Clinical UM Guideline

 

Subject: Asparagine Specific Enzymes (Asparaginase)
Guideline #:  CG-DRUG-42 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018

Description

This document addresses indications for the commercially available forms of asparagine specific enzymes:

Clinical Indications

Medically Necessary:

  1. Pegaspargase is considered medically necessary as a component of a multi-agent chemotherapeutic regimen when the following criteria are met:
    1. Individual has one of the following diagnoses:
      1. Acute lymphoblastic lymphoma or acute lymphocytic (lymphoblastic) leukemia (ALL); or
      2. Extranodal natural killer T-cell lymphoma, nasal type (ENKL); and
    2. Individual does not have any of the following contraindications:
      1. History of serious thrombosis with prior L-asparaginase therapy; or
      2. History of serious pancreatitis with prior L-asparaginase therapy; or
      3. History of serious hemorrhagic events with prior L-asparaginase therapy.
  2. Asparaginase Erwinia chrysanthemi is considered medically necessary as a component of a multi-agent chemotherapeutic regimen when all of the following criteria are met:
    1. Individual has one of the following diagnoses:
      1. Acute lymphoblastic lymphoma or acute lymphocytic (lymphoblastic) leukemia (ALL); or
      2. Extranodal natural killer T-cell lymphoma, nasal type (ENKL); and
    2. Individual has developed a documented systemic allergic reaction or anaphylaxis to prior treatment with pegaspargase; and
    3. Individual does not have any the following contraindications:
      1. History of serious thrombosis with prior L-asparaginase therapy; or
      2. History of serious pancreatitis with prior L-asparaginase therapy; or
      3. History of serious hemorrhagic events with prior L-asparaginase therapy.

Not Medically Necessary:

Asparaginase Erwinia chrysanthemi and pegaspargase are considered not medically necessary when the above criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J9019

Injection, asparaginase (Erwinaze), 1,000 iu

J9020

Injection, asparaginase, not otherwise specified, 10,000 units

J9266

Injection, pegaspargase, per single dose vial (Oncaspar)

 

 

ICD-10 Diagnosis

 

C83.50-C83.59

Lymphoblastic (diffuse) lymphoma

C86.0

Extranodal NK/T-cell lymphoma, nasal type

C91.00-C91.02

Acute lymphoblastic leukemia (ALL)

Discussion/General Information

Asparagine specific enzymes, also known as asparaginase, are derived from bacteria. Asparaginase works by depleting blood plasma levels of asparagine, an amino acid necessary for cellular function. Normal cells create more asparagine; however; some leukemic cells are not able to synthesize asparagine and subsequently die (Avramis, 2002). Asparaginase, also known as L-asparaginase or ASNase, was approved by the U.S. Food and Drug Administration (FDA) in 1978 for a main component of ALL first-line therapy and refractory disease regimens. This native form of asparaginase, marketed as Elspar, is no longer commercially available in the United States (U.S).

Currently in the U.S., asparagine specific enzymes are available in two forms: (1) Pegaspargase (Oncaspar), a pegylated L-asparaginase, derived from the gram-negative bacterium Escherichia coli (E. coli); and (2) Asparaginase Erwinia chrysanthemi (Erwinaze), derived from the gram-negative bacillus bacterium Erwinia chrysanthemi.

Pegaspargase (Oncaspar)

Pegaspargase, also referred to as PEG-L-asparaginase, pegylated asparaginase (PEG-ASP), and PEG-asparaginase, was initially approved by the FDA in 1994 for individuals with ALL and hypersensitivity to native asparaginase. In 2006, an expanded indication was granted to make pegaspargase a component of a multi-agent chemotherapeutic regimen for the first-line treatment of individuals with ALL. Pegaspargase is L-asparaginase (L-asparagine amidohydrolase) that is conjugated to monomethoxypolyethylene glycol (mPEG). Because pegaspargase is pegylated, it lasts longer and causes less hypersensitivity than native asparaginase (Avramis, 2002). It can be administered intramuscularly (IM) or intravenously (IV).

Contraindications from the product information label (2017):

The pegaspargase FDA approval was based on a Children’s Cancer Group (CCG) trial protocol 1962 that included 118 children, ages 1 through 9, with ALL. Pegaspargase was compared to multiple doses of native E. coli asparaginase (ASNase) as part of a three-phase, multidrug regimen during remission induction and delayed intensifications (DI). Participants were randomized to pegaspargase or to ASNase at the time of induction therapy. The primary endpoint of the study was to determine the incidence of high-titer anti-ASNase antibodies in children treated with pegaspargase compared to native ASNase in the first DI phase. Faster clearance of ASNase and shorter periods of asparagine depletion were associated with poorer response rates seen in children with circulating antibodies. Children treated with pegaspargase had 2% high-titer antibodies compared to 26% of those treated with native ASNase. Clearance of blasts from the bone marrow on day 7 and day 14 were more rapid with pegaspargase compared to ASNase (p=0.05 and p=0.015, respectively) (Avramis, 2002; Oncaspar Product Information Label, 2017).

