Commercial

Medical Policy

Notification

Asparaginase Erwinia Chrysanthemi (recombinant)-rywn (Rylaze®)

Notification Issued Date:

This version of the policy will become effective 12/16/2019.

The policy has been updated to communicate changes based on National Comprehensive Cancer Network (NCCN). Criteria have been revised to include use of Erwinase® as first-line therapy for adult individuals over 65 years of age and use in pediatric individuals with acute lymphoblastic leukemia.

Title:

Asparaginase Erwinia Chrysanthemi (recombinant)-rywn (Rylaze®)

Policy #:

08.01.35k

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

ASPARAGINASE ERWINIA CHRISANTHEMI [RECOMBINANT]-RYWN (RYLAZE^®)

Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) is considered medically necessary and, therefore, covered for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric individuals 1 month or older when all of the following criteria are met:

Asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) is being used as a component of a multi-agent chemotherapeutic regimen
The individual has developed hypersensitivity to Escherichia coli (E. coli)–derived asparaginase (e.g., calaspargase pegol-mknl [Asparlas], pegaspargase [Oncaspar])
The individual does not have any of the following conditions/contraindications:

History of serious hypersensitivity reactions to asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze), including anaphylaxis
History of serious pancreatitis during previous L-asparaginase therapy
History of serious hemorrhagic event or serious thrombosis during previous L-asparaginase therapy
Severe hepatic impairment

Extranodal natural killer/T-cell lymphomas

Asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) is considered medically necessary and, therefore, covered for the treatment of extranodal natural killer (NK)/T-cell lymphomas in adult individuals when all of the following criteria are met:

Asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) is being used as a component of a multi-agent chemotherapeutic regimen
The individual has developed hypersensitivity to E. coli-derived asparaginase (e.g., calaspargase pegol-mknl [Asparlas], pegaspargase [Oncaspar])
The individual does not have any of the following conditions/contraindications:

History of serious hypersensitivity reactions to asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze), including anaphylaxis
History of serious pancreatitis during previous L-asparaginase therapy
History of serious hemorrhagic event or serious thrombosis during previous L-asparaginase therapy
Severe hepatic impairment

NOT ELIGIBLE FOR REIMBURSEMENT

Asparaginase erwinia chrysanthemi (Erwinaze^®) is no longer manufactured and has been withdrawn from the market; therefore, it is not eligible for reimbursement.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for asparaginase Erwinia chrysanthemi [recombinant]-rywn (Rylaze) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

MANDATES

PENNSYLVANIA MEMBERS
In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents (08.01.08)" for additional information regarding the applicable coverage of drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS

The National Cancer Institute Common Terminology Criteria for Adverse Events describes the severity of adverse events (i.e., organ toxicity) for individuals receiving chemotherapy. Adverse events are evaluated on a Grade Scale of 1 to 5 with unique clinical descriptions of severity for each adverse event. The general guideline is:

Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
Grade 2: Moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3: Severe or medically significant but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death related to adverse event

For additional information about organ-specific clinical descriptions refer to https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION STATUS

Asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) was approved by the US Food and Drug Administration (FDA) on June 30, 2021, for the treatment of individuals with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric individuals 1 month or older who have developed hypersensitivity to Escherichia coli (E. coli)–derived asparaginase.

PEDIATRIC
The safety and effectiveness of asparaginase erwinia chrysanthemi [recombinant]-rywn (Rylaze) have been established in pediatric individuals ages 1 month and older as a component of a multiagent chemotherapeutic regimen for the treatment of individuals with ALL and LBL who have developed hypersensitivity to E. coli–derived asparaginase.

Description

According to the American Cancer Society, there are approximately 6590 new cases of acute lymphoblastic leukemia (ALL) (occurring in children and adults) in the United States. Children younger than 5 years of age have the highest level of risk for developing ALL. ALL, also known as acute lymphocytic leukemia, is a cancer that starts in the white blood cell precursors in the bone marrow and progresses rapidly to spread to other parts of the body.

Treatment for ALL is typically divided into several phases: induction, consolidation, and maintenance. Induction therapy is the initial phase of treatment with the objective of achieving complete remission. Consolidation, or the intensification phase, is a shorter period of chemotherapy to further reduce the amount of leukemic cells and to prevent the development of drug resistance. The individual's level of risk will determine the intensity of the chemotherapy regimen. The maintenance phase helps to prolong the duration of remission.

Asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. Cancer cells need a source of L-asparagine to survive and function. The cancer cells cannot produce L-asparagine on their own, so they rely on an external source. Asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) exhausts any supply of L-asparagine in the cancer cells, which results in an anticancer effect through cell death. Asparaginase is commonly used for the treatment of ALL. Clinical studies have demonstrated that asparaginase can be used to achieve complete remission for individuals during their first relapse.

