Medical Policy: 08.01.29
Original Effective Date: October 2018
Reviewed: October 2019
Revised: October 2019
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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).
Yescarta (axicabtagene ciloleucel), a CD19 directed genetically modified autologous T-cell immunotherapy, binds to CD19 expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of evens leads to killing of CD19-expressing cells.
After Yescarta (axicabtagene ciloleucel) infusion, pharmacodynamic responses are evaluated by measuring transient elevation of cytokines and chemokines (i.e., IL-6, IL-8, IL-10, IL-15, TNF-a, IFN-y and SIL2Ra).
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 2019, an estimated 74,200 people will be diagnosed with NHL and there will be approximately 19,970 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 30% 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. 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
CI, confidence interval.
aPer 2007 revised International Working Group criteria, as assessed by the independent review committee.
|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.
In 2019, Locke et. al. reported on two-year follow-up data from the ZUMA-1 trail of Yescarta (axicabtagene ciloleucel) in adult patients with relapsed for refractory large B-cell lymphoma. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15.4 months (IQR 13.7-17.3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved response, and complete response was noted in 63 (58%) patients. This study reports on the long-term activity and safety outcomes of the ZUMA-1 study. As of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27.1 months (IQR 25·7–28·8). According to investigator assessment, 84 (83%) of 101 patients had an objective response to axicabtagene ciloleucel 59 (58%) complete responses and 25 (25%) partial responses. Ten (10%) patients had stable disease, five (5%) had progressive disease as best response, and two (2%) could not be assessed. Concordance between investigator assessments and Independent Central Review Committee assessments was 81% for objective response and 90% for complete response. Median time to response was 1 month (IQR 1–1).10 11 of 33 patients with partial responses at 1 month, and 11 of 24 patients with stable disease at 1 month, subsequently achieved a complete response, with most conversions occurring by 6 months. Among the 33 patients with double-expressor and high-grade B-cell lymphoma, 30 (91%) achieved an objective response and 23 (70%) achieved a complete response by investigator assessment. The median duration of response for all 101 patients was 11.1 months (95% CI 4–2 not estimable) by investigator assessment and was not reached by independent central review committee review. The median duration of response for participants with complete responses was not reached (95% CI 12.9 not estimable). Thirty-nine (39%) patients had ongoing responses and were censored at the last disease assessment before the data cutoff, including 37 (37%) with ongoing complete responses. Only two (5%) of the 39 patients with ongoing responses underwent allogeneic stem-cell transplantation, and none underwent autologous stem-cell transplantation while in axicabtagene-ciloleucel-induced remission. Ongoing responses were consistent across key baseline and clinical covariates.
By investigator assessment, 61 of 101 patients had disease progression or died on study. Median progression-free survival was 5.9 months (95% CI 3.3–15.0). In post-hoc analyses, the estimated proportion of patients with progression-free survival at 24 months was 72·0% (95% CI 56.0-83.0) among those with complete responses at 3 months, 75 (31.5–93.1) among those with partial responses at 3 months, and 22.2% (3.4–51.3) among those with stable disease at 3 months. The median overall survival was not reached (95% CI 12.8 not estimable), with an estimated 24 month survival proportion of 50.5% (95% CI 40.2–59.7). No patients were lost to follow-up.
Consistent with previously reported results for objective response, 10 ongoing response at 24 months was associated with higher CAR T-cell peak concentrations and area under the curve in the first 28 days after axicabtagene ciloleucel infusion. By 24 months, 11 (34%) of 32 assessable patients maintained ongoing responses but no longer had detectable gene-marked CAR T cells.
The safety profile of axicabtagene ciloleucel 2 years after infusion was largely similar to that in previous reports. All 108 treated patients had adverse events, and 106 (98%) had grade 3 or worse adverse events. Fifty-two (48%) of 108 patients had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients and grade 3 or worse neurological events occurred in 35 (32%); all these events were manageable and largely reversible. Since the 12-month analysis (data cutoff Aug 11, 2017), no new cases of cytokine release syndrome or neurological events related to axicabtagene ciloleucel were reported.
