Medical Policy

Policy Num:       08.001.053
Policy Name:     Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma
Policy ID:           [08.001.053] [Ac / B/  M+/ P+] [8.01.63]

Last Review:       January 20, 2025
Next Review:      January 20, 2026
 

Related Policies:

08.001.025 - Adoptive Immunotherapy
08.001.027 - Cellular Immunotherapy for Prostate Cancer

Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma

summary

Description

Chimeric antigen receptor (CAR) T-cells are genetically engineered cells that represent a novel class of cancer immunotherapy. In general, the process of autologous CAR T-cell therapy begins with harvesting white blood cells from the patient via leukapheresis followed by T-cell receptor activation and genetic engineering via retroviral or lentiviral transduction. After the CAR T-cells are generated, they are expanded to clinically relevant numbers, undergo quality control testing, and are cryopreserved. Commercial CAR T-cell products are manufactured at a centralized facility, necessitating transfer of the apheresis product to the manufacturing site, and the final cryopreserved CAR T-cell product back to the treatment facility. Typically, the patient undergoes lymphodepleting chemotherapy to create a favorable immune environment for CAR T-cell activity prior to receiving a single intravenous infusion of the product. Multiple commercial CAR T-cell products have been approved by the U.S. Food and Drug Administration for the treatment of lymphoma and leukemia. Tisagenlecleucel and brexucabtagene autoleucel are approved for treatment of subsets of patients with leukemia and lymphoma and axicabtagene ciloleucel and lisocabtagene maraleucel are approved to treat subsets of patients with lymphoma.

Summary of Evidence

Tisagenlecleucel

For individuals who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are overall survival (OS), disease-specific survival (DSS), quality of life (QOL), and treatment-related mortality and morbidity. The pivotal single-arm trial, ELIANA, reported a 81% response rate (measured by complete response [CR] or complete remission with incomplete blood count [CRi]) in heavily pretreated (after 2 or more lines of treatment) patients. All patients who achieved CR or CRi were also minimal residual disease (MRD)-negative, which is predictive of survival in ALL patients. After a median follow-up of 13.1 months, the median duration of response (DOR) was not reached. Overall survival at 1-year, 2-year and 3-year was 76%, 66%, and 63% respectively. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse events (AEs). Cytokine release syndrome (CRS) was observed in more than half (77%) of patients, and approximately 88% had an adverse event at grade 3 or higher. Tisagenlecleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma who failed first-line chemoimmunotherapy in the randomized controlled BELINDA trial. The primary endpoint of event-free survival (EFS) was not superior in the tisagenlecleucel treated arm compared to standard salvage therapy. 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 large B-cell lymphoma (eg, diffuse large B-cell lymphoma [DLBCL] not otherwise specified, high-grade B-cell lymphoma, transformed follicular lymphoma) who receive tisagenlecleucel, the evidence includes a single-arm prospective trial (JULIET). Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 52% overall response rate (ORR; measured by complete or partial responses) in heavily pretreated patients. Overall survival at 1-year and 2-years was 49% and 42%, respectively. The observed benefits were offset by a high frequency and severity of AEs. Any grade CRS was observed in 58% of the patients, and 63% had an adverse event suspected to be related to study drug at grade 3 or higher. 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 who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The ELARA study enrolled adult participants 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 98 participants who received axicabtagene ciloleucel, interim data for 90 consecutive participants who completed at least 9 months of follow-up from date of first response was reported with a median follow-up of 9.1 months. The primary efficacy analysis demonstrated an ORR of 86% with a 68% rate of CR. The median DOR was not reached. At 12 months, 71% remained event-free. Long-term follow-up and real-world evidence are required to assess the generalizability of tisagenlecleucel efficacy and safety outside of the clinical trial setting. The 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 large B-cell lymphoma (eg, 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 2 single-arm prospective trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal single-arm trial, ZUMA-1, after 2 or more lines of treatment reported an 83% ORR (measured by complete or partial remission) in heavily pretreated patients. Overall survival at 1, 2, and 5 years was 59%, 50%, and 42.6%, respectively. The observed benefits were offset by a high frequency and severity of AEs. Cytokine release syndrome was observed in more than half of patients, and 98% had an adverse event at grade 3 or higher. Axicabtagene ciloleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma who failed first-line chemoimmunotherapy in the randomized controlled ZUMA-7 trial. Axicabtagene ciloleucel treatment resulted in more than 60% improvement in the primary endpoint of event free survival as well as multiple secondary outcomes such as response rate compared with standard of care. The expected level of high-grade toxic effects were observed. 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 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 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 DOR was not reached. At 12 months, 76% remained in remission. Overall survival at 1-year survival was 93%. Updated results after 24-month follow-up reported durable long-term responses. 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 mantle cell lymphoma (MCL) who receive brexucabtagene autoleucel, 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%). The primary efficacy analysis demonstrated an ORR of 87% with a 62% rate of CR. Overall survival at 1-year was 86%. 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. Results of long term follow-up at a median follow-up of 35.6 months showed durable long-term responses with manageable safety. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with relapsed or refractory B-cell ALL who receive brexucabtagene autoleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The pivotal ZUMA-3 single-arm trial reported a 52% response rate (measured by CR or CRi) in heavily pretreated patients. A majority of patients who achieved a CR or CRi were also MRD negative, which is predictive of survival in ALL patients. Overall survival at 1-year was 71%. The observed benefits seen with brexucabtagene autoleucel must be balanced with consideration of a high frequency and severity of (AEs). Cytokine release syndrome was observed in more than half (89%) of the patients and approximately 24% had an adverse event at grade 3 or higher. Results of 2-year follow-up showed durable long-term responses with manageable safety. 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. 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%). The primary efficacy analysis demonstrated an ORR of 73%. 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 or a partial response. 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. One-year survival was 58%. Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% of patients, including Grade 3 or higher disease in 4% of patients. Lisocabtagene maraleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma after 1 prior therapy in the randomized controlled TRANSFORM trial and single-arm study PILOT. The primary endpoint of event free survival in the lisocabtagene maraleucel treated arm was superior to standard therapy (10.1 versus 2.3 months; HR= 0.35) in the TRANSFORM trial. The primary endpoint of ORR was 80% in the PILOT trial that enrolled transplant-ineligible patients with relapsed or refractory LBCL after 1 line of chemoimmunotherapy. 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 who receive lisocabtagene maraleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The TRANSCEND-FL study enrolled adult participants 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 107 participants who received lisocabtagene maraleucel, data for 94 participants who had PET-positive disease at study baseline or confirmation of PET-positive disease after bridging therapy, received conforming product in intended dose range and had at least 9 months of follow up from the date of first response. The primary efficacy analysis demonstrated an ORR of 96% with a 73% rate of CR. The median DOR was not reached. Long-term follow-up and real-world evidence are required to assess the generalizability of lisocabtagene maraleucel 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 CLL or SLL, the evidence for lisocabtagene maraleucel includes a single-arm prospective trial. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The TRANSCEND-CLL study enrolled adult patients with relapsed refractory CLL/SLL after 2 or more lines of systemic therapy, including an BTK inhibitor and a BCL-2 inhibitor. The primary interim efficacy analysis demonstrated an ORR of 45% with a 20% rate of CR. The median DOR was 30.5 months. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with relapsed or refractory MCL who receive lisocabtagene maraleucel, the evidence includes one phase I single-arm study. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The TRANSCEND-MCL study enrolled adult patients with relapsed refractory MCL who were heavily pre-treated. Of the 71 patients enrolled, results were reported for 68 evaluable patients with a median follow-up of 16.1 months. The primary efficacy analysis demonstrated an ORR of 85% with a 68% rate of CR. The median DOR was 13.3 months. Fifty-one percent of patients remained in remission at 12 months. 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. Results of long term follow-up at a median follow-up of 35.6 months showed durable long-term responses with manageable safety. 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.

