| Coverage Policy Manual | |
| Policy #: | 1998109 |
| Category: | Pharmacy |
| Initiated: | February 1998 |
| Last Review: | August 2023 |
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| Chimeric Antigen Receptor Therapy for Hematologic Malignancies (CAR-T) (e.g., Kymriah™, Yescarta™, Tecartus™, Breyanzi®, Abecma®, Carvykti™) | |
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| Description: |
The spontaneous regression of certain cancers e.g., renal cell carcinoma, melanoma) supports the idea that an individual’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunotherapies designed to stimulate an individual’s own immune system. Chimeric antigen receptor T-cell therapy is a specific form of adoptive immunotherapy that involves harvesting cells from a individual or donor, a manufacturing process during which cells are genetically modified with engineered CAR protein to permit targeted activation and therapy, and infusion of cells into the individual.
ACUTE LYMPHOBLASTIC LEUKEMIA
Acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those individuals who fail to obtain complete response with induction therapy, e.g., failure to eradicate all detectable leukemia cells (<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 a complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a 2017 meta-analysis of 20 studies of 11,249 pediatric ALL, the hazard ratio for event-free survival in MRD-negative individuals compared with MRD-positive individuals was 0.23 (95% confidence interval, 0.18 to 0.28) (Berry, 2017).
Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,4 and approximately 620 pediatric and young adult individuals with B-cell ALL will relapse each year in the United States (Maude, 2015). It is largely a disease of the young with approximately 60% of cases occurring in individuals younger than 20 years old with a median age at diagnosis of 15 years.4 While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL individuals are primary refractory (Pui, 2011). Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.7 The 2-year survival rate among individuals with ALL who relapse after hematopoietic cell transplantation is 15% (Bajwa, 2013). The Food and Drug Administration approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response were 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively (Jeha, 2006; von Stackelberg, 2016). Note that the percentages of individuals treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for individuals with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases (Swerdlow, 2016). DLBCL exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories.
It has been estimated that 27,650 new cases of DLBCL were diagnosed in the United States in 2016 (Teras, 2016). Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) is associated with a 5-year survival rate ranging from 60% to 70%.14 However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy (International Non-Hodgkin's Lymphoma Prognostic Factors P., 1993; Sehn, 2007). The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A 2017 retrospective analysis of the SCHOLAR-1 study, which pooled data from 2 phase 3 clinical trials and 2 observational cohorts, included 636 individuals with refractory DLBCL (Crump, 2017). The objective response rate to the next line of therapy was 26%, with 7% achieving a complete response. Median overall survival was 6.3 months and 2-year survival was 20%. Refractory DLBCL was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or as relapse 12 or fewer months after autologous cell transplantation.
ADOPTIVE CELL TRANSFER
The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing individuals. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.
Adoptive cellular therapy is “the administration of an individual’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lympho-depleting preparative regimen” (Rosenberg, 2008). Protocols vary, but include these common steps:
CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY
Due to difficulties in expanding innate TILs, genetic modification techniques have been harnessed to decorate propagated T cells with engineered chimeric antigen receptors (CARs) that are composed of several functional components: a tumor antigen-targeting single chain variable fragment (scVF) (e.g., anti-CD19), a hinge region, a T-cell activation domain (e.g., CD3), and one or more costimulatory domains (e.g., CD28, 4-1 BB). Viral vector genetic modification approaches (e.g., retroviral, lentiviral) have traditionally been used to transfect T cells with CAR genes.
TISAGENLECLEUCEL
Tisagenlecleucel is an adoptive immunotherapy in which the T cells of a individual are modified by genetic engineering using lentiviral vector. The resulting genetic modified cells express a CD-19 directed chimeric antigen receptor protein that consists of an extracellular portion that has a murine anti-CD19 single-chain antibody fragment as well as an intracellular portion that contains T-cell signaling and co-stimulatory domains. 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. Subsequently, the intracellular signaling domains play crucial roles in T-cell activation, persistence, and effector functions (Novartis Pharmaceuticals, 2017).
AXICABTAGENE CILOLEUCEL
Similar to tisagenlecleucel, axicabtagene ciloleucel is an adoptive immunotherapy in which the T cells of an individual are modified genetically using a retroviral vector. The resulting genetically modified cells express a CD-19 directed chimeric antigen receptor protein that has a murine single-chain variable fragment with specificity for CD19. Once injected, the genetically modified T cells selectively target and bind to CD19 antigen expressed on the surface of normal and malignant B cells (Kite Pharma Inc., 2017).
BREXUCABTAGENE AUTOLEUCEL
Brexucabtagene autoleucel is a CD19-directed genetically modified autologous T cell immunotherapy. It contains human blood cells that are genetically modified with replication-incompetent retroviral vector.Once injected, genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. (Kite Pharma Inc., 2020)
IDECABTAGENE VICLEUCEL
Idecabtagene vicleucel is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen(BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. This product is prepared from the individual's peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, which are then transduced with the replication incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved.
CILTACABTAGENE AUTOLEUCEL
Ciltacabtagene autoleucel is a BCMA (B cell maturation antigen)-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a individual’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. The CARVYKTI CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.
REGULATORY STATUS
On August 30, 2017, tisagenlecleucel (e.g., Kymriah™; Novartis) was approved by the FDA for the treatment of individuals 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 (e.g., Kymriah™; Novartis) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
On October 18, 2017, axicabtagene ciloleucel (e.g., Yescarta™; Kite Pharma) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel have a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Individuals should be monitored for neurologic events after treatment.
