Description
The spontaneous regression of certain cancers (eg, renal cell carcinoma, melanoma) supports the idea that a patient’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 a patient’s own immune system. Chimeric antigen receptor T-cell therapy is a specific form of adoptive immunotherapy that involves harvesting cells from a patient 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 patient.

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 a single-arm prospective trials. The relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trials reported a 81% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved 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 events. Cytokine release syndrome 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 the 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 lymphoma (e.g., diffuse large B-cell lymphoma 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 OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 52% overall response rate (measured by complete or partial responses) 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, real-world evidence, and post-marketing studies are required to assess the generalizability of tisagenlecleucel 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.

Axicabtagene Ciloleucel
For individuals who are adults with a histologically confirmed diagnosis of aggressive non-Hodgkin lymphoma (e.g., 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. The relevant outcomes are OS, DSS, QOL, 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 events. 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 are 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.

Background 
Acute Lymphoblastic Leukemia (ALL)
B-cell 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 three 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, 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).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. 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 meta-analysis of 20 studies of 11249 pediatric ALL, Berry et al. (2017) reported 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).¹

Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,² and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year in the United States.³ B-cell ALL is largely a disease of the young, with approximately 60% of cases occurring in patients younger than 20 years old with a median age at diagnosis of 15 years.²

Treatment
While treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse and 2% to 3% of ALL patients are primary refractory.⁴, Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.⁵ The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15%.⁶ The Food and Drug Administration (FDA) 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 mediandurations of response were 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively.^7,8 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.

Diffuse Large B Cell Lymphoma (DLBCL)
DLBCL is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases.⁹ 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. Teras et al. (2016) has estimated that 27650 new cases of DLBCL were diagnosed in the United States in 2016.¹⁰

Treatment
Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is associated with a 5-year survival rate ranging from 60% to 70%.¹¹ However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy.^12,13 The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A retrospective analysis of the SCHOLAR-1 study by Crump et al. (2017), which pooled data from 2, phase 3 clinical trials and 2 observational cohorts, included 636 patients with refractory DLBCL.¹⁴ 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 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 Immunotherapy
Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. The nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them ex vivo with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells (DC) that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. Expansion of TIL for clinical use is labor intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases.¹⁵

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 patients.

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) antitumor lymphocytes following a lymphodepleting preparative regimen.”¹⁶ Protocols vary, but include these common steps:

1. lymphocyte harvesting (either from peripheral blood, tumor biopsy, or donor blood)
2. propagation of tumor-specific lymphocytes in vitro using various immune modulators
3. selection of lymphocytes with reactivity to tumor antigens and/or modification of lymphocytes to bear tumor-antigen targeted receptors
4. lymphodepletion of the host with immunosuppressive agents
5. adoptive transfer (i.e., transfusion) of lymphocytes back into the tumor-bearing host.

In an attempt to regulate the host immune system further, recent protocols have used various cytokines (e.g., IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.

Allogeneic stem cell transplantation following nonmyeloablative conditioning of the recipient (i.e., reduced-intensity conditioning) may also be referred to as “adoptive immunotherapy” in the literature. However, reduced-intensity conditioning cell transplantation relies on a donor-vs-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily. The use of reduced-intensity conditioning in cell transplantation is discussed for specific cancers in individual policies related to stem cell transplantion.

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.¹⁷

Tisagenlecleucel
Tisagenlecleucel is adoptive immunotherapy in which the T-cells of a patient are modified by genetic engineering using a 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.¹⁸

Axicabtagene Ciloleucel
Similar to tisagenlecleucel, axicabtagene ciloleucel is adoptive immunotherapy in which the T-cells of a patient 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.¹⁹

Regulatory Status
On August 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the FDA 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 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 (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.

On July 24, 2020 the FDA approved Tecartus (brexucabtagene autoleucel), a cell-based gene therapy for treatment of adult patients diagnosed with mantle cell lymphoma (MCL) who have not responded to or who have relapsed following other kinds of treatment. Tecartus, a chimeric antigen receptor (CAR) T cell therapy, is the first cell-based gene therapy approved by the FDA for the treatment of MCL.

Policy 
Chimeric antigen receptor T-cell (CAR-T) therapy with tisagenlecleucel intravenous infusion is considered MEDICALLY NECESSARY for relapsed^a or refractory^b patients with B-cell acute lymphoblastic leukemia if they meet all of the following criteria:

• Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement ( ≥ 5% lymphoblasts)
• Are up to 25 years old at the time of infusion
• Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy
• Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis
• If the patient has Philadelphia Chromosome positive (Ph+) ALL, they have tried and failed, is intolerant to, or has a contraindication to at least 2 tyrosine kinase inhibitors (TKI)
• The patient has been treated with 2 cycles of standard chemotherapy without a complete response or achieved a complete response and experienced multiple relapses following standard chemotherapy (at least 2 cycles)
• The patient does not have active central nervous system (CNS) 3 acute lymphoblastic leukemia.
• Do not have any of the following
  • Burkitt lymphoma
  • Active hepatitis B, C, or any uncontrolled infection
  • Grade 2 to 4 graft-versus-host disease
  • Concomitant genetic syndrome with the exception of Down syndrome
  • Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion
  • Patient has active central nervous system 3 acute lymphoblastic leukemia (i.e., white blood cell count ≥ 5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).

^a 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.
^b Refractory (resistant) disease is defined as those patients 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).

CAR-T therapy with tisagenlecleucel intravenous (except as indicated^a) infusion is considered MEDICALLY NECESSARY for relapsed or refractory^b patients with aggressive types of non-Hodgkin lymphoma if they meet all of the following criteria:

• Are adults (age ≥18) at the time of infusion
• Histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified; or primary mediastinal large B-cell lymphoma^a or high-grade B-cell lymphoma or diffuse large B-cell lymphoma arising from follicular lymphoma.
• Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy
• Received adequate prior therapy with disease progression follow a trial of all the following:
  • Anti-CD20 monoclonal antibody for CD20-positive tumor
  • Anthracycline-containing chemotherapy regimen
  • For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to diffuse large B-cell lymphoma:
    • Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist
    • Have not received prior CD19-directed CAR T-cell therapy treatment or any other gene therapy or are being considered for treatment with any other gene therapy.
• do not have primary central nervous system lymphoma.
• The patient does not have human immunodeficiency virus (HIV), active Hepatitis B or C, active uncontrolled infection and any autoimmune disease requiring immune suppression.

^a Tisagenlecleucel intravenous infusion is considered INVESTIGATIONAL for the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma.
^b 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).

CAR-T therapy with axicabtagene ciloleucel infusion is considered MEDICALLY NECESSARY for relapsed or refractory^a patients with aggressive types of non-Hodgkin lymphoma if they meet all of the following criteria:

• Are adults (age ≥ 18) at the time of infusion
• Histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified; or primary mediastinal large B-cell lymphomaor high-grade B-cell lymphoma or diffuse large B-cell lymphoma arising from follicular lymphoma.
• Have not received prior treatment with axicabtagene or any other gene therapy or are being considered for treatment with any other gene therapy
• Received adequate prior therapy with disease progression follow a trial of all the following:
  • Anti-CD20 monoclonal antibody for CD20-positive tumor
  • Anthracycline-containing chemotherapy regimen
  • For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to diffuse large B-cell lymphoma:
    • Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist
    • Have not received prior CD19-directed CAR T-cell therapy treatment or any other gene therapy or are being considered for treatment with any other gene therapy.
• do not have primary central nervous system lymphoma.
• The patient does not have human immunodeficiency virus (HIV), active Hepatitis B or C, active uncontrolled infection and any autoimmune disease requiring immune suppression.

CAR-T therapy with axicabtagene ciloleucel infusion is considered MEDICALLY NECESSARY for relapsed or refractory Follicular lymphoma, if they meet all of the following criteria:

• Are adults (age ≥ 18) at the time of infusion
• Treatment of relapsed or refractory follicular lymphoma in adults after ≥ 2 lines of systemic therapy defined as disease progression after last treatment regimen
• Refractory/suboptimal response to the most recent therapy
• Previous treatments must have included, but are not limited to all of the following:
  • a combination of anti-CD20 monoclonal antibody (e.g., rituximab); and
  • an alkylating agent (e.g., bendamustine, cyclophosphamide) containing regimen
• Does not have primary central nervous system (CNS) lymphoma.
• The patient does not have human immunodeficiency virus (HIV), active Hepatitis B or C, active uncontrolled infection and any autoimmune disease requiring immune suppression

^a 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).