Additional Information

Not applicable

Objective

The objective of this evidence review is to determine whether the use of chimeric antigen receptor T-cell therapy in individuals with leukemia or lymphoma improves the net health outcome.

Policy Statements

For all therapies, basic criteria include:

1. Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis OR Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist, AND

2. Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy, AND

3. Individual is using as a one-time, single administration treatment.

Additional criteria:

Tisagenlecleucel

Tisagenlecleucel is considered medically necessary for individuals meeting the following criteria:

1. Meet the basic criteria above, AND

2. Criteria for one of the following indications is met:

   1. Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND

      • Are up to 25 years of age at the time of infusion, AND

      • Relapsed after a transplant, or relapsed for a second or later time, or refractory.

   2. Histologically confirmed diagnosis of large B-cell lymphoma including diffuse large B-cell lymphoma not otherwise specified, high grade B-cell lymphoma, or diffuse large B-cell lymphoma arising from follicular lymphoma AND do not have primary central nervous system lymphoma; AND

      • Are 22 year or older at the time of infusion, AND

      • Relapsed or refractory after ≥2 lines of systemic therapy.

   3. Histologically confirmed diagnosis of follicular lymphoma; AND

      • Are 22 year or older at the time of infusion, AND

      • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.

Brexucabtagene autoleucel

Brexucabtagene autoleucel is considered medically necessary for individuals meeting the following criteria:

1. Meet the basic criteria above, AND

2. Criteria for one of the following indications is met:

   1. Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND

      • Are 22 year or older at the time of infusion, AND

      • Relapsed after a transplant, or relapsed for a second or later time, or refractory.

   2. Histologically confirmed diagnosis of mantle cell lymphoma; AND

      • Are 22 year or older at the time of infusion, AND

      • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.

Axicabtagene ciloleucel

Axicabtagene ciloleucel is considered medically necessary for individuals meeting the following criteria:

1. Meet the basic criteria above, AND

2. Criteria for one of the following indications is met:

   1. Histologically confirmed diagnosis of large B-cell lymphoma which is refractory to first-line chemoimmunotherapy or relapsed within 12 months of first-line chemoimmunotherapy; AND

      • Are 22 year or older at the time of infusion, AND

      • Do not have primary central nervous system lymphoma.

