ModifiedAnthemPolicy CC-0104

Levoleucovorin Agents — Clinical Coverage Criteria

Clinical coverage criteria for levoleucovorin agents (including Khapzory and generic levoleucovorin calcium) for prior authorization and medical necessity determinations under Anthem plans.

Policy Summary

PayerAnthem

PolicyLevoleucovorin Agents — Clinical Coverage Criteria

Policy CodePolicy CC-0104

Change TypeUpdated NCCN 2A indicationscoding revisions (HCPCS/ICD-10) — material change

Effective DateOct 1, 2025

Next Review DateN/A

Key ActionSubmit prior authorization requests that meet one of the enumerated clinical criteria (I–VII) and include indication-specific documentation and updated HCPCS/ICD-10 codes.

SourceLink

POLICY UPDATE CHANGES

Update NCCN 2A recommendations for use in Pediatric ALL, Pediatric Aggressive Mature B-cell lymphomas, B-cell Lymphomas, T-cell lymphomas, and Waldenström Macroglobulinemia.

Updated description for HCPCS J0642 and changed description for J0641 to generic levoleucovorin calcium; removed All Diagnoses and added a specified list of ICD-10-CM codes.

Clarify products for generic levoleucovorin calcium.

Annual review entries documenting previous additions and removals to indication criteria and coding updates through 2025.

7Primary allowable uses

21+NCCN 2A cancer types

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multipleICD-10 updates

2019-2022Annual review years noted

Coverage Criteria for Levoleucovorin Agents

Initial/Approved Indications

Requests for levoleucovorin agents (Levoleucovorin calcium, Khapzory) may be approved for any ONE of the following:

Primary allowable uses: I. As a component of high-dose methotrexate therapy in osteosarcoma

Supports FDA‑approved rescue use.

Primary allowable uses: II. As a treatment of impaired methotrexate elimination

FDA‑approved indication to diminish toxicity when methotrexate elimination is impaired.

Primary allowable uses: III. As a treatment of inadvertent over‑dosage of folic acid antagonists

FDA‑approved indication.

Primary allowable uses: IV. In combination chemotherapy with fluorouracil‑based regimens to treat colorectal adenocarcinoma

Used to enhance 5‑FU efficacy in colorectal adenocarcinoma.

Primary allowable uses: V. In combination with high‑dose methotrexate when leucovorin is not available in Pediatric Acute Lymphoblastic Leukemia or Pediatric Aggressive Mature B‑Cell Lymphomas

Supported by NCCN 2A recommendations (document history).

Primary allowable uses: VI. In combination with high‑dose methotrexate when leucovorin is not available for management of symptomatic Bing‑Neel syndrome in Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma

Referenced as NCCN 2A support.

Primary allowable uses: VII. In combination chemotherapy for any of the tumor types listed under NCCN Category 2A (see NCCN 2A tumor list)

See separate NCCN 2A tumor list criteria group for enumerated cancers.

NCCN 2A combination chemotherapy indications

The following tumor types are included under the NCCN Category 2A combination‑chemotherapy allowance (any one applies):

NCCN 2A tumor list: A. Acute lymphoblastic leukemia (ALL)

NCCN 2A tumor list: B. Acute Myeloid Leukemia (AML) including Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

NCCN 2A tumor list: C. Anal carcinoma

NCCN 2A tumor list: D. Ampullary adenocarcinoma

NCCN 2A tumor list: E. B‑Cell Lymphoma, including Follicular Lymphoma (grade 1‑2), Diffuse Large B‑Cell Lymphoma, High‑Grade B‑Cell Lymphomas (NOS), Post‑Transplant Lymphoproliferative Disorders, Mantle Cell Lymphoma, HIV‑Related B‑Cell Lymphomas, or Burkitt Lymphoma

Indication coverage and historical changes

Coverage and indication lists reference multiple NCCN disease‑specific guidelines; policy includes additions and removals to specific indication criteria across prior annual reviews.

policy‑updates‑history: Documented annual review actions include: addition of ampullary adenocarcinoma (08/19/2022); historical additions in 08/20/2021 expanding NCCN 2A recommendations (e.g., AML/BPDCN, follicular lymphoma grade 1‑2, DLBCL, high‑grade B‑cell lymphomas, PTLD, CLL/SLL, well‑differentiated grade 3 NET, pediatric aggressive mature B‑cell lymphomas) and removal of cervical cancer criteria when NCCN downgraded to 2B; coding changes (addition/removal of HCPCS/J‑codes) are recorded in prior reviews.