CAR-T therapy with Brexucabtagene autoleucel infusion is considered MEDICALLY NECESSARY for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) when the following criteria are met: 

• The patient has been diagnosed with relapsed/refractory mantle cell lymphoma (MCL)
• The patient is 18 years of age and older
• Have not received prior treatment with Brexucabtagene autoleucel or any other gene therapy or are being considered for treatment with any other gene therapy
• Received adequate prior therapy with disease progression follow a trial of all the following:
  • Anti-CD20 monoclonal antibody for CD20-positive tumor
  • Anthracycline or bendamustine-containing chemotherapy regimen
  • A Bruton tyrosine kinase (BTK) inhibitor indicated for mantle cell lymphoma (e.g., acalabrutinib, ibrutinib)
• The patient has not had a prior allogeneic hematopoietic stem cell transplant (HSCT)
• The patient does not have detectable malignant cells in the cerebrospinal fluid or brain metastases
• The patient does not have any history of central nervous system (CNS) lymphoma;
• The patient does not have active infection including Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV).

Length of authorization for brexucabtagene autoleucel (Tecartus) is one (1) treatment course per lifetime

Chimeric antigen receptor T-cell (CAR-T) therapy with Brexucabtagene autoleucel infusion is considered MEDICALLY NECESSARY for relapsed^a or refractory^b patients with B-cell acute lymphoblastic leukemia if they meet all of the following criteria:

• Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥ 5% lymphoblasts)
• Are up to 25 years old at the time of infusion
• Have not received prior treatment with Brexucabtagene or any other gene therapy or are being considered for treatment with any other gene therapy
• Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis
• If the patient has Philadelphia Chromosome positive (Ph+) ALL, they have tried and failed, is intolerant to, or has a contraindication to at least 2 tyrosine kinase inhibitors (TKI)
• The patient has been treated with 2 cycles of standard chemotherapy without a complete response or achieved a complete response and experienced multiple relapses following standard chemotherapy (at least 2 cycles)
• The patient does not have active central nervous system (CNS) 3 acute lymphoblastic leukemia.

CAR-T therapy with Lisocabtagene Maraleucel infusion is considered MEDICALLY NECESSARY for the treatment of patients with relapsed or refractory large B-cell lymphoma when the following criteria are met:

• The patient has been diagnosed with CD-19 positive relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (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
• The patient is 18 years of age and older
• Previous treatments must have included, but are not limited to all of the following:
  • CD20-targeted agent (e.g., rituximab); and
  • Anthracycline-based chemotherapy (e.g., doxorubicin, epirubicin);
• Does not have primary central nervous system (CNS) lymphoma.
• The patient does not have human immunodeficiency virus (HIV), active Hepatitis B or C, active uncontrolled infection and any autoimmune disease requiring immune suppression. 

CAR-T therapy with Idecabtagene vicleucel infusion is considered MEDICALLY NECESSARY for the treatment of patients with relapsed or refractory multiple myeloma when the following criteria are met:

• Documentation supports Member has a diagnosis of active, measurable multiple myeloma, relapsed or refractory after four or more lines of therapy.
• The patient is 18 years of age and older
• Previous treatments must have included, but are not limited to all of the following:
  • an immunomodulatory agent (e.g., lenalidomide, pomalidomide); and
  • a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib); and
  • an anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab)
• Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless progressive disease was the best response to the regimen
• The patient does not have human immunodeficiency virus (HIV), active Hepatitis B or C, active uncontrolled infection and any autoimmune disease requiring immune suppression.

CAR-T therapy is considered investigational/unproven, therefore NOT MEDICALLY NECESSARY for all other applications.

Policy Guidelines 
Autologous lymphocytes used as part of chimeric antigen receptor T-cell (CAR-T) therapy may be harvested with an apheresis procedure or may be isolated from resected tumor tissue.

The recommended dosage of tisagenlecleucel for patients with B-cell acute lymphoblastic leukemia who are 50 kg or less is 0.2 to 5.0×10⁶ chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously; for patients above 50 kg, dose is 0.1 to 2.5×10⁸ total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.

The recommended target dose of tisagenlecleucel for patients with large B-cell lymphoma is 0.6 to 6.0 × 10⁸ chimeric antigen receptor-positive viable T cells intravenously.

The recommended target dose of axicabtagene ciloleucel for patients with large B-cell lymphoma is 2×10⁶ CAR-positive viable T cells per kg body weight, with a maximum of 2×10⁸ chimeric antigen receptor- positive viable T cells intravenously.

Central nervous system (CNS) disease for B-cell acute lymphoblastic leukemia 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 (e.g., facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

Tisagenlecleucel and axicabtagene ciloleucel have black box warnings because of the risks of cytokine release syndrome (CRS) and neurologic toxicities (NT) that include fatal or life-threatening reactions. They should not be administered to patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening CRS be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.

Tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS and Yescarta REMS, respectively. The requirement for the REMS components are as follows:

• Health care facilities that dispense and administer tisagenlecleucel or axicabtagene ciloleucel 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 of tocilizumab are available for each patient for administration within 2 hours after tisagenlecleucel or axicabtagene ciloleucel infusion, if needed for treatment of cytokine release syndrome.
• Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer tisagenlecleucel or axicabtagene ciloleucel are trained to manage cytokine release syndrome and neurologic toxicities.

Benefit Application
BlueCard/National Account Issues
Adoptive immunotherapies such as chimeric antigen receptor T-cell therapies are a specialized service that may require an out-of-network referral.

Some Plans may participate in voluntary programs offering coverage for patients participating in National Institutes of Health approved clinical trials of cancer immunotherapies, including chimeric antigen receptor T-cell therapy.

Rationale 
This evidence review was created in October 2019 with searches with of the PubMed database. The most recent literature update was performed through May 18, 2021. 

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 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. Randomized controlled trials 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.

Tisagenlecleucel
B-Cell Acute Lymphoblastic Leukemia
Clinical Context and Therapy Purpose
The purpose of tisagenlecleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The question addressed in this evidence review is: does the use of chimeric antigen receptor (CAR)-T therapy in patients with leukemia or lymphoma improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals who are up to 25 years of age with relapsed or refractory CD19-positive B-cell ALL. 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 patients who fail to obtain a 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).⁴¹

Interventions 
The therapy being considered is tisagenlecleucel. Therapy with tisagenlecleucel involves patient apheresis for harvesting of cells to be utilized for autologous T-cell expansion, manufacturing of CAR-positive T-cells, patient completion of a lymphodepleting chemotherapy regimen, and intravenous infusion of tisagenlecleucel at a body weight-dependent target dose.

Comparators 
In general, the only curative therapy for relapsed or refractory ALL is allogeneic hematopoietic cell transplantation (HCT). The primary goal in patients who have relapsed or refractory disease is achievement of complete remission or sufficient cytoreduction to enable allogeneic HCT. The choice of remission induction therapy depends on the disease subtype and clinical characteristics and includes participation in a clinical trial, immunotherapeutic approaches (e.g., blinatumomab, inotuzumab ozogamicin, CAR T-cell therapy) or chemotherapy regimens. All options have a category 2A recommendation in the National Comprehensive Cancer Network (NCCN) guidelines.

Outcomes 
The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), quality of life (QOL), treatment-related mortality, and treatment-related morbidity. Follow-up at 15 years is of interest for tisagenlecleucel to monitor relevant outcomes. 

Objective or overall response rates are typically calculated as the sum of patients achieving complete response (CR) and CR with incomplete blood count recovery. Partial response (PR) is not defined for this disease. Response criteria utilizing conventional morphological features are published by the NCCN.⁴¹ 

A minimal residual disease (MRD) can also be calculated for patients. Minimal residual disease refers to the presence of leukemic cells below the limit of detection by conventional morphologic and cytogenetic methods. Patients who achieve a CR by morphologic assessment alone can potentially harbor a significant number of leukemic cells in the bone marrow, and this has been shown to contribute to risk of future relapse. Regular MRD monitoring is consider an essential component of patient evaluation. Flow cytometry or polymerase chain reaction (PCR) methods are recommended for MRD monitoring. 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 pediatric ALL (N = 11,249), Berry et al. (2017) reported a hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients of 0.23 (95% confidence interval [CI], 0.18 to 0.28).¹ Event-free survival in the context of CAR-T therapy is typically defined as the date of infusion to the date of treatment failure (e.g., relapse, development of a second neoplasm, or death in remission). 

Cytokine release syndrome (CRS) and neurologic toxicity, also known as CAR-T-related encephalopathy syndrome, are 2 significant CAR-T therapy-mediated adverse events that contribute to treatment-related morbidity and mortality outcomes. Cytokine release syndrome manifests with a variety of symptoms, including fever, organ toxicity, hypotension, and hypoxia, and may be life-threatening. Several grading scales have been used to rate CRS. However, consensus criteria published by the American Society for Transplantation and Cellular Therapy (ASTCT) is preferred to grade CAR-T therapy-mediated CRS and neurotoxicity. ^42,43

Study Selection Criteria 
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence 
Pivotal Trials 
In the pivotal trial phase 2 single-arm, international, multicenter trial (ELIANA), patients with CD19-positive relapsed or refractory B-cell ALL were treated with tisagenlecleucel and followed for a median duration of 13.1 months. Maude et al. (2018) published the trial results.^44, Study characteristics and results are summarized in Tables 1 to 3. 

The prespecified primary efficacy endpoint was the proportion of patients who achieved an objective remission rate (CR or CR with incomplete blood count recovery [CRi]) as assessed by an independent review committee within 3 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 3 months of receiving tisagenlecleucel. Key secondary endpoints were tested sequentially (after the 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 the 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 3 months of follow-up data available at data cutoff. Median 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. No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Table 4.

Table 1. Summary of Key Pivotal Trial Characteristics 

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up, mo
Maude et al. (2018); ELIANA44	Single-cohort, multicenter, phase 1-2a study NCT02435849	Multiple	2015 –2017	Inclusion: Patients aged between 3 and 15 years at diagnosis with at least 5% lymphoblasts in bone marrow at screening. With CD19-positive second or greater bone marrow relapse or primary refractory B-cell ALL. Exclusion: Prior treatment with anti-CD19 therapy. Trial enrolled 92 patients (product manufactured for 82 and administered to 75)	Single intravenous infusion consisting of a median dose of 3.1 x 106 CAR-positive viable T cells per kg of body weight for a median total dose of 1.0 x 108.	13.1

ALL: acute lymphoblastic leukemia; CAR: chimeric antigen receptor..

Table 2. Summary of Key Pivotal Trial Efficacy Results 

Study; Trial	ORRa, n (%) (95% CI)	CR, n (%) (95% CI)	CRi, n (%) (95% CI)	Median DOR, mo (95% CI)	EFS, % (95% CI)b	OS, % (95% CI)b
Maude et al. (2018); ELIANA44	N = 75	N = 75	N = 75	N = 61	N = 75	N = 75
Tisagenlecleucel	61 (81) (71 – 89)	45 (60) (NR)	16 (21) (NR)	NRE (NR)	73 (60 – 82)	90 (81 – 95)

CI: confidence interval; CR: complete response; CRi: complete response with incomplete hematologic recovery; DOR: duration of response: EFS: event-free survival; NR: not reported; NRE: not reached; ORR: objective response rate; OS: overall survival.
^a ORR is a sum of complete response (CR) and complete response with incomplete hematologic recovery (CRi).
^b Rates at 6 months post-infusion.

Table 3. Summary of Key Trial Safety Results 

Study; Trial	CRS Grade ≥ 3, n (%)1	Neurological Toxicity Grade ≥ 3, n (%)	Any AE Grade ≥ 3, n (%)
Maude et al. (2018); ELIANA44	N = 75	N = 75	N = 75
Tisagenlecleucel	35 (46)	10 (13)	66 (88)

AE: adverse event; CRS: cytokine release syndrome.
¹ CRS was graded according to the Penn/CHOP scale.^45,46

Table 4. Study Design and Conduct Limitations 

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Maude et al. (2018) ELIANA44,	1. Participants not randomly allocated	1. Not blinded to treatment assignment

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Subsection Summary: Tisagenlecleucel for B-Cell Acute Lymphoblastic Leukemia 
The evidence for use of tisagenlecleucel for CD19+ relapsed or refractory B-cell ALL in pediatric and young adult patients includes a single-arm prospective trial in which 81% (61 of 75) of patients achieved an overall response rate (measured by CR or CRi). However, the observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome and neurotoxicity are known "class adverse effects" of CAR T-cell therapies with an immunologic basis. Cytokine release syndrome 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 
Clinical Context and Therapy Purpose 
The purpose of tisagenlecleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are adults with specific types of aggressive non-Hodgkin lymphoma (NHL). 

The question addressed in this evidence review is: does the use of CAR-T therapy in patients with leukemia or lymphoma improve the net health outcome? 

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals who are adults with specific types of relapsed or refractory aggressive NHL. This includes diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma. Relapsed or refractory disease is defined as disease progression after 2 or more lines of systemic therapy, which may or may not include therapy supported by autologous cell transplant.⁴³

Interventions 
The therapy being considered is tisagenlecleucel.

Comparators 
Treatment of relapsed/refractory cases is generally stratified according to HCT 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. For patients who have chemoresistant disease (i.e., an inadequate response to salvage therapy) or relapse after autologous transplant, allogeneic HCT and CAR- T therapy are appropriate options. U.S. Food and Drug Administration (FDA) approved agents for refractory/relapsed DLBCL include pembrolizumab (Keytruda), polutuzumab vedotin-piiq (Polivy), selinexor (Xpovio), and tafasitamab-cxix (Monjuvi).

Outcomes 
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity. 

International Working Group response criteria for malignant lymphoma⁴⁷ or Lugano criteria⁴⁸ are used to assess response in patients with lymphoma. Responses are categorized as complete, partial, stable, or progressive. The primary endpoint in clinical trials is generally the proportion of patients with an objective response (complete or partial response) as assessed by an independent radiology review committee. 

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and neurologic toxicity is assessed by ASTCT criteria.^42,43

Study Selection Criteria  
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence 
Pivotal Trials 
The pivotal phase 2 single-arm, multicenter trial (JULIET; NCT02445248) enrolled 165 patients with relapsed or refractory DLBCL.⁴⁹ Tables 5 and 6 summarize study characteristics and results. 

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 objective response rate (ORR), based on Lugano criteria⁴⁰ 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 a CR, as compared with patients with the best response of PR. The response was consistent across subgroups ( < 65 or ≥ 65 years, sex, ≤ 2 or > 2 antineoplastic therapies, nongerminal or germinal cancer, and rearranged MYC/BCL2/BCL6 or not) (data not shown). Table 7 summarizes safety data assessed for the 111 patients treated with tisagenlecleucel. No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Tables 8.

Table 5. Summary of Key Pivotal Trial Characteristics 

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up, mo
Schuster et al. (2019); JULIET49	Single-group, open-label, multicenter, international phase 2a study	Multiple	2015 –2017	Inclusion: Patients with relapsed or refractory DLBCL, who received ≥ 2 lines of chemotherapy, including rituximab and anthracycline, or relapsed following HCT Exclusion: Active CNS malignancy, prior allogeneic HCT, ECOG Performance Status ≥ 2, CrCl < 60 L/min, ALT > 5 times normal, cardiac ejection fraction < 45%, or absolute lymphocyte concentration < 300/μL Trial enrolled 165 patients (111 received infusion; for 12 individuals, product could not be manufactured)	Single intravenous infusion consisting of a median dose of 3.0 x 108 CAR-positive viable T cells.	14 (Range: 0.1 - 26.0)

ALT: alanine aminotransferase; CAR: chimeric antigen receptor; CI: confidence interval; CNS: central nervous system; CrCl: creatinine clearance; DLBCL: diffuse large B-cell lymphoma; ECOG: Eastern Cooperative Oncology Group; HCT: hematopoietic cell transplantation.

Table 6. Summary of Key Pivotal Trial Efficacy Results 

Study; Trial	ORRa, n (%) (95% CI)	CR, n (%) (95% CI)	PR, n (%) (95% CI)	Median DOR, mo (95% CI)	Estimated rate of PFS at 12 mo for those achieving OR, %	Median OS, mo (95% CI)
Schuster et al. (2019); JULIET49	N = 93	N = 93	N = 93	N = 48	N = 48	N = 93
Tisagenlecleucel	48 (52) (41 - 62)	37 (40) (NR)	11 (12) (NR)	NRE (10 - NE)b	83	12 (7 - NE)

CI: confidence interval; CR: complete response; CRR: complete response rate; DOR: duration of response: NE: not estimable; NR: not reported; NRE: not reached; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PR: partial response.
^a ORR is a sum of complete (CR) and partial (PR) responses.
^b Among all responders, DOR measured from date of first objective response to date of progression or death from relapse. 

