Asparaginase Erwinia Chrysanthemi (Erwinaze and Rylaze)

Number: 0864

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Asparaginase Erwinia chrysanthemi (Erwinaze)

  1. Criteria for Initial Approval

    Aetna considers Erwinaze (asparaginase Erwinia chrysanthemi) medically necessary as a component of a multiagent chemotherapeutic regimen for persons with the following malignancies:

    1. Acute lymphoblastic leukemia (ALL) and Lymphoblastic lymphoma
      1. For persons who are hypersensitive to Oncaspar (pegaspargase); or
      2. As induction therapy for members age 65 years and older;
    2. Extranodal Natural Killer/T-cell lymphoma

      When both of the following criteria are met:

      1. The member has previously received and developed hypersensitivity to an E. coli-derived asparaginase (e.g., pegaspargase); and
      2. The requested medication is used in conjunction with multi-agent chemotherapy.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    Aetna considers of Erwinaze (asparaginase Erwinia chrysanthemi) therapy medically necessary in members requesting reauthorization for an indication listed in section I when there is no evidence of disease progression or an unacceptable toxicity while on the current regimen.

Note: Elspar (L-Asparaginase Escherichia coli) has been discontinued.

Asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze)

  1. Criteria for Initial Approval

    1. Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LBL)

      Aetna considers asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) medically necessary for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in members 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase (e.g., pegaspargase) and the requested medication will be used in conjunction with multi-agent chemotherapy.

    2. Extranodal Naturual Killer (NK)/T-cell Lymphoma

      Aetna considers asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) medically necessary for the treatment of extranodal NK/T-cell lymphoma when both of the following criteria are met:

      1. The member has previously received and developed hypersensitivity to an E. coli-derived asparaginase (e.g., pegaspargase); and
      2. The requested medication will be used in conjunction with multi-agent chemotherapy.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    Aetna considers continuation of asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Asparaginase Erwinia chrysanthemi (Erwinaze)

Asparaginase Erwinia chrysanthemi (Erwinaze) is available as 10,000 International Units as a lyophilized powder in single-dose vial for reconstitution for injection for intramuscular or intravenous use.

Acute lymphoblastic leukemia (ALL)

The recommended dosage is as follows:

  • To substitute for a dose of pegaspargase: The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase.
  • To substitute for a dose of native E. coli asparaginase: The recommended dose is 25,000 International Units/m2 administered intramuscularly for each scheduled dose of native E. coli asparaginase.

Source: Jazz Pharmaceuticals, Inc., 2019

Asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze)

Asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) is available as 10 mg/0.5 mL solution in a single-dose vial for intramuscular injection.

Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL)

The recommended dosage of Rylaze is 25 mg/m2 administered intramuscularly every 48 hours.

Experimental and Investigational

Aetna considers therapeutic drug monitoring of asparaginase activity experimental and investigational.


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

96401 Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96409 Chemotherapy administration; intravenous, push technique, single or initial substance/drug
+96411     intravenous, push technique, each additional substance/drug (List separately in addition to code for primary procedure)
96413 - 96417 Chemotherapy administration; intravenous infusion technique

HCPCS codes covered if selection criteria are met:

J9019 Injection, asparaginase, (Erwinaze), 1,000 iu
J9021 Injection, asparaginase, recombinant, (rylaze), 0.1 mg

Other HCPCS codes related to the CPB:

J9020 Injection, asparaginase, not otherwise specified, 10,000 units
J9266 Injection, pegaspargase, per single dose vial [Oncaspar]

ICD-10 codes covered if selection criteria are met:

C83.50 - C83.59 Lymphoblastic (diffuse) lymphoma
C86.0 - C86.6 Other specified types of T/NK-cell lymphoma
C91.00 - C91.02 Acute lymphoblastic leukemia [ALL]

ICD-10 codes not covered for indications listed in the CPB:

