severe or symptomatic coagulopathy.1 (See Therapy Interruption for Toxicity under Dosage and Administration: Dosage.)
Hepatotoxicity
Hepatotoxicity and abnormal liver function, including elevations in aminotransferase and bilirubin (direct and indirect) concentrations and reduced serum albumin and plasma fibrinogen concentrations, can occur in patients receiving calaspargase pegol.1
Bilirubin and aminotransferase concentrations should be monitored at least weekly during treatment cycles including calaspargase pegol and for 6 weeks after the last dose of the drug.1 If serious hepatotoxicity occurs, calaspargase pegol should be discontinued and supportive care provided.1 (See Therapy Interruption for Toxicity under Dosage and Administration: Dosage.)
Fetal/Neonatal Morbidity and Mortality
There are no adequate data regarding use of calaspargase pegol in pregnant women; however, results of animal studies suggest that the drug may cause fetal harm if administered to pregnant women.1 While there was no evidence of adverse developmental outcomes (e.g., structural abnormalities, embryofetal mortality) when calaspargase pegol-mknl was administered at doses of 0.2-1 times the maximum recommended human dose (MRHD) during the period of organogenesis in pregnant rats, studies in pregnant rabbits administered L-asparaginase suggest that asparagine depletion may harm animal offspring.1
Pregnancy should be avoided during calaspargase pegol therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of calaspargase pegol therapy.1 Women of childbearing potential should be advised to use effective methods of contraception, including a barrier method, while receiving calaspargase pegol and for at least 3 months after the last dose.1 Concomitant use of oral contraceptives and calaspargase pegol should be avoided.1 (See Drug Interactions: Oral Contraceptives.) Patients should be apprised of the potential fetal hazard if calaspargase pegol is used during pregnancy or if the patient becomes pregnant while receiving the drug.1
Immunogenicity
There is a potential for immunogenicity with calaspargase pegol therapy.1 Although development of antibodies to calaspargase pegol-mknl has been reported,4,6 the immunogenic potential of the drug has not been fully established.5
Specific Populations
Pregnancy
Calaspargase pegol may cause fetal harm if administered to pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
Lactation
It is not known whether calaspargase pegol is distributed into human milk.1 The effects of the drug on nursing infants and on milk production also are unknown.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to calaspargase pegol in nursing infants, women should be advised to discontinue nursing during calaspargase pegol therapy and for at least 3 months after the last dose.1
Pediatric Use
Safety and efficacy of calaspargase pegol-mknl for the treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) in pediatric patients 1 month through 16 years of age are supported by evidence from an adequate and well-controlled clinical trial and an additional safety trial in a total of 208 pediatric patients (19 infants, 128 children, 61 adolescents).1 No clinically meaningful differences in safety or serum trough asparaginase activity were noted across age groups.1 (See Uses: Acute Lymphocytic Leukemia.)
Geriatric Use
Safety and efficacy of calaspargase pegol-mknl have not been established in geriatric patients.1
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of calaspargase pegol have not been established.1 (See Cautions: Contraindications.)
Renal Impairment
The effects of renal impairment on the pharmacokinetics of calaspargase pegol have not been established.1
Common Adverse Effects
Adverse effects of grade 3 or greater severity reported in 10% or more of patients receiving calaspargase pegol-mknl include elevated concentrations of aminotransferases and bilirubin, pancreatitis, and abnormal clotting studies.1
Drug Interactions ⬆ ⬇
Oral Contraceptives
Asparaginase-induced hepatotoxicity may impair hepatic clearance of oral contraceptives.41 Since there is a potential for an indirect interaction between calaspargase pegol and oral contraceptives, concomitant use of calaspargase pegol and oral contraceptives is not recommended.1
Other Information ⬆ ⬇
Description
Calaspargase pegol selectively kills leukemic cells by depleting them of plasma l-asparagine, an amino acid that is essential for synthesis of protein, RNA, and DNA.1,2,41 Because of a lack of asparagine synthetase, some leukemic cells cannot synthesize l-asparagine and depend on an exogenous source for protein synthesis and cell survival.1,2,41 Treatment with the enzyme l-asparaginase catalyzes the conversion of l-asparagine into aspartic acid and ammonia.1 Because normal cells are able to synthesize l-asparagine, they are less affected by l-asparaginase-induced depletion of the amino acid.41
Calaspargase pegol-mknl contains Escherichia coli -derived asparaginase conjugated to monomethoxy polyethylene glycol (mPEG) via a succinimidyl carbonate (SC) linker.1,4 The SC linker in calaspargase pegol-mknl replaces the longer succinimidyl succinate (SS) linker found in pegaspargase and creates a more stable molecule.4,5 Calaspargase pegol-mknl suppresses plasma and CSF asparagine concentrations to a similar extent as pegaspargase;3,5 however, calaspargase pegol-mknl results in more prolonged suppression of asparagine concentrations given its longer half-life.4 Although asparaginase does not appear to cross the blood-brain barrier, CSF asparagine depletion occurs as a result of plasma asparagine depletion following treatment with the enzyme.2
