Medical Policy

Subject: Axicabtagene ciloleucel (Yescarta®)
Document #: MED.00123 Publish Date:    12/27/2018
Status: Revised Last Review Date:    07/26/2018


This document addresses the uses of axicabtagene ciloleucel (Kite Pharma, Inc, Santa Monica, CA) autologous chimeric antigen receptor (CAR) T-cell, CD3/CD28-based therapy, that targets the CD19 surface antigen expressed in B cell malignancies, in particular, non-Hodgkin’s lymphoma (NHL). Axicabtagene ciloleucel is produced by engineering an individual’s own functioning immune cells to express tumor antigen recognition signals that target and destroy malignant cells in some types of cancer.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Axicabtagene ciloleucel is considered medically necessary in individuals with non-Hodgkin’s lymphoma (NHL) when all of the following criteria in 1 through 7 are met:

  1. 18 years of age or older; and
  2. Histologically confirmed diagnosis of one of the following types of aggressive NHL:
    1. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified; or
    2. High-grade B-cell lymphoma; or
    3. Primary mediastinal large B-cell lymphoma; or
    4. Transformed follicular lymphoma; and
  3. Relapsed or refractory disease, defined as progression after two or more lines of systemic therapy (which may or may not include therapy supported by autologous stem cell transplant); and
  4. Must have received adequate prior therapy including, at a minimum, all of the following:
    1. An anthracycline-containing chemotherapy regimen; and
    2. For CD20+ disease, anti-CD20 monoclonal antibody; and
    3. For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma with chemotherapy refractory disease after transformation to DLBCL; and
  5. Documentation of all of the following clinical findings:
    1. Absolute neutrophil count (ANC) ≥ 1000/uL; and
    2. Absolute lymphocyte count (ALC) > 100/uL; and
    3. Platelet count ≥ 75,000/uL; and
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and
  7. One-time, single administration treatment.

Note: According to the black box warning in the FDA Product Information Label, axicabtagene ciloleucel should be administered at a designated treatment center that has received site certification.

Investigational and Not Medically Necessary:

Axicabtagene ciloleucel is considered investigational and not medically necessary as a treatment for relapsed or refractory non-Hodgkin’s lymphoma when the medically necessary criteria are not met, and for all other indications, including but not limited to:

  1. Use in combination with other chemotherapy agents;
  2. Any central nervous system (CNS) disease (for example, brain metastases, CNS lymphoma, and a history or presence of CNS disorders such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement);
  3. History of allogeneic stem cell transplant, chimeric antigen receptor therapy or other genetically modified T-cell therapy;
  4. Active, uncontrolled infection;
  5. Human immunodeficiency virus (HIV);
  6. Hepatitis B or C (if viral load is detectable).


On October 18, 2017, the U.S. Food and Drug Administration (FDA) approved axicabtagene ciloleucel for the treatment of adults with “relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma”. Axicabtagene ciloleucel was granted breakthrough and priority review status by the FDA (Product Information [PI] Label, 2017).

FDA approval was based on the results of a single arm, open-label, multicenter, phase 1/2 study (ZUMA-1) in 111 adults (18 years and older) diagnosed with DLBCL, primary mediastinal B-cell lymphoma or transformed follicular lymphoma, which are types of aggressive NHL (Neelapu, 2016). A total of 101 study participants were successfully treated with a single infusion of axicabtagene ciloleucel. All study enrollees received lymphodepleting chemotherapy (fludarabine and cyclophosphamide) prior to infusion with the axicabtagene ciloleucel. Inclusion criteria included chemotherapy refractive disease, prior treatment with an adequate chemotherapy regimen, at least one measurable lesion per revised International Working Group (IWG) Response Criteria, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, absolute neutrophil count (ANC) ≥ 1000/uL, absolute lymphocyte count (ALC) > 100/uL, platelet count ≥ 75,000/uL, and adequate organ function. Study exclusion criteria included a history of malignancy other than non-melanoma skin cancer or carcinoma in situ (for example, cervix, bladder, breast), history of allogeneic stem cell transplantation, prior therapy with a genetically modified T-cell therapy, presence of an uncontrolled infection, positive for human immunodeficiency virus (HIV), hepatitis B or C virus (history of hepatitis B or C is permitted if the viral load is undetectable per quantitative polymer chain reaction [PCR] and/or nucleic acid testing), subjects with detectable central nervous system (CNS) disease, or brain metastases, a history of CNS lymphoma, or a history or presence of CNS disorders such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement. The median age of study participants was 58 years (range, 23-76) and 85% had stage III or IV disease, 77% had disease that was resistant to second-line or later therapies and 21% had experienced disease relapse after transplantation. The study met its primary endpoint with an objective response rate of 72% (p<0.0001); 51% complete responses and 21% partial responses. With a median follow-up of 8.7 months, the median overall survival has not yet been reached. The overall duration of response was 9.2 months and has not yet been reached in those who achieved a complete response. The most common grade 3 or higher adverse events included decreased lymphocyte count (100%), decreased white blood cell count (96%), neutropenia (93%), anemia (66%), thrombocytopenia (58%) and encephalopathy (29%). Other grade 3 or higher serious adverse events that occurred in study participants included hemophagocytic lymphohistiocytosis (1%), cardiac failure (6%), cardiac arrest (4%), cytokine release syndrome (13%), and pulmonary edema (9%) (PI Label, 2017).

In 2017 Neelapu and colleagues published final results of the Phase 2 ZUMA trial. At study-end, the median follow-up was 15.4 months. The objective response rate was 82% (95% Confidence Interval [CI], 73-89%) with a 54% complete response rate. At 15.4 months, 42% continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52% and the median duration of response was 8.1 months. The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), and thrombocytopenia (38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the study participants, respectively. During treatment 2 participants died from disease progression and 1 from tumor lysis syndrome. Axicabtagene ciloleucel continues to demonstrate a durable response with an unfavorable safety profile for use prior to two or more lines of systemic therapy.

