A Comprehensive Monograph on Calaspargase Pegol (Asparlas®): A Novel Long-Acting Asparaginase Formulation for Acute Lymphoblastic Leukemia

Executive Summary

Calaspargase pegol, marketed under the proprietary name Asparlas®, represents a significant advancement in the therapeutic armamentarium for acute lymphoblastic leukemia (ALL). As a biotech drug, it is an engineered, long-acting formulation of the enzyme L-asparaginase. Its primary indication is as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL in pediatric and young adult patients, specifically those aged one month to 21 years.[1] The antineoplastic effect of Calaspargase pegol is derived from its enzymatic activity, which depletes the systemic supply of the amino acid L-asparagine. This selectively targets and induces apoptosis in leukemic lymphoblasts, which are often unable to synthesize L-asparagine endogenously and are therefore dependent on an external supply for their survival.[3]

The defining characteristic of Calaspargase pegol is its optimized pharmacokinetic profile, which is a direct result of its unique molecular structure. The L-asparaginase enzyme is conjugated to monomethoxypolyethylene glycol (mPEG) via a highly stable succinimidyl carbonate (SC) linker.[3] This stable conjugation confers an extended plasma half-life of approximately 16.1 days, substantially longer than that of its predecessor, pegaspargase.[3] This prolonged duration of action allows for a less frequent intravenous dosing schedule of once every three weeks, a notable improvement in convenience for patients compared to the two-week interval required for pegaspargase.[1]

Regulatory approval in the United States and Canada was granted based on clinical trial evidence demonstrating the achievement and maintenance of a surrogate pharmacokinetic endpoint—nadir serum asparaginase activity (SAA) levels—above the established therapeutic threshold.[1] Pivotal studies established that this less frequent dosing regimen resulted in comparable clinical efficacy, including event-free survival and complete remission rates, and a similar safety profile to that of pegaspargase.[10] Beyond its clinical attributes, Calaspargase pegol offers a significant logistical advantage with an extended shelf life, which helps to mitigate the supply chain instability that has historically challenged the consistent availability of asparaginase products.[11] Health economic assessments, however, have concluded that its value is as a convenient and reliable alternative, recommending its cost should not exceed that of pegaspargase, thereby positioning it as a successor formulation based on improved pharmacokinetics and logistics rather than superior efficacy.[12]

Section 1: Molecular Profile and Biochemical Characteristics

1.1. Identification and Nomenclature

Calaspargase pegol is a complex biologic agent identified by a variety of proprietary, non-proprietary, and chemical names and codes across different regulatory and scientific databases. Establishing a clear and comprehensive list of these identifiers is fundamental for accurate referencing and research. The drug is most commonly known by its U.S. Adopted Name (USAN), Calaspargase pegol, and its trade name, Asparlas®.[1] The full non-proprietary name often includes the suffix "-mknl" (calaspargase pegol-mknl), which is a placeholder assigned by the U.S. Food and Drug Administration (FDA) to distinguish it from other related biologics.[1] During its development, it was referred to by the code designation EZN-2285 and described as SC-PEG E. coli L-asparaginase, highlighting its structural components.[5]

Its unique identity is cataloged globally through several key registry numbers. The Chemical Abstracts Service (CAS) has assigned it the number 941577-06-6.[1] In major drug databases, it is listed as DB14730 in DrugBank and D10096 in the KEGG DRUG database.[1] Other important identifiers include its UNII code T9FVH03HMZ and its ChEMBL ID, ChEMBL2108728.[1] For therapeutic classification, the World Health Organization has assigned it the Anatomical Therapeutic Chemical (ATC) code L01XX86, placing it among "Other antineoplastic agents".[1]

Table 1: Drug Identification and Key Properties

Property	Value
Proprietary Name	Asparlas®
Non-Proprietary Name	Calaspargase pegol-mknl
Drug Type	Biotech, Engineered Protein
DrugBank ID	DB14730
CAS Number	941577-06-6
ATC Code	L01XX86
Code Designations	EZN-2285, SC-PEG E. coli L-asparaginase
Molecular Formula (Monomer)	C1516​H2423​N415​O492​S8​
Approximate Molecular Weight	~313 kDa
Sponsor/Manufacturer	Servier Pharmaceuticals LLC

1.2. Structural Composition and Formulation

Calaspargase pegol is an engineered protein conjugate, the result of precise biochemical modifications to a naturally occurring enzyme to enhance its therapeutic properties.[1] Its structure can be deconstructed into three primary components: the core enzyme, the pegylation moiety, and the linker molecule that joins them.

The active component is L-asparaginase isoenzyme II, a homotetrameric enzyme produced by the bacterium Escherichia coli (specifically, strain K12).[14] Each of the four identical subunits (monomers) consists of a 326-amino acid polypeptide chain.[16] The full amino acid sequence of the monomer is as follows:

LPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG EQVVNIGSQD MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD LTVKCDKPVV MVGAMRPSTS MSADGPFNLY NAVVTAADKA SANRGVLVVM NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG YIHNGKIDYQ RTPARKHTSD TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV SAGVGNGNLY KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ KARVLLQLAL TQTKDPQQIQ QIFNQY.19

This core enzyme is covalently modified through a process known as pegylation. Approximately 31 to 39 molecules of monomethoxypolyethylene glycol (mPEG), also referred to as pegol, are attached to the surface of the L-asparaginase homotetramer.[14] This modification is central to the drug's enhanced pharmacokinetic profile.

The molecular innovation that distinguishes Calaspargase pegol from its predecessor, pegaspargase (Oncaspar®), lies in the chemistry of the linker molecule. Calaspargase pegol utilizes a succinimidyl carbonate (SC) linker to attach the mPEG chains to the epsilon-amino groups of lysine residues on the enzyme.[3] This reaction forms a highly stable carbamate (urethane) bond.[21] This bond is significantly more resistant to hydrolysis in plasma compared to the succinimidyl succinate (SS) linker used in pegaspargase, which forms a less stable ester bond.[22] This superior stability is the direct molecular cause of Calaspargase pegol's longer half-life and more sustained enzymatic activity. The total approximate molecular weight of the final conjugated protein is 313 kDa.[16]

The final drug product is formulated as a sterile, clear, colorless, and preservative-free solution for intravenous administration.[8] It is supplied in single-dose vials containing 3,750 units of activity in 5 mL of solution, for a concentration of 750 units/mL.[24]

1.3. Physicochemical Properties and Stability

The practical handling and stability of Calaspargase pegol are critical considerations in the clinical setting and represent a key area of improvement over older asparaginase formulations. The drug product must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) and must not be frozen or vigorously agitated, as this can denature the protein and lead to a loss of enzymatic activity.[8]

For administration, the required dose is diluted in 100 mL of either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.[24] The stability of the diluted solution is limited; it should be administered immediately but can be stored for up to 4 hours at room temperature (15°C to 25°C) or for up to 24 hours if refrigerated.[24]

A significant logistical advantage of Calaspargase pegol is its extended shelf life of 36 months, which is considerably longer than the 8-month shelf life of pegaspargase.[11] This attribute has profound implications beyond simple convenience. The supply of asparaginase products has historically been inconsistent, leading to drug shortages that can disrupt critical treatment protocols for patients with ALL.[12] A product with a longer shelf life is less prone to wastage due to expiration and allows healthcare systems to maintain a more stable and reliable inventory. This enhanced stability addresses a systemic vulnerability in oncology pharmacy and is a powerful non-clinical driver for its adoption, potentially positioning it to fully replace pegaspargase as the standard long-acting formulation.[11]

Section 2: Pharmacodynamics and Mechanism of Action

2.1. Primary Antineoplastic Mechanism: Asparagine Depletion

The therapeutic mechanism of Calaspargase pegol is an elegant example of exploiting a specific metabolic vulnerability inherent in certain cancer cells. The drug's effect is not cytotoxic in the conventional sense of directly damaging DNA or interfering with mitosis. Instead, it functions as a protein synthesis inhibitor by inducing a state of targeted starvation in malignant lymphoblasts.[3]

The core L-asparaginase enzyme catalyzes the hydrolysis of the non-essential amino acid L-asparagine, converting it into L-aspartic acid and ammonia.[3] When administered systemically, this enzymatic action rapidly depletes the circulating plasma pool of L-asparagine.[3] While most normal, healthy cells are unaffected by this depletion, many ALL lymphoblasts exhibit a critical metabolic flaw: they lack or have very low levels of the enzyme asparagine synthetase.[3] This enzyme is responsible for the endogenous synthesis of L-asparagine. Consequently, these malignant cells are unable to produce their own L-asparagine and are entirely dependent on an exogenous supply from the plasma to survive.[3]

By eliminating this external source of L-asparagine, Calaspargase pegol effectively cuts off the supply of a crucial building block for protein synthesis in the leukemic cells. The resulting cessation of protein synthesis leads to a halt in DNA and RNA synthesis, causing cell cycle arrest, primarily in the G1 phase, and ultimately triggering programmed cell death (apoptosis).[3] This selective killing of leukemic cells forms the basis of its potent antineoplastic activity in ALL.[3]

2.2. The Role of Pegylation and the SC Linker

The evolution from native E. coli L-asparaginase to pegaspargase and now to Calaspargase pegol represents a clear trajectory in biopharmaceutical engineering. This progression has been focused almost exclusively on optimizing the drug's pharmacokinetics and reducing its immunogenicity, rather than altering its fundamental enzymatic mechanism. The core therapeutic "warhead"—the L-asparaginase enzyme—has remained unchanged; the innovation lies in the technology used to deliver it and ensure its persistence in the body.

Pegylation, the process of covalently attaching mPEG chains to the enzyme, is central to this optimization.[1] This modification provides two key benefits:

1. Increased Half-Life: The mPEG chains increase the hydrodynamic radius of the protein molecule. This larger size dramatically slows its clearance from the body, primarily by reducing the rate of renal filtration and proteolytic degradation. This is the principal reason for the drug's extended plasma half-life.[1]
2. Reduced Immunogenicity: The mPEG chains form a hydrophilic cloud around the enzyme, which can physically mask antigenic epitopes on the surface of the foreign E. coli protein from the host's immune system. This "stealthing" effect can reduce the likelihood of eliciting an immune response and the formation of neutralizing anti-drug antibodies.[21]

As discussed previously, the use of a succinimidyl carbonate (SC) linker in Calaspargase pegol is a further refinement of this technology. The resulting stable urethane bond is more resistant to hydrolysis than the linker used in pegaspargase.[21] This enhanced stability prevents premature de-pegylation of the enzyme, ensuring that it remains large and protected for a longer duration, thereby contributing to its significantly prolonged half-life and more sustained enzymatic activity.[21]

2.3. Pharmacodynamic Targets

The primary pharmacodynamic target of Calaspargase pegol is the substrate of its enzymatic action: the amino acid L-asparagine.[3] The drug acts by catalyzing the degradation of L-asparagine throughout the systemic circulation, thereby achieving the therapeutic goal of plasma depletion.[3] In addition to this primary action, it has also been identified as an inhibitor of the human enzyme Isoaspartyl peptidase/L-asparaginase.[3] The clinical significance of this secondary interaction is not fully characterized but the primary antineoplastic effect is overwhelmingly attributed to L-asparagine degradation.

