Medical Policy: 08.01.29
Original Effective Date: October 2018
Reviewed: October 2018
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Yescarta™ (Axicabtagene ciloleucel) is a genetically modified autologous cellular immunotherapy comprised of chimeric antigen receptor (CAR) T-cells specific to CD19, a cell surface protein found on normal and malignant B-cells. It is a customized treatment that is prepared using an individual patient’s own T-cells. Steps for preparing Yescarta (axicabtagene ciloleucel) include: collecting a patient’s immune cells from blood via leukapheresis; sending the cells to a manufacturing facility; genetically modifying the patient’s T-cells to produce CD19-specific CARs on their surface; expanding the number of CAR T-cells; returning the cells to the treatment facility; and infusing the CAR T-cells back into the patient. This process takes about 2 weeks. Patients typically receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) prior to intravenous infusion of Yescarta (axicabtagene ciloleucel). Once infused, the CAR T-cells selectively target and bind to CD19-expressing B-cells, thereby promoting T-cell expansion and activation, B-cell depletion, and persistence of the CAR T-cells.
Severe and life-threatening adverse reactions have occurred in patients receiving Yescarta (axicabtagene ciloleucel), including cytokine release syndrome (CRS) and neurologic toxicities (headache, encephalopathy, delirium, anxiety, dizziness, aphasia and tremor). Due to these safety concerns, the FDA regulates Yescarta (axicabtagene ciloleucel) through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. Under the REMS, only certified healthcare facilities can administer Yescarta (axicabtagene ciloleucel). The prescribing information for Yescarta (axicabtagene ciloleucel) also includes a black box warning. The required components of REMS are:
Yescarta (Axicabtagene ciloleucel) is currently FDA approved and indicated in the treatment of adult patients 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.
Non-Hodgkin’s lymphoma (NHL) is a type of cancer that originates in lymphoid tissue and can spread to other organs. Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes or natural killer (NK) cells. In 2018, an estimated 74,680 people will be diagnosed with NHL and there will be approximately 19,910 deaths due to the disease.
NHL can be divided into two prognostic groups: indolent lymphomas and aggressive lymphomas.
Sometimes lymphoma changes from a slow growing type into a faster growing type, this is known as transformation. The transformed lymphoma has to be treated as a high grade lymphoma.
Non-Hodgkin’s lymphoma is called “high grade” when the cells appear to be dividing quickly. These may be called aggressive lymphomas.
Diffuse large B-cell lymphoma (DLBCL) are the most common lymphoid neoplasms in adults, accounting for approximately 32.5% of NHLs diagnosed annually. Subtypes include primary mediastinal large B-cell lymphoma, high grade B cell lymphoma and diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell Lymphoma).
Refractory (resistant) disease is suggested by a less than 50 percent decrease in lesion size with treatment in the absence of new lesion development. In contrast progressive disease usually manifests as the appearance of any new lesion, a 50 percent increase in the longest diameter of a previously identified lesion or new/recurrent involvement in the bone marrow. Relapsed disease reflects the appearance of any new lesion after attainment of an initial complete remission.
Refractory or progressive disease is identified during the post-treatment response evaluation. The majority of relapses occur during the first two years after completion of treatment. However, as many as 18 percent of relapses occur more than five years after initial treatment. Relapses are usually symptomatic and rarely identified solely on the basis of routine imaging. Progressive or relapse can present with systemic B symptoms (i.e. fever, night sweats, weight loss), cytopenias, the development of an extranodal mass, or as the symptomatic or asymptomatic enlargement of the lymph nodes, liver or spleen.
When relapse is suspected, a biopsy of the involved lymph node or mass is recommended to confirm relapse and evaluate a potential change in histology, for example indolent non-Hodgkin’s lymphoma to an aggressive non-Hodgkin’s lymphoma.
Outcomes for patients with refractory diffuse large B-cell lymphoma (DLBCL) are poor.
