Levoleucovorin Agents Form

Overview Coding References Clinical criteria Document history Overview This document addresses the use of levoleucovorin agents (Fusilev, Khapzory). Levoleucovorin is a folate analogue primarily used to diminish the toxicity and counteract the effects of impaired folic acid antagonists (such as methotrexate) and to enhance the therapeutic effects of fluoropyrimidines (such as 5-fluorouracil) in the treatment of various types of cancer. Levoleucovorin (l-LV) is the l-isomer, or biologically active moiety of leucovorin and is dosed at one-half that of the racemic mixture d,l-leucovorin (d-LV).
The FDA approved indications for levoleucovorin agents (Fusilev, Khapzory) include rescue following high-dose methotrexate in osteosarcoma, to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdosage of folic acid antagonists, and in combination chemotherapy with 5-fluorouracil for advanced metastatic colorectal cancer. The National Comprehensive Cancer Network® (NCCN) provides additional recommendations with a category 2A level of evidence for the use in combination with high dose methotrexate or 5- fluorouracil in various types of cancer.
Definitions and Measures Analogue: A drug or substance which is similar to, but not identical, to another drug or substance. Antagonist: An agent which blocks the binding of an agonist (a substance that binds to a specific receptor and triggers a response in the cell) at a receptor site. Adenocarcinoma: Cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties. Anal cancer: Cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body. Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals. Colon cancer: Cancer originating in the tissues of the colon (the longest part of the large intestine). Most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids. Colorectal cancer: Cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus). Isomer: Drugs or substances that share the same chemical formula but have different molecular arrangements. l-LV and d-LV are stereoisomers that are non-superimposable mirror images of each other. Though some isomers show different chemical properties, l-LV and d-LV have been shown to have equivalent therapeutic effects. Metastasis: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread. Neuroendocrine Tumor (NET): A tumor that forms from cells that release hormones into the blood in response to a signal from the nervous system. NETs may make higher-than-normal amounts of hormones, which can cause many different symptoms. These tumors may be benign (not cancerous) or malignant (cancerous). 1

Rectal cancer: Cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus). Summary of FDA-Approved Indications or Indications Meeting Off-Label Use Policy for Leucovorin Agents: Indications Fusilev (levoleucovorin)
Khapzory (levoleucovorin) Leucovorin Levoleucovorin Osteosarcoma; after high dose methotrexate therapy Methotrexate; to diminish toxicity and counteract the effects of impaired elimination Inadvertent over-dosage of folic acid antagonists
Colorectal cancer; in combination with fluorouracil
Megaloblastic anemia due to folic acid deficiency Acute lymphoblastic leukemia (ALL) Acute Myeloid Leukemia
• Blastic Plasmacytoid Dendritic Cell Neoplasm Ampullary Adenocarcinoma Anal Carcinoma B-Cell Lymphoma • Follicular Lymphoma (grade 1-2) • Diffuse Large B-Cell Lymphoma • High Grade B-Cell Lymphomas with Translocations • Post Transplant Lymphoproliferative Disorders • Mantle Cell Lymphoma • AIDS-Related B-Cell Lymphomas • Burkitt Lymphoma Bladder Cancer Central nervous system (CNS) cancers • Primary CNS Lymphoma • Limited Brain Metastases • Extensive Brain Metastases • Leptomeningeal Metastases Cervical Cancer Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Esophageal and Esophagogastric Junction Cancers Gastric Cancer Gestational Trophoblastic Neoplasia Hepatobiliary, Biliary Tract Lymphoplasmacytic Lymphoma Neuroendocrine and Adrenal Tumors, including Well Differentiated Grade 3, Poorly Differentiated (High Grade)/Large or Small Cell Occult Primary Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer, including Mucinous Carcinoma Pancreatic Adenocarcinoma Pediatric Aggressive Mature B-Cell Lymphomas X X X X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y X X X X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y X X X X X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y X X X X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 2

Pediatric Acute Lymphoblastic Leukemia Rectal Cancer Small Bowel Adenocarcinoma T-Cell Lymphomas
• Peripheral T-Cell Lymphomas • Adult T-Cell Leukemia/Lymphoma • Extranodal NK/T-Cell Lymphoma, nasal type • Hepatosplenic Gamma-Delta Thymomas and Thymic Carcinomas Y = off-label use Clinical Criteria Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose.
Levoleucovorin agents (Fusilev, Khapzory) Requests for levoleucovorin agents (Fusilev, Khapzory) may be approved for the following: I. II. III. IV. V. As a component of high-dose methotrexate therapy in osteosarcoma; OR As a treatment of impaired methotrexate elimination; OR As a treatment of inadvertent over-dosage of folic acid antagonists; OR In combination chemotherapy with fluorouracil-based regimens to treat colorectal adenocarcinoma; OR In combination chemotherapy for any of the following cancers (NCCN 2A):
A. Acute lymphoblastic leukemia (ALL); OR B. Acute Myeloid Leukemia (AML) including Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN); OR C. Anal Carcinoma; OR D. Ampullary adenocarcinoma; OR E. B-Cell Lymphoma, including Follicular Lymphoma (grade 1-2), Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphomas High-Grade B-Cell Lymphomas (NOS), Post-Transplant Lymphoproliferative Disorders, Mantle Cell Lymphoma, AIDS-Related B-Cell Lymphomas or Burkitt Lymphoma; OR F. Bladder Cancer; OR G. Central nervous system (CNS) cancers, including Primary CNS Lymphoma, Limited Brain Metastases, Extensive Brain Metastases or Leptomeningeal Metastases; OR H. Cervical Cancer; OR I. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; OR J. Lymphoplasmacytic Lymphoma; OR K. Esophageal and Esophagogastric Junction Cancers; OR L. Gastric Cancer; OR M. Gestational Trophoblastic Neoplasia; OR N. Hepatobiliary Cancers, Biliary Tract Cancers; OR O. Neuroendocrine and Adrenal Tumors, Well Differentiated Grade 3 NET, including Poorly Differentiated (High Grade)/Large or Small Cell; OR P. Occult Primary; OR Q. Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer, including Mucinous Carcinoma; OR R. Pancreatic Adenocarcinoma; OR S. Pediatric Aggressive Mature B-Cell Lymphomas; OR T. Pediatric Acute Lymphoblastic Leukemia; OR U. Rectal Cancer; OR V. Small Bowel Adenocarcinoma; OR W. T-Cell Lymphomas, including Hepatosplenic Gamma-Delta, Peripheral T-Cell Lymphomas, Adult T-Cell Leukemia/Lymphoma, or Extranodal NK/T-Cell Lymphoma, nasal type; OR X. Thymomas and Thymic Carcinomas. Requests for levoleucovorin agents (Fusilev, Khapzory) may not be approved when the above criteria are not met and for all other indications.
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Coding The following codes for treatments and procedures applicable to this document 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
J0641 J0642 ICD-10 Diagnosis ALL DIAGNOSES Injection, levoleucovorin, not otherwise specified, 0.5 mg. [Fusilev] (Effective 10/1/19) Injection, levoleucovorin 0.5 mg [Khapzory] (Effective 10/1/2019) Document History Revised: 08/18/2023