See referenced annual review entries and NCCN disease‑specific guideline citations for details.

Requests for levoleucovorin agents (Levoleucovorin calcium, Khapzory) may be approved only for indications specifically listed in this policy. Requests may not be approved for indications not listed, and authorization is contingent on meeting one of the enumerated coverage criteria for these agents.

As documented in the policy history, criteria for cervical cancer were removed following the NCCN update that reclassified that indication to a Category 2B recommendation (noted in the 08/20/2021 annual review). The removal is recorded in the revision history to reflect alignment with the current NCCN recommendation.

Use of levoleucovorin for indications other than the enumerated FDA-approved uses and the NCCN Category 2A listed uses is not approved under this policy. Requests that do not match an FDA indication or an NCCN 2A-listed tumor/regimen should be expected to be denied or not approved.

Operationally, this section of the document does not contain explicit language designating any listed use as “not medically necessary.” Instead, the policy states which indications are approvable and documents that uses outside the enumerated indications will not be approved.

Regimens and Clinical Uses

Regimen	Indication / Context	Coverage status
Fluorouracil-based chemotherapy regimens (with 5‑fluorouracil)
To enhance the therapeutic efficacy of 5‑fluorouracil in the treatment of colorectal adenocarcinoma
Covered
Fluorouracil + leucovorin (levoleucovorin as the active l‑isomer substitute)
Component of combination chemotherapy regimens for metastatic or colorectal adenocarcinoma per policy allowance
Covered

Regimen / Use	Indication / Context	Coverage status
High‑dose methotrexate therapy with levoleucovorin rescue
Rescue following high‑dose methotrexate (e.g., osteosarcoma) to diminish methotrexate toxicity and manage impaired methotrexate elimination or inadvertent folic acid antagonist over‑dosage
Covered
Levoleucovorin administered as rescue when leucovorin not available
Use in combination with high‑dose methotrexate in pediatric ALL, pediatric aggressive mature B‑cell lymphomas, or other contexts where leucovorin is unavailable per policy allowances
Covered

Coding — HCPCS and ICD-10

HCPCSHCPCS

J0641	Injection, levoleucovorin, not otherwise specified, 0.5 mg. [levoleucovorin calcium]
J0642	Injection, levoleucovorin 0.5 mg [Khapzory]

ICD-10ICD-10

B20	Human immunodeficiency virus [HIV] disease
C15.3-C17.9	Malignant neoplasm of esophagus, stomach, small intestine
C18.0-C21.8	Malignant neoplasm of colon, rectosigmoid junction, rectum, anus and anal canal
C23	Malignant neoplasm of gallbladder
C24.1	Malignant neoplasm of ampulla of Vater
C24.8	Malignant neoplasm of overlapping sites of biliary tract
C24.9	Malignant neoplasm of biliary tract, unspecified
C25.0-C25.9	Malignant neoplasm of pancreas
C37	Malignant neoplasm of thymus
C40.00-C41.9	Malignant neoplasm of bone and articular cartilage of limbs, other and unspecified sites

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Coding history and relevant HCPCS/CodesHCPCS

J0641	HCPCS code added (levoleucovorin) as noted in coding review
J0642	HCPCS code added (levoleucovorin) as noted in coding review
J3490	HCPCS code deleted (effective 10/1/19) as noted in coding review
C9043	Deleted (Effective 1/1/2020) / previously added and later referenced in coding history

Levoleucovorin dosing relation (inv-11)

Dosing relationLevoleucovorin (l-LV) is dosed at one-half the dose of racemic d,l‑leucovorin (d‑LV).

Isomer identityl‑LV is the l‑isomer and the biologically active moiety of leucovorin.

Clinical implicationWhen converting from racemic d,l‑leucovorin to l‑LV, use approximately half the total racemic dose to achieve equivalent activity.