Section 3: Clinical Pharmacology and Pharmacokinetics

3.1. Absorption, Distribution, Metabolism, and Elimination (ADME)

The pharmacokinetic profile of Calaspargase pegol is defined by its large molecular size and engineered stability, which collectively govern its behavior in the body and provide the scientific rationale for its clinical dosing schedule.

• Route of Administration and Absorption: Calaspargase pegol is administered exclusively via intravenous (IV) infusion.[1] Following a one-hour infusion, the mean time to reach maximum plasma concentration (Tmax) is approximately 1.7 hours.[3]
• Distribution: The drug exhibits a small steady-state volume of distribution (Vss) of approximately 2.96 L.[3] This value is close to the plasma volume in an adult, indicating that the drug is primarily confined to the intravascular space and does not distribute extensively into tissues. This is a typical characteristic of very large molecules like pegylated proteins.
• Metabolism and Elimination: As a large protein conjugate, Calaspargase pegol is not a substrate for hepatic cytochrome P450 enzymes and is not eliminated via renal excretion.[7] Instead, its clearance is believed to occur primarily through uptake by the reticuloendothelial system, where it is catabolized into smaller peptides and amino acids.[7] The systemic clearance rate is slow, measured at approximately 0.147 L/day.[3]
• Half-Life: The most clinically significant pharmacokinetic parameter is its long elimination half-life, which has a mean value of approximately 16.1 days.[3] This is the direct consequence of its large size and stable pegylation, and it is substantially longer than the half-life of pegaspargase (approximately 5.7 days).[7] This extended half-life is the key attribute that allows for a 21-day (3-week) dosing interval, as it ensures that therapeutic concentrations of the enzyme are maintained in the plasma for the entire period.

Table 2: Summary of Pharmacokinetic Parameters

Parameter	Value
Tmax (Time to Peak Concentration)	~1.7 hours
Vss (Volume of Distribution)	~2.96 L
Clearance	~0.147 L/day
Elimination Half-Life	~16.1 days
Therapeutic Threshold (Nadir SAA)	≥ 0.1 U/mL

3.2. Therapeutic Activity Thresholds and Pharmacodynamic Endpoint

The clinical efficacy of asparaginase therapies is directly correlated with the extent and duration of L-asparagine depletion. This is quantified by measuring the enzymatic activity of the drug in the patient's serum, known as Serum Asparaginase Activity (SAA).[10] A consensus has been established that a nadir (trough) SAA level of at least 0.1 International Units per milliliter (U/mL) is the minimum threshold required to ensure complete depletion of plasma asparagine and thus maintain a therapeutic antileukemic effect.[1]

The regulatory approval of Calaspargase pegol was granted on the basis of its ability to meet this pharmacodynamic surrogate endpoint. The pivotal clinical studies were designed to demonstrate that a dose of 2,500 U/m² administered intravenously every three weeks could consistently achieve and maintain nadir SAA levels above the 0.1 U/mL threshold throughout the treatment course.[1] In the key study supporting this endpoint, 123 out of 124 patients (99%) successfully maintained nadir SAA levels above 0.1 U/mL at all measured time points through 30 weeks of therapy.[24]

The reliance on this surrogate PK/PD endpoint for approval, rather than requiring a demonstration of superior clinical outcomes like event-free survival (EFS) or overall survival (OS) in a large phase 3 trial, is significant. It reflects a regulatory pathway that accepts a "bioequivalence" or "bio-better" argument for next-generation biologics where the core mechanism of action is unchanged. This approach can streamline the development and approval process for formulations that offer improvements in convenience or safety. However, it also places a greater emphasis on post-marketing surveillance and health economic analyses to determine the drug's ultimate value and place in therapy, as its approval is based on being pharmacodynamically comparable to, not clinically superior to, the existing standard of care.[11]

Section 4: Clinical Efficacy and Pivotal Trial Evidence

4.1. Regulatory Approval Basis and Pivotal Studies

The clinical development program for Calaspargase pegol was strategically designed to establish its efficacy and safety relative to the existing standard of care, pegaspargase. Approval from the U.S. FDA was granted on December 20, 2018, followed by authorization from Health Canada on November 8, 2023.[1] The evidence supporting these approvals was derived primarily from two multicenter, open-label, randomized, active-controlled clinical trials conducted in pediatric and young adult patients with newly diagnosed ALL or lymphoblastic lymphoma.[1]

The two pivotal studies were:

1. DFCI 11-001 (NCT01574274): A study conducted by the Dana-Farber Cancer Institute ALL Consortium.
2. COG AALL07P4 (NCT00671034): A study conducted by the Children's Oncology Group.

These trials were structured not to prove that Calaspargase pegol was superior to pegaspargase, but rather to demonstrate that its less frequent dosing schedule could achieve comparable pharmacodynamic activity and clinical outcomes, thereby establishing it as a valid and more convenient alternative.