   2. Histologically confirmed diagnosis of large B-cell lymphoma including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma which is relapsed or refractory after two or more lines of systemic therapy; AND

      • Are 22 year or older at the time of infusion, AND

      • Do not have primary central nervous system lymphoma.

   3. Histologically confirmed diagnosis of follicular lymphoma; AND

      • Are 22 year or older at the time of infusion, AND

      • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.

Lisocabtagene maraleucel

Lisocabtagene maraleucel is considered medically necessary for individuals meeting the following criteria:

1. 1. Meet the basic criteria above, AND

   2. Criteria for one of the following indications is met:

      1. Histologically confirmed diagnosis of large B-cell lymphoma (LBCL), 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; AND

         • Are 22 year or older at the time of infusion, AND

         • Refractory to first-line chemoimmunotherapy or relapsed within 12 months of first-line chemoimmunotherapy, OR Refractory to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age, OR Relapsed or refractory after 2 or more lines of systemic therapy, AND

         • Do not have primary central nervous system lymphoma.

      2. Histologically confirmed diagnosis of follicular lymphoma; AND

         • Are 22 year or older at the time of infusion, AND

         • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy.

      3. Histologically confirmed diagnosis of mantle cell lymphoma; AND

         • Are 22 year or older at the time of infusion, AND

         • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including a Bruton tyrosine kinase inhibitor.

      4. Histologically confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma; AND

         • Are 22 year or older at the time of infusion, AND

         • Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including a Bruton tyrosine kinase inhibitor and a B-cell lymphoma 2 inhibitor.

All above-mentioned therapies are considered investigational when the above criteria are not met.

Policy Guidelines

The NCCN Clinical Practice Guidelines on Acute Lymphoblastic Leukemia Version 2.2024 published July 19, 2024 define

1. Refractory ALL as complete remission not achieved at the end of induction.

2. Relapsed disease as reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a complete remission.

3. Complete remission as

• • No circulating lymphoblasts or extramedullary disease

  • No lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, CNS involvement, or other extramedullary involvement

  • Trilineage hematopoiesis (TLH) and <5% leukemic blasts

  • ANC ≥1000/microL

  • Platelets≥100,000/microL

No consensus was identified for defining relapsed or refractory disease for the other hematological conditions.

FDA Recommended Dose of Tisagenlecleucel for B-cell Acute Lymphoblastic Leukemia

1. 1. • Patients who are 50 kg or less: 0.2 to 5.0×10⁶ chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously.

      • Patients above 50 kg: 0.1 to 2.5×10⁸ chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.

FDA Recommended Dose of Tisagenlecleucel for Non-Hodgkin Lymphoma and Follicular Lymphoma

1. 1. • 0.6 to 6.0 × 10⁸ chimeric antigen receptor-positive viable T cells intravenously.

FDA Recommended Dose of Axicabtagene Ciloleucel for Non-Hodgkin Lymphoma and Follicular Lymphoma

1. 1. • 2×10⁶ chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 2×10⁸ chimeric antigen receptor-positive viable T cells intravenously.

FDA Recommended Dose of Brexucabtagene Autoleucel for Mantle Cell Lymphoma

1. 1. • 2×10⁶ chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 2×10⁸ chimeric antigen receptor-positive viable T cells intravenously.

FDA Recommended Dose of Brexucabtagene Autoleucel for B-cell Acute Lymphoblastic Leukemia

1. 1. • 1×10⁶ chimeric antigen receptor-positive viable T cells per kg body weight, with a maximum of 1×10⁸ chimeric antigen receptor-positive viable T cells intravenously.

FDA Recommended Dose of Lisocabtagene Maraleucel for Non-Hodgkin Lymphoma

1. 1. • 90 to 110 ×10⁶ chimeric antigen receptor-positive viable T cells as a single intravenous infusion for relapsed or refractory large B-cell lymphoma after 1 line of therapy.

      • 50 to 110 ×10⁶ chimeric antigen receptor-positive viable T cells as a single intravenous infusion for relapsed or refractory large B-cell lymphoma after ≥2 lines of therapy.

Central nervous system (CNS) disease for B-cell Acute Lymphoblastic Leukemia

Disease is defined by the following groups:

1. 1. • CNS 1: Absence of blasts on cerebrospinal fluid cytospin preparation, regardless of the white blood cell (WBC) count

      • CNS 2: WBC count of less than 5/mL and blasts on cytospin findings

      • CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

Boxed Warning and Associated Restricted Program under a Risk Evaluation and Mitigation Strategy (REMS)

Tisagenlecleucel (Kymriah^®), axicabtagene ciloleucel (Yescarta^®), brexucabtagene autoleucel (Tecartus^®), and lisocabtagene maraleucel (Breyanzi^®) have boxed warnings regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities (NT) that include fatal or life-threatening reactions. These agents should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening CRS be treated with tocilizumab. Individuals should be monitored for NTs after treatment.

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

1. 1. • Health care facilities that dispense and administer these chimeric antigen receptor (CAR) T therapies must be enrolled and comply with the REMS requirements.

      • Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses are available for each patient for administration within 2 hours after infusion of these chimeric antigen receptor (CAR) T-cell therapies, if needed for treatment of CRS.

      • Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer these CAR T-cell therapies are trained to manage CRS and NT.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Adoptive immunotherapies such as chimeric antigen receptor (CAR) 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 CAR T-cell therapy.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those patients who fail to obtain a complete response (CR) with induction therapy (ie, failure to eradicate all detectable leukemia cells [<5% blasts] from the bone marrow and blood with subsequent restoration of normal hematopoiesis [>25% marrow cellularity and normal peripheral blood counts]). Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Minimal residual disease positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be the strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a meta-analysis of 20 studies of 11,249 pediatric ALL patients, 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 5,000 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.^3, B-cell ALL is largely a disease of the young, with approximately 60% of cases occurring in patients younger than 20 years, with a median age at diagnosis of 15 years.^2,

Treatment

While treatable in 85% of cases, approximately 15% of children and young adults with ALL will relapse and 2% to 3% of ALL patients are primary refractory.^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 U.S. Food and Drug Administration (FDA) approved clofarabine (as a single agent or in combination therapy) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates (ORRs) in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response were 2.5 months and 6 months, and median overall survival (OS) durations were 3 months and 7.5 months, respectively.^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.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is a diverse group of lymphoid malignancies and is the sixth most common cancer diagnosed in the United States. They can be categorized based on whether they originate from B cells or T cells. Approximately 85% of NHL cases arise from B cell precursors. Indolent lymphomas constitute the majority of NHL cases and are characterized by a slow growth pattern. These lymphomas are often managed with watchful waiting, but they typically respond well to treatment and can be controlled for long periods, often without the need for therapy. The most common subtypes in the indolent category are follicular lymphoma, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), with marginal zone lymphoma being less common. The other major group of NHLs are the aggressive lymphomas, which grow rapidly and can be life-threatening. However, despite their severity, they are often curable with chemotherapy. Patients who do not respond to initial chemotherapy or who relapse after frontline therapy generally have a poor prognosis. The most common type of aggressive NHL is diffuse large B-cell lymphoma (DLBCL).^9,

Other types in this group include high-grade B-cell lymphoma and primary mediastinal large B-cell lymphoma, with Burkitt lymphoma and Mantle cell lymphoma (MCL) being much less common.

Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories. The incidence of DLBCL is approximately 7 cases per 100,000 persons per year.^10,

Treatment

Treatment in the first-line setting includes multiple chemotherapy and/or immunotherapy options that typically involve rituximab. While the majority of patients respond well to first-line immunochemotherapy combinations containing rituximab, 10 to 15% have primary refractory disease within 3 months after treatment initiation and another 20 to 35% have a relapse.^11, Of those who relapse or are refractory, 40 to 60% of patients may respond to second-line chemotherapy. Treatment of relapsed/refractory cases is generally stratified according to hematopoietic cell transplant eligibility. There is general consensus that salvage therapy followed by autologous transplantation is the preferred treatment for medically eligible patients with a first relapse of DLBCL or primary refractory DLBCL. Approximately 50% of patients who relapse or are refractory to first line agents proceed to autologous hematopoietic stem-cell transplantation, and of these, approximately 30 to 40% remain progression-free 3 years after transplantation.^{12,13,14,15,16,}For patients who are ineligible for second-line therapy that includes high-dose chemotherapy and hematopoietic stem-cell transplantation, prognosis is often poor with a median OS of 4.4 months. Overall survival at 1 year is 23% and 16% at year 2. For patients who relapse after autologous transplantation, options are limited and include allogeneic hematopoietic stem-cell transplantation. However, the procedure can only be performed if the patient is chemo-responsive and a donor is available. Further, the procedure is associated with a high risk of complications. The mortality risk unrelated to disease relapse is 23% at 1 year.^17,18,19,

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare B-cell malignancy classified as an aggressive form of NHL that arises from cells originating in the “mantle zone” of the lymph node and typically affects men over the age of 60. It accounts for approximately 3 to 6% of all NHL in the United States and differs from DLBCL.^20,21,22, In 2018, the overall incidence of MCL in the U.S was 3,500 with a 5-year and 10-year prevalence of 12,000 and 18,000 cases, respectively. The median age at the time of diagnosis is 68, a majority of patients are non-Hispanic white males and more than 70% of patients present with stage IV disease.^23,24, The majority (75%) of cases initially present with lymphadenopathy while presentation is extranodal in the remaining 25%. In most cases of MCL, chromosomal translocation results in aberrant expression of cyclin D1, leading to cell cycle dysregulation.^25, Many signaling pathways are constitutively activated and/or deregulated in MCL, including the B-cell receptor signaling pathway.^26,

Treatment

There is no standard of care that exists for second-line and higher chemotherapy when a patient has relapsed or refractory MCL.^27, Second line therapies typically depend on the front line therapy utilized, comorbidities, the tumor’s sensitivity to chemotherapy, and overall risk-benefit. Potential salvage regimens include ibrutinib, acalabrutinib, lenalidomide, combination chemotherapy, and bortezomib.