C70.0 Malignant neoplasm of cerebral meninges
C71.0 - C71.9 Malignant neoplasm of brain
C81.00 - C83.39, C83.70 - C85.99, C88.0 - C90.32, C91.10 - C91.92 Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue [excluding ALL, lymphoblastic lymphoma, extranodal NK/T-Cell Lymphoma, nasal type]
D33.0 - D33.2 Benign neoplasm of brain

ICD-10 codes contraindicated for this CPB:

I66.01 - I66.9 Occlusion and stenosis of cerebral artery
I74.2 - I74.4 Embolism and thrombosis of arteries of the extremities
I81 Portal vein thrombosis
I82.0 - I82.91 Other venous embolism and thrombosis
K85.00 - K85.92 Pancreatitis
T50.995+ Adverse effect of other drugs, medicaments and biological substances [hypersensitivity to Erwinase]

Background

U.S. Food and Drug Administration (FDA)-Approved Indications for asparaginase Erwinia chrysanthemi (Erwinaze)

  • Erwinaze is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase.

Compendial Uses for asparaginase Erwinia chrysanthemi (Erwinaze)

  • Extranodal natural killer/T-cell lymphoma: as a component of multi-agent chemotherapeutic regimen
  • Lymphoblastic lymphoma (managed in the same manner as ALL)
  • Acute lymphoblastic leukemia (ALL) as induction therapy for adults aged 65 years and older as a component of multi-agent chemotherapeutic regimen, or as a substitute for pegaspargase in cases of systemic allergic reaction or anaphylaxis due to pegaspargase hypersensitivity
  • Pediatric acute lymphoblastic leukemia (ALL) as a substitute for pegaspargase in cases of systemic allergic reaction or anaphylaxis due to pegaspargase hypersensitivity

Asparaginase Erwinia chrysanthemi is available as Erwinaze (Jazz Pharmaceuticals, Inc.) and contains an asparaginase specific enzyme derived from Erwinia chrysanthemi and which catalyzes the deamidation of asparaginase to aspartic acid and ammonia thereby causing a decrease in circulating levels of asparagine. The mechanism of action is postulated on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that rely on an exogenous source of amino acid asparagine for their protein metabolism and survival (Jazz Pharmaceuticals, 2019).

Per the prescribing information, asparaginase Erwinia chrysanthemi (Erwinaze) is contraindicated in patients with a history of the following:

  • Serious hypersensitivity reactions to Erwinaze, including anaphylaxis
  • Serious pancreatitis with prior L-asparaginase therapy
  • Serious thrombosis with prior L-asparaginase therapy
  • Serious hemorrhagic events with prior L-asparaginase therapy

Per the prescribing information, asparaginase Erwinia chrysanthemi (Erwinaze) carries the following warnings and precautions:

  • Hypersensitivity reactions: Grade 3 and 4 hypersensitivity reactions following Erwinaze use has been reported in 5% of patients in clinical trials.
  • Pancreatitis: Pancreatitis has been noted in 4% of patients in clinical trials.
  • Glucose intolerance: Glucose intolerance has been noted in 5% of patients receiving Erwinaze in clinical trials.
  • Thrombosis and hemorrhage
The most common adverse reactions (occurrence ≥ 1%) per the prescribing information include: systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

In November 2011, the FDA approved Erwinaze (asparaginase erwinia chrysanthemi), an asparagine specific enzyme, as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase. Erwinaze (asparaginase Erwinia chrysanthemi) catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of Erwinaze (asparaginase Erwinia chrysanthemi)is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine for their protein metabolism and survival.