Table 3: Comparative Summary of Pivotal Clinical Trials

Feature	DFCI 11-001 (NCT01574274)	COG AALL07P4 (NCT00671034)
Patient Population	Newly diagnosed ALL or Lymphoblastic Lymphoma	Newly diagnosed High-Risk B-precursor ALL
Age Range	1 to 21 years	1 to 30 years
Number of Patients	Calaspargase pegol (n=119), Pegaspargase (n=120)	Calaspargase pegol (n=42), Pegaspargase (n=54)
Chemotherapy Backbone	DFCI ALL Consortium regimen	Augmented Berlin-Frankfurt-Münster (BFM) regimen
Calaspargase Pegol Arm	2,500 U/m² IV every 3 weeks	2,500 U/m² IV (per protocol phase)
Comparator Arm	Pegaspargase 2,500 U/m² IV every 2 weeks	Pegaspargase 2,500 U/m² IV (per protocol phase)
Primary Outcome	Nadir Serum Asparaginase Activity (SAA)	Pharmacokinetic (PK) comparability
Key Efficacy Finding	Comparable EFS/CR; longer SAA duration with Calaspargase pegol	Longer half-life and asparagine depletion; comparable toxicity

4.2. Detailed Analysis of Pivotal Trial: DFCI 11-001

The DFCI 11-001 trial was a cornerstone of the regulatory submission for Calaspargase pegol.[7] This randomized, open-label study enrolled 239 eligible patients (230 with ALL, 9 with lymphoblastic lymphoma) between 1 and 21 years of age.[10] Patients were randomized to receive either IV Calaspargase pegol or IV pegaspargase as part of the DFCI ALL Consortium backbone therapy.[24]

The intervention arms were designed to test the feasibility of the extended dosing interval for Calaspargase pegol. The Calaspargase pegol arm (n=119) received 2,500 U/m² intravenously every 3 weeks for a total of 10 post-induction doses. The active comparator arm (n=120) received pegaspargase at the same dose of 2,500 U/m², but administered every 2 weeks for a total of 15 post-induction doses.[1]

The study's key findings were:

• Pharmacodynamics (SAA): The trial successfully demonstrated the prolonged enzymatic activity of Calaspargase pegol. After a single induction dose, SAA levels remained above the therapeutic threshold of 0.1 U/mL in ≥95% of patients in both arms at day 18. However, the key difference emerged at day 25, where 88% of patients in the Calaspargase pegol arm still had therapeutic SAA levels, compared to only 17% in the pegaspargase arm (P <.001), confirming its longer duration of action.[10] During the post-induction phase, the median nadir SAA levels were similar for both arms and remained high (≥ 1.0 IU/mL), well above the therapeutic minimum.[10]
• Clinical Outcomes: The trial found no statistically significant differences in major clinical efficacy endpoints between the two arms. The rate of complete remission was 95% for the Calaspargase pegol group versus 99% for the pegaspargase group (P =.12).[10] With a median follow-up of 5.3 years, the 5-year event-free survival was also comparable at 88.1% for Calaspargase pegol and 84.9% for pegaspargase (P =.65).[10]

The conclusion from DFCI 11-001 was that Calaspargase pegol administered every 3 weeks provided similar nadir SAA, toxicity, and survival outcomes when compared to pegaspargase administered every 2 weeks, validating its use as a longer-acting alternative.[10]

4.3. Detailed Analysis of Pivotal Trial: AALL07P4

The COG AALL07P4 study provided further supportive evidence for the pharmacokinetic and pharmacodynamic profile of Calaspargase pegol.[23] This trial enrolled patients with newly diagnosed high-risk B-precursor ALL and randomized them to receive either Calaspargase pegol (at doses of 2,100 U/m² or 2,500 U/m²) or pegaspargase (2,500 U/m²) within an augmented BFM chemotherapy regimen.[22]

The primary focus of this study was to compare the pharmacokinetic properties of the two drugs.[30] The results confirmed that Calaspargase pegol has a significantly longer half-life, approximately 2.5 times that of pegaspargase.[7] This translated into a more sustained period of therapeutic asparaginase activity and a longer duration of complete plasma asparagine depletion following a single dose.[23] After one dose on induction day 4, plasma asparagine remained undetectable for 18 days in the Calaspargase pegol groups, compared to 11 days for the pegaspargase group.[23] While the study was not powered for definitive comparison of clinical outcomes, subsequent analyses suggested little to no difference in overall survival or event-free survival between the treatment arms.[11]

A particularly noteworthy finding from the DFCI 11-001 study, with profound implications for the entire drug class, was the observation that the median nadir SAA levels in both arms were ≥ 1.0 IU/mL.[10] This is an order of magnitude higher than the 0.1 U/mL threshold considered necessary for therapeutic effect. This suggests that the standard dosing of 2,500 U/m² for both pegylated asparaginases may represent a significant overdose relative to what is required for complete asparagine depletion. This observation, highlighted by the trial investigators themselves, opens a critical avenue for future research into dose optimization.[10] It raises the possibility that lower doses or even further extended dosing intervals could be used, which could potentially reduce the incidence of dose-dependent toxicities and lower the substantial cost of treatment without compromising efficacy.

4.4. Current and Investigational Clinical Landscape

Calaspargase pegol has been rapidly integrated into the standard of care for pediatric ALL and is now being actively investigated in a broad range of clinical trials to expand its use and refine its role in combination therapy.[32] Current research is exploring its efficacy in other related hematologic malignancies, including:

• Lymphoblastic Lymphoma [33]
• Mixed Phenotype Acute Leukemia (MPAL) [35]
• T-cell Acute Lymphoblastic Leukemia (T-ALL) [35]
• Central Nervous System (CNS) Leukemia [37]
• Refractory or Relapsed B-cell ALL [38]

These trials are evaluating Calaspargase pegol in combination with a wide array of other antineoplastic agents, including immunotherapies like blinatumomab and inotuzumab ozogamicin, targeted therapies such as the tyrosine kinase inhibitors imatinib and dasatinib, and novel agents like venetoclax.[32] The ongoing SPARK-ALL trial (NCT04817761) is specifically designed to gather more data on its use in adult patients with ALL, an important area where tolerability of asparaginase can be a challenge.[34] This robust clinical trial activity underscores its establishment as a foundational component of modern ALL therapy.