Fifty-four (50%) of 108 patients who received treatment have died since study initiation (four patients in phase 1 and 50 in phase 2). Fifty patients have died from progressive disease. Six of these deaths occurred after the 12-month analysis. No new axicabtagene ciloleucel-related deaths occurred since the 12-month analysis, but, as previously reported, four adverse-event-related deaths occurred during phases 1 and 2 of the study, two of which were related to axicabtagene ciloleucel. We noted no cases of replication-competent retroviruses or axicabtagene-ciloleucel-related secondary cancers as of this data cutoff.
To our knowledge, this long-term analysis of ZUMA-1 represents the longest follow-up of a large, registrational study of anti-CD19 CAR T-cell therapy. A substantial proportion of patients with refractory large B-cell lymphoma treated with a single infusion of axicabtagene ciloleucel achieved durable responses lasting more than 2 years and needed no further consolidation therapy. Additionally, in this population of patients refractory to several lines of treatment, which included a large proportion of patents with activated B-cell-like, double expressor, and high-grade B-cell lymphoma, outcomes were similar across all patient subgroups. Median overall survival was not yet reached at 2 years, with an estimated 24-month survival proportion of 50.5% (95% CI 40.2–59.7). This finding represents a major improvement in clinical outcomes for these patients, for whom the expected median overall survival with conventional therapies is approximately 6 months, with a 2-year overall survival of approximately 20%. These estimates build on two single-center trials of anti-CD19 CAR T cells that previously showed durable remissions without substantial late toxicities in a total of ten patients with diffuse large B-cell lymphoma.
The results of this updated analysis show continuity of the progression-free survival data at 6 months. With ten additional relapses occurring after 6 months, axicabtagene ciloleucel might offer long-term benefits for a substantial proportion of patients with refractory large B-cell lymphoma. Additionally, analysis of progression-free survival by response at 3 months suggests that achievement of complete or partial responses at 3 months might be predictive of long-term response durability. Results from large retrospective studies of lymphoma survivorship databases suggest that sustained responses 24 months after chemoimmunotherapy were associated with improved overall survival at 5 years in patients with diffuse large B-cell lymphoma who previously received first-line treatment or after autologous stem-cell transplantation for relapsed or refractory disease. Myers and colleagues reported that, among patients with diffuse large B-cell lymphoma who were progression free 24 months after autologous stem-cell transplantation, 5-year overall survival was 89% (95% CI 87–91).
Although allogeneic stem-cell transplantation could offer a potential chance of improved long-term overall survival in patients with relapsed or refractory diffuse large B-cell lymphoma, less than a fifth of patients who relapse after autologous stem-cell transplantation are able to undergo allogeneic stem-cell transplantation. In the randomized, phase 3 CORAL study comparing induction therapy versus rituximab, ifosfamide, carbo-platin, and etoposide (R-ICE) with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) before autologous stem-cell transplantation in relapsed or refractory diffuse large B-cell lymphoma, only 21 (5%) of the 458 enrolled patients underwent allogeneic stem-cell transplantation. A major difference between allogeneic stem-cell transplantation and axicabtagene ciloleucel is that allogeneic stem-cell transplantation is typically used as consolidation therapy for relapsed or refractory diffuse large B-cell lymphoma only after response to salvage chemotherapy. In a large series of patients receiving allogeneic stem-cell transplantation after relapse following autologous stem-cell transplantation, those with chemorefractory disease before allogeneic stem-cell transplantation had a 2-year progression-free survival of approximately 20% compared with approximately 40% for those who had chemosensitive disease. Furthermore, many patients with refractory disease are not candidates for allogeneic stem-cell transplantation because of poor response to salvage therapy, the absence of a donor, older age, or comorbidities. Patients who are candidates for the procedure often experience kinetic failure before the onset of graft-versus-lymphoma effects.
This study has several limitations. The study was designed to show an improvement in response. Additional studies in other large B-cell lymphoma settings are warranted to understand the benefits of axicabtagene ciloleucel in additional settings. Furthermore, we did not address the effect of axicabtagene ciloleucel on quality of life. Additional studies in large patient populations are needed to identify factors that could be associated with the risk of prolonged cytopenias with CAR T-cell therapy. Analysis of immunoglobulin concentrations would further elucidate the degree of functional immune recovery after axicabtagene ciloleucel treatment. However, data for immunoglobulin concentrations were not available because collection of immunoglobulin data was per investigator decision and not a protocol-specified assessment. Finally, mechanisms of relapse require further comprehensive analyses and additional studies.
The authors concluded, this 2-year analysis of the multicenter ZUMA-1 trial shows that a substantial proportion of patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel can achieve durable responses with manageable long-term safety. Additional studies are needed to confirm the overall survival results noted here and to establish whether axicabtagene ciloleucel can improve quality of life in this setting. Further research will also help to elucidate the mechanisms of resistance to this therapy.
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).
In 2019, Locke et. al. reported on two-year follow-up data from the ZUMA-1 trail of Yescarta (axicabtagene ciloleucel) in adult patients with relapsed for refractory large B-cell lymphoma. This long-term analysis of ZUMA-1 represents the longest follow-up of a large, registrational study of anti-CD19 CAR T-cell therapy. A substantial proportion of patients with refractory large B-cell lymphoma treated with a single infusion of axicabtagene ciloleucel achieved durable responses lasting more than 2 years and needed no further consolidation therapy. Additionally, in this population of patients refractory to several lines of treatment, which included a large proportion of patents with activated B-cell-like, double expressor, and high-grade B-cell lymphoma, outcomes were similar across all patient subgroups. Median overall survival was not yet reached at 2 years, with an estimated 24-month survival proportion of 50.5% (95% CI 40.2–59.7). This finding represents a major improvement in clinical outcomes for these patients, for whom the expected median overall survival with conventional therapies is approximately 6 months, with a 2-year overall survival of approximately 20%. These estimates build on two single-center trials of anti-CD19 CAR T cells that previously showed durable remissions without substantial late toxicities in a total of ten patients with diffuse large B-cell lymphoma.
The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Note: The below indications also meet the Wellmark policy 05.01.09 Off-Label Drug Use.
The National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium (2018) included the following category 2A recommendations for Yescarta (axicabtagene ciloleucel):
Non-Hodgkin’s lymphoma (NHL), Kaposi sarcoma (KS) and lung cancer are the most common cancer types diagnosed in people with human immunodeficiency virus (HIV) in the United States. Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and primary central nervous system lymphoma (PCNSL), are the most common subtypes of NHL in people living with HIV.
HHV8-positive diffuse large B-cell lymphoma, also called Kaposi sarcoma-associated herpesvirus or KSHV.
Post-transplant lymphoproliferative disorders (PTLD) are a heterogenous group of lymphomas that occur after solid organ transplant (SOT) or allogeneic hematopoietic cell transplant (HCT) that are related to immunosuppression and the Epstein-Barr virus (EBV). PTLD following SOT are of recipient origin in the majority of cases, often involving the grafted organ, whereas PTLD following allogeneic HCT are usually donor origin.
The incidence of PTLD following SOT varies significantly depending on the transplanted organ (kidney transplant 0.8 to 2.5%; pancreatic transplants, 0.5% to 5% liver transplants; heart transplants 2.0% to 8%; lung transplants 3% to 10%, and multiorgan and intestinal transplants ≤ 20%). The incidence of PTLD following allogeneic HCT varies depending on the degree of human leucocyte antigen (HLA) matching and the need for T-cell depletion protocol prior to transplantation. Thus, the incidence of PTLD is the highest following haploidentical allogeneic HCT especially in cases of selective T-cell depletion (> 20%) followed by cases of unrelated donors (4% to 10%); umbilical cord transplants (4% to 5%); and matched, related donors (1% to 3%).
There are six main types of PTLD based on World Health Organization (WHO). The type of PTLD is important in identifying treatment plans. Monomorphic PTLD is the most common subtype of PTLD and the majority are of B-cell origin with diffuse large B-cell lymphoma (DLBCL) being the most frequent subtype.
