Asparagine Specific Enzymes (Erwinaze, Rylaze, Oncaspar, Asparlas)
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Clinical coverage criteria and coding for asparagine-specific enzyme therapies (Erwinaze, Rylaze, Oncaspar, Asparlas) primarily for acute lymphoblastic leukemia (ALL) and select lymphomas; governs prior authorization/medical necessity determinations for Anthem members.
Added use in silent inactivation for asparaginase enzyme (Erwinaze and Rylaze) criteria.
Separated Asparlas from other agents in coding and clinical criteria.
Added ICD-10-CM C86.00 (Extranodal NK/T-cell lymphoma, nasal type) to applicable agent indications.
Coverage Criteria for Asparagine-Specific Enzymes
inv-01: Erwinaze / Rylaze - Initial eligibility
Covered when ALL of the following are met:
inv-02: Oncaspar - Initial eligibility
Covered when ALL of the following are met:
inv-03: Asparlas - Initial eligibility
Covered when ALL of the following are met:
This policy addresses coverage for asparagine-specific enzyme therapies (Erwinaze/Rylaze, Oncaspar, and Asparlas) when used for the listed hematologic malignancies. Coverage may be approved only when the agent-specific clinical criteria are met, including the required diagnoses (primarily acute lymphoblastic leukemia/lymphoma [ALL] and, where specified, Extranodal NK/T‑cell lymphoma [ENKL]), and when agent-specific contraindications are absent (for example, history of serious thrombosis, pancreatitis, hemorrhagic events, or severe hepatic impairment as specified per agent).
Erwinaze/Rylaze may be approved when there is a documented systemic allergic reaction or anaphylaxis to prior E. coli–derived asparaginase or laboratory evidence of silent inactivation (see definitions and thresholds), and when no disqualifying contraindications are present. Oncaspar coverage requires the listed diagnosis and absence of the specified contraindications. Asparlas coverage additionally requires that the individual be aged 1 month to 21 years and have no history of serious hypersensitivity to pegylated L‑asparaginase or other listed contraindications.
The document history reflects changes in product availability and corresponding policy updates. Notably, Erwinaze was previously removed from the criteria when it was not available and later added back once a new manufacturer became available. These availability-driven changes have influenced inclusion, coding, and preferred agent considerations over time.
Use of Erwinaze, Rylaze, Oncaspar, or Asparlas for indications other than those explicitly listed in this policy is not approved under these criteria. Requests for indications outside the specified diagnoses (e.g., indications not identified as ALL or ENKL where applicable) or that fail to meet the agent‑specific eligibility and contraindication requirements may be denied.
Coding and Diagnostic Codes
| J9118 | Injection, calaspargase pegol-mknl, 10 units [Asparlas] |
| C83.50-C83.59 | Lymphoblastic (diffuse) lymphoma |
| C84.Z0-C84.Z9 | Other mature T/NK-cell lymphomas |
| C84.90-C84.99 | Mature T/NK-cell lymphomas, unspecified |
| C86.00 | Extranodal NK/T-cell lymphoma, nasal type not having achieved remission |
| C91.00-C91.02 | Acute lymphoblastic leukemia (ALL) |
| J9118 | Injection, calaspargase pegol-mknl, 10 units [Asparlas] |
| C83.50-C83.59 | Lymphoblastic (diffuse) lymphoma |
| C91.00-C91.02 | Lymphoblastic (diffuse) lymphoma / Acute lymphoblastic leukemia (ALL) |
Provider Actions, Prior Authorization, and Documentation
Agent-specific prior authorization — Erwinaze/Rylaze
Prior authorization may be approved for Erwinaze or Rylaze when the individual has a qualifying diagnosis (ALL or Extranodal NK/T‑cell lymphoma [ENKL]) and either a documented systemic allergic reaction/anaphylaxis to prior E. coli–derived asparaginase or laboratory evidence of silent inactivation (day 7 asparaginase activity < 0.1 IU/mL and/or day 14 below LLQ). Also ensure there is no history of serious thrombosis, serious pancreatitis, or serious hemorrhagic events with prior L‑asparaginase therapy.
- Diagnosis: ALL or ENKL required (Label/NCCN 2A).
- Documented systemic allergic reaction or anaphylaxis to E. coli–derived asparaginase OR silent inactivation per trough activity thresholds (day 7 <0.1 IU/mL and/or day 14 below LLQ).
- No history of serious thrombosis, pancreatitis, or hemorrhagic events with prior L‑asparaginase therapy.
HCPCS coding and prior authorization (J9118 and other asparaginase codes)
When billing asparaginase products use the HCPCS codes listed in the policy (for example J9118 for Asparlas). Prior authorization requirements apply when submitting these HCPCS codes per plan policy.
- Asparlas: J9118 (Injection, calaspargase pegol‑mknl, 10 units) is the HCPCS code listed.
- Prior authorization applies to these codes as indicated by the policy coding and prior auth sections.
Step therapy — no explicit sequence; agent‑specific coverage
No formal step therapy sequence is specified in this policy; coverage decisions are agent‑specific and depend on diagnosis, presence of allergy or silent inactivation, patient age (Asparlas labeled for 1 month–21 years), and agent contraindications.
- Coverage is determined by agent criteria (Erwinaze/Rylaze, Oncaspar, Asparlas) rather than a defined step sequence.
- Asparlas age restriction: 1 month–21 years (label, NCCN 2A).
- Allergy or silent inactivation directs use of Erwinaze/Rylaze.
Document history may change preferred agents and prior‑auth handling
Document history shows changes that may affect prior authorization and utilization decisions, including removal and re‑addition of Erwinaze, separation of Asparlas coding/criteria, and coding updates (example: addition of J9118 and removal of other HCPCS codes).
- 08/15/2025: Added use in silent inactivation for Erwinaze/Rylaze; separated Asparlas from other agents; added ICD‑10‑CM C86.00.
- 08/16/2024 and 02/23/2024 entries document removal/addition of Erwinaze and coding changes that may alter prior authorization handling.
Required clinical documentation for authorization
Authorization requests must include diagnosis documentation (ALL or ENKL) and either documentation of a systemic allergic reaction/anaphylaxis to E. coli–derived asparaginase or laboratory evidence of silent inactivation (day 7 asparaginase activity < 0.1 IU/mL and/or day 14 below LLQ).
- Provide clinical notes confirming diagnosis (acute lymphoblastic lymphoma/ALL or ENKL where applicable).
- Provide allergy documentation OR trough asparaginase activity results consistent with silent inactivation (preferably two independent samples).
Cite package inserts and compendia to support indications
Reference package inserts and recognized compendia (DailyMed, DrugPoints, Lexi‑Comp) and NCCN guidance when submitting authorization requests to support labeled indications, dosing, and agent selection.
- Policy cites DailyMed package inserts, DrugPoints, Lexi‑Comp, and NCCN Clinical Practice Guidelines.
- Include relevant package insert or compendium citations in the request when available.
Potential denial triggers — non‑listed indications and contraindications
Requests may be denied if the indication is not one of the listed diagnoses (ALL or ENKL) or if agent‑specific contraindications are present (history of serious thrombosis, serious pancreatitis, serious hemorrhagic events, severe hepatic impairment, or hypersensitivity to pegylated therapy for Asparlas).
- Non‑listed indications are not approved under these criteria.
- Contraindications listed per agent (e.g., severe hepatic impairment for Oncaspar; hypersensitivity to pegylated L‑asparaginase for Asparlas) may trigger denial.
Regulatory and plan precedence may supersede policy
Federal/state laws, contract language, and Plan utilization management programs or policies may take precedence over these criteria and could alter coverage or trigger denial; verify contract and regulatory requirements when processing requests.
- Policy states federal and state laws, contract language, and Plan UM policies may supersede the clinical criteria.
Asparaginase-Containing Regimens and Regimen Guidance
| Regimen / Context | Intended use / line | Notes |
|---|---|---|
| Asparaginase-containing multi-agent regimens with pegaspargase (Oncaspar) | Component of first-line multi-agent chemotherapy for acute lymphoblastic leukemia (ALL) | Oncaspar is an E. coli–derived pegylated asparaginase used as a first-line component for ALL; may be dosed biweekly per product characteristics |
| Asparaginase-containing multi-agent regimens with calaspargase pegol (Asparlas) | Component of first-line multi-agent chemotherapy for pediatric/young adult ALL (age 1 month–21 years) | Asparlas is an E. coli–derived pegylated formulation with an mPEG moiety allowing dosing no more frequently than every 3 weeks; NCCN notes substitution for pegaspargase in patients ≤21 years |
| Asparaginase-containing multi-agent regimens using Erwinia-derived asparaginase (Erwinaze or Rylaze) | Used when hypersensitivity to E. coli–derived asparaginase or for documented silent inactivation | Erwinaze and Rylaze are Erwinia chrysanthemi–derived products administered more frequently than pegylated forms and are appropriate alternatives for patients with hypersensitivity to E. coli–derived agents |
| Topic | Guidance / recommendation | Practical implications |
|---|---|---|
| Identification of hypersensitivity vs silent inactivation | Consensus recommendations describe distinguishing clinical hypersensitivity (allergic reactions/anaphylaxis) from silent inactivation detected by trough asparaginase activity and anti-drug antibodies | Measure trough asparaginase activity to detect silent inactivation; document systemic allergic reaction/anaphylaxis for true hypersensitivity |
| Asparaginase activity thresholds for silent inactivation | Use trough activity thresholds (example: day 7 < 0.1 IU/mL and/or day 14 below lower limit of quantitation) to identify silent inactivation | Laboratory evidence of activity below threshold can support switching to an Erwinia-derived product per policy requirements |
| Management approach | Consensus and NCCN recommend using Erwinia-derived asparaginase for patients with hypersensitivity or silent inactivation to E. coli–derived pegylated products; NCCN prefers pegaspargase-based regimens for ENKL | When hypersensitivity or silent inactivation is documented, substitute with Erwinia-derived product (Erwinaze/Rylaze); consider NCCN recommendations for ENKL and age-based substitution of Asparlas for pegaspargase ≤21 years |
Definitions
Background
Asparagine-specific enzymes deplete circulating asparagine, exploiting the inability of certain leukemic cells to synthesize asparagine and thereby inhibiting tumor cell protein synthesis. Clinically, these agents are integrated into multi‑agent chemotherapy regimens for acute lymphoblastic leukemia and related lymphoblastic malignancies; formulations differ by source (E. coli–derived, pegylated, or Erwinia‑derived), dosing schedule, and their role when hypersensitivity or neutralizing antibodies develop.
Line of Therapy
Revision History and Policy Changes
Removed HCPCS J9019 and J9020 effective 2026-01-01.
Added use in silent inactivation for asparaginase enzyme (Erwinaze and Rylaze); separated Asparlas from other agents in coding and clinical criteria; added ICD-10-CM C86.00 to applicable agents.
Annual review; coding updated to add applicable agents to diagnosis descriptions and include Erwinaze, Rylaze, Oncaspar, and Asparlas in several diagnosis code ranges.
Reintroduced Erwinaze to the criteria document with new manufacturer information; coding reviewed and ICD-10-CM C84.90-C84.99 and C84.Z0-C84.Z9 added (effective 2024-02-23) and C86.1 removed (effective 2024-02-23).
Removed Erwinaze earlier in 2024 when unavailable; added NCCN 2A recommendation for Rylaze in ENKT cell lymphoma and updated Oncaspar criteria to remove NCCN recommendation for hepatosplenic T‑cell lymphoma; wording and formatting updates.
Updated criteria for Erwinaze, Oncaspar, and Asparlas; coding reviewed to add ICD-10-CM C86.1 and remove ICD-10-CM C86.0.
Annual review conducted with no changes to criteria or coding.
Added new agent Rylaze to clinical criteria and aligned criteria with label; coding updated to add HCPCS entries for Rylaze and later standardized to J9021.
Annual review recorded with no changes to criteria or coding.
Rolled in criteria from prior Asparlas policy (ING-CC-0138) and added HCPCS J9118 for Asparlas.
First review of asparaginase-specific enzymes; added a contraindication to Oncaspar criteria and references for off-label indications.
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