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines (CPG) for NHL (2018) currently has a 2A recommendation for the use axicabtagene ciloleucel as a therapeutic option in the treatment of adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

Axicabtagene ciloleucel is also being investigated for safety and efficacy in combination with atezolizumab for NHL, in children and young adults with NHL, and for the treatment of adults with relapsed/refractory acute lymphoblastic leukemia (ALL), multiple myeloma and mantle cell lymphoma (, 2018).


NHL is one of the most common cancers in the United States, accounting for approximately 4% of all cancer diagnoses. The National Cancer Institute (NCI) estimates that approximately 75,000 new cases of NHL will be diagnosed in 2018 (NCI, 2018). DLBCL is the most common type of NHL; 1 out of every 3 cases (American Cancer Society, 2018). While DLBCL is a relatively treatable malignancy, response rates to second-line therapy and beyond are much poorer and vary from about 14% to 60% (Locke, 2017).

Axicabtagene ciloleucel is a type of chimeric antigen receptor therapy (CAR-T). CAR T-cells are a novel therapeutic strategy proposed for the treatment of several malignancies, including relapsed/refractory DLBCL. The process of producing CAR-T cells begins with harvesting peripheral blood cells from an individual. The T-cells are isolated and genetically engineered to recognize an antigen on targeted tumor cells (the resulting genetically engineered cells are CAR-T cells). These cells are then stimulated to multiply and the final product is infused back into the individual, engineered to target and destroy malignant cells. (Locke, 2017).

Adverse Events and Warnings 

Black box warnings from the FDA PI Label (2017) include the following information and recommendations:

Additional warnings from the FDA PI Label (2017) include the following information and recommendations:


Allogeneic cells: Harvested from a histocompatible donor.

Autologous: From the individual's own body.

Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

ECOG (Eastern Cooperative Oncology Group) performance status: A scale used to assess how an individual's disease is progressing, determine how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis.

0= Fully active, able to carry on all pre-disease performance without restriction
1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3= Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4= Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5= Dead.

Hematopoietic stem cells: Cells that give rise to distinct daughter cells, one cell that replicates the stem cell and one cell that will further proliferate and differentiate into a mature blood cell.

Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment, also called partial remission.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of illness or disease.


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.

When services may be Medically Necessary when criteria are met:




Axicabtagene ciloleucel, up to 200 million autologous anti-CD19 CAR positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose [Yescarta]



Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day



Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)



Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration



Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous





ICD-10 Procedure




Introduction of engineered autologous chimeric antigen receptor T-cell immunotherapy into peripheral vein, percutaneous approach, new technology group 3 [when specified as Yescarta]



Introduction of engineered autologous chimeric antigen receptor T-cell immunotherapy into central vein, percutaneous approach, new technology group 3 [when specified as Yescarta]





ICD-10 Diagnosis




Follicular lymphoma



Diffuse large B-cell lymphoma



Mediastinal (thymic) large B-cell lymphoma



Encounter for antineoplastic immunotherapy


When services are Investigational and Not Medically Necessary:
For the procedure codes and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017; 25(1):285-295.
  2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017. 377 (26): 2531-2544.
  3. Neelapu S, Locke F, Bartlett N, et al. Late-Breaking Abstract: LBA-6 Kte-C19 (anti-CD19 CAR T Cells) induces complete remissions in patients with refractory diffuse large B-Cell lymphoma (DLBCL): results from the pivotal phase 2 ZUMA-1. American Society of Hematology (ASH) 58th Annual Meeting. December 6, 2016. Available at: Accessed on June 13, 2018.
  4. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-655.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Yescarta. [Product Information] Label. Santa Monica, CA. Updated October 18, 2017. Available at: Accessed on June 13, 2018.
  2. Kite Pharma, Inc. A Phase 1-2 multi-center study evaluating KTE-C19 in subjects with refractory aggressive non-hodgkin lymphoma (ZUMA-1). NCT 02348216. Updated June 13, 2018. Available at: Accessed on December 19, 2017.
  3. Kite Pharma, Inc. Authorized treatment centers for Yescarta (axicabtagene ciloleucel). Available at: Accessed on June 13, 2018. 
  4. NCCN Clinical Practice Guidelines in Oncology® (NCCN). © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: Accessed on June 13, 2018.
    • B-Cell Lymphomas (V4.2018). Revised May 15, 2018.
Websites for Additional Information
  1.  American Cancer Society (ACS). What Are the Key Statistics About Non-Hodgkin Lymphoma? Available at: Updated on January 04, 2018. Accessed on June 13, 2018.
  2. National Cancer Institute (NCI). Adult Non-Hodgkin Lymphoma Treatment (PDQ®). Updated April 20, 2018. Available at: Accessed on June 13, 2018.
Document History




  12/27/2018 Updated Coding section with 01/01/2019 CPT and HCPCS changes; added 0537T-0540T, revised Q2041 descriptor.



Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee Review. Updated title with registered trademark symbol. Reformatted and clarified MN criteria. Updated Rationale, Background/Overview and References sections.  Updated Coding section to remove not otherwise classified codes.



MPTAC review.



Hematology/Oncology Subcommittee Review. Added a Note to the MN Statement. Updated Rationale and References sections. Updated Coding section to include 04/01/2018 HCPCS changes, added Q2041.



MPTAC review.



Hematology/Oncology Subcommittee Review. Initial document development.

Preliminary Discussion


MPTAC Pre-FDA approval review.

Preliminary Discussion


Hematology/Oncology Subcommittee Review. Pre-FDA approval review.