The safety and efficacy of Erwinaze was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data were obtained in the Erwinaze Master Treatment Protocol (EMTP), an expanded access program. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/ mL. Serum trough asparaginase activity ≥ 0.1 International Units/ mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) and to serum levels that predict clinical efficacy. Patients received Erwinaze 25,000 International Units/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in Course 1. The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the prespecified trough asparaginase activity level of ≥ 0.1 International Units/ mL at 48 or 72 hours following the third dose. The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m2 Erwinaze dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose) ≥ 0.1 International Units/mL in the first 2 weeks of Erwinaze treatment. Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 years), 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native, or Indian). In Study 2, serum asparaginase activity of asparaginase Erwinia chrysanthemi was determined in 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) following intravenous administration of Erwinaze 25,000 International Units/m2 . Five minutes after the 60-minute infusion in Course 1, the mean asparaginase activity level was 12.65 ± 3.16 International Units/mL post-dose 1 and 12.11 ± 3.11 International Units/mL post dose 4. The main study objective was met with an asparaginase activity level of ≥ 0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 asparaginase activity level of ≥ 0.1 International Units/mL was the secondary endpoint, with 43% of patients achieving this endpoint.

U.S. Food and Drug Administration (FDA)-Approved Indications for asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze)

  • Rylaze is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase.

Compendial Uses for asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze)

  • Extranodal NK/T-cell lymphoma

Asparaginase erwinia chrysanthemi (recombinant)-rywn) is available as Rylaze (Jazz Pharmaceuticals, Inc.) and contains an asparagine specific bacterial enzyme (L-asparaginase). Asparaginase erwinia chrysanthemi (recombinant)-rywn) initiates the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The resultant pharmacologic effect is leukemic cell death due to a depletion of plasma asparagine. The low expression of asparagine synthetase in the leukemic cells and their diminished ability to synthesize asparagine cause their dependence on exogenous asparagine for survival (Jazz Pharmaceuticals, 2021b).

Per the prescribing information, asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) is contraindicated in patients with a history of the following:

  • Serious hypersensitivity reactions to Rylaze, including anaphylaxis
  • Serious pancreatitis during previous L-asparaginase therapy
  • Serious thrombosis during previous L-asparaginase therapy
  • Serious hemorrhagic events during previous L-asparaginase therapy

Per the prescribing information, asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze) carries the following warnings and precautions:

  • Hypersensitivity: The incidence of hypersensitivity reactions reported in patients following Rylaze treatment was 25% in clinical trials with 2% being severe.
  • Pancreatitis: The incidence of pancreatitis in patients was 14% with 6% being severe in clinical trials of Rylaze.
  • Thrombosis
  • Hemorrhage: Bleeding was noted in 17% of patients treated with Rylaze with 1% being severe.
  • Hepatotoxicity: The incidence of elevated bilirubin and/or transaminases was 62% in patients treated with Rylaze in clinical trials, and 12% had grade ≥ 3 elevations.

The most frequent adverse reactions (incidence > 20%) are abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia (Jazz Pharmaceuticals, 2021b).

Asparaginase Erwinia chrysanthemi (Erwinaze)

Acute Myeloid Leukemia

Emadi et al (2014) stated that asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration (FDA)-approved for the treatment of pediatric and adult ALL.  However, the effectiveness of these drugs for the treatment of other hematologic malignancies particularly acute myeloid leukemia (AML) is not well-established.  The mechanism of action of asparaginases has thought to be related to a swift and sustained reduction in serum L-asparagine, which is required for rapid proliferation of metabolically demanding leukemic cells.  However, asparagine depletion alone appears not to be sufficient for effective cytotoxic activity of asparaginase against leukemia cells, because glutamine can rescue asparagine-deprived cells by regeneration of asparagine via a transamidation chemical reaction.  For this reason, glutamine reduction is also necessary for full anti-leukemic activity of asparaginase.  Indeed, both Escherichia coli and Erwinia chrysanthemi asparaginases possess glutaminase enzymatic activity, and their administrations have shown to reduce serum glutamine level by deamidating glutamine to glutamate and ammonia.  Emerging data have provided evidence that several types of neoplastic cells require glutamine for the synthesis of proteins, nucleic acids, and lipids.  This fundamental role of glutamine and its metabolic pathways for growth and proliferation of individual malignant cells may identify a special group of patients whose solid or hematologic neoplasms may benefit significantly from interruption of glutamine metabolism.  The authors stated that asparaginase products deserve a second look particularly in non-ALL malignant blood disorders.

