ASPARLAS (calaspargase pegol-mknl) is indicated as a component of a multiagent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) in pediatric and young adult patients aged 1 month to 21 years.
Asparaginase is an important agent used to treat acute lymphoblastic leukemia (ALL) [rx]. Asparagine is incorporated into most proteins, and the synthesis of proteins is stopped when asparagine is absent, which inhibits RNA and DNA synthesis, resulting in a halt in cellular proliferation. This forms the basis of asparaginase treatment in ALL.
Calaspargase pegol, also known as asparlas, is an asparagine-specific enzyme that is indicated as a part of a multi-agent chemotherapy regimen for the treatment of ALL [rx]. The asparagine-specific enzyme is derived from Escherichia coli, as a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker to create a stable molecule which increases the half-life and decreases the dosing frequency.
Calaspargase pegol, by Shire pharmaceuticals, was approved by the FDA on December 20, 2018, for acute lymphoblastic anemia (ALL) [rx].
Mechanism of action
L-asparaginase (the main component of this drug) is an enzyme that catalyzes the conversion of the amino acid L-asparagine into both aspartic acid and ammonia. This process depletes malignant cells of their required asparagine. The depletion of asparagine then blocks protein synthesis and tumor cell proliferation, especially in the G1 phase of the cell cycle. As a result, tumor cell death occurs. Asparagine is important in protein synthesis in acute lymphoblastic leukemia (ALL) cells which, unlike normal cells, cannot produce this amino acid due to a lack of the enzyme asparagine synthase [rx].
Pegylation decreases enzyme antigenicity and increases its half-life. Succinimidyl carbamate (SC) is used as a PEG linker to facilitate attachment to asparaginase and enhances the stability of the formulation [rx]. SC-PEG urethane linkages formed with lysine groups are more hydrolytically stable [rx].
The effect of this drug is believed to occur by the selective killing of leukemic cells due to the depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase are less capable of producing L-asparagine and therefore rely on exogenous L-asparagine for survival. When asparagine is depleted, tumor cells cannot proliferate [rx].
During remission induction, one dose of SC-PEG (2500 IU/m2) results in a sustained therapeutic serum asparaginase activity (SAA) without excessive toxicity or marked differences in the proportion of patients with low end-induction minimum residual disease (MRD) [rx].
Pharmacodynamic (PD) response was studied through the measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations with an LC-MS/MS assay (liquid chromatography-mass spectrometry). Asparagine concentration in plasma was sustained below the assay limit of quantification for more than 18 days after one dose of pegaspargase pegol, 2,500 U/m2, during the induction phase of treatment. Average cerebrospinal asparagine concentrations decreased from a pretreatment concentration of 0.8 μg/mL (N=10) to 0.2 μg/mL on Day 4 (N=37) and stayed decreased at 0.2 μg/mL (N=35) 25 days after the administration of one of 2,500 U/m2 in the induction phase [rx].
Indications
- This drug is an asparagine-specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients aged 1 month to 21 years.
- The pharmacokinetics of calaspargase pegol were examined when given in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL [rx]. The FDA approval of this drug was based on the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when administering calaspargase, 2500 U/m2 intravenously, at 3-week intervals.
Associated Conditions
- Acute Lymphoblastic Leukemia (ALL)
- Acute lymphoblastic leukemia in children and young adults aged 1 month to 21 years. It is used with combination chemotherapy.
Calaspargase pegol-mknl is also being studied in the treatment of other types of cancer.
Contraindications
- Hypersensitivity (including anaphylaxis) to the active component or any of the ingredients
- History of serious thrombosis during previous L-asparaginase therapy
- History of serious pancreatitis during previous L-asparaginase therapy
- History of serious hemorrhagic events during previous L-asparaginase therapy
- Severe hepatic impairment
Dosage
Strengths: mknl 750 units/mL
Acute Lymphoblastic Leukemia
18 to 21 years:
- 2500 units/m2 IV over 60 minutes no more frequently than every 21 days
Usual Pediatric Dose for Acute Lymphoblastic Leukemia
1 month and older:
- 2500 units/m2 IV over 60 minutes no more frequently than every 21 days
Dose Adjustments
DOSE MODIFICATIONS:
INFUSION REACTION/HYPERSENSITIVITY REACTION:
- Grade 1: Reduce infusion rate by 50%.
- Grade 2: Interrupt infusion; treat symptoms; when symptoms resolve, resume infusion at a 50% reduced rate.
- Grade 3 or 4: Permanently discontinue therapy.
HEMORRHAGE:
- Grade 3 or 4: Withhold therapy; evaluate for coagulopathy and consider clotting factor replacement as needed; resume therapy with the next scheduled dose if bleeding is controlled.
PANCREATITIS:
- Grade 3 or 4: Withhold therapy for elevations in lipase or amylase greater than 3 times the upper limit of normal (ULN) until enzyme levels stabilize or are declining. Discontinue therapy permanently if clinical pancreatitis is confirmed.
THROMBOEMBOLISM:
- Uncomplicated deep vein thrombosis: Withhold therapy; treat with antithrombotics; when symptoms resolve consider resuming therapy while continuing antithrombotics.