Histologic transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) occurs in approximately 15% of patients with an estimated annual rate of 2% to 3% and is generally associated with a poor clinical outcome.
Based on the FDA approval, chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) is included as an option for patients who have received ≥ 2 prior chemotherapy regimens for indolent or transformed disease.
Based on the FDA approval, CAR-T cell therapy (axicabtagene ciloleucel or tisagenlecleucel) is included as an option for patients who have received ≥ 2 prior chemoimmunotherapy regimens for indolent or transformed disease.
Consolidation therapy with HDT/ASCR with or without ISRT (if not previously given) or observation are included as treatment options for patients achieving CR. Allogeneic HCT should be considered only in selected patients.
For patients receiving PR to initial therapy of TFL, treatment options include second line regimens for DLBCL, allogeneic HCT with or without ISRT (only in the context of a clinical trial), CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel for patients who have received ≥ 2 prior chemoimmunotherapy regimens for indolent or transformed disease) if not previously given, or ISRT for localized residual disease and/or residual FDG – avid disease not previously irradiated. However, it should be noted that data on the insufficiency of transplant in patients who have received CAR T-cell therapy are not available. HDT/ASCR is not recommended after CAR-T cell therapy. Allogeneic HCT could be considered but remains investigational.
Axicabtagene ciloleucel or tisagenlecleucel) are anti-CD19 CAR-T cell therapies that are FDA approved for the treatment of adult patients with relapsed/refractory DLBCL, HBBL and transformed follicular lymphoma (TFL) after ≥ 2 prior chemoimmunotherapy regimens based on the results for ZUMA-1 and JULIET trials. Axicabtagene ciloleucel is also approved for relapsed for refractory PMBL after ≥ 2 prior chemoimmunotherapy regimens.
The NCCN guidelines recommend CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) for patients achieving PR following second-line therapy (regardless of their eligibility for transplant) and for those with disease relapse after achieving CR to second line therapy or progressive disease. Bendamustine should be used with caution (unless immediately prior to CAR T-cell therapy) in patients intended to receive CAR T-cell therapy, since it could impact the success of the patient’s T-cell collection.
Relapsed/refractory disease should be managed as described for DLBCL. However, limited data are available regarding the outcome of relapsed/refractory disease following HDT/ASCR or allogeneic HCT in patients with HGBL with translocation of MYC and BCL2 and/or BCL6 or DEL. Polatzumab vedotin + BR is an appropriate treatment option for patients with relapsed or refractory HGBL with translocations of MYC and BCL2 and/or BCL6 (after ≥ 2 prior lines of therapies) ineligible for HDT/ASCR. CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) is FDA approved for the treatment of relapsed/refractory HGBL after ≥ 2 prior systemic therapy regimens.
The National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium (2018) included the following category 2A recommendations for Yescarta (axicabtagene ciloleucel):
Adoptive immunotherapy is not a U.S. Food and Drug Administrationâ€’regulated procedure.
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.
aAmong all responders. DOR is measured from the date of first objective response to the date of progression or death from relapse or toxicity.
cA + sign indicates a censored value.
CI, confidence interval.
aPer 2007 revised International Working Group criteria, as assessed by the independent review committee.
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:
See Related Medical Policy:
Yescarta (axicabtagene ciloleucel) is considered medically necessary for the following off-label uses when ALL of the following criteria are met:
Yescarta (axicabtagene ciloleucel) is considered investigational for all other indications to include when the above medical necessity criteria is not met as the safety and efficacy has not yet been established in the peer reviewed medical literature. The evidence is insufficient to determine the effects on net health outcomes.
Repeat treatment of Yescarta (axicabtagene ciloleucel) for any indication is considered investigational, as the safety and efficacy beyond one dose has not been studied and is also not indicated in the current FDA approval for Yescarta (axicabtagene ciloleucel). 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.
Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
*CPT® is a registered trademark of the American Medical Association.