Emadi and associates (2018) stated that depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of AML, as neoplastic cells require Gln for synthesis of cellular components essential for survival.  Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases.  In this phase-I study, these researchers determined the dose of Erwinaze that safely and effectively depletes plasma Gln levels to less than or equal to 120 μmol/L in patients with relapsed or refractory (R/R) AML.  A total of 5 patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply.  All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously 3 times weekly for 2 weeks.  Median trough plasma Gln level at 48 hours after initial Erwinaze administration was 27.6 μmol/L, and 80 % (lower limit of 1-sided 95 % confidence interval [CI]: 34 %) of patients achieved at least 1 undetectable plasma Gln value (less than 12.5 μmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1).  No dose-limiting toxicities (DLTs) were identified; 2  patients responded, 1 achieved partial remission (PR) and 1 achieved hematologic improvement after 6 doses of Erwinaze monotherapy.  The authors concluded that these findings suggested that asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and supported more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.

Brain Tumors (e.g. , Medulloblastomas)

Sanghez and colleagues (2018) noted that anti-metabolites are less myelosuppressive than DNA-damaging anti-cancer drugs and may be useful against brain tumors.  These researchers evaluated the asparagine/glutamine-deaminating agent Erwinaze with/without temozolomide against brain tumor cells and mouse medulloblastomas.  Erwinaze treatment of cell lines and neuro-spheres led to dose-dependent reductions of cells (reversible by L-glutamine), with half maximal inhibitory concentrations (IC50s) of 0.12 to greater than 10 IU/ml.  Erwinaze at less than 1 IU/ml reduced temozolomide IC50s by 3.6- to 13-fold (300 to 1,200 μM to 40 to 330 μM).  In this study, 7-week-old SMO/SMO mice treated with Erwinaze (regardless of temozolomide treatment) had better survival 11 weeks post-therapy, compared to those not treated with Erwinaze (81.25 % versus 46.15 %, p = 0.08).  Temozolomide-treated mice developed 10 % weight loss, impairing survival.  All 16 mice treated with temozolomide (regardless of Erwinaze treatment) succumbed by 40 weeks of age, whereas 5/8 animals treated with Erwinaze alone and 2/6 controls survived (p = 0.035).  The authors concluded that Erwinaze enhanced cytotoxicity of temozolomide in-vitro, and improved survival in SMO/SMO mice, likely by reducing cerebrospinal fluid (CSF) glutamine. Moreover, temozolomide-associated toxicity prevented demonstration of any potential combinatorial advantage with Erwinaze in-vivo.

Asparaginase erwinia chrysanthemi (recombinant)-rywn) (Rylaze)

Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL)

The incidence of acute lymphoblastic leukemia is estimated at 5,700 patients annually with half of whom are children (FDA, 2021). According to Horton and Steuber (2021), acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) is the most common malignancy in childhood. Additionally, leukemia and lymphoma overlap in clinical presentation for the same disease. ALL involves the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. In general, patients with LBL benefit from ALL-like treatment regimens and should seek treatment in a center experienced with LBL (NCCN, 2022a).

On June 30, 2021, the United States Food and Drug Administration (FDA) approved Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) for use as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in pediatric and adult patients one month and older who are allergic to the E. coli-derived asparaginase products used most commonly for treatment. Additionally, Rylaze received Fast Track and Orphan Drug designations for ALL and LBL. The FDA approval for Rylaze was based on supporting clinical data from Study JZP458-201 (NCT04145531) (FDA, 2021; Jazz Pharmaceuticals, 2021a).