Relapse or refractory diffuse large B-cell lymphomas is treated with systemic chemotherapy with or without rituximab with plans to proceed to high dose chemotherapy and hematopoietic stem cell transplantation (HCT) in those with chemotherapy sensitive disease. The treatment of patients who are not candidates for HCT, who fail to respond to second-line chemotherapy regimens, or who relapse after HCT is generally palliative.
In the absence of HCT, conventional chemotherapy regimens provide only transient disease control for the majority of patients with relapsed or refractory disease. Patients with primary refractory disease rarely achieve complete remission when treated with a second chemotherapy regimen. Following relapses from a first complete remission, a subset of patients will achieve a second complete remission with chemotherapy; however, these remissions are generally not durable, and long term disease free survivors are rare. In contrast, approximately half of patients who respond to a second chemotherapy regimen and proceed to HCT will maintain their response for two years. Given the lack of options for these patients, despite the high risk of adverse events Yescarta (axicabtagene ciloleucel) is now being considered as a treatment option for adult patients with relapsed or refractory large B-cell lymphoma (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( follicular lymphoma with histologic transformation to diffuse large B-cell lymphoma) after two or more lines of systemic therapy.
Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as non-comparability of treatment groups, placebo effect, and variable natural history of the condition.
The approval for axicabtagene ciloleucel (Yescarta™) is supported by data from the ZUMA-1 pivotal trial. The ZUMA-1 study is a phase 1/2, single arm, open-label study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Eligible patients must have had all of the following: 1) histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), or transformation follicular lymphoma (TFL); 2) chemotherapy refractory disease, defined as one or more of the following: progressive disease or stable disease lasting ≤ 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence ≤ 12 months after prior ASCT), if salvage therapy is given post ASCT, the subject must have had no response to or relapsed after the first line of therapy; 3) prior therapy must have included at a minimum: an anti-CD20 monoclonal antibody containing regimen (unless tumor is CD20 negative) and an anthyracycline-containing chemotherapy regimen; for patients with transformed follicular lymphoma must have received prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL; 4) at least one measurable lesion per revised International Working Group (IWG) Response Criteria; 5) no evidence of CNS lymphoma by magnetic resonance imaging; and 6) ≥ 2 weeks since prior radiation therapy or systemic therapy at the time of leukophoresis. Eligible patients are also aged ≥ 18 years, with ECOG performance status of 0 or 1, absolute neutrophil count of ≥ 1,000/uL, absolute lymphocyte count >100/uL and platelet count of ≥ 75,000/uL. Patient must have had adequate renal, hepatic, and cardiac function defined as creatinine clearance >60 mL/min, serum ALT/AST of ≤ 2.5 times the upper limit of normal, total bilirubin of ≤ 1.5 mg/Dl (except in patients with Gilbert’s syndrome), cardiac ejection fraction of ≥ 50%, and no evidence of pericardial effusion, as determined by an echocardiogram (ECHO), and baseline oxygen saturation >92% on room air. Key exclusion criteria included history of malignancy other than non-melanoma skin cancer or carcinoma in-situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years, ASCT within 6 weeks of informed consent, history of allogeneic hematopoietic stem cell transplant, prior CAR therapy or other genetically modified T cell therapy or history or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease or any autoimmune disease with CNS involvement. All patients provided written, informed consent. The Institutional Review Board/Independent Ethics Committee of each study site approved the protocol.
Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL) in the United States, accounting for approximately 30%-40% of cases of NHL. Studies examining outcomes in patients with relapsed/refractory DLBCL show that the response rates to subsequent therapy varies from 14% to 63%. However, relapse/refractory DLBCL is broadly defined and consists of a heterogeneous patient population. Outcomes are particularly poor in those patients with truly refractory DLBCL, defined as no response to last line of chemotherapy or relapse within 1 year of autologous stem cell transplant (ASCT). A large patient level meta-analysis of patients with refractory DLBCL (Retrospective Non-Hodgkin Lymphoma Research, SCHOLAR-1) found that outcomes in this homogenous population are significantly worse, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months, indicating a major unmet need for effective therapies in these patients.