Section 5: Safety, Tolerability, and Risk Management

5.1. Comprehensive Adverse Reaction Profile

The safety profile of Calaspargase pegol is largely consistent with the well-documented class effects of E. coli-derived L-asparaginase preparations.[9] The adverse reactions are primarily driven by the enzymatic depletion of asparagine, which affects protein synthesis in non-malignant tissues (particularly the liver and pancreas), and by the immunogenic potential of the foreign bacterial protein.[2]

Data from the pivotal DFCI 11-001 trial provide a direct comparison of the safety profiles of Calaspargase pegol and pegaspargase. The most common Grade 3 or higher adverse reactions observed in patients receiving Calaspargase pegol (with an incidence of ≥10%) were elevated transaminase (52%), increased bilirubin (20%), pancreatitis (18%), and abnormal clotting studies (14%).[1] Other frequently reported adverse events included hypoalbuminemia, hypertriglyceridemia, and hyperglycemia.[9]

Table 4: Incidence of Grade ≥3 Adverse Reactions (DFCI 11-001)

Adverse Reaction	Calaspargase Pegol (n=118) %	Pegaspargase (n=119) %
Elevated transaminase	52	57
Bilirubin increased	20	24
Pancreatitis	18	17
Abnormal clotting studies	14	13
Hypersensitivity reaction	12	13
Thrombosis	9	10
Hemorrhage	3	4

Source: Adapted from FDA Prescribing Information [24]

While the pivotal trials suggested comparable overall toxicity, a more recent retrospective "real-world" evaluation identified a potentially favorable difference. This study found a significantly lower rate of hyperbilirubinemia in patients treated with Calaspargase pegol compared to pegaspargase (34% vs. 58.6%; P=0.01), suggesting it may be associated with less hepatic toxicity in this specific regard.[39]

However, the same retrospective study introduced a critical and counter-intuitive finding that challenges the narrative of simple equivalence. Despite observing similar rates of overt hypersensitivity reactions and silent inactivation (the development of neutralizing antibodies without clinical symptoms), the study found that patients receiving Calaspargase pegol required conversion to an alternative, short-acting asparaginase significantly more often than those on pegaspargase (26% vs. 10.3%; P=0.03).[39] This discrepancy suggests that in routine clinical practice, factors not fully captured in the controlled trial setting may lead to discontinuation. This could be due to a lower threshold for switching therapies when a toxicity occurs with a very long-acting drug, or it may point to subtle differences in tolerability or immunogenicity that warrant further investigation. This finding tempers the assumption of perfect interchangeability between the two formulations.

5.2. Significant Warnings and Precautions

The use of Calaspargase pegol is associated with several serious and potentially life-threatening risks that require diligent monitoring and management.

• Hypersensitivity: Grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in 7% to 21% of patients in clinical trials.[2] Manifestations can include angioedema, bronchospasm, hypotension, and rash.[8] To mitigate this risk, administration must occur in a clinical setting equipped to manage anaphylaxis. Mandatory premedication with an H1-receptor blocker (e.g., diphenhydramine), an H2-receptor blocker (e.g., famotidine), and acetaminophen is required 30-60 minutes before infusion. Patients must be observed for at least one hour after administration. In the event of a serious hypersensitivity reaction, Calaspargase pegol must be permanently discontinued.[2]
• Pancreatitis: Pancreatitis, which can be severe, hemorrhagic, or fatal, was reported in 12% to 16% of patients in clinical trials.[2] Patients should be monitored for clinical signs and symptoms (e.g., abdominal pain), and serum amylase and/or lipase levels should be assessed. If pancreatitis is suspected, the drug should be held; if confirmed, it must be permanently discontinued.[2]
• Thrombosis: Serious thrombotic events, including venous thromboembolism such as sagittal sinus thrombosis, were reported in 9% to 12% of patients.[2] Calaspargase pegol should be discontinued in patients who experience a serious thrombotic event.[2]
• Hemorrhage: Hemorrhagic events can occur, often in the context of coagulopathy caused by decreased synthesis of clotting factors in the liver. This can manifest as increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia.[2] Coagulation parameters should be monitored, and appropriate factor replacement therapy should be considered for patients with severe or symptomatic coagulopathy. The drug should be held or discontinued for severe hemorrhage.[2]
• Hepatotoxicity: Hepatotoxicity is a common toxicity, ranging from elevated transaminases to severe, life-threatening, and potentially fatal conditions, including hepatic veno-occlusive disease (VOD).[2] Liver function tests (bilirubin and transaminases) must be monitored prior to each dose and at least weekly during treatment cycles, continuing for up to 6 weeks after the last dose. Calaspargase pegol should be discontinued in the event of serious liver toxicity.[2]

5.3. Contraindications and Specific Populations

The use of Calaspargase pegol is strictly contraindicated in patients with [4]:

• A history of serious hypersensitivity reactions, including anaphylaxis, to any pegylated L-asparaginase product.
• A history of serious thrombosis, pancreatitis, or serious hemorrhagic events during previous L-asparaginase therapy.
• Severe pre-existing hepatic impairment.[15]

Special considerations are required for certain populations:

• Pregnancy: Based on its mechanism of action and animal studies, Calaspargase pegol can cause fetal harm. Females of reproductive potential must be advised of this risk and should use effective non-hormonal contraception during treatment and for at least 3 months after the final dose.[24]
• Lactation: It is not known whether Calaspargase pegol is excreted in human milk. Due to the potential for serious adverse reactions in a breastfed infant, breastfeeding is not recommended during treatment and for 3 months after the final dose.[15]
• Pediatrics: The safety and effectiveness of Calaspargase pegol have been established in the approved patient population of 1 month to 21 years of age.[1]
• Geriatrics: There is no available information on the use of Calaspargase pegol in geriatric patients.[15]