Table 7. Summary of Key Trial Adverse Events 

Study; Trial	CRS Grade ≥ 3, n (%)1	Neurological Toxicity Grade ≥ 3, n (%)	Any AE Grade ≥ 3, n (%)
Schuster et al. (2019); JULIET49	N = 111	N = 111	N = 111
Tisagenlecleucel	36 (32)	13 (12)	70 (63)

AE: adverse event; CRS: cytokine release syndrome.
¹ CRS was graded according to the Lee criteria. 

Table 8. Study Design and Conduct Limitations 

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Schuster et al. (2019); JULIET49	1. Participants not randomly allocated	1. Not blinded to treatment assignment

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Subsection Summary: Tisagenlecleucel for Diffuse Large B-Cell Lymphoma 
The evidence for use of tisagenlecleucel for relapsed or refractory aggressive DLBCL (including multiple subsets) includes a single-arm prospective trial in which 52% (48 of 93) of patients with relapsed or refractory DLBCL who were ineligible for or had disease progression after autologous HCT achieved best overall response rate. Forty percent of the patients had CR s, and 12% had PR s. However, the observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome and neurotoxicity are known "class adverse effects" of CAR T-cell therapies with an immunologic basis. Any grade CRS was observed in 58% of treated patients in the pivotal trial. Grade 3 or 4 CRS and neurologic events were observed in 22% and 12% of patients. Long-term follow-up, real-world evidence, and post-marketing studies are required to assess the generalizability of the efficacy and safety of tisagenlecleucel outside of a clinical trial setting.

Axicabtagene Ciloleucel
Diffuse Large B-Cell Lymphoma
Clinical Context and Therapy Purpose
The purpose of axicabtagene ciloleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are adults with specific types of aggressive NHL.

The question addressed in this evidence review is: does the use of CAR-T therapy in patients with leukemia or lymphoma improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals who are adults with specific types of relapsed or refractory aggressive NHL. This includes DLBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma. Relapsed or refractory disease is defined as disease progression after 2 or more lines of systemic therapy, which may or may not include therapy supported by autologous cell transplant.⁴⁰

Interventions
The therapy being considered is axicabtagene ciloleucel. Therapy with axicabtagene ciloleucel involves patient apheresis for harvesting of cells to be utilized for autologous T-cell expansion, manufacturing of CAR-positive T-cells, and patient completion of a lymphodepleting chemotherapy regimen.

Comparators
Treatment of relapsed/refractory cases is generally stratified according to HCT 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. For patients who have chemoresistant disease (i.e., an inadequate response to salvage therapy) or relapse after autologous transplant, allogeneic HCT and CAR- T therapy are appropriate options. FDA approved agents for refractory/relapsed DLBCL include pembrolizumab (Keytruda), polutuzumab vedotin-piiq (Polivy), selinexor (Xpovio), and tafasitamab-cxix (Monjuvi).

Outcomes 
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity. 

International Working Group response criteria for malignant lymphoma⁴⁷ or Lugano criteria⁴⁸ are used to assess response in patients with lymphoma. Responses are categorized as complete, partial, stable, or progressive. The primary endpoint in clinical trials is generally the proportion of patients with an objective response (complete or partial response) as assessed by an independent radiology review committee. 

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and neurologic toxicity is assessed by ASTCT criteria.^42,43

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Pivotal Trial 
The approval of axicabtagene ciloleucel was based on the results of an open-label, multicenter, phase 1-2 study (ZUMA-1).⁵⁰ Study characteristics and results are summarized in Tables 9 to 11. Adults with aggressive B-cell NHL that was primary refractory, refractory to a second or greater line of therapy, or relapsed within 1 year after autologous HCT were enrolled in the study. Patients with prior allogeneic HCT, any history of central nervous system (CNS) lymphoma, Eastern Cooperative Oncology Group (ECOG) 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 DLBCL and 32% had double- or triple-hit lymphoma. The median age of enrolled patients 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. Tables 9, 10, and 11 summarize study characteristics, results, and safety data, respectively. 

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). The study protocol mandated hospitalization of patients for the infusion and for 7 days after the 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 endpoint was the ORR based on a modified intention-to-treat population, which was defined as all patients treated with at least 1.0 × 10⁶CAR -positive T cells per kilogram. No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Table 12.

Table 9. Summary of Key Trial Characteristics 

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up, mo (IQR)
ZUMA-150	Single-arm, multicenter, prospective, phase 1-2	US; Israel	2015 – 2018	Adult Individuals with histologically confirmed aggressive B-cell NHL (e.g., DLBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, transformed follicular lymphoma) that was primary refractory, refractory to second or greater line of therapy, or relapsed within 1 year of autologous HCT (N=101).	Axicabtagene ciloleucel as a single intravenous infusion 2 x 106 CAR T cells/kg	27.1 (25.7 –28.8)

CAR: chimeric antigen receptor; DLBCL: diffuse large B-cell lymphoma; HCT: hematopoietic cell transplantation; IQR: interquartile range; NHL: non-Hodgkin lymphoma.

Table 10. Summary of Key Trial Efficacy Results

Trial	Response Rate1	Duration of Response
ZUMA-1 (N=101)
Prescribing Label (median duration of follow-up: 7.9 months)51	ORR: 73 (72%; 95% CI: 62 to 81%) CR: 52 (51%; 95% CI: 41 to 62%) PR: 21 (21%; 95% CI: 13 to 30%)	Median duration of ORR: 9.2 months (95% CI: 5.4 to NE)
Neelapu et al., 2017 (updated analysis, median duration of follow-up: 8.7 months)52	ORR: 82 (82%) CR: 54 (55%) PR: 28 (28%)	Median duration of ORR: 11.1 months (95% CI: 3.9 to NE)
Locke et al., 2019 (updated analysis, median duration of follow-up: 27.1 months) 50	ORR: 84 (83%) CR: 59 (58%) PR: 25 (25%)	Median duration of ORR: 11.1 months (95% CI: 4.2 to NE)

CI: confidence interval; CR: complete response; NE: not estimable ; ORR: objective response rate; PR: partial response.
¹ The objective response (OR) is the sum of complete (CR) and partial (PR) responses and was graded according to 2007 revised International Working Group criteria⁴⁷ as assessed by the independent review committee.

Table 11. Summary of Key Trial Safety Results 

Study; Trial	CRS Grade ≥ 3, n (%)1	Neurological Toxicity Grade ≥ 3, n (%)	Any AE Grade ≥ 3, n (%)
Adapted from Kite Pharma (2017); ZUMA-153,	N = 108	N = 108	N = 108
Axicabtagene ciloleucel	14 (13)	34 (31)	NR

AE: adverse event; CRS: cytokine release syndrome; NR=not reported.
¹ CRS was graded according to the Lee criteria.

Table 12. Study Design and Conduct Limitations 

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Locke et al. (2019); ZUMA-150,	1. Participants not randomly allocated	1. Not blinded to treatment assignment

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of c crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Subsection Summary: Axicabtagene Ciloleucel for Diffuse Large B-Cell Lymphoma 
The evidence for use of axicabtagene ciloleucel for relapsed or refractory aggressive DLBCL (including multiple subsets) includes a single-arm prospective trial in which 72% (73 of 101) of patients with relapsed or refractory DLBCL who were ineligible for or had disease progression after autologous HCT achieved best overall response rate. Fifty-two percent of the patients had CR s, and 21% had PR s. However, the observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome and neurotoxicity are known "class adverse effects" of CAR T-cell therapies with an immunologic basis. Any grade CRS was observed in more than half of the patients in the pivotal trial and 98% of patients had an adverse event at grade 3 or higher. Post-marketing studies and real-world evidence are required to assess the generalizability of the efficacy and safety of axicabtagene ciloleucel outside of a clinical trial setting.

Follicular Lymphoma
Clinical Context and Therapy Purpose 
The purpose of axicabtagene ciloleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. The question addressed in this evidence review is: does the use of CAR-T therapy in patients with relapsed or refractory follicular lymphoma improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals who are adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. Relapsed or refractory disease is defined as disease progression after 2 or more lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent.

Interventions 
The therapy being considered is axicabtagene ciloleucel. Therapy with axicabtagene ciloleucel involves patient apheresis for harvesting of cells to be utilized for autologous T-cell expansion, manufacturing of CAR-positive T-cells, and patient completion of a lymphodepleting chemotherapy regimen prior to infusion.