Despite the availability of multiple treatments, MCL is not curable. Median OS in modern trials incorporating intensive therapy is 8 to 10 years with no plateau in the survival curve. Shorter survival times are seen with less intensive therapy. Multiple prognostic indices are used in MCL patients to guide course of treatment. First-line treatment of MCL can consist of aggressive or less-aggressive therapy, depending on patient status at baseline.^26, It generally consists of chemotherapy in combination with rituximab. Only 30 to 40% of patients have a durable long term remission after first line chemo-immunotherapy.^28, Progression is common, with a median time to treatment failure of less than 18 months. Virtually all patients will have refractory or recurrent disease. Treatment of recurrent MCL is difficult, due to the rapid development of chemotherapy resistance. There are multiple preferred chemotherapy regimens that may be offered and choice is primarily made based on prior treatment history, patient comorbidities, and performance status. The expected toxicities of a given regimen as well as clinician’s experience with the regimens are additional considerations. A preferred order for their use has not been established. Most of these regimens have not been compared directly in randomized trials. Given the limited efficacy of these agents and the paucity of data comparing these various treatment options, participation in a clinical trial is encouraged whenever possible. Complete response rates in previously treated or relapsed MCL are generally low (<30%) and have limited response durations. Among patients who have disease progression after the receipt of Bruton’s kinase inhibitor (BTK) therapy, the reported ORRs ranges from 25% to 42% with a median OS of 6 to 10 months with salvage therapies.^29,30,31,32, Allogeneic stem-cell transplantation may be an option for selected patients. However, non–relapse-related mortality remains high at 10 to 24%.^33,

While the clinical course of MCL is generally aggressive, a small proportion of patients with low stage and low-risk disease may have an indolent course, managed by observation, splenectomy, or treatment with alkylating agents analogous to the treatment of patients with small lymphocytic lymphoma or follicular lymphoma.

Follicular Lymphoma

Follicular lymphoma is the second most common subtype of NHL and is associated with an excellent prognosis for most patients with a median OS >20 years.^34, Approximately 40 to 80% of patients treated respond to initial chemoimmunotherapy while 10% do not respond (ie, refractory disease). However, conventional therapy for follicular lymphoma is not curative and most of these patients ultimately develop progressive disease.^35, The prevalence of follicular lymphoma in the United States is approximately 2.7 per 100,000 individuals per year. The 5-year survival rate may be as high as 89.7% and the median age at diagnosis is 63 years.^36, Patients with advanced-stage follicular lymphoma after 2 or more lines of therapy reported a CR rate with approved therapies ≤14%, and median duration of response (DOR) less than 13 months.^37,38,39,

Treatment

Initial treatment depends on the stage of disease at presentation. The first and second line treatments for Grade 1 to 2 follicular lymphoma include excision, radiation therapy, and a systemic therapy with a combination or a single use of an alkylating agent (eg, bendamustine, cyclophosphamide, and chlorambucil), an anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab ), and an immunomodulatory agent (eg, lenalidomide).^40, Other systemic agents, such as vinca alkaloid (eg, vincristine), anthracycline (eg, doxorubicin), and a corticosteroid (eg, prednisone) are also often included in the treatment regimens. Allogeneic hematopoietic cell transplant is used selectively.

There is no standard therapy for patients with relapsed or refractory follicular lymphoma and practice varies widely. Patients with late relapse are treated with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) either alone or in combination with chemotherapy or lenalidomide. The choice between immunotherapy alone versus combination therapy in late relapse depends largely on patient performance status. Novel FDA approved agents for treatment in the multiple relapse/refractory setting include lenalidomide and tazemetostat. The choice is primarily made based on the patient's prior treatment, the expected toxicity profile of the selected regimen, route of administration, and clinician experience with the regimens.^40,

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are mature B cell cancers characterized by the gradual buildup of identical B lymphocytes. CLL and SLL are essentially the same disease with different presentations. The cancer cells in both CLL and SLL share the same pathological and immunophenotypic characteristics. The term CLL is used when the disease is mainly found in the blood, while SLL is used when it primarily affects the lymph nodes. CLL/SLL is more common in men. In the United States, the incidence rates are about 4.6 cases per 100,000 individuals each year. Annually, around 20,700 new cases are diagnosed in the U.S. CLL/SLL primarily affects older adults, with a median age at diagnosis of around 70 years. However, it can also be diagnosed in younger individuals, typically between 30 and 39 years of age.^41,

Treatment

Most individuals will have a complete or partial response to initial therapy. However, conventional therapy for CLL is not curative and most experience relapse. Treatment of individuals with multiply relapsed/refractory CLL/SLL with prior exposure to both a BTK inhibitor and B-cell lymphoma 2 (BCL-2) inhibitor is individualized. Available options have not been directly compared in a clinical trial, and a choice depends on prior response, comorbidities, and access to cellular therapies.

