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| Axicabtagene Ciloleucel (e.g., Yescarta) | |
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| Description: |
The spontaneous regression of certain cancers e.g., renal cell carcinoma, melanoma) supports the idea that an individual’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunotherapies designed to stimulate an individual’s own immune system. Chimeric antigen receptor T-cell therapy is a specific form of adoptive immunotherapy that involves harvesting cells from an individual or donor, a manufacturing process during which cells are genetically modified with engineered CAR protein to permit targeted activation and therapy, and infusion of cells into the individual.
ACUTE LYMPHOBLASTIC LEUKEMIA
Acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those individuals who fail to obtain complete response with induction therapy, e.g., failure to eradicate all detectable leukemia cells (less than 5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (greater than 25% marrow cellularity and normal peripheral blood counts). Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a 2017 meta-analysis of 20 studies of 11,249 pediatric ALL, the hazard ratio for event-free survival in MRD-negative individuals compared with MRD-positive individuals was 0.23 (95% confidence interval, 0.18 to 0.28) (Berry, 2017).
Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,4 and approximately 620 pediatric and young adult individuals with B-cell ALL will relapse each year in the United States (Maude, 2015). It is largely a disease of the young with approximately 60% of cases occurring in individuals younger than 20 years old with a median age at diagnosis of 15 years.4 While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL individuals are primary refractory (Pui, 2011). Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.7 The 2-year survival rate among individuals with ALL who relapse after hematopoietic cell transplantation is 15% (Bajwa, 2013). The Food and Drug Administration approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response were 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively (Jeha, 2006; von Stackelberg, 2016). Note that the percentages of individuals treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for individuals with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases (Swerdlow, 2016). DLBCL exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories.
It has been estimated that 27,650 new cases of DLBCL were diagnosed in the United States in 2016 (Teras, 2016). Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) is associated with a 5-year survival rate ranging from 60% to 70%.14 However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy (International Non-Hodgkin's Lymphoma Prognostic Factors P., 1993; Sehn, 2007). The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A 2017 retrospective analysis of the SCHOLAR-1 study, which pooled data from 2 phase 3 clinical trials and 2 observational cohorts, included 636 individuals with refractory DLBCL (Crump, 2017). The objective response rate to the next line of therapy was 26%, with 7% achieving a complete response. Median overall survival was 6.3 months, and 2-year survival was 20%. Refractory DLBCL was defined as progressive disease or stable disease as best response at any point during chemotherapy (greater than 4 cycles of first-line or 2 cycles of later-line therapy) or as relapse 12 or fewer months after autologous cell transplantation.
ADOPTIVE CELL TRANSFER
The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing individuals. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.
Adoptive cellular therapy is “the administration of an individual’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lympho-depleting preparative regimen” (Rosenberg, 2008). Protocols vary, but include these common steps:
CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY
Due to difficulties in expanding innate TILs, genetic modification techniques have been harnessed to decorate propagated T cells with engineered chimeric antigen receptors (CARs) that are composed of several functional components: a tumor antigen-targeting single chain variable fragment (scVF) (e.g., anti-CD19), a hinge region, a T-cell activation domain (e.g., CD3), and one or more costimulatory domains (e.g., CD28, 4-1 BB). Viral vector genetic modification approaches (e.g., retroviral, lentiviral) have traditionally been used to transfect T cells with CAR genes.
AXICABTAGENE CILOLEUCEL
Similar to tisagenlecleucel, axicabtagene ciloleucel is an adoptive immunotherapy in which the T cells of an individual are modified genetically using a retroviral vector. The resulting genetically modified cells express a CD-19 directed chimeric antigen receptor protein that has a murine single-chain variable fragment with specificity for CD19. Once injected, the genetically modified T cells selectively target and bind to CD19 antigen expressed on the surface of normal and malignant B cells (Kite Pharma Inc., 2017).
REGULATORY STATUS
On October 18, 2017, axicabtagene ciloleucel (e.g., Yescarta; Kite Pharma) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Axicabtagene ciloleucel has a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Individuals should be monitored for neurologic events after treatment.
Axicabtagene ciloleucel (e.g., Yescarta) is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Yescarta REMS respectively. The requirements for the REMS components are as follows:
On April 1, 2022, the Food and Drug Administration approved axicabtagene ciloleucel (e.g., YESCARTA, Kite Pharma, Inc.) for adult individuals with large B-cell lymphoma (LBCL) that is refractory to first line chemoimmunotherapy or relapses within 12 months of first line chemoimmunotherapy. It is not indicated for the treatment of individuals with primary central nervous system lymphoma.