Adoptive cell therapy with T-cells genetically engineered to express chimeric antigen receptor (CAR) targeting CD19 is a promising approach for treatment of B cell malignancies. The following information is based on the ZUMA-1 trial evaluating the safety and efficacy of anti-CD19 CAR T cells in patients with refractory non-Hodgkin’s lymphoma (NHL) (NCT02348216) and what the FDA approval is based on:
Following lymphodepleting chemotherapy, YESCARTA was administered as a single intravenous infusion at a target dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose: 2 × 108 cells). The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 IV, both given on the fifth, fourth, and third day before YESCARTA. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. All patients were hospitalized for YESCARTA infusion and for a minimum of 7 days afterward.
Of 111 patients who underwent leukapheresis, 101 received YESCARTA. Of the patients treated, the median age was 58 years (range: 23 to 76), 67% were male, and 89% were white. Most (76%) had DLBCL, 16% had transformed follicular lymphoma, and 8% had primary mediastinal large B-cell lymphoma. The median number of prior therapies was 3 (range: 1 to 10), 77% of the patients had refractory disease to a second or greater line of therapy, and 21% had relapsed within 1 year of autologous HSCT.
One out of 111 patients did not receive the product due to manufacturing failure. Nine other patients were not treated, primarily due to progressive disease or serious adverse reactions following leukapheresis. The median time from leukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range: 16 to 73 days). The median dose was 2.0 × 106 CAR-positive viable T cells/kg (range: 1.1 to 2.2 × 106 cells/kg).
Efficacy was established on the basis of complete remission (CR) rate and duration of response (DOR), as determined by an independent review committee (Table 1 and Table 2). The median time to response was 0.9 months (range: 0.8 to 6.2 months). Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR) (Table 2). Of the 52 patients who achieved CR, 14 initially had stable disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range: 1.6 to 5.3 months).
|Response rate||Recipients of Yescarta (N=101)|
|Objective Response Rate Per 2007 revised International Working Group criteria, as assessed by the independent review committee.||73 (72%)
95% confidence interval = 62, 81
|Complete Remission Rate||52 (51%)
95% confidence interval = 41, 62
|Partial Remission Rate||21 (21%)
95% confidence interval = 13, 30
|Duration of responses||73 responses from N of 101)|
|duration of response (Months) Among all responders. Duration of response is measured from the date of first objective response to the date of progression or death from relapse or toxicity.|
|95% confidence interval||5.4, not estimable|
|Range A + sign indicates a censored value||14.4+|
|duration of response if best response is complete remission (Months)|
|Median Kaplan-Meier estimate|
|95% confidence interval||8.1, not estimable|
|Range||0.4 - 14.4+|
|duration of response if best response is partial remission(Months)|
|Median Kaplan-Meier estimate||2.1|
|95% confidence interval||1.3, 5.3|
|Follow-up for duration of response (Months) Among all responders. Duration of response is measured from the date of first objective response to the date of progression or death from relapse or toxicity., Kaplan-Meier estimate|
|Median Kaplan-Meier estimate||7.9|
The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%) and decreased lymphocyte count (20%). As compared to the interim analysis, grade 3 or higher cytokine release syndrome decreased from 18% to 13% and neurologic events decreased from 34% to 28%. There were no cases of cerebral edema.