Commercial Chimeric Antigen Receptor T-Cell Therapies Available in the United States

As of September 2023, there are 4 chimeric antigen receptor (CAR) T-cell therapies approved by the FDA for the treatment of cancer. All 4 are CD19-targeting CAR T-cell immunotherapies in which a patient's own T-cells are genetically engineered using a viral vector to express a synthetic receptor called the chimeric antigen receptor. Once injected, the genetically modified T-cells selectively target and bind to CD19 antigen expressed on the surface of B cells and tumors derived from B cells. Tisagenlecleucel, brexucabtagene autoleucel and lisocabtagene maraleucel are approved for treatment of subsets of patients with leukemia and lymphoma. Axicabtagene ciloleucel is approved to treat subsets of patients with lymphoma.

Regulatory Status

Tisagenlecleucel (Kymriah; Novartis) Approvals

On August 30, 2017, approved for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

On May 1, 2018, approved for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

On May 27, 2022, approved for the treatment of adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

• The FDA, under the accelerated approval regulations, requires that Novartis conduct a randomized phase 3 trial in adult patients with relapsed or refractory follicular lymphoma. Patients will be randomized to tisagenlecleucel or an investigator’s choice of regimens consistent with the standard of care. The primary endpoint will be progression-free survival with secondary endpoints that include overall survival and objective response rate. The expected date of trial completion is March 31, 2028 and final report submission to the FDA by September 30, 2028.

Axicabtagene ciloleucel (Yescarta; Kite Pharma) Approvals

On October 18, 2017, approved for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

On March 5, 2021, approved for the treatment of adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

• The FDA, under the accelerated approval regulations, requires that Kite Pharma conduct a randomized phase 3 trial of axicabtagene ciloleucel in patients with relapsed or refractory follicular lymphoma. Patients will be randomized to axicabtagene ciloleucel or to an investigator’s choice of regimens consistent with the standard of care. The primary endpoint will be progression-free survival, with secondary endpoints that include objective response rate and overall survival. The expected date of trial completion is June 30, 2027 and final report submission to the FDA by September 30, 2027.

On April 1, 2022, approved for the treatment of adults patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.

Brexucabtagene autoleucel (Tecartus; Kite Pharma) Approvals

On July 24, 2020, approved for the treatment of adult patients with relapsed or refractory MCL. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

• The FDA, under the accelerated approval regulations, requires that Kite Pharma conduct a study of brexucabtagene autoleucel treatment of subjects with relapsed or refractory MCL who have not been exposed to a BTK inhibitor. A cohort of subjects naïve to BTK inhibitor therapy will be added to the ongoing ZUMA-2 study to fulfill this requirement. Eighty-six subjects will be enrolled. The primary efficacy endpoint will be objective response rate with a supportive efficacy endpoint of duration of response based on a minimum follow-up of 18 months after first objective disease response. The expected date of trial completion is April 30, 2025 and final report submission to the FDA by October 31, 2025.

On October 1, 2021, approved for the treatment of adult patients with relapsed or refractory B-cell precursor ALL.

Lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc.) Approvals

On February 5, 2021, approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

On June 24, 2022, approved for the treatment of adult patients with large B-cell lymphoma, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy or refractory disease to first-line chemoimmunotherapy or relapse after first line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.

On March 14, 2024, approved for adult patients with relapsed or refractory CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

• The FDA, under the accelerated approval regulations, requires that Juno Therapeutics conduct a single arm study of lisocabtagene maraleucel in patients with relapsed or refractory CLL or SLL who have received at least 2 prior lines of therapy, including a prior BTK inhibitor and a BCL-2 inhibitor, to evaluate overall response rate and durability. The study must include a total of 50 treated patients and durable response should be based on a minimum follow-up of 15 months after first objective disease response. The expected date of trial completion is March 31, 2027 and final report submission to the FDA by May 31, 2027.

On May 15, 2024, approved for adults with relapsed or refractory follicular lymphoma who have received two or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

• The FDA, under the accelerated approval regulations, requires that Juno Therapeutics collect and submit the final report, including datasets from the TRANSCEND FL clinical trial (NCT04245839) to verify and describe the clinical benefit of lisocabtagene maraleucel in adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent). All partial and complete responders should have completed at least 24 months of follow up starting from the initial objective response. The expected date of trial completion is May 31, 2025 and final report submission to the FDA by August 31, 2025.

On May 30, 2024, approved for adult patients with relapsed or refractory MCL who have received at least two prior lines of systemic therapy, including a BRK inhibitor.

Rationale

This evidence review was created in October 2019 with searches of the PubMed database. The most recent literature update was performed through September 2, 2024.

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 (AEs) 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

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 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 (CR) with induction therapy (ie, failure to eradicate all detectable leukemia cells [<5% blasts] from the bone marrow and blood with subsequent restoration of normal hematopoiesis [>25% marrow cellularity and normal peripheral blood counts)]).^42,

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 (eg, blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor [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.

Objective or overall response rates are typically calculated as the sum of patients achieving CR and CR with incomplete blood count recovery (CRi). Partial response (PR) is not defined for this disease. Response criteria utilizing conventional morphological features are published by the NCCN.^40,

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 considered 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 (HR) for event-free survival (EFS) 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 (eg, relapse, development of a second neoplasm, or death in remission).