Comparators 
Treatment options for patients who have had multiple relapses or have refractory follicular lymphoma include lenalidomide, PI3K inhibitors (e.g., copanlisib, duvelisib, idelalisib, and umbralisib ) and EZH2 inhibitor (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.

Outcomes 
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity. 

International Working Group response criteria for malignant lymphoma⁴⁷ or Lugano criteria⁴⁸ are used to assess response in patients with lymphoma. Responses are categorized as complete, partial, stable, or progressive. The primary endpoint in clinical trials is generally the proportion of patients with an objective response (complete or partial response) as assessed by an independent radiology review committee. 

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and neurologic toxicity is assessed by ASTCT criteria.^42,43

Study Selection Criteria 
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence 
The approval of axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma was based on the results of an ongoing open-label, phase 2 study called ZUMA-5. Study characteristics and results are summarized in Table 13 and 14. This trial enrolled 146 patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Patients received a single infusion of axicabtagene ciloleucel at 2 × 10⁶ CAR T cells/kg after leukapheresis and a lymphodepleting therapy (cyclophosphamide/fludarabine). The median time from leukapheresis to product delivery was 17 days (range: 13 to 33 days) and leukapheresis to product infusion was 27 days (range: 19 to 250 days). All treated patients received infusion on day 0 and were hospitalized until at least day 7. The primary endpoint was the objective response rate (ORR) by central review (per Lugano classification). 

Of the 120 patients dosed, data of 81 consecutive patients who had at least 9 months of follow-up from date of first response were included in the primary efficacy analysis. Patients were heavily pre-treated. The median number of prior systemic therapies was 3 (range: 2 to 9), with 32% having 2 prior lines, 22% having 3 prior lines, and 46% having ≥ 4 prior lines. Thirty-one percent had received a PI3K inhibitor, 72% had progression within 6 months of the most recent regimen, and 56% had progression within 24 months of initiating their first anti-CD20 combination therapy. The ORR was 91% and median time to response was 1.0 month (range: 0.8 – 3.1 months). 

No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Table 15. 

Table 13. Summary of Key Trial Characteristics 

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up
ZUMA-551 (NCT03105336)	Single-arm, multicenter, prospective, phase 2	US and France	2017-ongoing	Adult Individuals with histologically proven relapsed or refractory indolent non-Hodgkin lymphoma (follicular lymphoma grades 1-3a or marginal zone lymphoma) that has progressed after at least 2 lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agenta	Single intravenous infusion of axicabtagene ciloleucel 2x106 CAR T cells/kg	Median follow-up: 14.5 months

CAR: chimeric antigen response
^a Of 123 patients who underwent leukapheresis, 120 received axicabtagene ciloleucel. Reasons for not receiving treatment= 3 (ineligible due to thrombocytopenia, one went into remission prior to initiating lymphodepletion, and one died of cardiac arrest).
^b Included in primary efficacy analysis: 81 consecutive patients who completed at least 9 months of follow-up from date of first response

Table 14. Summary of Key Trial Efficacy Results 

Study	Response Rate, n (%) [95% CI]	Secondary Outcomes	Safety
ZUMA-551, (NCT03105336)	Efficacy-Evaluable Patients (N = 81) ORRa: 74 (91%) [83, 96] CRb: 49 (60%) [49, 71] PR: 25 (31%) [21, 42] All Leukapheresed Patients (ITT) N = 123 ORR: 110 (89%) [83, 94] CR: 76 (62%) [53, 70] PR: 34 (28%) [20, 36]	Median Duration of Response, months [95% CI] (range), (N = 81)c,d NE [20.8, NE] (0.0 to 52.0+)e Rate of Continued Remissiona,c,d,f At 12 months (95% CI), %: 76.2 (63.9, 84.7) At 18 months (95% CI), %: 74.2 (61.5, 83.2)	Safety-Evaluable Patients (N = 146) Most common ( ≥ 10%) Grade 3 or higher reactions: Febrile neutropenia, encephalopathy, and infections Serious adverse reactions in > 2% of patients: Febrile neutropenia, encephalopathy, fever, CRS, infections with pathogen unspecified, pneumonia, hypoxia, and hypotension. Fatal adverse reactions: 1% of patients and included CRS and fungal infection Patients received tocilizumab: 51% (75/146)

^a Per the International Working Group Lugano Classification (Cheson 2014), as assessed by the independent review committee.
^b Complete remission required documentation of a negative bone marrow biopsy after treatment, in patients who did not have a negative bone marrow biopsy between their most recent disease progression prior to ZUMA-5 and initiation of lymphodepleting chemotherapy.
^c Among all responders in the primary efficacy population. DOR is measured from the date of first objective response to the date of progression or death from any cause.
^d Kaplan-Meier estimate.
^e A “+” sign indicates a censored value.
^f. Measured from the date of first objective response to the date of progression or death.
CI: confidence interval; CR: complete response; CRS: cytokine release syndrome; ITT: intention to treat; NE: not estimable; ORR: objective response rate; PR: partial response. 

Table 15. Study Design and Conduct Limitations 

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
ZUMA-551 (NCT03105336)	1. Participants not randomly allocated	Not blinded to treatment assignment

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Axicabtagene Ciloleucel for Follicular Lymphoma 
The evidence for axicabtagene ciloleucel for individuals with relapsed or refractory follicular lymphoma consists of one phase II single-arm study. The ZUMA-5 study enrolled adult patients with relapsed refractory follicular lymphoma after 2 or more lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Of 120 patients who received axicabtagene ciloleucel, interim data for 81 consecutive patients who completed at least 9 months of follow-up from date of first response was reported with a median follow-up of 14.5 months. The primary efficacy analysis demonstrated an ORR of 91% with a 60% rate of CR. The median duration of response was not reached. At 12 months, 76% remained in remission. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified.

Brexucabtagene Autoleucel 
Clinical Context and Therapy Purpose 
The purpose of brexucabtagene autoleucel in adult patients who have relapsed or refractory mantle cell lymphoma (MCL) is to provide a treatment option that is an improvement on existing therapies. 

The question addressed in this evidence review is: does the use of CAR-T therapy in patients with leukemia or lymphoma improve the net health outcome? 

The following PICO was used to select literature to inform this review.

Populations 
The relevant population of interest is individuals who are adult with relapsed or refractory MCL.

Interventions 
The therapy being considered is brexucabtagene autoleucel. Therapy with brexucabtagene autoleucel involves patient apheresis for harvesting of cells to be utilized for autologous T-cell expansion, manufacturing of CAR-positive T-cells, patient completion of a lymphodepleting chemotherapy regimen, and intravenous infusion of brexucabtagene autoleucel at a body weight-dependent target dose.

Comparators 
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, bortezomib, and temsirolimus. 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.

Outcomes 
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity. 

International Working Group response criteria for malignant lymphoma^47, or Lugano criteria⁴⁸ are used to assess response in patients with lymphoma. Responses are categorized as complete, partial, stable, or progressive. The primary endpoint in clinical trials is generally the proportion of patients with an objective response (complete or partial response) as assessed by an independent radiology review committee. 

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and neurologic toxicity is assessed by ASTCT criteria.^42,43

Study Selection Criteria 
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence 
Pivotal Trial 
The approval of brexucabtagene autoleucel was based on the results of an open-label, phase 2 study (ZUMA-2).⁵⁴ This trial enrolled 74 patients (product manufactured for 71 and administered to 68) that had relapsed disease or were refractory after the receipt of up to 5 previous therapies. The median time from leukapheresis to the delivery of CAR T-cells in the trial was 16 days. The primary endpoint 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. In ZUMA-2, out of 74 participants enrolled, 68 received a single infusion of brexucabtagene autoleucel. Patients who had a high disease burden could receive bridging therapy at the investigator’s discretion between leukapheresis and before receiving conditioning therapy to keep the patient’s condition stable during the manufacturing period. Hospitalization after the infusion of brexucabtagene autoleucel was required through day 7. Of the 68 patients, data for the first 60 treated patients who completed at least 7 months of follow-up (as per protocol) were reported and are summarized in Table 16. Patients had high-risk disease characteristics, including cell population growth fraction measured by a Ki-67 index ≥ 30% (82%), intermediate-/high-risk simplified Mantle Cell Lymphoma International Prognostic Index score (56%), presence of a TP53 mutation (17%), and blastoid/pleomorphic morphology (31%). Sixty-two percent of patients were primary refractory to BTK inhibitor therapy, and 81% had received ≥ 3 lines of prior therapies. 

