Asparaginase Erwinia chrysanthemi (Erwinaze)

Number: 0864

Policy

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

• Acute lymphoblastic leukemia (ALL) and Lymphoblastic lymphoma

  • for persons who are hypersensitive to Oncaspar (pegaspargase); or
  • as induction therapy for members age 65 years and older.
    
    

• Extranodal NK/T-cell lymphoma, nasal type when the requested medication is used in conjunction with multi-agent chemotherapy.

Aetna considers continued use medically necessary for for a medically necessary indication when there is no evidence of disease progression or an unacceptable toxicity.

Aetna considers Erwinaze for all other indications experimental and investigational because its effectiveness for other indications has not been established.

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

Dosing Recommendations

The FDA-approved labeling of Erwinaze recommends the following dosages: 

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., 2016.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

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

• Extranodal natural killer/T-cell lymphoma, nasal type: 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

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.

Serious hypersensitivity reactions, including anaphylaxis have occurred after the use of Erwinaze (asparaginase Erwinia chrysanthemi) in 5% of patients in clinical trials.Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue Erwinaze (asparaginase Erwinia chrysanthemi) and initiate appropriate therapy.

Pancreatitis has been reported with Erwinaze (asparaginase Erwinia chrysanthemi) therapy in 4% of patients in clinical trials. Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue Erwinaze (asparaginase Erwinia chrysanthemi) for severe or hemorrhagic pancreatitis manifested by abdominal pain >72 hours and amylase elevation ≥ 2.0 x ULN. Severe pancreatitis is a contraindication to additional asparaginase administration. In the case of mild pancreatitis, hold Erwinaze (asparaginase Erwinia chrysanthemi) until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with Erwinaze (asparaginase Erwinia chrysanthemi) may be resumed.

Glucose intolerance has been reported with Erwinaze (asparaginase Erwinia chrysanthemi) therapy in 2% of patients in clinical trials, and, in some cases, may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

Serious thrombotic events, including sagittal sinus thrombosis have been reported with both E. coli and Erwinia‐derived L‐asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2‐week course of  Erwinaze (asparaginase Erwinia chrysanthemi): fibrinogen, protein C activity, protein S activity, and anti‐thrombin III. Discontinue Erwinaze (asparaginase Erwinia chrysanthemi) for athrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with Erwinaze (asparaginase Erwinia chrysanthemi) may be resumed.

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.

Appendix

Table: Common Terminology Criteria for Adverse Events v4.03 (CTCAE)

Grade	1One	2Two	3Three	4Four	5Five
Signs and symptoms	Transient flushing or rash; drug fever <38°C (<100.4°F) intervention not indicated	Intervention or infusion interruption indicated; responds promptly to symptomatic treatment; prophylactic medications indicated for < 24 hours	Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion; recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae	Life-threatening consequences; urgent intervention indicated	Death

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
Other HCPCS codes related to the CPB:
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	Extranodal NK/T-Cell Lymphoma, nasal type
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, C86.1 - 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]

The above policy is based on the following references: