Asparagine Specific Enzymes (Erwinaze, Rylaze, Oncaspar, Asparlas) Coverage Criteria
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Clinical coverage criteria for asparagine specific enzymes (Erwinaze, Rylaze, Oncaspar, Asparlas) for treatment of acute lymphoblastic leukemia and select NK/T-cell lymphomas; applies to Anthem medical benefit reviews and prior authorization for covered members.
Removed contraindications from criteria and moved them to 'may not be approved' (may not be approved criteria).
Removed HCPCS J9019 and J9020 from coding effective 1/1/26.
Added use in silent inactivation for Erwinaze and Rylaze criteria.
Removed contraindications from criteria and moved them to 'may not be approved' criteria.
Removed HCPCS J9019 and J9020 effective 1/1/26.
Added use in silent inactivation for asparaginase enzyme (Erwinaze and Rylaze) criteria.
Coverage Criteria for Asparagine-Specific Enzymes
Erwinaze / Rylaze approval criteria
Erwinaze or Rylaze may be approved when ALL of the following are met:
ENKL per NCCN 2A
Silent inactivation preferably confirmed in two independent samples
Oncaspar approval criteria
Oncaspar may be approved when ALL of the following are met:
ENKL per NCCN 2A; Drugdex cited
Asparlas approval criteria
Asparlas may be approved when ALL of the following are met:
Asparlas label and NCCN 2A support use through age 21
Criteria updates and context
Criteria updates, document history, and guidance context:
See referenced NCCN guidance and expert recommendations in References
Requests may be may not be approved when the individual has a documented history of serious adverse events related to prior L‑asparaginase therapy, including: a history of serious thrombosis, a history of serious pancreatitis, or a history of serious hemorrhagic events. These conditions are listed as exclusionary for Erwinaze/Rylaze, Oncaspar, and Asparlas when present with prior L‑asparaginase exposure and, for Oncaspar and Asparlas, severe hepatic impairment is an additional condition that may preclude approval.
Operationally, contraindications previously embedded in the main agent criteria were removed during the 02/20/2026 annual review and reclassified under the policy’s may not be approved section. This change centralizes exclusion conditions and clarifies that those situations are managed as denial triggers rather than as part of the positive approval logic.
For clarity in policy structure, conditions that had been labeled as contraindications in earlier versions are now located in the operational may not be approved area of the coverage criteria. See the document history (02/20/2026) for the formal change; the specific agent sections continue to list the same clinical events (e.g., serious thrombosis, pancreatitis, hemorrhagic events, and for some agents severe hepatic impairment) as reasons that a request may not be approved.
Coding: HCPCS and Diagnosis 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) |
Provider Actions, Prior Authorization, and Documentation Requirements
Agent-specific prior authorization
Prior authorization is required for Erwinaze (asparaginase [erwinia chrysanthemi]) and Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) and is conditioned on age, diagnosis, and supporting documentation of allergy or silent inactivation. Requests will be reviewed against the clinical criteria (e.g., age <19 and diagnosis of ALL/related ICD-10 codes) and may be denied if criteria are not met.
- Prior authorization required and clinical review applies to medical benefit drug requests.
- Approval contingent on meeting age, diagnosis, and documentation criteria per policy.
Therapy sequencing note
Erwinaze/Rylaze are positioned for patients who cannot receive or have failed E. coli–derived asparaginase products (Oncaspar/Asparlas) due to documented systemic allergic reaction/anaphylaxis or silent inactivation. Sequencing should reflect the label and NCCN-based indications; document why switching to an Erwinia-derived product is clinically necessary.
- Use Erwinaze/Rylaze when patient has hypersensitivity or silent inactivation to E. coli–derived asparaginase (e.g., pegaspargase).
- Oncaspar and Asparlas remain first-line where not contraindicated; Erwinaze/Rylaze are alternatives when allergies or inactivation occur.
Silent inactivation laboratory documentation
Documented laboratory evidence of silent inactivation is required when approval is based on suspected silent inactivation. Provide trough asparaginase activity results demonstrating inactivation (preferably two independent samples). Specifically, for pegaspargase regimens: a day 7 asparaginase activity <0.1 IU/mL and/or a day 14 level below the laboratory's lower limit of quantification (LLQ) supports silent inactivation.
- Preferred confirmation: two independent trough activity measurements to minimize false positives.
- Accepted thresholds: day 7 <0.1 IU/mL and/or day 14 < LLQ (per van der Sluis et al.).
Required clinical documentation
Providers must supply clinical documentation supporting the requested agent, including diagnosis codes and clinical rationale aligned with NCCN guidance. Include the member's diagnosis (ICD-10 ranges used in the policy such as ALL and related lymphomas), prior asparaginase agent(s) administered, details of any systemic allergic reactions or anaphylaxis, and prior therapy toxicities or contraindications that justify switching agents.
- Include relevant ICD-10 diagnosis codes (policy-added ranges for ALL/lymphomas).
- Document prior E. coli–derived asparaginase exposure and timing.
- If denying prior therapy was due to thrombosis, pancreatitis, or hemorrhagic events, provide clinical notes and imaging/lab evidence.
Common denial triggers and coding consistency
Common denial triggers include absence of documented allergy or laboratory-confirmed silent inactivation, history of serious thrombosis, pancreatitis, or hemorrhagic events with prior L-asparaginase therapy, or requests with inconsistent coding or references to removed HCPCS codes. Ensure clinical rationale and coding are consistent with the current HCPCS list and document rationale when deviating from first-line agents.
- Denial risks: no documented systemic allergic reaction or no lab evidence of silent inactivation.
- Denial risks: prior serious thrombosis, pancreatitis, or hemorrhagic events with L-asparaginase therapy.
- Denial risks: use of removed HCPCS codes (e.g., J9019/J9020 removed effective 1/1/26) or inconsistent product coding.
Background and Rationale
Asparagine‑specific enzymes (asparaginase products) work by depleting circulating asparagine, exploiting the inability of some leukemic and lymphomatous cells to synthesize asparagine de novo; deprivation of this amino acid leads to leukemic cell death. These agents include E. coli–derived pegylated formulations and Erwinia‑derived formulations used in acute lymphoblastic leukemia (ALL) and selected NK/T‑cell lymphomas. Clinically, asparaginase is used both as a component of first‑line multi‑agent regimens (pegylated forms) and as a replacement option when patients develop hypersensitivity or silent inactivation to E. coli–derived products; silent inactivation is identified by low trough asparaginase activity and reflects neutralizing anti‑asparaginase antibodies that reduce drug activity without overt allergic symptoms.
Definitions and Key Terms
Line of Therapy Positioning
first-line
First‑line use context:
See product labels and NCCN guidance
salvage
Salvage / replacement therapy context:
Silent inactivation defined by asparaginase activity thresholds
first-line (alternate)
Additional first‑line guidance context:
See References for guideline versions
Biomarker and Laboratory Requirements
Preferred Regimens and Agent Use
| Regimen / Context | NCCN recommendation | Coverage stance |
|---|---|---|
| Pegaspargase-based regimens for extranodal NK/T‑cell lymphoma, nasal type (ENKL) | NCCN: category 2A — pegaspargase-based regimens preferred | Preferred (covered with criteria) |
| Agent | Permitted uses / place in therapy | Relevant criteria or labeling notes | Coverage stance |
|---|---|---|---|
| Oncaspar (pegaspargase) | Component of multi‑agent first‑line chemotherapy for ALL; use in ENKL noted by NCCN (pegaspargase‑based regimens preferred) | Approved per label for first‑line use in eligible patients; NCCN 2A supports pegaspargase regimens in ENKL | Covered with criteria (age/diagnosis requirements) |
| Erwinaze (asparaginase, Erwinia chrysanthemi) | Used as replacement therapy for patients with documented systemic allergic reaction/anaphylaxis to E. coli‑derived asparaginase or for silent inactivation | Criteria allow use when patient has hypersensitivity or silent inactivation (day 7 activity <0.1 IU/mL and/or day 14 | Covered with criteria (replacement therapy for hypersensitivity or silent inactivation) |
| Rylaze (recombinant asparaginase) | Positioned as replacement for E. coli‑derived asparaginase in patients with hypersensitivity or silent inactivation; added to criteria and coding in document history | Use permitted for documented systemic allergic reaction or silent inactivation (asparaginase activity thresholds apply) per criteria; HCPCS J9021 applicable | Covered with criteria (replacement therapy for hypersensitivity or silent inactivation) |
| Asparlas (calaspargase pegol‑mknl) | Indicated/approved as component of first‑line multi‑agent chemotherapy for ALL; NCCN notes Asparlas may be substituted for pegaspargase in patients ≤21 years for more sustained activity | Label and NCCN support use in patients ≤21 years as an alternative to pegaspargase; separated from other agents in coding updates | Covered with criteria (age/diagnosis requirements) |
Document History and Changes
Removed contraindications from the main coverage criteria and relocated them to 'may not be approved' criteria; coding reviewed with no changes.
Removed HCPCS codes J9019 and J9020 effective 2026-01-01.
Added use for silent inactivation to Erwinaze and Rylaze criteria and updated ICD-10 coding (added C86.00); separated Asparlas from other agents in coding review.
No clinical changes to criteria; coding reviewed with additions of applicable agents to diagnosis descriptions (Erwinaze, Rylaze, Oncaspar, Asparlas added to several ICD-10 ranges).
Reintroduced Erwinaze to the criteria document; coding reviewed with addition of ICD-10-CM ranges C84.90-C84.Z0 and removal of C86.1 effective 2024-02-23.
Removed Erwinaze from the document (no longer available) earlier in the year; added NCCN 2A use in ENKL for Rylaze and updated Oncaspar criteria to remove an NCCN recommendation for hepatosplenic T-cell lymphoma.
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