On February 6, 2026, the Food and Drug Administration approved axicabtagene ciloleucel label update removing the previous Limitations of Use in patients with relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL).
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
For coverage criteria prior to August 21, 2024, for Axicabtagene Ciloleucel (e.g., Yescarta), please email
codespecificinquiry@arkbluecross.com for a hardcopy print of the coverage policy.
Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.
Prior Approval is required for axicabtagene ciloleucel (e.g., Yescarta.
The use of this drug/therapy requires documentation of direct involvement and ordering by a physician with expertise in specified condition and in a center approved for administration of CAR-T or gene product.
STANDARD REVIEW FOR DURATION OF TREATMENT COURSE OR 12 MONTHS (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
Effective October 7, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) meets member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts
without Primary Coverage Criteria, is considered Medically Necessary and is covered when member receives a “recommended” determination from criteria review in InterQual® for Axicabtagene ciloleucel (e.g., Yescarta) based on diagnosis and requested product.
Click the following link to view the specific criteria in InterQual® criteria:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
FDA Labeled Indications
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
LARGE B-CELL LYMPHOMA (non-follicular lymphoma)
FOLLICULAR LYMPHOMA
Off-label Indications:
The use of this drug for off-label indications not listed below is subject to policy 2000030.
The following indications are covered when the individual meets the related NCCN category 1 or 2A recommendations specific to the indications below (e.g., histology, cancer staging, surgical status, mono- or combination therapy, and previous lines of therapy):
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) for any indication or circumstance not described above, does not meet member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For individuals with contracts without Primary Coverage Criteria, axicabtagene ciloleucel (e.g., Yescarta) for any indication or circumstance not described above, is considered
not Medically Necessary and is not covered or is
investigational. Not Medically Necessary or
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma does not meet member certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered..
For individuals without Primary Coverage Criteria, the repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance not described above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For individuals without Primary Coverage Criteria, the use of axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Click the following link to view the specific criteria in InterQual® criteria:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
POLICY GUIDELINES
*Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”). The use of this drug for off-label indications not listed above is subject to policy 2000030.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.
Effective August 1, 2026 to October 6, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) meets member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts
without Primary Coverage Criteria, is considered Medically Necessary and is covered when member receives a “recommended” determination from InterQual® criteria review for Axicabtagene ciloleucel (e.g., Yescarta) based on diagnosis and requested product.
Click the following link to view the InterQual® criteria:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
See Criteria below.
FDA Labeled Indications
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
FOLLICULAR LYMPHOMA
Off-label Indications:
The use of this drug for off-label indications not listed below is subject to policy 2000030.
The following indications are covered when the individual meets the related NCCN category 1 or 2A recommendations specific to the indications below (e.g., histology, cancer staging, surgical status, mono- or combination therapy, and previous lines of therapy):
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) for any indication or circumstance not described above, does not meet member benefit certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For individuals with contracts without Primary Coverage Criteria, axicabtagene ciloleucel (e.g., Yescarta) for any indication or circumstance not described above, is considered
not Medically Necessary and is not covered or is
investigational. Not Medically Necessary or
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma does not meet member certificate
Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered..
For individuals without Primary Coverage Criteria, the repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance not described above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For individuals without Primary Coverage Criteria, the use of axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Click the following link to view the InterQual® criteria:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
POLICY GUIDELINES
*Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)]. The use of this drug for off-label indications not listed above is subject to policy 2000030.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031)) for pharmacologic/biologic medications.
Effective July 23, 2025 to July 31, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following conditions:
For FDA labeled indications, Axicabtagene ciloleucel (e.g., Yescarta)
must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
FOLLICULAR LYMPHOMA
Off-label Indications:
The use of this drug for off-label indications not listed below is subject to policy 2000030.
The following indications are covered when the individual meets the related NCCN category 1 or 2A recommendations specific to the indications below (e.g., histology, cancer staging, surgical status, mono- or combination therapy, and previous lines of therapy):
Policy Guidelines
*Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)]. The use of this drug for off-label indications not listed above is subject to policy 2000030.