This study is an ongoing pivotal Phase 2/3 single-arm, open-label, multi-cohort, multicenter dose confirmation trial evaluating pediatric and adult patients with ALL or LBL who experienced and allergic reaction to E. coli-derived asparaginase and have not previously received asparaginase erwinia chrysanthemi. The study consists of two parts of which 102 patients with a median age of 10 years (age range, 1 to 24 years) and 94% of patients had experienced a hypersensitivity reaction to pegaspargase. Patients were treated with Rylaze at various dosages administered intramuscularly every Monday, Wednesday, and Friday for a total of 6 doses to replace each dose of pegaspargase. Treatment efficacy was based on the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL. The results of modeling and simulations demonstrated that for a Rylaze dosage of 25 mg/m2 administered intramuscularly every 48 hours, the proportion of patients maintaining NSAA ≥ 0.1 U/mL at 48 hours after a dose of Rylaze was 93.6% (95% Confidence Interval: 92.6%, 94.6%). The second part of this study is still active to confirm the dose and schedule for the intravenous route of administration. (Jazz Pharmaceuticals, 2021a; 2021b).

Therapeutic Drug Monitoring of Asparaginase Activity

Wurthwein et al (2020) stated that therapeutic drug monitoring (TDM) could identify patients with sub-therapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a pre-condition for targeted dosing and the diagnosis of SI. In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, a total of 2,771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Munster. Two bi-weekly administrations of pegylated ASNase during induction and a 3rd dose during re-induction or the high-risk block, which was administered several weeks later, were monitored. These researchers calculated the incidence of SI; and the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time-points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intra-patient variability and to evaluate the predictivity of ASNase activity for the subsequent administration. The overall incidence of SI was low (4.9 %). The positive predictive value (PPV) of SI identified by 1 sample was 21 % or less. Confirmation of SI by a 2nd sample indicated a high PPV of 100 % for bi-weekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25 % of the patients. These patients were likely to fail dose individualization based on TDM data. The authors concluded that ASNase activity is used as basis for clinical decisions, especially to identify patients with inadequate ASNase activity or to individualize dosing regimens. Therefore, not only specific and sensitive analytical methods are needed, but also standardized procedures for the daily clinical routine to avoid potential misinterpretation. In addition, the high intra-individual variability has to be taken into account. Therapeutic targeting at the lowest ASNase trough activities may result in under-dosing in a considerable number of patients. Model-dependent approaches, such as population pharmacokinetics, accounting for the intra-individual and inter-individual variability of the drug may be helpful in the future development of TDM concepts.

Pike et al (2021) stated that pegaspargase can cause anti-asparaginase antibody formation, which can decrease its effectiveness without causing any clinically apparent reaction (silent inactivation). When a patient has silent inactivation, a switch to Erwinia anti-asparaginase is needed; however, there is currently a global shortage of Erwinia. The only way to identify silent inactivation is to measure an asparaginase level. However, routine asparaginase level monitoring is not currently standard of care (SOC) at all Canadian centers. These researchers identified variations in practice regarding asparaginase level monitoring and Erwinia use. A 21-item survey was developed using OPINIO software and distributed to all Pediatric Hematology-Oncologists in Canada from February to October 2020. Respondents represented 15 hospitals across each region of Canada (response rate = 52 %). Only 39.2 % of respondents reported routinely measuring asparaginase levels, yet 53 % of respondents had modified therapy from pegaspargase to Erwinia in up to 50 % of their patients. The most common reason for not measuring asparaginase levels was not knowing how to use levels clinically (25.5 %). There was variation in the timing of levels and their target. The authors identified substantial variation in asparaginase activity monitoring practices across Canada. These investigators stated that future research should aim in developing a national practice guideline on asparaginase activity monitoring.