Cytokine release syndrome (CRS) and neurologic toxicity (NT), also known as CAR-T-related encephalopathy syndrome, are 2 significant CAR-T therapy-mediated AEs 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 NT.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 approval of tisagenlecleucel after 2 or more lines of systemic therapy was based on the pivotal, phase 2, single-arm, international, multicenter trial (ELIANA), in which patients with CD19-positive relapsed or refractory B-cell ALL were treated with tisagenlecleucel. ^45, Study characteristics and results are summarized in Tables 1 through 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. 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. Laetsch et al (2023) reported results at a median follow-up of 38.8 months.^46, Results showed that treatment with tisagenlecleucel induced durable long-term responses with manageable safety. Any grade CRS was observed in 77% of patients. No major limitations in study relevance, design and conduct were noted.

Quality of life outcomes from the ELIANA trial were published in a report by Laetsch et al (2019).^47, A prespecified secondary endpoint of Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D) showed that at baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13.3 [95% CI, 8.9 to 17.6] for the PedsQL total score and 16.8 [9.4 to 24.3] for the EQ-5D visual analogue scale). Additionally, 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale.

Tisagenlecleucel was evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma in the second-line setting in the open-label, multicenter BELINDA trial.^48, Individuals with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy were randomly assigned to receive tisagenlecleucel or salvage chemotherapy and autologous hematopoietic stem-cell transplantation. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. The primary endpoint was EFS, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Tables 1, 2, and 3 summarize study characteristics, results, and safety data, respectively. As noted in Table 2, tisagenlecleucel therapy was not superior to standard care.

Table 1. Summary of Key Pivotal Trial Characteristics

     ALL: acute lymphoblastic leukemia; CAR: chimeric antigen receptor; ECOG: Eastern Cooperative Oncology Group; HSCT: hematopoietic stem cell transplantation; RCT: randomized controlled trial;

Table 2. Summary of Key Pivotal Trial Efficacy Results

     CI: confidence interval; CR: complete response; CRi: complete response with incomplete hematologic recovery; DOR: duration of response: EFS: event-free survival; HR: hazard ratio; 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).

Table 3. Summary of Key Trial Safety Results

     AE: adverse event; CRS: cytokine release syndrome; NT: neurological toxicity. 1 CRS was graded according to the Penn/CHOP scale.49,50,

Other Studies

Leahy et al (2021)^51, published a post hoc analysis of 195 patients (1 to 29 years of age) with relapsed or refractory CD19-positive ALL from 5 clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022). All 5 trials were performed at the Children’s Hospital of Philadelphia in which participants received CD19-directed CAR T-cell therapy between April 17, 2012 and April 16, 2019. Of the 5 trials, only 2 trials (ENSIGN and ELIANA) used tisagenlecleucel as the interventional CAR-T cell therapy. Of the 195 patients included in the analysis, 34% (n=66) were categorized as having central nervous system (CNS)-positive disease while the remaining 66% (n=129) were classified as having CNS-negative disease with a median follow-up of 39 months and 36 months, respectively. The proportion of patients in the CNS-positive stratum with a CR at 28 days after infusion was 97% versus 94% in the CNS-negative stratum (p=.74) with no significant difference in relapse-free survival (60% vs 60%) or OS (83% vs 71%) at 2 years between the 2 groups. Authors concluded that the preliminary findings of their study support the use of CAR T-cell therapies for patients with CNS relapsed or refractory B-cell ALL. However, among the 66 patients with CNS-positive disease, only 1 patient was from the ENSIGN trial who received tisagenlecleucel. Therefore, data demonstrating clinical efficacy and safety of tisagenlecleucel among patients with CNS-positive disease are lacking.

Levine at al (2021)^52, published a pooled analysis of 137 patients from the ELIANA (n=79) and ENSIGN (n=58) trials reporting comprehensive safety data for tisagenlecleucel. Grade 3 or 4 treatment-related AEs were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks post-infusion included CRS (any grade: 79% and grade 4: 22%), infections (any grade: 42% and grade 3 or 4: 19%), prolonged (not resolved by day 28) cytopenias (any grade: 40%; grade 3 or 4: 34%), NT (any grade: 36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). It is important to note that Levine et al (2021) used the University of Pennsylvania (Penn) CRS grading scale while other studies have used the CRS Revised Grading System developed by Lee et al (2014)^53, or the ASTCT CRS Consensus Grading scale.^43,

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 after 2 or more lines of treatment 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 was observed in more than half (77%) of the patients and approximately 88% had an adverse event at grade 3 or higher. Tisagenlecleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma who failed first-line chemoimmunotherapy in the randomized controlled BELINDA trial. The primary endpoint of EFS in the tisagenlecleucel treated arm was not superior to standard salvage therapy.

Population Reference No. 2

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 B-cell lymphomas.

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 large B-cell lymphomas.. 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.^44,

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 (ie, 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 lymphoma^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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.^56, Tables 4 and 5 summarize study characteristics and results.

The prespecified primary efficacy endpoint was objective response rate (ORR), based on Lugano criteria^42, as assessed by an independent review committee, and duration of response (DOR). Patients were heavily pretreated with a median of 3 prior therapies (range, 1 to 6), 56% had refractory disease, and 45% 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. Table 6 summarizes safety data assessed for the 111 patients treated with tisagenlecleucel. No major limitations in study relevance, design and conduct were noted.