Tisagenlecleucel (e.g., Kymriah), axicabtagene ciloleucel (e.g., Yescarta), and brexucabtagene autoleucel (e.g., Tecartus) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS, Yescarta REMS, and Tecartus REMS, respectively. The requirements for the REMS components are as follows:
On July 24, 2020, the Food and Drug Administration approved brexucabtagene autoleucel (e.g., Tecartus) for the treatment of adult individuals with relapsed or refractory mantle cell lymphoma.
On April 1, 2022, the Food and Drug Administration approved axicabtagene ciloleucel (e.g., YESCARTA, Kite Pharma, Inc.) for adult individuals with large B-cell lymphoma (LBCL) that is refractory to first line chemoimmunotherapy or relapses within 12 months of first line chemoimmunotherapy. It is not indicated for the treatment of individuals with primary central nervous system lymphoma.
On February 28, 2022, the Food and Drug Administration approved ciltacabtagene autoleucel (e.g., Carvykti) for the treatment of adult individuals with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
On May 27, 2022, the Food and Drug Administration approved tisagenlecleucel (e.g., Kymriah) for the treatment of adult individuals with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy, and to include a major modification to the approved Risk Evaluation and Mitigation Strategy (REMS). 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 conformity trial(s).
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.
Prior Approval is required for tisagenlecleucel (e.g., Kymriah), axicabtagene ciloleucel (e.g., Yescarta), brexucabtagene autoleucel (e.g., Tecartus), lisocabtagene maraleucel (e.g., Breyanzi®), Idecabtagene Vicleucel (e.g., Abecma), ciltacabtagene autoleucel (e.g., Carvykti).
The initial use of this drug requires documentation of direct physician (MD/OD) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.
Effective October 2023
TISAGENLECLEUCEL (e.g., KYMRIAH) FOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of Tisagenlecleucel intravenous infusion as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for relapsed (*see definition below) or refractory (**see definition below) individuals with B-cell acute lymphoblastic leukemia when ALL the following criteria are met:
* Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.
** Refractory (resistant) disease is defined as those individuals who fail to obtain complete response with induction therapy, i.e., 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).
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended dosage of tisagenlecleucel for individuals 50 kg or less is 0.2 to 5.0×1 million chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously.
For individuals above 50 kg, dose is 0.1 to 2.5×100 million total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
TISAGENLECLEUCEL (e.g., KYMRIAH) FOR NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of Tisagenlecleucel infusion as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for relapsed or refractory* (see definition below) individuals with aggressive types of non-Hodgkin lymphoma when ALL the following criteria met:
* Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
** Central nervous system (CNS) disease for B-cell acute lymphoblastic leukemia is defined by the following groups:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended target dose of tisagenlecleucel for individuals with large B-cell lymphoma is 0.6 to 6.0 × 100 million chimeric antigen receptor−positive viable T cells intravenously.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
TISAGENLECLEUCEL (e.g., KYMRIAH) FOR FOLLICULAR LYMPHOMA (FL)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of Tisagenlecleucel intravenous infusion as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for relapsed (*see definition below) or refractory (**see definition below) individuals with follicular lymphoma when ALL the following criteria are met:
* Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
** Central nervous system (CNS) disease for B-cell acute lymphoblastic leukemia is defined by the following groups:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended target dose of tisagenlecleucel for individuals with follicular lymphoma is 0.6 to 6.0 x 100 million CAR-positive viable T cells intravenously.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of tisagenlecleucel does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of any indication or circumstance other than those described above.
For individuals with contracts without primary coverage criteria, the use of tisagenlecleucel for any indication or circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of tisagenlecleucel for the treatment of B-cell acute lymphoblastic leukemia or of non-Hodgkin lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of tisagenlecleucel for treatment of B-cell acute lymphoblastic leukemia or of non-Hodgkin lymphoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of tisagenlecleucel after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of tisagenlecleucel after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
AXICABTAGENE CILOLEUCEL (e.g., YESCARTA) FOR NON-HODGKIN LYMPHOMA (non-follicular lymphoma)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of Axicabtagene ciloleucel infusion as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for relapsed or refractory* individuals with aggressive types of non-Hodgkin lymphoma when ALL the following criteria are met:
*Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
AXICABTAGENE CILOLEUCEL (e.g., YESCARTA) FOR FOLLICULAR LYMPHOMA
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of Axicabtagene ciloleucel infusion as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals for relapsed or refractory follicular lymphoma when ALL the following criteria are met:
*Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended target dose of axicabtagene ciloleucel is 2×1 million CAR-positive viable T cells per kg body weight, with a maximum of 2×100 million chimeric antigen receptor− positive viable T cells intravenously.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of axicabtagene ciloleucel for the treatment of any indication or circumstance not described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals with contracts without primary coverage criteria, the use of axicabtagene ciloleucel for any indication or circumstance other than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of axicabtagene ciloleucel for the treatment of non-Hodgkin lymphoma or follicular lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of axicabtagene ciloleucel for the treatment of non-Hodgkin lymphoma or follicular lymphoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of axicabtagene ciloleucel after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance not described above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of axicabtagene ciloleucel after administration of tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
BREXUCABTAGENE AUTOLEUCEL (e.g., TECARTUS) FOR RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of brexucabtagene autoleucel as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of relapsed or refractory* Mantle Cell Lymphoma when ALL the following criteria are met:
*Relapsed or refractory disease is defined as disease progression after last regimen or failure to achieve a partial remission or complete remission to the last regimen
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended target dose of brexucabtagene autoleucel for individuals with relapsed and refractory mantle cell lymphoma is 2 × 1 million CAR-positive viable T cells per kg body weight, with a maximum of 2 × 100 million CAR-positive viable T cells.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of brexucabtagene autoleucel does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of any indication or circumstance other than those described above.
For individuals with contracts without primary coverage criteria, the use of brexucabtagene autoleucel for any indication or any circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of brexucabtagene autoleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication does not meet primary coverage criteria that there scientific be evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of brexucabtagene autoleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
BREXUCABTAGENE AUTOLEUCEL (e.g., TECARTUS) FOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use brexucabtagene autoleucel meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for relapsed* or refractory** individuals with B-cell acute lymphoblastic leukemia when ALL the following criteria are met:
* Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.
**Refractory (resistant) disease is defined as those individuals who fail to obtain complete response with induction therapy, i.e., 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).
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended of brexucabtagene autoleucel for mantle cell lymphoma is 1 X 1 million chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 1 X 100 million chimeric antigen receptor-positive viable T cells intravenously.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of brexucabtagene autoleucel for the treatment of any indication or circumstance other than those described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes
For individuals with contracts without primary coverage criteria, the use of brexucabtagene autoleucel for any indication or any circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
LISOCABTAGENE MARALEUCEL (e.g., BREYANZI®) for Non-Hodgkin Lymphoma
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of lisocabtagene maraleucel as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of relapsed or refractory* individuals with aggressive types of non-Hodgkin lymphoma when ALL the following criteria are met:
*Relapsed or refractory disease is defined as disease progression after last regimen or failure to achieve a partial remission or complete remission to the last regimen.
*Relapsed or refractory disease is defined as disease progression after last regimen or failure to achieve a partial remission or complete remission to the last regimen.
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended target dose for lisocabtagene maraleucel for individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma is 50 to 100 ×1 million CAR-positive viable T cells as single intravenous infusion.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of lisocabtagene maraleucel for the treatment of any indication or circumstance other than those described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals with contracts without primary coverage criteria, the use of lisocabtagene maraleucel for any indication or circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The repeat treatment of lisocabtagene maraleucel for the treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the repeat treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of lisocabtagene maraleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For individuals without primary coverage criteria, the use of lisocabtagene maraleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
IDECABTAGENE VICLEUCEL (e.g., ABECMA®) and CILTACABTAGENE AUTOLEUCEL (E.G., CARVYKTI) FOR MULTIPLE MYELOMA
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of idecabtagene vicleucel or ciltacabtagene autoleucel meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adults (age > 18 years old) with relapsed or refractory multiple myeloma after four or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [FDA, 2021, NCCN 2A] when ALL the following criteria are met:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Idecabtagene vicleucel
The recommended dose range for adult individuals with relapsed or refractory multiple myeloma is 300-400 x 1 million CAR-positive T cells as a single dose infusion.
Ciltacabtagene autoleucel
The recommended dose range is 0.5-1.0X1 million CAR-positive viable T cells per kg of body weight, with a maximum dose of 1X100 million Car-positive viable T cells per single infusion.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of idecabtagene vicleucel or ciltacabtagene autoleucel for any indication or circumstance other than those described above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to the following criteria:
For individuals without primary coverage criteria, the use of idecabtagene vicleucel or ciltacabtagene autoleucel for any indication or circumstance other than those described above is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to October 2023 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.
Tisagenlecleucel
B-Cell Acute Lymphoblastic Leukemia (ALL)
In the pivotal trial phase 2 single-arm, international, multicenter trial (ELIANA), 92 patients ages 3 to 21 years of screening with CD19-positive relapsed or refractory B-cell ALL were treated with tisagenlecleucel and followed for a median duration of 13.1 months. Trial results were published by Maude et al (2018).
The prespecified primary efficacy endpoint was the proportion of patients who achieved objective remission rate (CR or CR with incomplete blood count recovery [CRi]) as assessed by an independent review committee within three months after tisagenlecleucel infusion. The trial would meet its primary objective if the lower bound of the 2-sided 95% CIs for objective remission rate was greater than 20%. The key secondary outcome was the proportion of patients who achieve the best objective remission rate (CR or CRi with MRD-negative bone marrow) within three months of receiving tisagenlecleucel. Key secondary endpoints were tested sequentially (after primary endpoint was significant) to control for overall type I error.
Of the 107 patients who were screened, 92 met the trial inclusion criteria and of these 75 (81.5%) were infused with tisagenlecleucel. Patients received investigator choice bridging chemotherapy as needed to control their leukemia while waiting for tisagenlecleucel infusion. Patients also received protocol mandated lymphocyte-depleting chemotherapy 2 to 14 days prior to tisagenlecleucel infusion. An overall response rate of 81% was reached for patients who had at least three months of follow-up data available at data cutoff. Median overall survival (OS) was not reached but OS at 6 months post-infusion was 90% and 76% (95% CI: 63 to 86) at 12 months after infusion. Any grade CRS was observed in 77% of patients.
Observed outcomes in single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the 81% response rate (measured by CR or CRi) seen in the pivotal single-arm trial of tisagenlecleucel in patients with relapsed or refractory ALL could be the result of noninterventional effect. An unbiased estimate of the safety of tisagenlecleucel cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, tisagenlecleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug mediated. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half (77%) of the patients and approximately 88% had an adverse event at grade 3 or higher. Long-term follow-up, real-world evidence, and post-marketing studies are required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting.
Diffuse Large B-Cell Lymphoma (DLBCL)
The pivotal trial phase 2 single-arm, multicenter trial (JULIET; NCT02445248) enrolled 165 patients with relapsed or refractory DLBCL. Data were obtained from Schuster et al (2019) containing published outcomes at a median data cutoff of 14 months.
Of the 165 patients enrolled in the study, 95 patients were retrospectively identified and analyzed for the major efficacy outcome. The prespecified primary efficacy endpoint was ORR based on Lugano criteria (NCCN 2019), as assessed by an independent review committee and duration of response. Patients were heavily pretreated with a median of 3 prior therapies (range, 1-6), 56% had refractory disease and 44% relapsed after their last therapy. Response durations were longer in patients who achieved CR, as compared with patients with the best response of partial response. The response was consistent across subgroups (2 antineoplastic therapies, nongerminal or germinal cancer, rearranged MYC/BCL2/BCL6 or not)
Supportive Studies
Two single-arm studies that included a total of 84 patients were conducted using product manufactured at a university cell and vaccine production facility (Novartis Briefing Document, 2017; Novartis Presentations for the July 12, 2017 Meeting of the Oncologic Drugs Advisory Committee, 2017). The first study was a phase 1/2a single-center study in 55 patients enrolled between March 2012 and November 2015. The ORR rate (CR or CRi) was 95% (52/55), and best ORR (CR or CRi with MRD-negative bone marrow) was 89% (49/55). Median OS was 32.7 months (95% CI, 21.0 to inestimable). First pediatric patient treated in the study has been in remission for 5 years. The second study was a phase 2 multicentric study that enrolled 29 patients between August 2014 and February 2016. The ORR rate (CR or CRi) was 69% (20/29).
Safety
Safety data included 68 patients (63 patients received who U.S.-manufactured product plus 5 patients who received EU-manufactured product) (FDA, 2017). Cytokine release syndrome (CRS) was the most common serious life-threatening adverse event in the pivotal study and required aggressive supportive measures. One fatality due to CRS-related coagulopathy was observed in the pivotal study. Any grade CRS occurred in 78% (53/68) patients while 47% (32/68) experienced a grade 3 or 4 CRS. The severity of CRS was associated with high tumor burden of greater than 50% blasts in the bone marrow at screening. CRS occurred after a median of 3 days (range, 1-22 days) after tisagenlecleucel infusion and lasted for a median duration of 8 days. CRS resulted in significant morbidity burden as indicated by intensive care unit admission (31 [46%]), ventilatory support (10 [15%]), dialysis (7 [10%]), hypotension (35 [51%]), and hypotension requiring high-dose vasopressor support (17 [25%]).
The next most important adverse event of tisagenlecleucel was neurotoxicity such as encephalopathy and seizures. Any grade neurotoxicity was reported in 44% (30/68) patients, and grade 3 neurotoxicity was reported in 15% (10/68) patients. No cases of grade 4 neurotoxicity were reported. Although neurotoxicity was reversible with the use of optimal and best supportive care, the severity of these toxicities requires monitoring for airway protection.
The FDA also noted infection as a special adverse event of interest. In the first 8 weeks after infusion, 43% (29/68) of patients developed infection of which 24% (16/68) were grade 3 and 3% (2/68) were grade 4. Infection included gram-positive, gram-negative systemic infections, Clostridium difficile, candida, herpes simplex, and encephalitis due to herpesvirus 6. Three deaths occurring within 60 days and related to infection with herpesvirus 6, bacterial infection, and fungal sepsis was reported. Other adverse events of special interest included prolonged cytopenia, cardiac disorders, and B-cell aplasia. Three patients experienced congestive heart failure that required treatment. Most patients in the pivotal trial had previously been treated with chemotherapy and radiotherapy that predisposed them to cardiotoxicity; it is an anticipated risk in the intended population that would receive treatment with tisagenlecleucel. Acquired hypogammaglobulinemia is an expected side effect of tisagenlecleucel because it not only kills pre-B acute lymphoblastic leukemia cells but also normal B cells because they are CD19-positive. Patients in the trial were maintained on supplemental treatment with intravenous gamma globulin after tisagenlecleucel. It is unclear as to how long intravenous gamma globulin would be required.
Multiple design features of the tisagenlecleucel retroviral vector such as minimal homology between packaging plasmids and vector sequences, segregation on 4 different DNA plasmids, deletion of HIV accessory genes, and use of “self-inactivating” vector design aim to reduce the risk the potential of replication competent virus generation and insertional mutagenesis. However, the theoretical risk of formation of replication competent virus, their clonal growth or neoplastic transformation of transduced cells cannot be ruled out. If approved each vector batch and production cells will be tested for the presence of replication competent retrovirus. However, Novartis does not plan to collect patient samples for replication competent retrovirus testing. It is expected that over next 5 years, approximately 5000 patients may be enrolled in the first 5 years in a postmarketing registry that will follow-up patients up to 15 years after tisagenlecleucel infusion.
Axicabtagene Ciloleucel
The approval of axicabtagene ciloleucel was based on the results of an open-label, multicenter phase 1/2 study called ZUMA-1, which reported response rates and duration of response demonstrated in the phase 2 portion of the study. Data were obtained from the FDA documents and the approved label and a recent publication by Locke and coworkers with 2-year follow-up results (Kite Pharma Inc., 2017; Locke et al, 2019; FDA, 2017; Center for Biologics Evaluation and Research, Food and Drug Administration, 2017). Adults with aggressive B-cell non-Hodgkin lymphoma that was primary refractory, refractory to a second or greater line of therapy, or relapsed within 1 year after autologous hematopoietic cell transplantation were enrolled in the study. Patients with prior allogeneic hematopoietic cell transplantation, any history of central nervous system lymphoma, Eastern Cooperative Oncology Group Performance Status score of 2 or greater, absolute lymphocyte count less than 100/μL, creatinine clearance less than 60 mL/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction less than 50%, or active serious infection were excluded. Most patients (74%) had de novo diffuse large B-cell lymphoma and 32% had double- or triple-hit lymphoma. The median age was 58, with 24% being aged 65 years or older; the median number of prior therapies was 3; 77% had refractory disease to a second or greater line of therapy; and 21% had relapsed within 1 year after autologous HCT.
All patients received a lymphodepleting regimen consisted of cyclophosphamide and fludarabine prior to infusion of axicabtagene ciloleucel. Of the 111 patients who underwent leukapheresis, 101 received the infusion (9 were not treated due to progressive disease or serious adverse reactions following leukapheresis and there was a manufacturing failure in 1 patient). Study protocol mandated hospitalization of patients for infusion and 7 days after infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. The median time from leukapheresis to product delivery was 17 days (range, 14-51 days). The primary end point was objective response rate based on a modified intention-to-treat population, which was defined as all patients treated with at least 1.0 × 106 chimeric antigen receptor (CAR)-positive T cells per kilogram.
Safety
Safety data assessed 108 patients treated with axicabtagene ciloleucel. All patients experienced at least 1 adverse event following infusion and 94% (n=102) experienced grade 3 or higher events. Serious adverse events were observed in 56 (52%) of patients, and serious adverse events that were grade 3 or higher occurred in 48 (44%) patients. Overall, 34 deaths were reported from the time of informed consent to the trial data cutoff (January 27, 2017). Thirty patients died of progressive disease and 4 deaths were attributed to axicabtagene ciloleucel as per FDA analysis, of which 3 occurred within 30 days of infusion.
The median time to onset for CRS was 2 days (range, 1-12 days), and the median time to resolution was 7 days (range for CRS duration, 2-58 days). Forty-five percent (49/108) of patients received tocilizumab for CRS management. The median time to onset of neurologic toxicity was 4 days (range, 1-43 days). The median duration was 17 days. Prolonged encephalopathy lasting up to 173 days was noted. Most common neurologic toxicities included encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety. Neurologic toxicities were managed with supportive care and/or corticosteroids. Almost all neurologic toxicities at grade 2 or higher occurred within 7 days following infusion.
Observed outcomes in a single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the high response rate (measured by CR/CRi or CR plus PR) seen in the pivotal trials of axicabtagene ciloleucel could be the result of noninterventional effect. An unbiased estimate of the safety of these CAR T cells cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, axicabtagene ciloleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug mediated. The observed benefits seen with axicabtagene ciloleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half of the patients in the pivotal trials and more than 40% patients had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of efficacy and safety of axicabtagene ciloleucel outside of a clinical trial setting.
Follicular Lymphoma
Approval for axicabtagene ciloleucel for follicular lymphoma was based on data from the ZUMA-5 clinical trial (NCT03105336). ZUMA-5 was a single-arm, open-label, multicenter trial that enrolled 146 patients with either relapsed or refractory follicular lymphoma and marginal zone lymphoma who had previously received 2 or more lines of systemic therapy, including treatment with an anti-CD20 monoclonal antibody and an alkylating agent. To be eligible for enrollment, patients had to have an ECOG performance status of 0 or 1. The primary endpoint of the trial was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T-cells.
Axicabtagene ciloleucel (Yescarta) showed a response in 91% of patients with relapsed/refractory follicular lymphoma (n = 81); this included 60% of patients who achieved a complete remission (CR). Seventy-four percent of patients had a continued remission at 18 months. Among all patients with follicular lymphoma, the median duration of response (DOR) was not yet reached at a median follow-up of 14.5 months.
Data regarding side effects in 146 patients showed that grade 3 or higher cytokine release syndrome (CRS) was reported in 8% of patients, while grade 3 or higher neurologic toxicities were reported in 21%. The median time to onset of these effects was 4 days (range, 1–20 days) and 6 days (range, 1–79 days), respectively. The most frequently reported toxicities that were grade 3 or higher in severity were febrile neutropenia, encephalopathy, and infections with unspecified pathogens.
Lisocabtagene Maraleucel
The approval of lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND) [Abramson, et al. 2020]. Trial participants were required to have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 lines of systemic therapy or auto-HSCT. Of 299 patients who received leukapheresis, 15% (n=44) did not receive CAR-positive T-cells either due to manufacturing failures (n=2), death (n=29), disease complications (n=6), or other reasons (n=7). Of the 255 patients who received treatment, 192 were evaluable for efficacy. Twelve were not evaluable due to absence of positron emission tomography (PET) positive disease at study baseline or after bridging therapy and 51 (17%) either received CAR T-cells outside of the intended dose range (n=26) or received CAR T-cells that did not meet product specifications (manufacturing failures; n=25). The primary end point was the percentage of patients with treatment–emergent adverse events and the ORR (complete or partial response).
The primary endpoint was the objective response, defined as the proportion of patients who achieved a best overall response of CR or PR, based on assessment by the independent review committee according to the Lugano classification. The median age was 63 (range, 18 to 86) years including older subpopulations (≥65 years, 42%; ≥75 years, 10%). Patients were heavily pretreated and had aggressive disease. Of these patients, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior HCT, and 2.6% had CNS involvement. The primary efficacy analysis demonstrated an ORR of 73% with a 55% rate of CR among 192 patients evaluable for efficacy. The median DOR was 16.7 months. Response durations were longer in patients who achieved a CR, as compared to patients with a best response of a PR (Table 17). Of the 104 patients who achieved a CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months.
Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% (122/268) of patients receiving lisocabtagene maraleucel, with ≥ Grade 3 CRS (Lee grading system, Lee et al 2014) in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. Cytokine release syndrome resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death. No major limitations in study relevance were noted
SUMMARY OF EVIDENCE
Tisagenlecleucel
For individuals who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia who receive tisagenlecleucel, the evidence includes multiple single-arm prospective trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trials reported an 81% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a complete remission or complete remission with incomplete blood count were also minimal residual disease negative, which is predictive of survival in acute lymphoblastic leukemia patients. After a median follow-up of 13.1 months, the median duration of response was not reached. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (77%) of the patients, and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who are adults with a histologically confirmed diagnosis of aggressive Non-Hodgkin’s Lymphoma (eg, DBLCL not otherwise specified, high-grade B-cell lymphoma, transformed follicular lymphoma) who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. The relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 52% overall response rate (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 14 months, the median duration of response was not reached. The observed benefits were offset by a high frequency and severity of adverse events. Any grade cytokine release syndrome was observed in 58% of the patients, and 63% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence are required to assess the generalizability of tisagenlecleucel efficacy and safety outside of the clinical trial setting. The manufacturer has agreed to a post marketing requirement observational registry study to collect safety information for patients treated with the marketed product. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Axicabtagene Ciloleucel
For individuals who are adults with histologically confirmed diagnosis of aggressive non-Hodgkin lymphoma (eg, diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, transformed follicular lymphoma) who receive axicabtagene ciloleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 83% overall response rate (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 27.1 months, the median duration of response was 11.1 months. The observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half of the patients, and 98% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of axicabtagene ciloleucel efficacy and safety outside of the clinical trial setting. The manufacturer has agreed to a postmarketing requirement observational registry study to collect safety information for patients treated with the marketed product. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Brexucabtagene Autoleucel
For individuals who are adults with relapsed or refractory MCL , the evidence includes 1 phase II single-arm study. Relevant outcomes are OS , DSS , QOL , and treatment-related mortality and morbidity. The ZUMA-2 study enrolled adult patients with relapsed refractory MCL who were heavily pre-treated. Of 74 patients enrolled, therapy was successfully manufactured for 71 (96%) and administered to 68 (92%). Results were reported for 60 pre-specified evaluable patients with a median follow-up (as of the July 24, 2019 data cutoff date) of 12.3 months (range, 7.0 to 32.3). The primary efficacy analysis demonstrated an ORR of 87% with a 62% rate of CR. The median DOR , PFS and median OS were not reached. Fifty-seven percent of patients remained in remission at data cutoff, and the estimated 12-month PFS and OS rates were 61% and 83%, respectively. Among patients who have disease progression after Bruton’s kinase inhibitor therapy, the reported ORR ranges from 25 to 42% with a median OS of 6 to 10 months with salvage therapies. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
Lisocabtagene Maraleucel
For individuals who are adults with relapsed or refractory DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma); high-grade B-cell lymphoma or primary mediastinal large B-cell lymphoma or follicular lymphoma grade 3B who receive lisocabtagene maraleucel, the evidence includes a single-arm prospective trial (TRANSCEND). Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. In 299 patients who underwent leukapheresis, therapy was successfully administered to 255 (85%). Of these, 192 were evaluable for efficacy. Twelve were not evaluable due to absence of PET positive disease at study baseline or after bridging therapy and 51 (17%) either received CAR T-cells outside of the intended dose range (n=26) or received CAR T-cells that did not meet product specifications (manufacturing failures; n=25). The primary efficacy analysis demonstrated an ORR of 73% with a 55% rate of CR. The median DOR was 16.7 months. Response durations were longer in patients who achieved a CR, as compared to patients with a best response of a PR. Of the 104 patients who achieved a CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months. Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% of patients including ≥ Grade 3 CRS in 4% of patients. The median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death. No notable study limitations were identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
PRACTICE GUIDELINES AND POSITION STATEMENTS
Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreatic, stomach, or thyroid, melanoma, Hodgkin lymphoma, or non-small-cell lung cancer (NCCN, 2017).
Current NCCN guidelines for acute lymphoblastic leukemia (v.2.2019) recommend (category 2A) tisagenlecleucel as a treatment option for:
Current Network guidelines for B-cell non-Hodgkin lymphoma (v.5.2019) recommend (category 2A) axicabtagene ciloleucel or tisagenlecleucel as a treatment option for:
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed as follows:
Tisagenlecleucel
NCT02445248- A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma. Planned enrollment of 116 subjects with an estimated completion date of Feb. 2023.
NCT0244522- Long Term Follow-Up of Patients Exposed to Lentiviral-Based CD19 Directed CAR T-Cell Therapy. Planned enrollment of 620 subjects with an estimated completion date of May 2035.
NCT03876769 - A Phase II Trial of Tisagenlecleucel in First-Line High-Risk (HR) Pediatric and Young Adult Patients with B-cell Acute Lymphoblastic Leukemia (B-ALL) Who Are Minimal Residual Disease Positive at the End of Consolidation Therapy. Planned enrollment of 140 subjects with an estimated completion date of Aug. 2027.
Unpublished
NCT02228096- A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia. Planned enrollment of 64 subjects with a completed date of May 2019.
Axicabtagen ciloleucel
NCT02614066- A Study Evaluating KTE-C19 in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3) (ZUMA-3). Planned enrollment of 100 subjects with an estimated completion date of Mar. 2034.
NCT02625480 - A Multi-Center Study Evaluating KTE-C19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ZUMA-4). Planned enrollment of 100 subjects with an estimated completion date of Jan. 2036.
NCT03105336 - A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5). Planned enrollment of 160 with an estimated completion date of Mar. 2035
Brexucabtagene autoleucel
NCT02625480 – (Zuma-4) Study evaluating brexucabtagene autoleucel in pediatric and adolescent participants with r/r ALL or r/r B-cell NHL. Planned enrollment of 116 with estimated completion date of August 2023.
NCT03624036 – (Zuma-8) Safety and Efficacy of brexucabtagene autoleucel in adults with r/r CLL . Planned enrollment of 108, with an estimated completion date of March 2021.
Lisocabtagene maraleucel
NCT03484702 – (Transcend World) Trial to determine the efficacy and safety of lisocabtagene maraleucel in aggressive B-Cell NHL. Planned enrollment of 116, with estimated completion date of August 2021.
NCT03575351 – (Transform) A study to compare the efficacy and safety of lisocabtagene maraleucel to standard of care in high-risk, transplant-eligible r/r aggressive B-cell NHL. Planned enrollment of 182, with estimated completion date of January 2024.
NCT04245839 - A study to evaluate the efficacy and safety of lisocabtagene maraleucel in r/r indolent B-cell NHL. Planned enrollment of 188, with estimated completion date of October 2022.
NCT03331198 - Study evaluating safety and efficacy of lisocabtagene maraleucel in subjects with r/r CLL or SLL. Planned enrollment of 200, with estimated completion date of October 2021.
NCT03743246 - A study to evaluate the safety and efficacy of lisocabtagene maraleucel r/r B-cell ALL and B-cell NHL. Planned enrollment of 121, with estimated completion date of October 2022.
NCT03310619 – (Platform) A safety and efficacy Trial of lisocabtagene maraleucel combinations in r/r B-cell malignancies. Planned enrollment of 75, with estimated completion date of August 2023.
NCT03483103 – (Pilot) A study to evaluate the efficacy and safety of lisocabtagene maraleucel in aggressive B-Cell NHL as second-line therapy. Planned enrollment of 56, with estimated completion date of April 2021.
NCT03744676 – (Outreach-007) A safety trial of lisocabtagene maraleucel for r/r) B-cell NHL in the outpatient setting. Planned enrollment of 80, with estimated completion date of April 2021.
December 2020 Update
In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.
A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.
KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (NCT02601313). (Wang M, Munoz J, Goy A, et. al., 2020)
August 2021 Update
From UpToDate: “Chimeric antigen receptor (CAR)-T cell therapy is an option for patients with MM relapsed after four or more lines of systemic therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The use of CAR-T therapy is individualized weighing disease tempo, availability of other treatments, and expected toxicity. While initial studies suggest that CAR-T therapy has activity against relapsed or refractory MM, the quality of the evidence is low, treatment is associated with substantial toxicity, and the manufacturing process is complex and expensive.”
In a phase 2 study of the anti-BCMA CAR-T cell product idecabtagene vicleucel (ide-cel) in 128 patients with RRMM, objective responses were seen in 73 percent with an estimated median progression-free survival of 8.8 months . All but one patient experienced at least one grade 3 or 4 toxicity, with hematologic toxicity being most common. Cytokine release syndrome occurred in 84 percent and was usually grade 1 or 2. Grade ≥ 3 CRS occurred in 5% (7/128) of patients (Munshi et al., 2021).
Neurologic toxicities, including severe or life-threatening. In clinical trial, neurological toxicities (NT) occurred in 18% (23/128) of patients. Grade 3 neurologic toxicities occurred in 3% (4/128) of patients and no NT greater than grade 3 occurred (Munshi et al. 2021). Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), including fatal and life-threatening reactions. In clinical trial, HLH/MAS occurred in 4% (5/127) of patients (Celgene, 2021a).
Persistent cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery. In clinical trial, neutropenia occurred in 91% (117/128) of patients, anemia occurred in 70% (89/128), and thrombocytopenia occurred in 63% (81/128) (Munshi et al., 2021).
Response durations were longer in patients who achieved a stringent complete response (CR) as compared to patients with a partial response (PR) or very good partial response (VGPR). Of the 28 patients who achieved a stringent CR, it is estimated that 65% (95% CI: 42%, 81%) had a remission lasting at least 12 months. The median duration of response for VGPR patients (n=25) was 11.1 months (95% CI: 8.7, 11.3) and the median duration of response for PR patients (n=19) was 4.0 months (95% CI: 2.7, 7.2). Results of the KarMMa study support Abecma (idecabtagene vicleucel) induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma.