In a review on “Current evidence and place in therapy of asparaginase in the treatment of ALL in adults”, Juluri et al (2022) stated that “Therapeutic drug monitoring (TDM) may allow for individualized asparaginase dosing and maximization of treatment efficacy with reduction of toxicity, but this is not yet widely practiced”. Furthermore, these investigators noted that because asparaginase hypersensitivity is often associated with activity-neutralizing antibodies, recognition and mitigation is critical to ensure that therapeutic efficacy is not impacted. Multiple studies have established inferior outcomes with early discontinuation or dose reduction. This could be challenging since transient infusion reactions may mimic low-grade hypersensitivity reactions, and the use of pre-medication may mask a reaction that would signify the development of neutralizing antibodies. “Silent inactivation” of asparaginase could occur in the absence of detectable antibodies or clinical hypersensitivity. While there is evidence that TDM could be beneficial in these settings, no standard algorithm for TDM currently exists, and its use has generally been limited to the context of clinical trials. The authors concluded that ongoing areas of investigation include the incorporation of asparaginase into current adult treatment paradigms, combination with immunotherapy or targeted agents, novel formulations, as well as TDM.

Sidhu et al (2022) noted that in successive United Kingdom clinical trials (UKALL 2003, UKALL 2011) for pediatric ALL, polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1,000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received 2 PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (regimens A, B) received 1 to 2 doses in delayed intensification (DI) while high-risk regimen C patients received 6 to 10 PEG-EcASNase doses, including 2 in DI. Trial sub-studies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (a total of 1,112 patients). Median (inter-quartile range [IQR]) trough plasma ASNase activity (14 ± 2 days post-dose) following 1st and 2nd induction doses and 1st DI dose was respectively 217 iu/L (144 to 307 iu/L), 265 iu/L (165 to 401 iu/L) and 292 iu/L (194 to 386 iu/L); 15 % (138/910) samples showed sub-threshold ASNase activity (less than 100 iu/L) at any trough time-point. Older age was associated with lower (regression coefficient -9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8 % (UKALL 2003) and 6 % (UKALL 2011) of patients, and in 90 % or more in regimen C. A 7 % (10/149) silent inactivation rate was observed in UKALL 2003. The authors concluded that PEG-EcASNase schedule in UKALL pediatric trials was associated with low toxicity but wide inter-patient variability; TDM potentially permits optimization via individualized asparaginase dosing.

Furthermore, the Prescribing Information notes that there is insufficient information to characterize the incidence of antibodies to Erwinaze; and there is no mentioning of TDM. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125359lbl.pdf.


References

The above policy is based on the following references:

  1. DRUGDEX System [Internet database]. Asparaginase Erwinia chrysanthemi. Armonk, NY: IBM Watson Health; updated periodically.
  2. Emadi A, Law JY, Strovel ET, et al. Asparaginase erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018;81(1):217-222.
  3. Emadi A, Zokaee H, Sausville EA. Asparaginase in the treatment of non-ALL hematologic malignancies. Cancer Chemother Pharmacol. 2014;73(5):875-883.
  4. EUSA Pharma (USA), Inc. Erwinaze (asparaginase Erwinia chrysanthemi) for injection, intramuscular use. Prescribing Information. Langhorne, PA: EUSA Pharma; revised November 2011.
  5. Figueiredo L, Cole PD, Drachtman RA. Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase. Expert Rev Hematol. 2016;9(3):227-234.
  6. Gupta S, Wang C, Raetz EA, et al. Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia: A report from the Children's Oncology Group. J Clin Oncol. 2020;38(17):1897-1905.
  7. Horton TM, Steuber CP, Aster JC. Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2022.
  8. Jazz Pharmaceuticals, Inc. Erwinaze (asparaginase Erwinia chrysanthemi) for injection, intramuscular or intravenous use. Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals; revised December 2019.
  9. Jazz Pharmaceuticals, Inc. Jazz Pharmaceuticals announces U.S. FDA approval of Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) for the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma. News Release. Dublin, Ireland: Jazz Pharmaceuticals; June 30, 2021a.
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