ASPARAGINASE ERWINIA CHRISANTHEMI (RECOMBINANT)-RYWN (RYLAZE)

On June 30, 2021, asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) was approved by the US Food and Drug Administration (FDA) for use as a component of a multiagent chemotherapeutic regimen for the treatment of ALL or LBL in pediatric and adult individuals aged 1 month and older who have developed hypersensitivity to Escherichia coli (E. coli)–derived asparaginase.

Asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) contains an asparagine-specific bacterial enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 35-kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is identical to native asparaginase erwinia chrysanthemi (also known as crisantaspase). The activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount of enzyme that catalyzes the conversion of 1 μmol of L-asparagine per reaction minute, per mg of protein. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the DNA that encodes for asparaginase erwinia chrysanthemi.

The safety of asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) was evaluated in a cohort of 33 individuals from the study JZP458-201 (NCT04145531) who received asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) 25 mg/m2 intramuscularly on Monday, Wednesday, and Friday for six doses as a replacement for a single dose of pegaspargase (Oncaspar) as a component of multiagent chemotherapy. The individuals had a median age of 11 years (range, 1 to 24 years); the majority of individuals were male (51 percent) and white (73 percent). The individuals received a median of four courses of Rylaze (range, 1 to 14 cycles); 48 percent of individuals received at least four courses.

The safety and effectiveness of asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) in the treatment of ALL and LBL have been established in pediatric individuals 1 month to less than 17 years who have developed hypersensitivity to a long-acting E. coli–derived asparaginase. The trial included 84 pediatric individuals, including two infants (1 month to <2 years), 62 children (2 years to <12 years old), and 20 adolescents (12 years to <17 years old). The safety and effectiveness of asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) have not been established in pediatric individuals younger than 1 month of age. The most frequent serious adverse reactions (in 5 percent or greater of individuals) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection. Permanent discontinuation due to an adverse reaction occurred in 9 percent of individuals who received the asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) 25 mg/m2 dosage. Adverse reactions resulting in permanent discontinuation included hypersensitivity (6 percent) and infection (3 percent).

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). AHFS Drug Information 2025. [UpToDate Lexidrug Web site]. 02/17/2025. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed May 21, 2025.

Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. 04/2024. Available at: https://www.rylazepro.com/. Accessed May 21, 2025.

ClinicalTrials.gov. An open-label study of JZP-458 (RC-P) in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). ClinicalTrials.gov Identifier: NCT04145531. First Posted: October 30, 2019; Last Update Posted: November 18, 2023. Available at: https://clinicaltrials.gov/. Accessed May 21, 2025.

Einsiedel HG, von Stackelberg A, Hartmann R, et. al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol. 2005;23(31):7942-7950.

Elsevier's Clinical Pharmacology Compendium. Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). [Clinical Key Web site]. 04/29/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed May 21, 2025.

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.

Keating GM. Asparaginase Erwinia chrysanthemi (Erwinase^®): a guide to its use in acute lymphoblastic leukemia in the USA. BioDrugs. 2013;27(4):413-418.

Maese L, Loh ML, Choi MR, et al. Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study. Blood. 2023;141(7):704-712.

Merative Micromedex^® DRUGDEX^® (electronic version). Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). [Micromedex Web site]. 02/17/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Acute Lymphoblastic Leukemia V1.2025. [NCCN Web site]. 05/15/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed May 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Pediatric Acute Lymphoblastic Leukemia V3.2025. [NCCN Web site]. 03/17/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed May 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. T-Cell Lymphomas V1.2025. [NCCN Web site]. 11/11/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. Accessed May 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed May 21, 2025.

Ribera JM, Garcia O, Oriol A, et al. Feasibility and results of subtype-oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia: results of three prospective parallel trials from the PETHEMA group. Leuk Res. 2016;41:12-20.

Salzer WL, Asselin B, Supko JG, et al. Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group. Blood. 2013;122(4):507-514.

Seiter K. Acute lymphoblastic leukemia (ALL) treatment & management. [Medscape Web site]. 11/18/2024. Available at: http://emedicine.medscape.com/article/207631-treatment. Accessed May 21, 2025.

UpToDate^® Lexidrug^TM. Asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze^®). [UpToDate Lexidrug Web site]. 05/05/2025. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed May 21, 2025.

US Department of Health and Human Services. Common terminology criteria for adverse events (CTCTAE). V5.0. 02/01/2025. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed May 21, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Asparaginase (Erwinia chrysanthemi [recombinant)-rywn]) (Rylaze^®). Prescribing information. [FDA Web site]. 04/15/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed May 21, 2025.

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.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9021 Injection, asparaginase, recombinant, (Rylaze), 0.1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Version Effective Date:

1/1/2026

Version Issued Date:

1/2/2026

Version Reissued Date: