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A.8.01.63
Aucatzyl (obecabtagene autoleucel)
Breyanzi (lisocabtagene maraleucel)
Kymriah (tisagenlecleucel)
Tecartus (brexucabtagene autoleucel)
Yescarta (axicabtagene ciloleucel)
Chimeric antigen receptor (CAR) T-cells are genetically engineered cells that represent a novel class of cancer immunotherapy. In general, the process of autologous CAR T-cell therapy begins with harvesting white blood cells from the patient via leukapheresis followed by T-cell receptor activation and genetic engineering via retroviral or lentiviral transduction. After the CAR T cells are generated, they are expanded to clinically relevant numbers, undergo quality control testing, and are cryopreserved. Commercial CAR T-cell products are manufactured at a centralized facility, necessitating transfer of the apheresis product to the manufacturing site, and the final cryopreserved CAR T-cell product back to the treatment facility. Typically, the patient undergoes lymphodepleting chemotherapy to create a favorable immune environment for CAR T-cell activity prior to receiving a single intravenous infusion of the product. Multiple commercial CAR T-cell products have been approved by the U.S. Food and Drug Administration for the treatment of lymphoma and leukemia. Kymriah (tisagenlecleucel) and Tecartus (brexucabtagene autoleucel) are approved for treatment of subsets of patients with leukemia and lymphoma and Yescarta (axicabtagene ciloleucel) and Breyanzi (lisocabtagene maraleucel) are approved to treat subsets of patients with lymphoma.
Acute Lymphoblastic Leukemia (ALL)
B-cell 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 patients who fail to obtain a complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>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 complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Minimal residual disease positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be the 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 meta-analysis of 20 studies of 11,249 pediatric ALL patients, a hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients of 0.23 (95% confidence interval, 0.18 to 0.28) was reported.
Approximately 5,000 cases of B-cell ALL are diagnosed every year in the United States, and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year. B-cell ALL is largely a disease of the young, with approximately 60% of cases occurring in patients younger than 20 years, with a median age at diagnosis of 15 years.
Treatment
While treatable in 85% of cases, approximately 15% of children and young adults with ALL will relapse and 2% to 3% of ALL patients are primary refractory. Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate. The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15%.
The U.S. Food and Drug Administration (FDA) approved clofarabine (as a single agent or in combination therapy) 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 (OS) durations were 3 months and 7.5 months, respectively. Note that the percentages of patients treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for patients with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is a diverse group of lymphoid malignancies and is the sixth most common cancer diagnosed in the United States. They can be categorized based on whether they originate from B cells or T cells. Approximately 85% of NHL cases arise from B cell precursors. Indolent lymphomas constitute the majority of NHL cases and are characterized by a slow growth pattern. These lymphomas are often managed with watchful waiting, but they typically respond well to treatment and can be controlled for long periods, often without the need for therapy. The most common subtypes in the indolent category are follicular lymphoma, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), with marginal zone lymphoma being less common. The other major group of NHLs are the aggressive lymphomas, which grow rapidly and can be life-threatening. However, despite their severity, they are often curable with chemotherapy. Patients who do not respond to initial chemotherapy or who relapse after frontline therapy generally have a poor prognosis. The most common type of aggressive NHL is diffuse large B-cell lymphoma (DLBCL).
Other types in this group include high-grade B-cell lymphoma and primary mediastinal large B-cell lymphoma, with Burkitt lymphoma and Mantle cell lymphoma (MCL) being much less common.
Diffuse Large B Cell Lymphoma
Diffuse large B cell lymphoma 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. The incidence of DLBCL is approximately 7 cases per 100,000 persons per year.
Treatment
Treatment in the first-line setting includes multiple chemotherapy and/or immunotherapy options that typically involve rituximab. While the majority of patients respond well to first-line immunochemotherapy combinations containing rituximab, 10 to 15% have primary refractory disease within 3 months after treatment initiation and another 20 to 35% have a relapse. Of those who relapse or are refractory, 40 to 60% of patients may respond to second-line chemotherapy. Treatment of relapsed/refractory cases is generally stratified according to hematopoietic cell transplant eligibility. There is general consensus that salvage therapy followed by autologous transplantation is the preferred treatment for medically eligible patients with a first relapse of DLBCL or primary refractory DLBCL. Approximately 50% of patients who relapse or are refractory to first line agents proceed to autologous hematopoietic stem-cell transplantation, and of these, approximately 30 to 40% remain progression-free 3 years after transplantation. For patients who are ineligible for second-line therapy that includes high-dose chemotherapy and hematopoietic stem-cell transplantation, prognosis is often poor with a median OS of 4.4 months. Overall survival at 1 year is 23% and 16% at year 2. For patients who relapse after autologous transplantation, options are limited and include allogeneic hematopoietic stem-cell transplantation. However, the procedure can only be performed if the patient is chemo-responsive and a donor is available. Further, the procedure is associated with a high risk of complications. The mortality risk unrelated to disease relapse is 23% at 1 year.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is a rare B-cell malignancy classified as an aggressive form of non-Hodgkin lymphoma that arises from cells originating in the “mantle zone” of the lymph node and typically affects men over the age of 60. It accounts for approximately 3 to 6% of all non-Hodgkin lymphoma in the United States and differs from DLBCL. In 2018, the overall incidence of MCL in the U.S was 3,500 with a 5-year and 10-year prevalence of 12,000 and 18,000 cases, respectively. The median age at the time of diagnosis is 68, a majority of patients are non-Hispanic white males and more than 70% of patients present with stage IV disease. The majority (75%) of cases initially present with lymphadenopathy while presentation is extranodal in the remaining 25%. In most cases of MCL, chromosomal translocation results in aberrant expression of cyclin D1, leading to cell cycle dysregulation. Many signaling pathways are constitutively activated and/or deregulated in MCL, including the B-cell receptor signaling pathway.
Treatment
There is no standard of care that exists for second-line and higher chemotherapy when a patient has relapsed or refractory MCL. Second line therapies typically depend on the front line therapy utilized, comorbidities, the tumor’s sensitivity to chemotherapy, and overall risk-benefit. Potential salvage regimens include ibrutinib, acalabrutinib, lenalidomide, combination chemotherapy, and bortezomib.
Despite the availability of multiple treatments, MCL is not curable. Median OS in modern trials incorporating intensive therapy is 8 to 10 years with no plateau in the survival curve. Shorter survival times are seen with less intensive therapy. Multiple prognostic indices are used in MCL patients to guide course of treatment. First-line treatment of MCL can consist of aggressive or less-aggressive therapy, depending on patient status at baseline. It generally consists of chemotherapy in combination with rituximab. Only 30 to 40% of patients have a durable long term remission after first line chemo-immunotherapy. Progression is common, with a median time to treatment failure of less than 18 months. Virtually all patients will have refractory or recurrent disease. Treatment of recurrent MCL is difficult, due to the rapid development of chemotherapy resistance. There are multiple preferred chemotherapy regimens that may be offered and choice is primarily made based on prior treatment history, patient comorbidities, and performance status. The expected toxicities of a given regimen as well as clinician’s experience with the regimens are additional considerations. A preferred order for their use has not been established. Most of these regimens have not been compared directly in randomized trials. Given the limited efficacy of these agents and the paucity of data comparing these various treatment options, participation in a clinical trial is encouraged whenever possible. Complete response rates in previously treated or relapsed MCL are generally low (<30%) and have limited response durations. Among patients who have disease progression after the receipt of Bruton’s kinase inhibitor (BTK) therapy, the reported objective response rate ranges from 25% to 42% with a median OS of 6 to 10 months with salvage therapies. Allogeneic stem-cell transplantation may be an option for selected patients. However, non–relapse-related mortality remains high at 10 to 24%.
While the clinical course of MCL is generally aggressive, a small proportion of patients with low stage and low-risk disease may have an indolent course, managed by observation, splenectomy, or treatment with alkylating agents analogous to the treatment of patients with small lymphocytic lymphoma or follicular lymphoma.
Follicular Lymphoma
Follicular lymphoma is the second most common subtype of non-Hodgkin lymphomas and is associated with an excellent prognosis for most patients with a median overall survival >20 years. Approximately 40 to 80% of patients treated respond to initial chemoimmunotherapy while 10% do not respond (ie, refractory disease). However, conventional therapy for follicular lymphoma is not curative and most of these patients ultimately develop progressive disease. The prevalence of follicular lymphoma in the United States is approximately 2.7 per 100,000 individuals per year. The 5-year survival rate may be as high as 89.7% and the median age at diagnosis is 63 years old. Patients with advanced-stage follicular lymphoma after 2 or more lines of therapy reported a complete response rate with approved therapies ≤14%, and median duration of response less than 13 months.
Treatment
Initial treatment depends on the stage of disease at presentation. The first and second line treatments for Grade 1 to 2 follicular lymphoma include excision, radiation therapy, and a systemic therapy with a combination or a single use of an alkylating agent (e.g., bendamustine, cyclophosphamide, and chlorambucil), an anti-CD20 monoclonal antibody (e.g, rituximab, obinutuzumab), and an immunomodulatory agent (e.g., lenalidomide). Other systemic agents, such as vinca alkaloid (e.g., vincristine), anthracycline (e.g., doxorubicin), and a corticosteroid (e.g., prednisone) are also often included in the treatment regimens. Allogeneic hematopoietic cell transplant is used selectively.
There is no standard therapy for patients with relapsed or refractory follicular lymphoma and practice varies widely. Patients with late relapse are treated with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) either alone or in combination with chemotherapy or lenalidomide. The choice between immunotherapy alone versus combination therapy in late relapse depends largely on patient performance status. Novel FDA approved agents for treatment in the multiple relapse/refractory setting include lenalidomide and tazemetostat. The choice is primarily made based on the patient's prior treatment, the expected toxicity profile of the selected regimen, route of administration, and clinician experience with the regimens.
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are mature B cell cancers characterized by the gradual buildup of identical B lymphocytes. CLL and SLL are essentially the same disease with different presentations. The cancer cells in both CLL and SLL share the same pathological and immunophenotypic characteristics. The term CLL is used when the disease is mainly found in the blood, while SLL is used when it primarily affects the lymph nodes. CLL/SLL is more common in men. In the United States, the incidence rates are about 4.6 cases per 100,000 individuals each year. Annually, around 20,700 new cases are diagnosed in the U.S. CLL/SLL primarily affects older adults, with a median age at diagnosis of around 70 years. However, it can also be diagnosed in younger individuals, typically between 30 and 39 years of age.
Treatment
Most individuals will have a complete or partial response to initial therapy. However, conventional therapy for CLL is not curative and most experience relapse. Treatment of individuals with multiply relapsed/refractory CLL/SLL with prior exposure to both a BTK inhibitor and B-cell lymphoma 2 (BCL-2) inhibitor is individualized. Available options have not been directly compared in a clinical trial, and a choice depends on prior response, comorbidities, and access to cellular therapies.
Commercial Chimeric Antigen Receptor T-Cell Therapies Available in the United States
As of September 2023, there are 4 chimeric antigen receptor (CAR) T-cell therapies approved by the FDA for the treatment of cancer. All 4 are CD19-targeting CAR T-cell immunotherapies in which a patient's own T-cells are genetically engineered using a viral vector to express a synthetic receptor called the chimeric antigen receptor. Once injected, the genetically modified T-cells selectively target and bind to CD19 antigen expressed on the surface of B cells and tumors derived from B cells. Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel), and Breyanzi (lisocabtagene maraleucel) are approved for treatment of subsets of patients with leukemia and lymphoma. Yescarta (axicabtagene ciloleucel) is approved to treat subsets of patients with lymphoma.
Tisagenlecleucel (Kymriah; Novartis) Approvals
On August 30, 2017, tisagenlecleucel (Kymriah; Novartis) was approved for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
On May 1, 2018, tisagenlecleucel (Kymriah; Novartis) was approved 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, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
On May 27, 2022, tisagenlecleucel (Kymriah; Novartis) was approved for the treatment of adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.
The FDA, under the accelerated approval regulations, requires that Novartis conduct a randomized phase 3 trial in adult patients with relapsed or refractory follicular lymphoma. Patients will be randomized to tisagenlecleucel (Kymriah) or an investigator’s choice of regimens consistent with the standard of care. The primary endpoint will be progression-free survival with secondary endpoints that include overall survival and objective response rate. The expected date of trial completion is March 31, 2028 and final report submission to the FDA by September 30, 2028.
Axicabtagene ciloleucel (Yescarta; Kite Pharma) Approvals
On October 18, 2017, axicabtagene ciloleucel (Yescarta; Kite Pharma) was approved 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.
On March 5, 2021, axicabtagene ciloleucel (Yescarta; Kite Pharma) was approved for the treatment of adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.
The FDA, under the accelerated approval regulations, requires that Kite Pharma conduct a randomized phase 3 trial of axicabtagene ciloleucel (Yescarta) in patients with relapsed or refractory follicular lymphoma. Patients will be randomized to axicabtagene ciloleucel (Yescarta) or to an investigator’s choice of regimens consistent with the standard of care. The primary endpoint will be progression-free survival, with secondary endpoints that include objective response rate and overall survival. The expected date of trial completion is June 30, 2027 and final report submission to the FDA by September 30, 2027.
On April 1, 2022, axicabtagene ciloleucel (Yescarta; Kite Pharma) was approved for the treatment of adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Brexucabtagene autoleucel (Tecartus; Kite Pharma) Approvals
On July 24, 2020, brexucabtagene autoleucel (Tecartus; Kite Pharma) was approved for the treatment of adult patients with relapsed or refractory MCL. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.
The FDA, under the accelerated approval regulations, requires that Kite Pharma conduct a study of brexucabtagene autoleucel treatment of subjects with relapsed or refractory MCL who have not been exposed to a BTK inhibitor. A cohort of subjects naïve to BTK inhibitor therapy will be added to the ongoing ZUMA-2 study to fulfill this requirement. Eighty-six subjects will be enrolled. The primary efficacy endpoint will be objective response rate with a supportive efficacy endpoint of duration of response based on a minimum follow-up of 18 months after first objective disease response. The expected date of trial completion is April 30, 2025 and final report submission to the FDA by October 31, 2025.
On October 1, 2021, brexucabtagene autoleucel (Tecartus; Kite Pharma) was approved for the treatment of adult patients with relapsed or refractory B-cell precursor ALL.
Lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) Approvals
On February 5, 2021, lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) was approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.
On June 24, 2022, lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) was approved for the treatment of adult patients with large B-cell lymphoma, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy or refractory disease to first-line chemoimmunotherapy or relapse after first line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.
On March 14, 2024, lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) was approved for adult patients with relapsed or refractory CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
The FDA, under the accelerated approval regulations, requires that Juno Therapeutics conduct a single arm study of lisocabtagene maraleucel (Breyanzi) in patients with relapsed or refractory CLL or SLL who have received at least 2 prior lines of therapy, including a prior BTK inhibitor and a BCL-2 inhibitor, to evaluate overall response rate and durability. The study must include a total of 50 treated patients and durable response should be based on a minimum follow-up of 15 months after first objective disease response. The expected date of trial completion is March 31, 2027 and final report submission to the FDA by May 31, 2027.
On May 15, 2024, lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) was approved for adults with relapsed or refractory follicular lymphoma who have received two or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
The FDA, under the accelerated approval regulations, requires that Juno Therapeutics collect and submit the final report, including datasets from the TRANSCEND FL clinical trial (NCT04245839) to verify and describe the clinical benefit of lisocabtagene maraleucel (Breyanzi) in adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent). All partial and complete responders should have completed at least 24 months of follow up starting from the initial objective response. The expected date of trial completion is May 31, 2025 and final report submission to the FDA by August 31, 2025.
On May 30, 2024, approved for adult patients with relapsed or refractory MCL who have received at least two prior lines of systemic therapy, including a BRK inhibitor.
I. Designated and Approved Providers for Immunotherapy and Gene Therapy
Benefits for Immunotherapy and Gene Therapy will not be provided unless Medically Necessary subject to Medical Policy and a treatment plan submitted by the Network Provider and approved by the Company prior to the initiation of treatment. Immunotherapy and Gene Therapy services must be received from a Network Provider designated and approved by the Company where the Company has a contract in place with the Network Provider, either directly or through BlueCard®, for the specific Immunotherapy and Gene Therapy service.
No benefits will be provided unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.
II. Medically Necessary Immunotherapy and Gene Therapy
For all therapies, basic criteria include:
Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis OR Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist, AND
Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy, AND
Individual is using as a one-time, single administration treatment.
Additional criteria:
Kymriah (tisagenlecleucel)
One treatment course (one dose) per lifetime of Kymriah (tisagenlecleucel) is considered medically necessary for individuals meeting the following criteria:
Meet the basic criteria above, AND
Criteria for one of the following indications is met:
Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND
Are up to 25 years of age at the time of infusion, AND
Relapsed after a transplant, or relapsed for a second or later time, or refractory.
Histologically confirmed diagnosis of large B-cell lymphoma including diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, or diffuse large B-cell lymphoma arising from follicular lymphoma AND do not have primary central nervous system lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory after ≥2 lines of systemic therapy.
Histologically confirmed diagnosis of follicular lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.
The prescriber will submit documentation to Blue Cross & Blue Shield of Mississippi Case Management of response to Kymriah (tisagenlecleucel) within 3 months following therapy as a follow-up to the prior approval request.
Tecartus (brexucabtagene autoleucel)
One treatment course (one dose) per lifetime of Tecartus (brexucabtagene autoleucel) is considered medically necessary for individuals meeting the following criteria:
Meet the basic criteria above, AND
Criteria for one of the following indications is met:
Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND
Are 22 years or older at the time of infusion, AND
Relapsed after a transplant, or relapsed for a second or later time, or refractory.
Histologically confirmed diagnosis of mantle cell lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.
The prescriber will submit documentation to Blue Cross & Blue Shield of Mississippi Case Management of response to Tecartus (brexucabtagene autoleucel) within 3 months following therapy as a follow-up to the prior approval request.
Yescarta (axicabtagene ciloleucel)
One treatment course (one dose) per lifetime of Yescarta (axicabtagene ciloleucel) is considered medically necessary for individuals meeting the following criteria:
Meet the basic criteria above, AND
Criteria for one of the following indications is met:
Histologically confirmed diagnosis of large B-cell lymphoma which is refractory to first-line chemoimmunotherapy or relapsed within 12 months of first-line chemoimmunotherapy; AND
Are 22 years or older at the time of infusion, AND
Do not have primary central nervous system lymphoma.
Histologically confirmed diagnosis of large B-cell lymphoma including diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, or diffuse B-cell lymphoma arising from follicular lymphoma which is relapsed or refractory after two or more lines of systemic therapy; AND
Are 22 years or older at the time of infusion, AND
Do not have primary central nervous system lymphoma.
Histologically confirmed diagnosis of follicular lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.
The prescriber will submit documentation to Blue Cross & Blue Shield of Mississippi Case Management of response to Yescarta (axicabtagene ciloleucel) within 3 months following therapy as a follow-up to the prior approval request.
Breyanzi (lisocabtagene maraleucel)
One treatment course (one dose) per lifetime of Breyanzi (lisocabtagene maraleucel) is considered medically necessary for individuals meeting the following criteria:
Meet the basic criteria above, AND
Criteria for one of the following indications is met:
Histologically confirmed diagnosis of large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified (including diffuse large B-cell lymphoma arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B; AND
Are 22 years or older at the time of infusion, AND
Refractory to first-line chemoimmunotherapy or relapsed within 12 months of first-line chemoimmunotherapy, OR Refractory to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age, OR Relapsed or refractory after 2 or more lines of systemic therapy, AND
Do not have primary central nervous system lymphoma.
Histologically confirmed diagnosis of follicular lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.
Histologically confirmed diagnosis of mantle cell lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including a Bruton tyrosine kinase inhibitor.
Histologically confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma; AND
Are 22 years or older at the time of infusion, AND
Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including a Bruton tyrosine kinase inhibitor and a B-cell lymphoma 2 inhibitor.
The prescriber will submit documentation to Blue Cross & Blue Shield of Mississippi Case Management of response to Breyanzi (lisocabtagene maraleucel) within 3 months following therapy as a follow-up to the prior approval request.
All above-mentioned therapies are considered investigational when the above criteria are not met.
Aucatzyl (obecabtagene autoleucel) is considered not medically necessary as there are other formulary alternatives available for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Self-Insured Groups
State Health Plan (State and School Employees) Participants
Federal Employee Program (FEP): Prior approval is required for gene therapy and cellular immunotherapy.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
The NCCN Clinical Practice Guidelines on Acute Lymphoblastic Leukemia Version 2.2024 published July 19, 2024 define
Refractory ALL as complete remission not achieved at the end of induction.
Relapsed disease as reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a complete remission.
Complete remission as
No circulating lymphoblasts or extramedullary disease
No lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, CNS involvement, or other extramedullary involvement
Trilineage hematopoiesis (TLH) and <5% leukemic blasts
ANC ≥1000/microL
Platelets≥100,000/microL
No consensus was identified for defining relapsed or refractory disease for the other hematological conditions.
FDA Recommended Dose of Kymriah (tisagenlecleucel) for B-cell Acute Lymphoblastic Leukemia
Patients who are 50 kg or less: 0.2 to 5.0×106 chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously.
Patients above 50 kg: 0.1 to 2.5×108 chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.
FDA Recommended Dose of Kymriah (tisagenlecleucel) for Non-Hodgkin Lymphoma and Follicular Lymphoma
0.6 to 6.0 × 108 chimeric antigen receptor-positive viable T cells intravenously.
FDA Recommended Dose of Yescarta (axicabtagene ciloleucel) for Non-Hodgkin Lymphoma and Follicular Lymphoma
2×106 chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 2×108 chimeric antigen receptor-positive viable T cells intravenously.
FDA Recommended Dose of Tecartus (brexucabtagene autoleucel) for Mantle Cell Lymphoma
2×106 chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 2×108 chimeric antigen receptor-positive viable T cells intravenously.
FDA Recommended Dose of Tecartus (brexucabtagene autoleucel) for B-cell Acute Lymphoblastic Leukemia
1×106 chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 1×108 chimeric antigen receptor-positive viable T cells intravenously.
FDA Recommended Dose of Breyanzi (lisocabtagene maraleucel) for Non-Hodgkin Lymphoma
90 to 110 ×106 chimeric antigen receptor-positive viable T cells as a single intravenous infusion for relapsed or refractory large B-cell lymphoma after 1 line of therapy.
50 to 110 ×106 chimeric antigen receptor-positive viable T cells as a single intravenous infusion for relapsed or refractory large B-cell lymphoma after ≥2 lines of therapy.
Central Nervous System (CNS) Disease for B-cell Acute Lymphoblastic Leukemia
Disease is defined by the following groups:
CNS 1: Absence of blasts on cerebrospinal fluid cytospin preparation, regardless of the white blood cell (WBC) count
CNS 2: WBC count of less than 5/mL and blasts on cytospin findings
CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic syndrome)
Boxed Warning and Associated Restricted Program under a Risk Evaluation and Mitigation Strategy (REMS)
Kymriah® (tisagenlecleucel), Yescarta® (axicabtagene ciloleucel), Tecartus® (brexucabtagene autoleucel), and Breyanzi® (lisocabtagene maraleucel) have boxed warnings regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities (NT) that include fatal or life-threatening reactions. These agents should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening CRS be treated with tocilizumab. Individuals should be monitored for neurologic toxicities after treatment.
Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (brexucabtagene autoleucel), and Breyanzi (lisocabtagene maraleucel) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS, Yescarta REMS, Tecartus REMS, and Breyanzi REMS, respectively. The requirement for the REMS components are as follows:
Health care facilities that dispense and administer these chimeric antigen receptor (CAR) T therapies must be enrolled and comply with the REMS requirements.
Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses are available for each patient for administration within 2 hours after infusion of these CAR T-cell therapies, if needed for treatment of CRS.
Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer these CAR T-cell therapies are trained to manage CRS and NT.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary. BCBSMS may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
07/13/2021: New separate policy for Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma added. Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), and Tecartus (brexucabtagene autoleucel) moved from medical policy A.8.01.01 to this policy. Coverage and medical necessity guidelines added for Breyanzi (lisocabtagene maraleucel). Reviewed and approved by Pharmacy & Therapeutics (P&T) Committee.
08/12/2021: Code Reference section updated to add HCPCS code C9076.
10/01/2021: Code Reference section updated to add new HCPCS code Q2054 and new ICD-10 procedure codes XW033C7, XW033H7, XW033J7, XW033M7, XW033N7, XW043C7, XW043H7, XW043J7, XW043M7, XW043N7. Effective 10/01/2021.
12/27/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.
09/15/2022: Policy description updated regarding FDA approval for Tecartus. Policy statement criteria regarding Kymriah for B-cell acute lymphoblastic leukemia revised to state "Concomitant genetic syndrome associated with bone marrow failure with the exception of Down syndrome." It previously stated: Concomitant genetic syndrome with the exception of Down syndrome. Added policy statement that Tecartus is considered medically necessary for relapsed or refractory patients with B-cell acute lymphoblastic leukemia meeting the specified criteria. Policy Guidelines updated regarding FDA recommended dose of Tecartus for B-cell acute lymphoblastic leukemia.
11/14/2022: Code Reference section updated to remove deleted HCPCS code C9076 and deleted ICD-10 procedure codes 30230C0 and 30240C0.
12/29/2022: Policy reviewed; no changes.
02/20/2023: Policy description updated regarding commercial chimeric antigen receptor T-cell therapies available in the U.S. Policy section updated to add dosing limits and medically necessary criteria for the following: 1) Kymriah (tisagenlecleucel) for follicular lymphoma; and 2) Yescarta (axicabtagene ciloleucel) for non-Hodgkin lymphoma. Updated medically necessary criteria for Breyanzi (lisocabtagene maraleucel) for non-Hodgkin lymphoma. Policy Guidelines updated to include the FDA recommended dose of Kymriah for follicular lymphoma. Code Reference section updated to add ICD-10 procedure codes XW033G7 and XW043G7.
07/01/2023: Policy Exceptions updated regarding State Health Plan (State and School Employees) Participants.
12/04/2023: Policy reviewed; no changes.
03/15/2024: Policy description updated regarding mantle cell lymphoma, treatment for follicular lymphoma, and CAR T-cell therapies available in the U.S. Policy statements revised to define relapsed and refractory within the policy criteria. Policy statements regarding Kymriah (tisagenlecleucel) and Tecartus (brexucabtagene autoleucel) for B-cell Acute Lymphoblastic Leukemia revised to address Philadelphia chromosome-positive individuals. Policy statements regarding Kymriah (tisagenlecleucel) and Breyanzi (lisocabtagene maraleucel) for Non-Hodgkin Lymphoma revised to change "aggressive types of non-Hodgkin lymphoma" to "large B-cell lymphoma." Policy statement regarding Yescarta (axicabtagene ciloleucel) for Non-Hodgkin Lymphoma revised to move "histologically confirmed diagnosis" from the policy statement to the policy criteria. Removed policy statement regarding Yescarta (axicabtagene ciloleucel) for individuals with aggressive types of non-Hodgkin lymphoma. Policy Guidelines updated regarding the FDA recommended dose of Breyanzi (lisocabtagene maraleucel) for Non-Hodgkin Lymphoma.