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
FOLLICULAR LYMPHOMA
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel (e.g., Yescarta) for the treatment of any indication or circumstance not described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals with contracts without primary coverage criteria, axicabtagene ciloleucel (e.g., Yescarta) for any indication or circumstance not described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of axicabtagene ciloleucel (e.g., Yescarta) for the treatment of non-Hodgkin lymphoma or follicular lymphoma is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance not described above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of axicabtagene ciloleucel (e.g., Yescarta) after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 21, 2024 to July 22, 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following conditions:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
FOLLICULAR LYMPHOMA
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Axicabtagene ciloleucel for the treatment of any indication or circumstance not described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals with contracts without primary coverage criteria, axicabtagene ciloleucel for any indication or circumstance not described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of axicabtagene ciloleucel for the treatment of non-Hodgkin lymphoma or follicular lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of axicabtagene ciloleucel for the treatment of non-Hodgkin lymphoma or follicular lymphoma is considered
investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Axicabtagene ciloleucel after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance not described above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of axicabtagene ciloleucel after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.
Axicabtagene Ciloleucel
The approval of axicabtagene ciloleucel was based on the results of an open-label, multicenter phase 1/2 study called ZUMA-1, which reported response rates and duration of response demonstrated in the phase 2 portion of the study. Data were obtained from the FDA documents and the approved label and a recent publication by Locke and coworkers with 2-year follow-up results (Kite Pharma Inc., 2017; Locke et al, 2019; FDA, 2017; Center for Biologics Evaluation and Research, Food and Drug Administration, 2017). Adults with aggressive B-cell non-Hodgkin lymphoma that was primary refractory, refractory to a second or greater line of therapy, or relapsed within 1 year after autologous hematopoietic cell transplantation were enrolled in the study. Patients with prior allogeneic hematopoietic cell transplantation, any history of central nervous system lymphoma, Eastern Cooperative Oncology Group Performance Status score of 2 or greater, absolute lymphocyte count less than 100/μL, creatinine clearance less than 60 mL/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction less than 50%, or active serious infection were excluded. Most patients (74%) had de novo diffuse large B-cell lymphoma and 32% had double- or triple-hit lymphoma. The median age was 58, with 24% being aged 65 years or older; the median number of prior therapies was 3; 77% had refractory disease to a second or greater line of therapy; and 21% had relapsed within 1 year after autologous HCT.
All patients received a lymphodepleting regimen consisted of cyclophosphamide and fludarabine prior to infusion of axicabtagene ciloleucel. Of the 111 patients who underwent leukapheresis, 101 received the infusion (9 were not treated due to progressive disease or serious adverse reactions following leukapheresis and there was a manufacturing failure in 1 patient). Study protocol mandated hospitalization of patients for infusion and 7 days after infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. The median time from leukapheresis to product delivery was 17 days (range, 14-51 days). The primary end point was objective response rate based on a modified intention-to-treat population, which was defined as all patients treated with at least 1.0 × 106 chimeric antigen receptor (CAR)-positive T cells per kilogram.
Safety
Safety data assessed 108 patients treated with axicabtagene ciloleucel. All patients experienced at least 1 adverse event following infusion and 94% (n=102) experienced grade 3 or higher events. Serious adverse events were observed in 56 (52%) of patients, and serious adverse events that were grade 3 or higher occurred in 48 (44%) patients. Overall, 34 deaths were reported from the time of informed consent to the trial data cutoff (January 27, 2017). Thirty patients died of progressive disease and 4 deaths were attributed to axicabtagene ciloleucel as per FDA analysis, of which 3 occurred within 30 days of infusion.
The median time to onset for CRS was 2 days (range, 1-12 days), and the median time to resolution was 7 days (range for CRS duration, 2-58 days). Forty-five percent (49/108) of patients received tocilizumab for CRS management. The median time to onset of neurologic toxicity was 4 days (range, 1-43 days). The median duration was 17 days. Prolonged encephalopathy lasting up to 173 days was noted. Most common neurologic toxicities included encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety. Neurologic toxicities were managed with supportive care and/or corticosteroids. Almost all neurologic toxicities at grade 2 or higher occurred within 7 days following infusion.
Observed outcomes in a single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the high response rate (measured by CR/CRi or CR plus PR) seen in the pivotal trials of axicabtagene ciloleucel could be the result of noninterventional effect. An unbiased estimate of the safety of these CAR T cells cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, axicabtagene ciloleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug mediated. The observed benefits seen with axicabtagene ciloleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half of the patients in the pivotal trials and more than 40% patients had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of efficacy and safety of axicabtagene ciloleucel outside of a clinical trial setting.
Follicular Lymphoma
Approval for axicabtagene ciloleucel for follicular lymphoma was based on data from the ZUMA-5 clinical trial (NCT03105336). ZUMA-5 was a single-arm, open-label, multicenter trial that enrolled 146 patients with either relapsed or refractory follicular lymphoma and marginal zone lymphoma who had previously received 2 or more lines of systemic therapy, including treatment with an anti-CD20 monoclonal antibody and an alkylating agent. To be eligible for enrollment, patients had to have an ECOG performance status of 0 or 1. The primary endpoint of the trial was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T-cells.