Pharmacokinetic assessment of calaspargase pegol-mknl is based on asparaginase activity.1 Following IV administration of the drug, the pharmacokinetics of plasma asparaginase activity are nonlinear.1 Following IV administration of a single 2500-unit/m2 dose of calaspargase pegol-mknl, peak plasma concentration was attained after approximately 1 hour, generally near the end of the 1-hour infusion.1 When administered at a dosage of 2500 unit/m2 every 3 weeks, steady-state concentrations of the drug were achieved around the fourth dose.5 Calaspargase pegol-mknl rapidly depleted plasma asparagine (i.e., concentrations were below the lower limit of quantification within 5 minutes after the dose) in the induction phase, and plasma asparagine concentrations remained less than the assay limit of quantification for more than 18 days following a single 2500-unit/m2 dose.1,4,5 Calaspargase pegol is not metabolized by hepatic enzymes, but is expected to undergo proteolytic degradation.5 The mean half-life of plasma asparaginase activity following a single 2500-unit/m2 dose of calaspargase pegol-mknl is 16 days,1 approximately 2.5-3 times the plasma asparaginase activity half-life of pegaspargase, and results in prolonged suppression of plasma asparagine.4,5
Advice to Patients
Risk of serious allergic reactions, including anaphylaxis.1 Importance of informing clinician immediately if symptoms of serious allergic reactions (e.g., angioedema, lip or eye swelling, hypotension, bronchospasm, dyspnea, rash) occur.1
Risk of pancreatitis.1 Importance of informing clinician immediately if severe abdominal pain occurs.1
Risk of hyperglycemia and glucose intolerance.1 Importance of informing clinician if excessive thirst or increased urinary volume or frequency occurs.1
Risk of thrombosis.1 Importance of informing clinician immediately if severe headache, swelling of arms or legs, shortness of breath, or chest pain occurs.1
Importance of informing clinician if any unusual bleeding or bruising occurs.1
Importance of informing clinician immediately if jaundice, severe nausea or vomiting, or easy bruising or bleeding occurs.1
Risk of fetal harm.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Necessity of advising women of reproductive potential that they should use effective methods of contraception while receiving the drug and for at least 3 months after the last dose.1 Importance of advising women that concomitant use of calaspargase pegol and oral contraceptives is not recommended.1
Importance of advising women to avoid breast-feeding while receiving calaspargase pegol and for at least 3 months after the last dose.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Calaspargase Pegol-mknl
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | Concentrate, for injection, for IV infusion | 750 units/mL | Asparlas® | Servier |
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
References ⬆
1. Servier Pharmaceuticals LLC. Asparlas® (calaspargase pegol-mknl) injection prescribing information. Boston, MA; 2019 Sep.
2. Schore RJ, Devidas M, Bleyer A et al. Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children's Oncology Group AALL07P4. Leuk Lymphoma . 2019; 60:1740-1748. [PubMed 30626253]
3. Li RJ, Jin R, Liu C et al. FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults. Clin Cancer Res . 2019; [PubMed 31444252]
4. Angiolillo AL, Schore RJ, Devidas M et al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol . 2014; 32:3874-82. [PubMed 25348002]
5. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 761102Orig1s000: Multi-discipline review. From FDA website. [Web]
6. Schore RJ, Devidas M, Bleyer A et al. Anti-pegaspargase, anti-calaspargase pegol, and anti-polyethylene glycol antibody incidence in high risk acute lymphoblastic leukemia patients receiving pegaspargase or calaspargase pegol and associated anaphylactic or hypersensitivity reaction rates: results from the Children's Oncology Group (COG) study AALL07P4. ASH Annual Meeting Abstracts. Blood . 2016; 128:3965. [Web]
7. Silverman LB, Blonquist TM, Hunt SK et al. Randomized study of pegaspargase (SS-PEG) and calaspargase pegol (SC-PEG) in pediatric patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma: results of the DFCI ALL consortium protocol 11-001. ASH Annual Meeting Abstracts. Blood . 2016; 128:175. [Web]
8. Childhood acute lymphoblastic leukemia treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2019 Oct 22. [Web]
9. Adult acute lymphoblastic leukemia treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2019 Feb 8. [Web]
10. Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am . 2015; 62:61-73. [PubMed 25435112]
11. Boissel N, Sender LS. Best Practices in Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia: A Focus on Asparaginase. J Adolesc Young Adult Oncol . 2015; 4:118-28. [PubMed 26421220]
41. Les Laboratoires Servier. Oncaspar® (pegasparase) summary of product characteristics. Suresnes, France; 2019 Nov 25.