- Severe or life-threatening thrombosis: Discontinue therapy permanently. Treat with antithrombotics.
HEPATOTOXICITY:
- Total bilirubin more than 3 x ULN to no more than 10 x ULN: Withhold therapy until total bilirubin levels go down to 1.5 x ULN or less.
- Total bilirubin more than 10 x ULN: Permanently discontinue therapy and do not make up for missed doses.
Reconstitution/preparation techniques:
- This drug is a clear and colorless solution.
- Visually inspect for particulate matter, cloudiness, or discoloration and discard the vial if any of these are present.
- Do not administer if the vial has been shaken or vigorously agitated, frozen, or stored at room temperature for more than 48 hours.
- Dilute vial in 100 mL of 0.9% sodium chloride injection 5% dextrose injection using sterile/aseptic technique.
- Discard any unused portion left in a vial.
- After dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, respectively.
- Administer the dose over a period of 1 hour.
- Do not infuse other drugs through the same IV line.
IV compatibility:
- Compatible with 0.9% sodium chloride injection or 5% dextrose.
Side Effects
The Most Common
- hives,
- itching,
- redness,
- lightheadedness,
- wheezing,
- difficulty breathing,
- swelling of your face, lips, tongue, or throat,
- easy bruising,
- unusual bleeding,
- increased thirst,
- increased urination,
- dry mouth,
- fruity breath odor,
- severe pain in your upper stomach spreading to your back,
More Common
- nausea,
- vomiting,
- loss of appetite,
- stomach pain (upper right side),
- dark urine,
- yellowing of the skin or eyes (jaundice),
- headache,
- sudden numbness or weakness,
- blurred vision,
- chest pain, and
- swelling or redness in an arm or leg
- pancreatitis,
- blood clotting problems, and
- abnormal liver function tests
Rare
- easy bruising, unusual bleeding;
- high blood sugar–increased thirst, increased urination, dry mouth, fruity breath odor;
- pancreatitis–severe pain in your upper stomach spreading to your back, nausea, and vomiting;
- liver problems–loss of appetite, stomach pain (upper right side), dark urine, jaundice (yellowing of the skin or eyes); or
- signs of a blood clot–headache, sudden numbness or weakness, blurred vision, chest pain, swelling or redness in an arm or leg.
- pancreatitis;
- blood clotting problems; or
- abnormal liver function tests.
Drug Interaction
| Cyproterone acetate | The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Calaspargase pegol. |
| Desogestrel | The therapeutic efficacy of Desogestrel can be decreased when used in combination with Calaspargase pegol. |
| Dienogest | The therapeutic efficacy of Dienogest can be decreased when used in combination with Calaspargase pegol. |
| Drospirenone | The therapeutic efficacy of Drospirenone can be decreased when used in combination with Calaspargase pegol. |
| Estetrol | The therapeutic efficacy of Estetrol can be decreased when used in combination with Calaspargase pegol. |
| Estradiol | The therapeutic efficacy of Estradiol can be decreased when used in combination with Calaspargase pegol. |
| Ethinylestradiol | The therapeutic efficacy of Ethinylestradiol can be decreased when used in combination with Calaspargase pegol. |
| Ethynodiol diacetate | The therapeutic efficacy of Ethynodiol diacetate can be decreased when used in combination with Calaspargase pegol. |
| Gestrinone | The therapeutic efficacy of Gestrinone can be decreased when used in combination with Calaspargase pegol. |
| Levonorgestrel | The therapeutic efficacy of Levonorgestrel can be decreased when used in combination with Calaspargase pegol. |
| Lynestrenol | The therapeutic efficacy of Lynestrenol can be decreased when used in combination with Calaspargase pegol. |
| Medroxyprogesterone acetate | The therapeutic efficacy of Medroxyprogesterone acetate can be decreased when used in combination with Calaspargase pegol. |
| Megestrol acetate | The therapeutic efficacy of Megestrol acetate can be decreased when used in combination with Calaspargase pegol. |
| Mestranol | The therapeutic efficacy of Mestranol can be decreased when used in combination with Calaspargase pegol. |
| Mifepristone | The therapeutic efficacy of Mifepristone can be decreased when used in combination with Calaspargase pegol. |
| Nomegestrol acetate | The therapeutic efficacy of Nomegestrol acetate can be decreased when used in combination with Calaspargase pegol. |
| Norethisterone | The therapeutic efficacy of Norethisterone can be decreased when used in combination with Calaspargase pegol. |
| Norethynodrel | The therapeutic efficacy of Norethynodrel can be decreased when used in combination with Calaspargase pegol. |
| Norgestimate | The therapeutic efficacy of Norgestimate can be decreased when used in combination with Calaspargase pegol. |
| Norgestrel | The therapeutic efficacy of Norgestrel can be decreased when used in combination with Calaspargase pegol. |
Pregnancy and Lactations
US FDA pregnancy category Not Assigned:
Pregnancy
There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation
There are no data on the presence of calaspargase pegol-mknl in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child, advise lactating women not to breastfeed while receiving ASPARLAS and for 3 months after the last dose.
References