5.4. Drug-Drug Interactions

• Live Vaccines: Due to the immunosuppressive nature of multi-agent chemotherapy regimens that include Calaspargase pegol, concomitant administration of live vaccines is not recommended due to the risk of vaccine-induced infection.[15]
• Methemoglobinemia: The risk or severity of methemoglobinemia may be increased when Calaspargase pegol is combined with certain drugs, including local anesthetics like articaine and benzocaine, as well as ambroxol and cocaine.[3]
• Other Interactions: Calaspargase pegol may decrease the therapeutic efficacy of other medications, such as cyproterone acetate.[3]

Section 6: Regulatory and Therapeutic Context

6.1. Global Regulatory History

Calaspargase pegol's path to market was supported by its potential to address an unmet need in a rare disease, leading to special regulatory designations. It was granted orphan drug designation in the European Union in 2008 and in the United States prior to its approval, facilitating its development.[1]

• United States: The U.S. Food and Drug Administration (FDA) approved Asparlas® on December 20, 2018, under Biologics License Application (BLA) 761102. The approval was granted to Servier Pharmaceuticals LLC.[1]
• Canada: Health Canada issued a Notice of Compliance for Asparlas® on November 8, 2023. The New Drug Submission was reviewed by the Biologic and Radiopharmaceutical Drugs Directorate (BRDD).[9]
• European Union: As of the latest available information, Calaspargase pegol has not been authorized for marketing by the European Medicines Agency (EMA). The related predecessor drug, pegaspargase (Oncaspar), is authorized for use in the EU.[44]

The regulatory decisions in both the U.S. and Canada were based on the evidence from the DFCI 11-001 and COG AALL07P4 trials, which established a favorable benefit-risk profile based on comparable efficacy and safety to pegaspargase, coupled with a more convenient dosing schedule.[1]

6.2. Dosing, Administration, and Clinical Practice

Calaspargase pegol is firmly established as a key component of combination chemotherapy for ALL in its approved population.

• Indication: It is 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.[1] Compendial sources and clinical practice guidelines also support its use for lymphoblastic lymphoma, which is managed with similar therapeutic protocols as ALL.[46]
• Recommended Dosage: The standard dose is 2,500 U/m² administered as a 1-hour intravenous infusion. This dose should be given no more frequently than every 21 days.[8]
• Administration Protocol: Due to the high risk of hypersensitivity reactions, a strict administration protocol must be followed. This includes mandatory premedication with acetaminophen, an H1-receptor blocker, and an H2-receptor blocker 30 to 60 minutes prior to the infusion.[24] The infusion must be administered in a setting with immediate access to resuscitation equipment.[2]
• Dose Modifications: The prescribing information contains specific guidelines for managing toxicities. Treatment should be held or permanently discontinued based on the severity of adverse reactions such as hypersensitivity, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity.[8]

6.3. Economic Considerations and Patient Access

The introduction of Calaspargase pegol has prompted significant discussion regarding its cost-effectiveness, particularly given its positioning as an alternative to, rather than a replacement for, an existing therapy.

• Cost: The cost of treatment is substantial. In Canada, a typical treatment course of seven doses was estimated to cost approximately $52,093.[12]
• Health Economic Assessment: The Canadian Agency for Drugs and Technologies in Health (CADTH), a key health technology assessment body, conducted a thorough review of Calaspargase pegol. Their analysis concluded that, based on the available evidence, the drug does not represent good value to the healthcare system at its submitted price.[11] The review found insufficient evidence to suggest that Calaspargase pegol provides superior clinical benefits compared to pegaspargase. Consequently, CADTH recommended that the cost of treatment with Calaspargase pegol should not exceed the drug program cost of treatment with pegaspargase.[13] This positions the drug to compete on convenience and logistical advantages (e.g., longer shelf life, fewer administrations) rather than on a claim of improved clinical outcomes.
• Patient Access: Recognizing the potential for financial barriers to access, the manufacturer, Servier, has established the ASPARLAS® Patient Assistance Program (PAP). This program is designed to provide the medication to eligible uninsured or underinsured patients, ensuring that financial constraints do not prevent access to prescribed treatment.[2] Such programs are a crucial component of the market access strategy for high-cost specialty drugs, especially those facing reimbursement restrictions based on cost-effectiveness evaluations.
• Billing and Reimbursement: For reimbursement purposes in the U.S., Calaspargase pegol is identified by the Healthcare Common Procedure Coding System (HCPCS) code J9118, which corresponds to an injection of 10 units of the drug.[41]

Section 7: Synthesis and Future Outlook

7.1. Conclusive Assessment: A Convenient and Reliable Alternative

Calaspargase pegol (Asparlas®) represents a significant and successful example of incremental innovation in oncology. It is not a paradigm-shifting therapy that alters the fundamental approach to treating acute lymphoblastic leukemia. Rather, it is a meticulously engineered second-generation biologic that refines and optimizes a proven therapeutic strategy. Its core value proposition is not superior efficacy, but superior pharmacokinetics and logistics.

The synthesis of all available evidence confirms that Calaspargase pegol, administered every three weeks, provides clinical outcomes that are comparable to the previous standard, pegaspargase, administered every two weeks. This is achieved through its novel succinimidyl carbonate linker, which creates a more stable molecule with a longer half-life, ensuring sustained therapeutic asparagine depletion over the extended dosing interval. The primary benefits for patients and healthcare systems are therefore convenience (fewer infusions) and reliability. Its extended shelf life directly addresses the well-documented and clinically disruptive problem of asparaginase supply shortages. For these reasons, Calaspargase pegol is well-positioned to become the new standard-of-care long-acting asparaginase formulation for pediatric and young adult ALL.

7.2. Future Research Directions

While Calaspargase pegol has solidified its place in ALL treatment, several critical questions remain that will shape its future use and the evolution of asparaginase therapy.