Recently, asparaginase research has demonstrated efficacy in non-Hodgkin lymphoma, specifically extranodal natural killer T-Cell lymphoma (ENKL), nasal type. This lymphoma is exceedingly rare, aggressive, and no single targeted therapy has been identified. In the past few years, increasing data have emerged demonstrating activity of asparaginase in treatment of this rare condition as both a first-line therapy and in relapsed or refractory cases. The National Comprehensive Cancer Network® (NCCN®) clinical practice guidelines for non-Hodgkin’s lymphoma include multiple phase I and II trials evaluating combination chemotherapy regimens to support a 2A recommendation of pegaspargase (Oncaspar) as part of a multi-chemotherapeutic regimen to treat this rare condition.

Yamaguchi and colleagues (2011) conducted a phase II trial of newly diagnosed stage IV, relapsed or refractory cases of ENKL treated with steroids, methotrexate, ifosfamide, L-asparaginase, and etoposide, the SMILE regimen. The primary endpoint was overall response rate (ORR) after two cycles of SMILE chemotherapy. A total of 38 participants were enrolled and 28 (74%) individuals were able to complete 2 cycles of the SMILE regimen. An ORR of 79% was observed (45% complete response [CR]). There were two early deaths attributed to severe infection. After the protocol was revised to include a lymphocyte count of ≥ 500µL into the eligibility criteria, there were no additional treatment-related deaths. Adverse events included grade 4 neutropenia (92%) and 45% grade 3 infection rates. Authors concluded that with an improved 1-year overall survival (OS) of 55%, compared to a previous treatment strategy and with careful monitoring for infection, SMILE chemotherapy was an effective treatment approach in this ENKL population.

A prospective phase II trial enrolled a total of 20 individuals with advanced relapsed or refractory ENKL from 13 European centers. The planned treatment regimen included three 21-day cycles of L-asparaginase, methotrexate, and dexamethasone (AspaMetDex). Participants with allergic responses to L-asparaginase were treated with Erwinia asparaginase. The primary endpoint was CR after 3 cycles of AspaMetDex. One participant was excluded from therapy after pathologic review. A total of 18 individuals were evaluated for response as 1 participant died of an unrelated cause after receiving 2 cycles of AspaMetDex. Anaphylactic reactions to asparaginase occurred in 4 individuals and hepatitis developed in 11 participants. There were 14 (78%) participants with an ORR, and 11 (61%) of the participants achieved a CR. Median follow-up was 26.2 months (range, 16.9-48.6 months). The median progression-free survival (PFS) was 12.2 months (95% confidence interval [CI], 5.0 months to not calculated). The authors concluded the results from the prospective trial confirm the outcomes from other phase II trials demonstrating efficacy of regimens which include asparaginase (Jaccard, 2011).

Adverse Reactions – Pegaspargase

According to the product information label (2017), the most common adverse reactions (≥ 2%) are allergic reactions (including anaphylaxis), central nervous system (CNS) thrombosis, coagulopathy, elevated transaminases, hyperbilirubinemia, hyperglycemia, and pancreatitis.

Additional warnings, precautions and recommendations from the product information label (2017) include the following:

Asparaginase Erwinia chrysanthemi (Erwinaze)

In 2011, the FDA approved asparaginase Erwinia chrysanthemi, also referred to as asparaginase Erwinia, Crisantapase, Erwinia ASNase, and Erwinia L-asparaginase, as an “asparagine specific enzyme 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” (Erwinaze Product Information Label, 2016). It can be administered intramuscularly (IM) or intravenously (IV).

Contraindications from the product information label (2016):

A single-arm, multicenter, open-label clinical trial was conducted to establish the safety and efficacy of Erwinaze. A total of 58 participants were enrolled and evaluated. The study’s main outcome of interest was demonstration of pre-specified trough asparaginase activity levels in over 50% of study participants; this outcome was met. Additional safety data information was established through the Erwinaze Master Treatment Protocol (EMTP) in which 843 participants were enrolled after developing hypersensitivity to pegaspargase. Study participants received a wide range of doses and treatments; over 75% were able to complete their prescribed treatment regimen. Appropriate dosing and scheduling was solidified through this large, open-access trial. Serum trough asparaginase level of ≥ 0.1 International Unit (IU)/mL has been associated with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) that is a predictor of clinical efficacy. The primary endpoint was met with 100% of the participants meeting ≥ 0.01 IU/mL of asparaginase activity at the 48-hour and the 72-hour sampling (Erwinaze Product Information Label, 2016).

Adverse Reactions – Asparaginase Erwinia chrysanthemi

The most common adverse reactions (1% or greater) reported in the product information label (2016) are systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

Additional warnings, precautions and recommendations from the product information label (2016) include the following:

Definitions

Acute leukemia: A type of leukemia where the number of leukemic cells develops rapidly and these abnormal cells do not perform the normal functions of the white blood cells.

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Hypersensitivity: An exaggerated response by the immune system to a drug or other substance.