12/06/2024: Policy reviewed; no changes.
12/31/2024: Code Reference section updated to add new CPT codes 38225, 38226, 38227, and 38228 effective 01/01/2025.
02/20/2025: Policy description updated regarding Non-Hodgkin Lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, and CAR-T cell therapies available in the United States. Policy statements extensively revised for simplification and clarity. Policy statement for Breyanzi (lisocabtagene maraleucel) revised to include medically necessary criteria for follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia or small lymphocytic leukemia. Policy Guidelines updated regarding the NCCN clinical practice guidelines on acute lymphoblastic leukemia.
08/01/2025: Policy updated to add Aucatzyl (obecabtagene autoleucel). Policy section updated to state that Aucatzyl (obecabtagene autoleucel) is considered not medically necessary as there are other formulary alternatives available for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Sources updated. Code Reference section updated to add HCPCS code Q2058 to the Not Medically Necessary Codes table.
Aucatzyl prescribing information. Autolus Inc. March 2025. Last accessed June 2025.
Blue Cross Blue Shield Association policy # 8.01.63
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
Medically Necessary Codes
Code Number | Description |
CPT-4 | |
0537T | Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day (Deleted 12/31/2024) |
0538T | Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage) (Deleted 12/31/2024) |
0539T | Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration (Deleted 12/31/2024) |
0540T | Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous (Deleted 12/31/2024) |
36511 | Therapeutic apheresis; for white blood cells |
38225 | Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day (New 01/01/2025) |
38226 | Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage) (New 01/01/2025) |
38227 | Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration (New 01/01/2025) |
38228 | Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous (New 01/01/2025) |
96411 - 96417 | Chemotherapy administration code range |
HCPCS | |
Q2041 | Axicabtagene ciloleucel, up to 200 million autologous anti-CD19 CAR positive T cells, including leukapheresis and dose preparation procedures, per therapeutic dose |
Q2042 | Tisagenlecleucel, up to 600 million CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose |
Q2053 | Brexucabtagene autoleucel, up to 200 million autologous anti-CD19 CAR positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose |
Q2054 | Lisocabtagene maraleucel, up to 110 million autologous anti-cd19 car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose |
ICD-10 Procedure | |
30233C0 | Transfusion of autologous hematopoietic stem/progenitor cells, genetically modified into peripheral vein, percutaneous approach |
30243C0 | Transfusion of autologous hematopoietic stem/progenitor cells, genetically modified into central vein, percutaneous approach |
XW033C7 | Introduction of autologous engineered chimeric antigen receptor T-cell immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW033G7 | Introduction of allogeneic engineered chimeric antigen receptor T-cell immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW033H7 | Introduction of axicabtagene ciloleucel immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW033J7 | Introduction of tisagenlecleucel immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW033M7 | Introduction of brexucabtagene autoleucel immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW033N7 | Introduction of lisocabtagene maraleucel immunotherapy into peripheral vein, percutaneous approach, new technology group 7 |
XW043C7 | Introduction of autologous engineered chimeric antigen receptor T-cell immunotherapy into central vein, percutaneous approach, new technology group 7 |
XW043G7 | Introduction of allogeneic engineered chimeric antigen receptor T-cell immunotherapy into central vein, percutaneous approach, new technology group 7 |
XW043H7 | Introduction of axicabtagene ciloleucel immunotherapy into central vein, percutaneous approach, new technology group 7 |
XW043J7 | Introduction of tisagenlecleucel immunotherapy into central vein, percutaneous approach, new technology group 7 |
XW043M7 | Introduction of brexucabtagene autoleucel immunotherapy into central vein, percutaneous approach, new technology group 7 |
XW043N7 | Introduction of lisocabtagene maraleucel immunotherapy into central vein, percutaneous approach, new technology group 7 |
ICD-10 Diagnosis |
Not Medically Necessary Codes
Code Number | Description |
CPT-4 | |
HCPCS | |
Q2058 | Obecabtagene autoleucel, 10 up to 400 million CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per infusion |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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