The NCCN guideline for Multiple Myeloma version 6.2021 idecabtagene vicleucel was added to therapy for previously treated multiple myeloma other recommended regimens and is indicated for patients who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
November 2021 Update
Leahy et al , 2021 published a post hoc analysis of 195 patients (aged 1–29 years) with relapsed or refractory CD19-positive ALL from 5 clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022). All 5 trials were performed at the Children’s Hospital of Philadelphia in which participants received CD19-directed CAR T-cell therapy between April 17, 2012 and April 16, 2019. Of the 5 trials, only 2 trials (ENSIGN and ELIANA) used tisagenlecleucel as the interventional CAR-T cell therapy. Of the 195 patients included in the analysis, 34% (n=66) were categorized as having central nervous system (CNS)-positive disease while the remaining 66% (n=129) were classified as having CNS-negative disease with a median follow-up of 39 months and 36 months, respectively. The proportion of patients in the CNS-positive stratum with a CR at 28 days after infusion was 97% versus 94% in the CNS-negative stratum (p=.74) with no significant difference in relapse-free survival (60% vs 60%) or OS (83% vs 71%) at 2 years between the 2 groups. Authors concluded that the preliminary findings of their study support the use of CAR T-cell therapies for patients with CNS relapsed or refractory B-cell ALL. However, among the 66 patients with CNS-positive disease, only 1 patient was from the ENSIGN trial who received tisagenlecleucel. Therefore, data demonstrating clinical efficacy and safety of tisagenlecleucel among patients with CNS-positive disease are lacking.
Levine at al 2021 published a pooled analysis of 137 patients from the ELIANA (n=79) and ENSIGN (n=58) trials reporting comprehensive safety data for tisagenlecleucel. Grade 3 or 4 treatment-related adverse events were reported in 77% of patients. Specific adverse events of interest that occurred ≤8 weeks post-infusion included CRS (any grade: 79% and grade 4: 22%), infections (any grade: 42% and grade 3 or 4: 19%), prolonged (not resolved by day 28) cytopenias (any grade: 40%; grade 3 or 4: 34%), neurologic events (any grade: 36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). It is important to note that Levine et al 2021 used the University of Pennsylvania (Penn) CRS grading scale while other studies have used the CRS Revised Grading System developed by Lee et al 2014 or the ASTCT CRS Consensus Grading scale.
April 2022 Update
In an international, phase 3 trial, patients were randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.
A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.
Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Filosto S, Shah J, Schupp M, et.al., 2021)
May 2022 Update
CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.
This single-arm, open-label, phase 1b/2 study done at 16 centers in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.
Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Hematological adverse events were common; grade 3-4 hematological adverse events were neutropenia (92 [95%] of 97 patients), anemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and hemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study: six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.
A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. (Berdeja JG, Madduri D, Usmani SZ, et.al., 2021)
August 2022 Update
The efficacy of KYMRIAH was evaluated in a multicenter, single-arm, open-label trial (ELARA, Study 3; NCT03568461) that included patients who were refractory to or relapsed within 6 months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent), relapsed during or within six months after completion of an anti-CD20 antibody maintenance therapy following at least two lines of therapy, or relapsed after autologous hematopoietic stem cell transplant (HSCT). The trial excluded patients with active or serious infections, transformed lymphoma, or other aggressive lymphomas, prior allogeneic HSCT, or disease with active CNS involvement. Following lymphodepleting (LD) chemotherapy, KYMRIAH was administered as a single dose intravenous infusion with Duration of Response Results Overall DOR for responders (months) N = 34 Median DORa,b NE (95% CI) (5.1, NE) Rangec (0.03+ – 11.3+) Median Follow-up (95% CI)b 9.4 (7.9, 10.8) DOR if BOR is CR N = 22 Median DORa,b NE (95% CI) (10.0, NE) Rangec (1.5+ – 11.3+) DOR if BOR is PR N = 12 Median DORa,b 3.4 (95% CI) (1.0, NE) Rangec (0.03+ – 11.3+) a target dose of 0.6 to 6.0 × 108 CAR-positive viable T cells. The median dose administered was 2.06 × 108 CAR-positive viable T-cells (range: 0.1 to 6.0 × 108 CAR-positive viable T cells). The LD chemotherapy regimen consisted of either fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine) or bendamustine (90 mg/m2 IV daily for 2 days); bridging chemotherapy between leukapheresis and LD chemotherapy was permitted as needed. Of the 90 patients included in the primary efficacy analysis, 40 patients (45%) were treated with bridging therapies. The most commonly used agents (in ≥ 5% of patients) were rituximab (22%), dexamethasone (13%), gemcitabine (12%), prednisone (11%), oxaliplatin (8%), etoposide (8%), and vincristine (6%). Of 98 patients who were enrolled and underwent leukapheresis, 97 patients received infusion with KYMRIAH and one patient without measurable disease did not receive KYMRIAH. There were no manufacturing failures for the 98 enrolled patients. Of the 97 patients infused with KYMRIAH, the efficacy evaluable population, as specified in the protocol, included the first 90 patients with measurable disease who received KYMRIAH consecutively and had at least 9 months follow-up from first objective response or discontinued earlier. Among the 90 patients with FL included in the efficacy analysis, the median age was 58 years (range: 29 to 73 years), 31% were female, 78% were White, 10% were Asian, and 1% were Black or African American. The median number of prior therapies was 4 (range: 2 to 13), with 24% receiving 2 prior lines, 21% receiving 3 prior lines, and 54% receiving ≥4 prior lines. Eighty-seven percent had Stage III-IV disease at study entry, 64% had bulky disease, 36% had a prior autologous HSCT, 79% were refractory to the most recent regimen, and 66% had progression within 24 months of initiating their first anti-CD20 combination therapy (POD24). Efficacy was established on the basis of objective response rate and duration of response (DOR) as determined by an independent review committee. The first disease assessment was scheduled to be performed at Month 3 post-infusion; the median time to first response was 2.9 months (range: 0.6 to 6.0 months). All responders achieved their response (complete response [CR] or partial response [PR]) at the first performed post-infusion disease assessment. (FDA, 2022)
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
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