Leukemia: A type of cancer that starts in blood-forming tissue, such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream.

Lymphoid leukemia: Leukemia that starts in lymphoid cells is called lymphoid, lymphoblastic, or lymphocytic leukemia.

References

Peer Reviewed Publications:

  1. Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002; 99(6):1986-1994.
  2. Duval M, Suciu S, Ferster A, et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002; 99(8):2734-2739.
  3. Jaccard A, Gachard N, Marin B, et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011; 117(6):1834-1839.
  4. Keating GM. Asparaginase Erwinia chrysanthemi (Erwinaze®): a guide to its use in acute lymphoblastic leukemia in the USA. BioDrugs. 2013; 27(4):413-418.
  5. Kwong YL, Kim WS, Lim ST, et al. SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 2012; 120(15):2973-2980.
  6. Li L, Zhang C, Zhang L, et al. Efficacy of a pegaspargase-based regimen in the treatment of newly-diagnosed extranodal natural killer/T-cell lymphoma. Neoplasma. 2014; 61(2):225-232.
  7. Vilmer E, Suciu S, Ferster A, et al., Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia. 2000; (12):2257-2266.
  8. Wang H, Wuxiao Z, Zhu J, et al. Comparison of gemcitabine, oxaliplatin, and L-asparaginase and etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: a multi-center retrospective study. Leuk Lymphoma. 2015; 56(4):971-977.
  9. Yamaguchi, M, Kwong, YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-cell Tumor Study Group Study. J Clin Oncol. 2011; 29(33):4410-4416.
  10. Yang L, Liu H, Xu XH, , et al. Retrospective study of modified SMILE chemotherapy for advanced-stage, relapsed, or refractory extranodal natural killer (NK)/T cell lymphoma, nasal type. Med Oncol. 2013; 30(4):720.
  11. Zhou Z, Li X, Chen C, et al. Effectiveness of gemcitabine, pegaspargase, cisplatin, and dexamethasone (DDGP) combination chemotherapy in the treatment of relapsed/refractory extranodal NK/T cell lymphoma: a retrospective study of 17 patients. Ann Hematol. 2014; 93(11):1889-1894.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Asparaginase (Erwinia chrysanthemi) Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2018. Accessed on October 1, 2018.
  2. Asparaginase. In: DrugPoints System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated November 11, 2016. Available at: http://www.micromedexsolutions.com. Accessed on October 1, 2018.
  3. Erwinaze (asparaginase Erwinia chrysanthemi) [Product Information], Palo Alto, CA. Jazz Pharmaceuticals, Inc. March 29, 2016. Available at: http://www.accessdata.fda.gov/‌drugsatfda_docs/‌label/2016/‌125359s088lbl.pdf. Accessed on October 1, 2018.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information see the NCCN website: http://www.nccn.org. Accessed on October 1, 2018.
  5. NCCN Clinical Practice Guidelines in Oncology™. Acute Lymphoblastic Leukemia. © 2017 National Comprehensive Cancer Network, Inc. For additional information see the NCCN website: http://www.nccn.org/index.asp. Accessed on October 1, 2018.
  6. Oncaspar (Pegaspargase) [Product Information], Lexington, MA, Baxalta US, Inc. October 2017. Available at: http://www.shirecontent.com/PI/PDFs/ONCASPAR_USA_ENG.pdf. Accessed on October 1, 2018.
  7. Pegaspargase. In: DrugPoints System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated September 10, 2018. Available at: http://www.micromedexsolutions.com. Accessed on October 1, 2018.
  8. Pegaspargase Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2018. Accessed on October 1, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/index. Accessed on October 1, 2018.
  2. National Cancer Institute. Leukemia. Available at: https://www.cancer.gov/types/leukemia/hp.  Accessed on October 1, 2018.
Index

Asparaginase
Asparaginase Erwinia
Crisantaspase
Elspar
Erwinaze
Erwinia ASNase
Erwinia L-asparaginase
L-asparaginase
Oncaspar
PEG
PEG-asparaginase
PEG-L-asparaginase
Pegylated Asparaginase (PEG-ASP)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

10/31/2018

Hematology/Oncology Subcommittee review. Discussion/General Information, References, and Websites sections updated.

Revised

11/02/2017

MPTAC review.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. Clarified terminology in Clinical Indications section. Updated Discussion/General Information, Index, References and Websites for Additional Information sections. The document header wording updated from “Current Effective Date” to “Publish Date.”

Reviewed

11/03/2016

MPTAC review.

Reviewed

11/02/2016

Hematology/Oncology Subcommittee review. Formatting updated in clinical indication statement. Description, Discussion and References sections updated.

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Discussion and References sections updated. Removed ICD-9 codes from Coding section.

Revised

05/07/2015

MPTAC review.

Revised

05/06/2015

Hematology/Oncology Subcommittee review. Clarified criteria for “serious” pancreatitis. Updated Discussion/General Information and References sections.

New

11/13/2014

MPTAC review.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development.