Coding — N/A placeholder (inv-12)

Coding placeholderN/A (no additional coding thresholds specified in this section).

ContextCoding section item present in the brief is marked N/A—no numeric threshold provided.

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required and requests may be approved only when the member’s clinical indication meets the enumerated criteria in this policy. Requests may not be approved when the listed criteria are not met or for indications not enumerated in the policy.

Prior authorization requirement applies to levoleucovorin agents (levoleucovorin calcium, Khapzory).

Note

Regulatory / Contract Precedence

Providers should reference the member's contract benefits and be aware that federal or state laws, contract language, and plan utilization management programs or policies may take precedence over the application of this clinical policy.

Documentation Required

Supporting Clinical and Coding Documentation

Definitions and Clinical Context

Levoleucovorin (l-LV) — definition and dosing (inv-22)

DefinitionLevoleucovorin (l‑LV) is the l‑isomer (biologically active moiety) of leucovorin.

Dosing relationl‑LV is dosed at approximately one‑half the dose of racemic d,l‑leucovorin.

Primary usesUsed as rescue following high‑dose methotrexate and in combination with fluorouracil for colorectal cancer per FDA‑approved indications.

Clinical role of levoleucovorin (inv-23)

Drug classFolate analogue.

Primary clinical rolesDiminishes toxicity and counteracts effects of impaired folic acid antagonists (e.g., methotrexate).

Line of Therapy

first-line

Use settings: Use as part of planned high‑dose methotrexate regimens or in combination chemotherapy where indicated; placement is considered first‑line when used as rescue or as the planned folate rescue/enhancement component of initial regimens as described in the primary indications.

Line‑of‑therapy specifics depend on tumor type and regimen.

Biomarker Requirements

Biomarker requirements (inv-26)

Biomarker requirementNone specified — no biomarker is required by this policy for levoleucovorin use.

Clinical referencesPolicy references FDA indications and NCCN disease‑specific guidance; no molecular or biomarker thresholds are listed.

Provider implicationAuthorization decisions are based on indication and regimen alignment with listed NCCN/FDA uses rather than biomarker status.

Background

Levoleucovorin is the l-isomer (l-LV) of leucovorin and represents the biologically active enantiomer used clinically. It is a folate analogue employed to rescue patients from high-dose methotrexate toxicity and to enhance the therapeutic effect of fluoropyrimidine chemotherapy (e.g., 5‑FU), such as in metastatic colorectal cancer. Clinically, levoleucovorin is dosed at approximately one-half the dose of the racemic d,l-leucovorin mixture because it is the active enantiomer.

Revision History and Policy Changes

2025-08-15Annual reviewLatest

Clarified products to specify generic levoleucovorin calcium and updated NCCN 2A recommendations across multiple tumor types (material clinical update).

2022-08-19Annual review

Removed translocation-based criteria in high-grade B‑cell lymphomas and added ampullary adenocarcinoma to the NCCN 2A indication list.

2021-08-20Annual review

Policy Summary

PayerAnthem

PolicyLevoleucovorin Agents — Clinical Coverage Criteria

Policy CodePolicy CC-0104

Change TypeUpdated NCCN 2A indicationscoding revisions (HCPCS/ICD-10) — material change

Effective DateOct 1, 2025

Next Review DateN/A

Key ActionSubmit prior authorization requests that meet one of the enumerated clinical criteria (I–VII) and include indication-specific documentation and updated HCPCS/ICD-10 codes.

SourceLink

On This Page

NCCN 2A tumor list: F. Bladder cancer

NCCN 2A tumor list: G. Central nervous system (CNS) cancers, including Primary CNS lymphoma, limited brain metastases, extensive brain metastases, or leptomeningeal metastases

NCCN 2A tumor list: H. Cervical cancer

NCCN 2A tumor list: I. Chronic lymphocytic leukemia/Small lymphocytic lymphoma

NCCN 2A tumor list: J. Esophageal and esophagogastric junction cancers

NCCN 2A tumor list: K. Gastric cancer

NCCN 2A tumor list: L. Gestational trophoblastic neoplasia

NCCN 2A tumor list: M. Biliary tract cancers

NCCN 2A tumor list: N. Neuroendocrine and adrenal tumors, including well differentiated grade 3 and poorly differentiated (high‑grade) NETs