Results are summarized in Table 17. While ZUMA-2 was ongoing, results of a pre-specified 60 patients resulted in an objective response in 87% of the patients and in a CR in 62%.⁵⁵ As per the published analysis, these responses were durable. Among the 60 patients analyzed, 57% continued to have a response after a median follow up of 12.3 months. Among 37 patients who had a CR , 78% continued to have a response after a median follow up of 12.3 months.⁵⁴ The median time to response was 28 days (range: 24 to 92 days) with a median follow-up time for duration of response (DOR) of 8.6 months.⁵⁵ The reported safety profile of brexucabtagene autoleucel was similar to that reported previously with anti-CD19 CAR T-cell therapies in patients with aggressive lymphoma.^52,49 Notable adverse events of grade 3 or higher were cytopenias (94%), infections (32%), neurologic events (31%), and CRS (15%). Grade 3 neurologic events were reported in 15 (22%) patients and included encephalopathy, confusional state, and aphaia in 7 (10%), 8 (12%), and 3(4%) patients, respectively. One patient had grade 4 cerebral edema and fully recovered with aggressive multimodality therapy including ventriculostomy. For the management of CRS , 59% of all treated patients received tocilizumab, 22% received glucocorticoids, and 16% received vasopressors. The median time after infusion to the onset of CRS of any grade was 2 days (range, 1 to 13).The corresponding interval to the onset of CRS of grade 3 or higher was 4 days (range, 1 to 9). All events resolved within a median of 11 days. No patient died from CRS. While the majority of adverse events were reported to occur during the course of the trial, 26% of the patients had cytopenias of grade 3 or higher more than 90 days after the administration of brexucabtagene autoleucel.

No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Tables 18.

Table 16. Summary of Key Trial Characteristics

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up
ZUMA-2 [NCT02601313]54,55	Single-arm, multicenter, prospective, phase 2	US and Europe (20 sites)	2016 – 2019	Males 18 years or older with histologically confirmed MCC with either cyclin D1 overexpression or presence of the translocation t(11;14) Disease that was either relapsed or refractory to up to 5 previous regimens for MCC Previous treated with anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor therapy with ibrutinib or acalabrutinib. Primary endpoint: % of patients with an OR (CR or PR) as assessed by IRRC N = 170a	Single intravenous infusion of brexucabtagene autoleucel 2x106 CAR T-cells/kg of body weight	Intended follow-up: after 60 patients had been treated and followed for 7 months Median follow-up: 12.3 months

BTK: Bruton's tyrosine kinase; CAR: chimeric antigen response; CR: complete response; FVIII: factor VIII; IRRC: independent radiology review committee; MCC: mantle cell carcinoma; OR: objective response; PR: partial response.
^a Of 74 patients enrolled, therapy was successfully manufactured for 71 (96%) and administered to 68 (92%). Reasons for not pursuing additional apheresis in these 3 patients with manufacturing failures were deep-vein thrombosis, death from progressive disease, and withdrawal of consent, respectively. Of the 3 patients who did not receive treatment even though therapy was successfully manufactured, 2 died from progressive disease while 1 patient was deemed ineligible later in the trial due to development of atrial fibrillation.

Table 17. Summary of Key Trial Efficacy Results

Study	Response Rate, n (%) [95% CI]	Median Duration of Response, months [95% CI] (range)	Safety
Trial (ZUMA-2)54,55	Efficacy-Evaluable Patients (N = 60) ORR: 52 (87%) [75, 94] CR: 37 (62%) [48, 74] PR: 15 (25%) [15, 38] All Leukapheresed Patients (ITT) N = 74 ORR: 59 (80%) [69, 88] CR: 41 (55%) [43, 67]] PR: 18 (24%) [15, 36]	Efficacy-Evaluable Patients (N = 60) NR [8.6, NE] (0.0 to 29.2) All Leukapheresed Patients (ITT) N = 74 NR [8.6, NE] (0.0 to 29.2)	At least 1 ADE of any grade: 100% ADE grade 3 or higher: 99% Notable ADEs: ≥ grade 3 cytopenias: 94% ≥ grade 3 CRS: 15% ≥ grade 3 neurologic events: 31% Infections: 32%

ADE: adverse drug event; CI: confidence interval; CRS: cytokine release syndrome; ITT: intention to treat; NE: not estimable; NR; not reached; ORR; objective response rate; PR: partial response.

Table 18. Study Design and Conduct Limitations 

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Trial (ZUMA-2)54,55,	1. Participants not randomly allocated	Not blinded to treatment assignment

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma
The evidence for brexucabtagene autoleucel for individuals with relapsed or refractory MCL consists of 1 phase II single-arm study. 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 , progression-free survival (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.

Lisocabtagene Maraleucel
Clinical Context and Therapy Purpose
The purpose of lisocabtagene maraleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are adults with specific types of aggressive non-Hodgkin lymphoma (NHL).

The question addressed in this evidence review is: does the use of CAR-T therapy in patients with leukemia or lymphoma improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who are adults with specific types of relapsed or refractory aggressive NHL. This includes 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. Relapsed or refractory disease is defined as disease progression after 2 or more lines of systemic therapy, which may or may not include therapy supported by autologous cell transplant.⁴⁰

The therapy being considered is lisocabtagene maraleucel. Therapy with lisocabtagene maraleucel involves patient apheresis for harvesting of cells to be utilized for autologous T-cell expansion, manufacturing of CAR-positive T-cells, and patient completion of a lymphodepleting chemotherapy regimen.

Comparators
Treatment of relapsed/refractory cases is generally stratified according to HCT 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. For patients who have chemoresistant disease (i.e., an inadequate response to salvage therapy) or relapse after autologous transplant, allogeneic HCT and CAR-T therapy are appropriate options. FDA approved agents for refractory/relapsed DLBCL include pembrolizumab (Keytruda), polutuzumab vedotin-piiq (Polivy), selinexor (Xpovio), and tafasitamab-cxix (Monjuvi).

Outcomes
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.

International Working Group response criteria for malignant lymphoma⁴⁷ or Lugano criteria⁴⁸ are used to assess response in patients with lymphoma. Responses are categorized as complete, partial, stable, or progressive. The primary endpoint in clinical trials is generally the proportion of patients with an objective response (complete or partial response) as assessed by an independent radiology review committee.

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and neurologic toxicity is assessed by ASTCT criteria.^42,43

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Pivotal Trial
The approval of lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND).⁵⁶ 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). Tables 19 and 20 summarize study characteristics and results, respectively.

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 system⁵⁷) 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. Identified design and conduct limitations are summarized in Table 21.

Table 19. Summary of Key Trial Characteristics

Study; Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up
Abramson et al. (2020) TRANSCEND56,58	Open-label, single-arm	US (14 sites)	2016 – 2019	Key eligibility criteria: 18 years or older with relapsed or refractory LBCL after ≥ 2 lines of therapy PET-positive disease by Lugano classification ECOG performance status of 0-1 Key ineligibility criteria: CrCl > 30 mL/min/1.73 m2 LVEF ≥ 40% were ineligible Endpoints: Primary: Safety and ORR per IRC Secondary: CR, DOR, PFS, PFS ratio, and OS NHL subtypes, n (%) de novo DLBCL: 53% Transformed from indolent lymphoma : 25% HGBCLa: 14% PMBCL: 7% FL3B: 1% Secondary CNS lymphoma: 3%	Single intravenous infusion of lisocabtagene maraleucel	Intended follow-up: 24 months and long term up to 15 years Median follow-up: 18.8 months (95% CI 15.0 to 19.3).

^a HGBCL with gene arrangements in MYC and either BCL2, BCL6, or both.
CI: confidence interval; CNS: central nervous system; CR: complete response; CrCl: creatinine clearance; DLBCL: diffuse large B-cell lymphoma; DOR: duration of response; ECOG : Eastern Cooperative Oncology Group ; FL(3B): follicular lymphoma (grade 3B); HGBCL, high-grade B-cell lymphoma; IRC: independent review committee; LVEF: left ventricular ejection fraction; LBCL: large B-cell lymphoma; NHL: non-Hodgkin lymphoma; ORR: objective response rate; OS: overall survival; PET: positron emission tomography; PFS: progression free survival; PMBCL: primary mediastinal large B-cell lymphoma.

Table 20. Summary of Key Trial Efficacy Results

Trial	Response Rate1	Duration of Response
TRANSCEND
Prescribing Label (N = 192)58	OR: 73% (95% CI: 67 to 80%) CR: 54% (95% CI: 47% to 61%) PR: 19% (95% CI: 14 to 26%)	Number of responders: 141 Median duration of response (months) All patients: 16.7 (5.3 to not reached) If best response was CR: not reached (16.7 to not reached) If best response was PR: 1.4 (1.1 to 2.2)
Abramson et al. (2020) (N = 256)56	OR: 73% (95% CI: 67 to 78) CR: 53% (95% CI: 47 to 59)	Median time to first CR or PR: 1 month (0.7, 8.9) DOR Median: not reached (8.6 to not reached) At 6 months: 4% (52.6 to 67.3) At 12 months: 7% (46.7 to 62.0) PFS Median: 6.8 months (3.3 to 14.1) At 6 months: 4% (44.6 to 57.7) At 12 months: 1% (37.3 to 50.7) OS Median: 21.1 months (13.3 to not reached) At 6 months: 7% (68.9 to 79.6) At 12 months: 57.9% (51.3 to 63.8)

CI: confidence interval; CR: complete response; DOR: duration of response; OR: objective response; OS: overall survival; PR: partial response; PFS: progression free survival
¹ The objective response (OR) is the sum of complete (CR) and partial (PR) responses and were graded according to 2014 Lugano criteria⁴⁸ as assessed by the independent review committee.

Table 21. Study Design and Conduct Limitations

Study; Trial	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Abramson et al. (2020) TRANSCEND56,58	1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear	1. Not blinded to treatment assignment		6. Not intent to treat analysis (5% excluded from efficacy analysis)

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^dData Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Subsection Summary: Lisocabtagene Maraleucel for Relapsed or Refractoy DLBCL
The evidence for use of lisocabtagene maraleucel for 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 includes a single-arm prospective trial (TRANSCEND). In 299 patients who underwent leukapheresis, therapy was successfully administered to 255 (85%). Of these, 192 were evaluable for efficacy. 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.

Summary of Evidence
Tisagenlecleucel
For individuals who are up to 25 years of age with relapsed or refractory B-cell ALL who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trials reported a 81% response rate (measured by CR or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a CR or complete remission with incomplete blood count were also MRD negative, which is predictive of survival in ALL patients. After a median follow-up of 13.1 months, the median DOR was not reached. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse events. Cytokine release syndrome was observed in more than half (77%) of 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 the clinical trial setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with a histologically confirmed diagnosis of aggressive NHL (e.g., DLBCL not otherwise specified, high-grade B-cell lymphoma, transformed follicular lymphoma) who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 52% ORR (measured by complete or partial responses) in heavily pretreated patients. After a median follow-up of 14 months, the median DOR was not reached. The observed benefits were offset by a high frequency and severity of adverse events. Any grade CRS was observed in 58% of patients, and 63% 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 the clinical trial setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Axicabtagene Ciloleucel
For individuals who are adults with a histologically confirmed diagnosis of aggressive NHL (e.g., DLBCL 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 OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 83% ORR (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 27.1 months, the median DOR was 11.1 months. The observed benefits were offset by a high frequency and severity of adverse events. Cytokine release syndrome was observed in more than half of patients, and 98% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence are required to assess the generalizability of axicabtagene ciloleucel efficacy and safety outside of the clinical trial setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with a histologically confirmed diagnosis of relapsed or refractory follicular lymphoma, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The ZUMA-5 study enrolled adult patients with relapsed refractory follicular lymphoma after 2 or more lines of systemic therapy including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Of 120 patients who received axicabtagene ciloleucel, interim data for 81 consecutive patients who completed at least 9 months of follow-up from date of first response was reported with a median follow-up of 14.5 months. The primary efficacy analysis demonstrated an ORR of 91% with a 60% rate of CR. The median duration of response was not reached. At 12 months, 76% remained in remission. Long-term follow-up and real-world evidence are required to assess the generalizability of axicabtagene ciloleucel efficacy and safety outside of the clinical trial setting. The evidence is sufficient to determine that the technology results in an 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.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (NCCN) guidelines^i.ii for acute lymphoblastic leukemia (v.1.2021)⁴¹ recommend (category 2A) tisagenlecleucel as a treatment option for relapsed or refractory

• Philadelphia chromosome-positive patients 26 years or less in age with refractory disease OR ≥ 2 relapses and failure of 2 tyrosine kinase inhibitors.
• Philadelphia chromosome-negative patients 26 years or less in age with refractory disease OR ≥ 2 relapses.

Current NCCN guidelines for B-cell lymphoma (v.4.2021)⁴⁰ recommend (category 2A) axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel as a treatment option:

• For histological transformation to diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥ 2 chemo-immunotherapy regimens for the indolent or transformed disease.
• For relapsed or refractory disease diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥ 2 chemo-immunotherapy regimens for the indolent or transformed disease.

Current NCCN guidelines for B-cell lymphoma (v.4.2021)⁴⁰ recommend (category 2A) brexucabtagene autoleucel as a treatment option for adult patients with relapsed or refractory mantle cell lymphoma only after chemoimmunotherapy and BTK inhibitor therapy.

Current NCCN guidelines for B-cell lymphoma (v.4.2021)⁴⁰ recommend (category 2A) axicabtagene ciloleucel as a third-line treatment option for adult patients with follicular lymphoma (grade 1 – 2) only after 2 or more lines of systemic therapy.

ⁱ Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia (v.1.2021) and B-Cell Lymphomas (v.4.2021).
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed May 20, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

ⁱⁱ NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 22.

Table 22. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Tisagenlecleucel
NCT02445248a	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	116	Feb 2023
NCT02445222a	Long Term Follow-Up of Patients Exposed to Lentiviral-Based CD19 Directed CAR T-Cell Therapy	620	May 2035
NCT03876769a	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	140	Aug 2027
Axicabtagene ciloleucel
NCT02926833a (ZUMA-6)	Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma	37	Aug 2033
NCT03391466a (ZUMA-7)	Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With r/r Diffuse Large B Cell Lymphoma	359	Jan 2035
NCT03704298a (ZUMA-11)	Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma	15	Aug 2022
NCT03761056a (ZUMA-12)	Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma	40	June 2036
NCT04002401a (ZUMA-14)	Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Rituximab in Participants With Refractory Large B-Cell Lymphoma	27	June 2036
Brexucabtagene autoleucel
NCT02614066a (ZUMA-3)	A study evaluating brexucabtagene autoleucel in adult with r/r ALL	125	August 2020
NCT02625480a (ZUMA-4)	Study evaluating brexucabtagene autoleucel in pediatric and adolescent participants with r/r ALL or r/r B-cell NHL	116	August 2023
NCT03624036a (ZUMA-8)	Safety and Efficacy of brexucabtagene autoleucel in adults with r/r CLL	108	March 2021
Lisocabtagene maraleucel
NCT03484702 (TRANSCEND WORLD)	Trial to determine the efficacy and safety of lisocabtagene maraleucel in aggressive B-Cell NHL	116	Aug 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	182	Jan 2024
NCT04245839	A study to evaluate the efficacy and safety of lisocabtagene maraleucel in r/r indolent B-cell NHL	188	Oct 2022
NCT03331198	Study evaluating safety and efficacy of lisocabtagene maraleucel in subjects with r/r CLL or SLL	200	Oct 2021
NCT03743246	A study to evaluate the safety and efficacy of lisocabtagene maraleucel r/r B-cell ALL and B-cell NHL	121	Oct 2022
NCT03310619 (PLATFORM)	A safety and efficacy Trial of lisocabtagene maraleucel combinations in r/r B-cell malignancies	75	Aug 2023
NCT03483103 (PILOT)	A study to evaluate the efficacy and safety of lisocabtagene maraleucel in aggressive B-Cell NHL as second-line therapy	56	Apr 2021
NCT03744676 (OUTREACH-007)	A safety trial of lisocabtagene maraleucel for r/r) B-cell NHL in the outpatient setting	80	Apr 2021
Unpublished
Tisagenlecleucel
NCT02228096a	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	64	May 2019