As previously reported at the American Society of Hematology Annual Meeting in 2016, there were three deaths not due to disease progression in the study. Two events, one hemophagocytic lymphohistiocytosis and one cardiac arrest in the setting of CRS, were deemed related to axicabtagene ciloleucel. The third case, a pulmonary embolism, was deemed unrelated. Between the interim analysis that included 62 patients, and the primary analysis which includes all 101 patients, there were no additional deaths due to adverse events
The approval for Yescarta™ (axicabtagene ciloleucel) is supported by data from the ZUMA-1 pivotal trial. The ZUMA-1 study is a phase 1/2, single arm, open-label study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in a 101 patients with refractory/relapsed aggressive non-Hodgkin lymphoma (NHL) (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma and transformed follicular lymphoma). The study met the primary endpoint of objective response rate (ORR), or rates of tumor response (complete response + partial response) recorded after a single infusion of Yescarta (axicabtagene ciloleucel) with 82%. The complete remission rate after treatment with Yescarta (axicabtagene ciloleucel) was 51%. This FDA approval brings an additional treatment option for these patients with few other options that have not responded to previous treatments. Also, the observed benefits seen with Yescarta (axicabtagene ciloleucel) were offset by a high frequency and severity of adverse reactions. In an interim analysis, grade 3 or higher cytokine release syndrome (CRS) decreased from 18% to 13% and neurologic events decreased from 34% to 28%. Due to the risk of CRS and neurologic toxicities, Yescarta (axicabtagene ciloleucel) was approved with a Risk Evaluation and Mitigation Strategy (REMS), which includes elements of safe use. To further evaluate the long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Yescarta (axicabtagene ciloleucel). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
All patients with relapsed or refractory DLBCL (diffuse large B-cell lymphoma) should be considered for enrollment in available clinical trials. High dose therapy (HDT)/ autologous stem cell rescue (ASCR) is the treatment of choice for patients with relapsed or refractory DLBCL that is chemosensitive at relapse. Patients who are candidates for HDT/ASCR should be treated with second line chemotherapy with or without rituximab (depending on whether the patient is deemed to be refractory to prior rituximab regimens).
Patients with CR (complete response) or PR (partial response) to second line therapy should be considered for further consolidation with high dose therapy (HDT)/autologous stem cell rescue (ASCR) (category 1 for patients with CR) with or without radiotherapy (RT).
Patients who are not eligible for high dose therapy (HDT)/autologous stem cell rescue (ASCR) should be treated in the context of a clinical trial.
Patients with disease relapse following high dose therapy (HDT)/autologous stem cell rescue (ASCR) should be treated in the context of a clinical trial or treatment should be individualized.
On October 18, 2017, Yescarta™, (axicabtagene ciloleucel Kite Pharma, Inc.) was approved by the Food and Drug Administration (FDA) for the treatment of adult patients 18 years and older 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. The safety and effectiveness of Yescarta™, (axicabtagene ciloleucel) in the pediatric population has not been established.
The FDA approval states that Yescarta™ (axicabtagene ciloleucel) is not indicated for the treatment of patients with primary central nervous system lymphoma. Primary Central nervous system (CNS) lymphoma is defined as a disease in which malignant cancer cells form in the lymph tissue of the brain and/or spinal cord. Because the eye is so close to the brain, primary CNS lymphoma can also start in the eye called ocular lymphoma.
Prior approval required
See related medical policies:
Yescarta (axicabtagene ciloleucel) as a one time, single administration intravenous infusion treatment is considered medically necessary when ALL of the following criteria are met:
Yescarta (axicabtagene ciloleucel) is considered investigational for all other indications not listed above as the safety and efficacy has not yet been established in the peer reviewed medical literature.
Repeat treatment of Yescarta (axicabtagene ciloleucel) is considered investigational, the safety and efficacy beyond one dose has not been studied and also is not indicated in the current FDA approval for Yescarta™. The evidence is insufficient to determine the effects on net health outcomes.
Required Documentation: The patient’s medical records submitted for review should document the above medical necessity criteria is met and should also include the following:
Autologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis (leukapheresis) procedure or may be isolated from resected tumor tissue.
Axicabtagene ciloleucel (Yescarta™) 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 patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.
Axicabtagene ciloleucel (Yescarta™) is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). The requirement for the REMS components are as follows:
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
October 2018 - Content moved from policy 08.01.26, New Policy Created
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