Axicabtagene ciloleucel (Yescarta) showed a response in 91% of patients with relapsed/refractory follicular lymphoma (n = 81); this included 60% of patients who achieved a complete remission (CR). Seventy-four percent of patients had a continued remission at 18 months. Among all patients with follicular lymphoma, the median duration of response (DOR) was not yet reached at a median follow-up of 14.5 months.
Data regarding side effects in 146 patients showed that grade 3 or higher cytokine release syndrome (CRS) was reported in 8% of patients, while grade 3 or higher neurologic toxicities were reported in 21%. The median time to onset of these effects was 4 days (range, 1–20 days) and 6 days (range, 1–79 days), respectively. The most frequently reported toxicities that were grade 3 or higher in severity were febrile neutropenia, encephalopathy, and infections with unspecified pathogens.
SUMMARY OF EVIDENCE
Axicabtagene Ciloleucel
For individuals who are adults with histologically confirmed diagnosis of aggressive non-Hodgkin lymphoma (eg, diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, transformed follicular lymphoma) who receive axicabtagene ciloleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trial reported an 83% overall response rate (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 27.1 months, the median duration of response was 11.1 months. The observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half of the patients, and 98% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of axicabtagene ciloleucel efficacy and safety outside of the clinical trial setting. The manufacturer has agreed to a post marketing requirement observational registry study to collect safety information for patients treated with the marketed product. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Axicabtagene ciloleucel
NCT02614066- A Study Evaluating KTE-C19 in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3) (ZUMA-3). Planned enrollment of 100 subjects with an estimated completion date of Mar. 2034.
NCT02625480 - A Multi-Center Study Evaluating KTE-C19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ZUMA-4). Planned enrollment of 100 subjects with an estimated completion date of Jan. 2036.
NCT03105336 - A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5). Planned enrollment of 160 with an estimated completion date of Mar. 2035
In an international, phase 3 trial, patients were randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.
A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.
Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Locke FL, Miklos DB, Jacobson CA, et.al., 2022)
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2024. No new literature was identified that would prompt a change in the coverage statement.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2025. Off-label indications and coverage criteria have been added according to NCCN 1 and 2A recommendations (if no labeled indication present).
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2026.
2026 Update
The U.S. Food and Drug Administration (FDA) approved an update to the Yescarta (axicabtagene ciloleucel) prescribing information removing the previous Limitations of Use in patients with relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL).
The FDA decision is based on positive results from a Phase 1 investigator-sponsored study conducted by Dana-Farber Cancer Institute, which included patients with R/R PCNSL.
The Phase 1 safety study enrolled 18 patients (13 PCNSL, 5 SCNSL), of whom the first six patients were observed for treatment-limiting toxicities (TLTs). The primary endpoint was safety, measured by rate of TLTs and ≥ Grade 3 adverse events (AEs). Secondary endpoints included objective response rate, complete response rate, duration of response, progression-free survival and overall survival (OS).
In the Phase 1 study, neurologic toxicities occurred in 85% (11/13) of patients with R/R PCNSL. Thirty-one percent (4/13) of patients had Grade 3 neurologic toxicities. The Grade 3 or 4 adverse events were hypotension (23%; 3/13), encephalopathy (15%; 2/13), seizure (15%; 2/13), gait disturbance (8%; 1/13), headache (8%; 1/13), hypoxia (8%; 1/13), muscular weakness (8%; 1/13), nausea (8%; 1/13), pyrexia (8%; 1/13), thrombosis (8%; 1/13), and tremor (8%; 1/13).
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| References: |
Lunning M, Deger KA, Liu FF, et.al.,(2023) CT-107 Cost-Effectiveness of the Chimeric Antigen Receptor (CAR) T-Cell Treatments, Lisocabtagene Maraleucel (liso-cel) Versus Axicabtagene Ciloleucel (axi-cel), as Second-Line (2L) Treatment of Large B-Cell Lymphoma (LBCL). Clinical Lymphoma Myeloma and Leukemia. 2023 Sep 1;23:S517.
N Engl J Med. 2023 Nov 30;389(22):2039-2051. doi: 10.1056/NEJMoa2306441. Epub 2023 Oct 21. PMID: 37870976.(2022) Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. doi: 10.1056/NEJMoa2116133. Epub 2021 Dec 11. PMID: 34891224. Yescarta(2024) package insert Kite Pharma, Inc.; Santa Monica, CA; 2024. |
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| Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants. | |
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