NCCN 2A tumor list: O. Occult primary

NCCN 2A tumor list: P. Ovarian, fallopian tube, or primary peritoneal cancer (including mucinous carcinoma)

NCCN 2A tumor list: Q. Pancreatic adenocarcinoma

NCCN 2A tumor list: R. Small bowel adenocarcinoma

NCCN 2A tumor list: S. T‑Cell lymphomas, including hepatosplenic T‑cell lymphoma, peripheral T‑cell lymphomas, adult T‑cell leukemia/lymphoma, or extranodal NK/T‑cell lymphoma (nasal type)

NCCN 2A tumor list: T. Thymomas and thymic carcinomas

NCCN 2A tumor list: U. Vaginal cancer

ReferenceSee coding history and annual review notes for specific HCPCS/ICD-10 updates elsewhere in the document.

Documentation submitted with the prior authorization request must support the indication-specific use per the policy and referenced NCCN indications. Include relevant clinical notes, diagnostic codes, prior therapies, and rationale for levoleucovorin use (for example, use as component of high‑dose methotrexate therapy, treatment of impaired methotrexate elimination, inadvertent overdose of folic acid antagonists, or specified NCCN 2A combination chemotherapy indications).

Submit supporting clinical notes and relevant ICD-10-CM codes.
Include prior treatment history and reason leucovorin is not available when applicable.

Note

Policy Language and Document History

Policy language, coding descriptions, and document history are maintained in the policy record. Providers should note the revision history and coding updates (including HCPCS/ICD-10 changes) when preparing requests and claims. Annual review changes and historical notes (e.g., addition of levoleucovorin to step therapy, HCPCS J0641/J0642 updates) may have operational and documentation implications.

Refer to the policy Document History for coding and criteria changes (e.g., revisions dated 08/15/2025, 08/16/2024).
Coding descriptions are informational; member contract determines coverage.

Billing Rule

Documentation and Coding

Providers should use the coding guidance included in this document for informational purposes and include appropriate codes on requests. Inclusion or exclusion of codes in the policy does not guarantee coverage; always verify member contract benefits. Submit clinical documentation to justify the requested HCPCS and ICD-10-CM coding.

Coding section is informational — verify member contract for coverage.
Ensure documentation supports the selected HCPCS (e.g., J0641/J0642) and ICD-10-CM codes.

Enhances therapeutic effects of fluoropyrimidines (such as 5‑fluorouracil) when used in combination chemotherapy.

NCCN guideline references (inv-24)

Guideline sourceNCCN Clinical Practice Guidelines in Oncology (disease‑specific guidelines cited).

Versions cited2025 disease‑specific NCCN guideline versions are referenced throughout the policy (V1/V2/V3/V4 as applicable).

ScopeNCCN guidance provides Category 2A recommendations supporting combination use of levoleucovorin in multiple tumor types listed in the policy.

Added criteria for AML (including BPDCN), follicular lymphoma (grade 1‑2), DLBCL, high‑grade B‑cell lymphomas (including translocation-defined and NOS), PTLD, CLL/SLL, well‑differentiated grade 3 NET, and pediatric aggressive mature B‑cell lymphomas; removed cervical cancer and certain cancer entries; coding reviewed with no coding changes noted.

2020-08-21Annual review

Updated NCCN 2A recommendation criteria for T‑cell lymphomas (including hepatosplenic, gamma‑delta) and added NCCN 2A recommendations for hepatobiliary, biliary tract, and small bowel adenocarcinoma; coding review: no changes.

2019-08-16Annual review

No clinical changes to policy content; coding reviewed with addition of HCPCS J0641 and J0642 (effective 2019-10-01) and deletion of J3490 (effective 2019-10-01) and planned deletion of C9043 (effective 2020-01-01).

2019-05-17Annual review

Wording and formatting changes to clarify approvable indications and summary table; coding reviewed with addition of C9043 (injection, levoleucovorin).