• Dose Optimization: Perhaps the most compelling area for future research stems from the observation in the DFCI 11-001 trial that standard doses of both Calaspargase pegol and pegaspargase result in nadir SAA levels far exceeding the therapeutic minimum.[10] This strongly suggests that current dosing regimens may be unnecessarily high. Future studies should be designed to investigate whether lower doses or further extended dosing intervals (e.g., every four weeks for Calaspargase pegol) can maintain therapeutic SAA levels. Such a strategy could significantly reduce the risk of dose-dependent toxicities and substantially lower the cost of care without compromising efficacy.
• Adult Populations: The tolerability of asparaginase is known to decrease with age, and robust data on Calaspargase pegol in adults older than 21 are limited. Clinical trials like SPARK-ALL (NCT04817761) are essential to define its safety and efficacy in the adult ALL population and to develop appropriate management strategies for this higher-risk group.[34]
• Understanding Immunogenicity and Tolerability: The real-world finding that patients on Calaspargase pegol may require more frequent conversion to alternative therapies despite similar rates of overt hypersensitivity needs to be prospectively investigated.[39] Research is needed to understand the underlying reasons for this discrepancy and to refine strategies for managing both clinical and subclinical immunogenicity, including the potential role of desensitization protocols.[39]
• Novel Therapeutic Combinations: The role of Calaspargase pegol will continue to be defined by its integration into new and evolving treatment backbones. Its place alongside novel immunotherapies (e.g., blinatumomab, inotuzumab ozogamicin) and targeted agents (e.g., venetoclax, TKIs) in various hematologic malignancies is the subject of numerous ongoing trials.[32] The results of these studies will determine its utility beyond standard frontline ALL therapy and into the treatment of relapsed/refractory disease and other leukemia subtypes.