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

1. Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol. Jul 13 2017; 3(7): e170580. PMID 28494052
2. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med. Oct 15 2015; 373(16): 1541-52. PMID 26465987
3. Maude SL, Teachey DT, Porter DL, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. Jun 25 2015; 125(26): 4017-23. PMID 25999455
4. Pui CH, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. Feb 10 2011; 29(5): 551-65. PMID 21220611
5. Tallen G, Ratei R, Mann G, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. May 10 2010; 28(14): 2339-47. PMID 20385996
6. Bajwa R, Schechter T, Soni S, et al. Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant. May 2013; 48(5): 661-5. PMID 23128573
7. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2006; 24(12): 1917-23. PMID 16622268
8. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. Dec 20 2016; 34(36): 4381-4389. PMID 27998223
9. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. May 19 2016; 127(20): 2375-90. PMID 26980727
10. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. Jan 01 2006; 107(1): 265-76. PMID 16150940
11. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. Jan 01 2015; 125(1): 22-32. PMID 25499448
12. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. Oct 19 2017; 130(16): 1800-1808. PMID 28774879
13. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. Sep 20 2010; 28(27): 4184-90. PMID 20660832
14. Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood. May 31 2012; 119(22): 5118-25. PMID 22438256
15. Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. Nov 01 2014; 32(31): 3490-6. PMID 25267740
16. Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. Jan 2016; 51(1): 51-7. PMID 26367239
17. Rigacci L, Puccini B, Dodero A, et al. Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study. Ann Hematol. Jun 2012; 91(6): 931-9. PMID 22245922
18. Lazarus HM, Zhang MJ, Carreras J, et al. A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report from the CIBMTR. Biol Blood Marrow Transplant. Jan 2010; 16(1): 35-45. PMID 20053330
19. Van Den Neste E, Schmitz N, Mounier N, et al. Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study. Bone Marrow Transplant. Feb 2017; 52(2): 216-221. PMID 27643872
20. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. Jun 01 1997; 89(11): 3909-18. PMID 9166827
21. Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer. Aug 15 2008; 113(4): 791-8. PMID 18615506
22. Teras LR, DeSantis CE, Cerhan JR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. Nov 12 2016; 66(6): 443-459. PMID 27618563
23. Fu S, Wang M, Lairson DR, et al. Trends and variations in mantle cell lymphoma incidence from 1995 to 2013: A comparative study between Texas and National SEER areas. Oncotarget. Dec 22 2017; 8(68): 112516-112529. PMID 29348844
24. Federal Register / Vol. 85, No. 104 / Friday, May 29, 2020 / Proposed Rules; KTEX19; Page 175. Federal Register / Vol. 85, No. 104 / Friday, May 29, 2020 / Proposed Rules. Removed June 16, 2021. https://www.govinfo.gov/content/pkg/FR-2020-05-29/pdf/2020-10122.pdf
25. Argatoff LH, Connors JM, Klasa RJ, et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood. Mar 15 1997; 89(6): 2067-78. PMID 9058729
26. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. Oct 2012; 122(10): 3416-23. PMID 23023712
27. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. Jan 01 2015; 125(1): 48-55. PMID 25499451
28. Flinn IW, van der Jagt R, Kahl B, et al. First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study. J Clin Oncol. Apr 20 2019; 37(12): 984-991. PMID 30811293
29. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol. Apr 10 2016; 34(11): 1256-69. PMID 26755518
30. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. Mar 24 2016; 127(12): 1559-63. PMID 26764355
31. Jain P, Kanagal-Shamanna R, Zhang S, et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. Br J Haematol. Nov 2018; 183(4): 578-587. PMID 30175400
32. Epperla N, Hamadani M, Cashen AF, et al. Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a real world study. Hematol Oncol. Dec 2017; 35(4): 528-535. PMID 28066928
33. Robinson SP, Boumendil A, Finel H, et al. Long-term outcome analysis of reduced-intensity allogeneic stem cell transplantation in patients with mantle cell lymphoma: a retrospective study from the EBMT Lymphoma Working Party. Bone Marrow Transplant. May 2018; 53(5): 617-624. PMID 29335632
34. Al-Hamadani M, Habermann TM, Cerhan JR, et al. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. Sep 2015; 90(9): 790-5. PMID 26096944
35. Randall C, Fedoriw Y. Pathology and diagnosis of follicular lymphoma and related entities. Pathology. Jan 2020; 52(1): 30-39. PMID 31791624
36. Cancer Stat Facts: NHL Follicular Lymphoma. https://seer.cancer.gov/statfacts/html/follicular.html. Accessed May 21, 2021.
37. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J Clin Oncol. Apr 10 2019; 37(11): 912-922. PMID 30742566
38. Gopal AK, Kahl BS, de Vos S, et al. PI3K inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. Mar 13 2014; 370(11): 1008-18. PMID 24450858
39. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. Dec 10 2017; 35(35): 3898-3905. PMID 28976790
40. National Comprehensive Cancer Network (NCCN). B-Cell Lymphomas. Version 2.2021. Feb 16; https://www.nccn.org/professionals/physician/gls/pdf/b-cell.pdf. Accessed May 21, 2021.
41. National Comprehensive Cancer Network (NCCN). Acute Lymphoblastic Leukemia. Version 2.2020. 2020 Oct 23; https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed May 21, 2021.
42. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. Apr 2019; 25(4): 625-638. PMID 30592986
43. National Cancer Institute. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017 Nov 27; https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed May 21, 2021.
44. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. Feb 01 2018; 378(5): 439-448. PMID 29385370
45. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. Sep 02 2015; 7(303): 303ra139. PMID 26333935
46. Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia. Crit Care Med. Feb 2017; 45(2): e124-e131. PMID 27632680
47. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. Feb 10 2007; 25(5): 579-86. PMID 17242396
48. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. Sep 20 2014; 32(27): 3059-68. PMID 25113753
49. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. Jan 03 2019; 380(1): 45-56. PMID 30501490
50. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. Jan 2019; 20(1): 31-42. PMID 30518502
51. Kite Pharma Inc. Prescribing Label: Yescarta (axicabtagene ciloleucel) suspension for intravenous infusion. 2017; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdf. Accessed May 21, 2021.
52. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. Dec 28 2017; 377(26): 2531-2544. PMID 29226797
53. Novartis Pharmaceuticals. Prescribing Label: Kymriah (tisagenlecleucel) suspension for intravenous infusion. 2018; https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed May 21, 2021.
54. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. Apr 02 2020; 382(14): 1331-1342. PMID 32242358
55. Tecartus (brexucabtagene autoleucel) suspension for intravenous infusion. Prescribing label. Accessed on February 18, 2021. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/tecartus/tecartus-pi.pdf
56. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. Sep 19 2020; 396(10254): 839-852. PMID 32888407
57. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. Jul 10 2014; 124(2): 188-95. PMID 24876563
58. Prescribing label for Breyanzi (lisocabtagene maraleucel) suspension for intravenous infusion. Accessed on February 18, 2021. Available at https://packageinserts.bms.com/pi/pi_breyanzi.pdf
59. Centers for Medicare & Medicaid Services (CMS). Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). 2017 Feb 15; https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291. Accessed May 21, 2021.

Coding Section 

Codes	Number	Description
CPT	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
	0538T	Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (e.g., cryopreservation, storage)
	0539T	Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration
	0540T	meric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous
HCPCS	Q2041	Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car positive viable 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 (effective 04/01/2021)	Brexucabtagene autoleucel, up to 200 million autologous anti-cd19 car positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
	Q2054 (effective 10/01/2021)	Lisocabtagene maraleucel, up to 110 million autologous anti-cd 19 car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeuti dose. C9076 is being deleted.
ICD10-CM	C82.00-C85.99	Non-Hodgkin Lymphoma range
	C91.00-C91.02	Acute lymphoblastic leukemia code range
	Z80.6	Family history of leukemia
	Z80.7	Family history of other malignant neoplasms of lymphoid, hematopoietic and related tissues
	Z85.72	Personal history of non-Hodgkin lymphomas
PCS	XW033C3	Introduction of Engineered Autologous Chimeric Antigen Receptor T-cell Immunotherapy into Peripheral Vein, Percutaneous Approach,
	XW043C3	Introduction of Engineered Autologous Chimeric Antigen Receptor T-cell Immunotherapy into Central Vein, Percutaneous Approach,
TOS	Therapy
POS	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2019 Forward     

11/29/2022	Annual review, adding coverage criteria for Brexuacatagene for relasped or refractory patients with B ceel acute lymphoblastic luekemia.
11/22/2021	Annual review, expanding policy indications for all therapies. Also updating rationale and references.
10/20/2021	Updating coding section adding code Q2054 effective 10/01/2021. No other changes made.
04/12/2021	Adding code 'Q2053' to Coding Section. No other changes made.
11/17/2020	Annual review with significant revisions. Adding Tecartus to policy verbiage.Adding numerous statements for clarity to policy. Also updating regulatory status.
11/05/2019	New Policy