Works cited

1. Calaspargase pegol - Wikipedia, accessed September 9, 2025, https://en.wikipedia.org/wiki/Calaspargase_pegol
2. HCP Support for ASPARLAS® (calaspargase pegol-mknl) | ServierONE™, accessed September 9, 2025, https://www.servierone.com/hcp/financial-support/asparlas
3. Calaspargase pegol: Uses, Interactions, Mechanism of Action ..., accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730
4. Asparlas - FEPBlue.com, accessed September 9, 2025, https://www.fepblue.org/-/media/PDFs/Medical-Policies/2024/January/Pharmacy-Policies-Dec-2023/Remove-and-Replace/521125-Asparlas-calaspargase.pdf
5. Definition of calaspargase pegol - NCI Dictionary of Cancer Terms, accessed September 9, 2025, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/calaspargase-pegol
6. Calaspargase pegol-mknl (Calaspargase pegol) API Manufacturers | GMP-Certified Suppliers - Pharmaoffer.com, accessed September 9, 2025, https://pharmaoffer.com/api-excipient-supplier/anticoagulants/calaspargase%20pegol-mknl
7. 11-001 Title: Randomized Study of Intravenous Calaspargase Pegol (SC-PEG asparaginase) and - ClinicalTrials.gov, accessed September 9, 2025, https://cdn.clinicaltrials.gov/large-docs/74/NCT01574274/Prot_SAP_000.pdf
8. Asparlas (calaspargase pegol-mknl) - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 9, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761102s000lbl.pdf
9. Regulatory Decision Summary for Asparlas - Drug and Health Products Portal, accessed September 9, 2025, https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1707229586312
10. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001 - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/34228505/
11. Pharmacoeconomic Review - Calaspargase Pegol (Asparlas) - NCBI Bookshelf, accessed September 9, 2025, https://www.ncbi.nlm.nih.gov/books/NBK604418/
12. Calaspargase Pegol (Asparlas) - NCBI Bookshelf, accessed September 9, 2025, https://www.ncbi.nlm.nih.gov/books/NBK602389/
13. Calaspargase Pegol (Asparlas) - Canada's Drug Agency, accessed September 9, 2025, https://www.cda-amc.ca/sites/default/files/DRR/2024/PC0321REC-Asparlas.pdf
14. Calaspargase Pegol - OEL Fastrac with ADE - Affygility Solutions, accessed September 9, 2025, https://affygility.com/oel/calaspargase-pegol.html
15. Calaspargase pegol-mknl (intravenous route) - Side effects & uses ..., accessed September 9, 2025, https://www.mayoclinic.org/drugs-supplements/calaspargase-pegol-mknl-intravenous-route/description/drg-20454132
16. CALASPARGASE PEGOL, accessed September 9, 2025, https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/calaspargase-pegol.pdf
17. Calaspargase pegol | TargetMol, accessed September 9, 2025, https://www.targetmol.com/compound/Calaspargase%20pegol
18. Calaspargase pegol - KEGG DRUG - genome.jp, accessed September 9, 2025, https://www.genome.jp/dbget-bin/www_bget?dr:D10096
19. CALASPARGASE PEGOL - Inxight Drugs, accessed September 9, 2025, https://drugs.ncats.io/drug/T9FVH03HMZ
20. Medical Policy: - Asparlas® (calaspargase pegol-mknl) Intravenous - EmblemHealth, accessed September 9, 2025, https://www.emblemhealth.com/content/dam/global/pdfs/provider/enterprise-policies/asparlas.pdf
21. Calaspargase pegol | New Drug Approvals, accessed September 9, 2025, https://newdrugapprovals.org/tag/calaspargase-pegol/
22. Pharmacokinetic (PK) and pharmacodynamics (PD) properties of SC-PEG e. coli L-asparaginase (EZN-2285) in the treatment of patients with acute lymphoblastic leukemia (ALL): Results from Children's Oncology Group (COG) study AALL07P4. - ASCO Publications, accessed September 9, 2025, https://ascopubs.org/doi/10.1200/jco.2012.30.15_suppl.9543
23. 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 - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/25348002/
24. ASPARLAS (calaspargase pegol - mknl) Label - accessdata.fda.gov, accessed September 9, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761102s008lbl.pdf
25. Purple Book Product Details forundefined - FDA Purplebook, accessed September 9, 2025, https://purplebooksearch.fda.gov/productdetails?query=761102
26. asparlas - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 9, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761102s003lbl.pdf
27. Study Results | SC-PEG Asparaginase vs. Oncaspar in Pediatric Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma | ClinicalTrials.gov, accessed September 9, 2025, https://www.clinicaltrials.gov/study/NCT01574274?term=PEGASPARGASE&rank=5&tab=results
28. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001 - ASCO Publications, accessed September 9, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.20.03692
29. Study Details | NCT00671034 | Calaspargase Pegol or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia | ClinicalTrials.gov, accessed September 9, 2025, https://clinicaltrials.gov/study/NCT00671034
30. Study Results | Calaspargase Pegol or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia | ClinicalTrials.gov, accessed September 9, 2025, https://www.clinicaltrials.gov/study/NCT00671034?term=CALASPARGASE%20PEGOL&rank=7&tab=results
31. Calaspargase Pegol (Asparlas) - Canada's Drug Agency, accessed September 9, 2025, https://www.cda-amc.ca/sites/default/files/DRR/2024/PC0321-Asparlas-Combined-Report.pdf
32. Clinical Trials Using Calaspargase Pegol - NCI, accessed September 9, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/calaspargase-pegol
33. Calaspargase pegol Recruiting Phase 2 Trials for Acute Lymphoblastic Leukemia (ALL) / Lymphoblastic Lymphoma Treatment | DrugBank Online, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0031335%2CDBCOND0032667&phase=2&purpose=treatment&status=recruiting
34. Calaspargase pegol Active Not Recruiting Phase 2 Trials for Acute Lymphoblastic Leukemia (ALL) Treatment - DrugBank, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0031335&phase=2&purpose=treatment&status=active_not_recruiting
35. Calaspargase pegol Recruiting Phase 3 Trials for Mixed Phenotype Acute Leukemia (MPAL) / T-cell Acute Lymphoblastic Leukemia / Lymphoblastic Lymphoma Supportive Care - DrugBank, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0032667%2CDBCOND0071898%2CDBCOND0065733&phase=3&purpose=supportive_care&status=recruiting
36. Calaspargase pegol Active Not Recruiting Phase 3 Trials for Acute Lymphoblastic Leukemia (ALL) / Mixed Phenotype Acute Leukemia (MPAL) / T-cell Acute Lymphoblastic Leukemia Treatment - DrugBank, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0031335%2CDBCOND0071898%2CDBCOND0065733&phase=3&purpose=treatment&status=active_not_recruiting
37. Calaspargase pegol Recruiting Phase 3 Trials for Central Nervous System Leukemia / Mixed Phenotype Acute Leukemia (MPAL) / Lymphoblastic B-Cell Lymphoma / B-cell Acute Lymphoblastic Leukemia Treatment - DrugBank, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0034372%2CDBCOND0053647%2CDBCOND0147805%2CDBCOND0071898&phase=3&purpose=treatment&status=recruiting
38. Calaspargase pegol Recruiting Phase 2 Trials for Refractory B Cell Acute Lymphoblastic Leukemia (ALL) Treatment - DrugBank, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14730/clinical_trials?conditions=DBCOND0138007&phase=2&purpose=treatment&status=recruiting
39. Comparing Tolerability and Toxicity of Calaspargase-Pegol and Pegaspargase in Pediatric Leukemia Patients - ResearchGate, accessed September 9, 2025, https://www.researchgate.net/publication/394851087_Comparing_Tolerability_and_Toxicity_of_Calaspargase-Pegol_and_Pegaspargase_in_Pediatric_Leukemia_Patients
40. Comparing Tolerability and Toxicity of Calaspargase-Pegol and Pegaspargase in Pediatric Leukemia Patients - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/40844276/
41. Asparlas® (calaspargase pegol-mknl) - OHSU, accessed September 9, 2025, https://www.ohsu.edu/sites/default/files/2025-03/OHSU-HS-MPS-Asparlas-01-25.pdf
42. Financial Support for Patients on ASPARLAS - ServierONE, accessed September 9, 2025, https://www.servierone.com/s/patient/asparlas
43. 761102Orig1s000 - accessdata.fda.gov, accessed September 9, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761102Orig1s000ChemR.pdf
44. Oncaspar | European Medicines Agency (EMA), accessed September 9, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/oncaspar
45. Oncaspar, INN-pegaspargase - European Medicines Agency, accessed September 9, 2025, https://www.ema.europa.eu/en/documents/product-information/oncaspar-epar-product-information_en.pdf
46. Asparlas(calaspargase pegol - mknl) - SPECIALTY GUIDELINE MANAGEMENT, accessed September 9, 2025, https://www.shpnc.gov/documents/files/asparlas/open
47. Asparlas 4616-A MedB CMS P2023.docx - Clover Health, accessed September 9, 2025, https://cdn.cloverhealth.com/filer_public/3c/60/3c60e76c-307d-4e62-b551-c78ef8a85643/asparlas_4616-a_medb_cms_p2023docx.pdf
48. Clinical Policy: Pegaspargase (Oncaspar), Calaspargase Pegol-mknl (Asparlas) - Superior HealthPlan, accessed September 9, 2025, https://www.superiorhealthplan.com/content/dam/centene/Superior/policies/pharmacy-policies/CP.PHAR.353-02012021.pdf