Schuster et al (2021) reported results of long term follow-up of the JULIET trial at a median follow-up of 40.3 months.^57, Reported overall response rate was 53.0% (95% CI, 43.5 to 62.4; 61 of 115 patients) with 45 (39%) patients having a CR as their best overall response. No treatment-related deaths were reported. Maziarz et al (2020) published patient-reported health-related quality of life from the JULIET trial with a median follow-up of 19.3 months.^58, Two validated instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey were used to measure health-related quality of life at baseline and months 3, 6, 12, and 18. Patients who achieved CR or PR reported sustained health-related quality of life improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales.

Table 4. Summary of Key Pivotal Trial Characteristics

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

Table 5. Summary of Key Pivotal Trial Efficacy Results

      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 6. Summary of Key Trial Adverse Events

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

Subsection Summary: Tisagenlecleucel for 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 CRs, and 12% had PRs. However, the observed benefits were offset by a high frequency and severity of adverse reactions. Any grade CRS was observed in 58% of treated patients in the pivotal trial. Grade 3 or 4 CRS and NT were observed in 22% and 12% of patients.

Population Reference No. 3

Follicular 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 relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy.

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 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, 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, phosphoinositide 3-kinase (PI3K) inhibitors (e.g., copanlisib, duvelisib, idelalisib, and umbralisib) and an 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 lymphoma^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 tisagenlecleucel for the treatment of relapsed or refractory follicular lymphoma was based on the results of an ongoing, open-label, phase 2 study called ELARA. Study characteristics and results are summarized in Table 7 and 8. This trial enrolled 98 participants with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. The primary endpoint was the ORR by central review (per Lugano classification).

Patients were heavily pre-treated. The median number of prior systemic therapies was 4 (range, 2 to 13), with 24% receiving 2 prior lines, 21% receiving 3 prior lines, and 54% receiving ≥4 prior lines. Eighty-seven percent had Stage III-IV disease at study entry, 64% had bulky disease, 36% had a prior autologous HSCT, 79% were refractory to the most recent regimen, and 66% had progression within 24 months of initiating their first anti-CD20 combination therapy. As per the prescribing label, the ORR was 86% and median time to response was 2.9 month (range, 0.6 to 6 months) after a median follow-up of 9.1 months. Pre-specified interim results of ELARA -5 trial were published by Fowler et al (2022).^59,Results at a longer-term median follow-up of 29 months (range 22 to 37) that included data from 97 trial participants continued to demonstrate durable efficacy with no new safety signals or treatment-related deaths.^60,No major limitations in study relevance, design and conduct were noted.

Table 7. Summary of Key Trial Characteristics

     aThe median follow up is the time from first objective response to last disease assessment.

Table 8. Summary of Key Trial Efficacy Results

     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; ORR is a sum of complete (CR) and partial (PR) responses. a Two patients, included in the primary efficacy population, with best overall response of CR, had their disease relapsed more than 6 months after the last line of therapy. b Of the 30 patients who initially achieved a PR, 14 patients (47%) converted to a CR, including 10 patients at the next subsequent visit and within 6 months post-infusion. c Among responders. DOR measured from date of first objective response to date of progression or death from relapse. d Kaplan-Meier estimate in months

Section Summary: Tisagenlecleucel for Follicular Lymphoma

The evidence for tisagenlecleucel for individuals with relapsed or refractory follicular lymphoma consists of a single phase II single-arm study. The ELARA 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. The primary interim efficacy analysis demonstrated an ORR of 86% with a 68% rate of CR. The median DOR was not reached. At 12 months, 71% remained event-free. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified.

Population Reference No. 4 

Axicabtagene Ciloleucel

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 large B-cell lymphomas.

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 B-cell lymphomas. This includes DLBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma.

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 (ie, 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 lymphoma^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 approval of axicabtagene ciloleucel after 2 or more lines of systemic therapy was based on the results of an open-label, multicenter, phase 1-2 study (ZUMA-1).^62, 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 consisting of cyclophosphamide and fludarabine prior to infusion of axicabtagene ciloleucel. 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 to 51). 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 × 10⁶ CAR-positive T cells per kilogram. Long term analysis with up to 5 years of follow-up reported a median OS of 25.8 months, estimated 5-year OS rate of 42.6%, DSS (excluding deaths unrelated to disease progression) of 51.0%. Thus, treatment with axicabtagene ciloleucel induced long-term survival with no new safety signals in patients with refractory LBCL.^63,

The approval of axicabtagene ciloleucel to include the treatment of adults with relapsed or refractory large B-cell lymphoma in the second-line setting was based on the results of the open-label, multicenter ZUMA-7 trial. Initial results were reported by Locke et al (2021)^64, Most patients (74%) had de novo DLBCL and 32% had double- or triple-hit lymphoma. The median age of enrolled participants was 59 with 30% being aged 65 years or older; 66% were male, 83% were White, 6% were Asian, and 5% were Black; 74% had primary refractory disease and 26% had relapsed within 1 year after first-line therapy. The median time from leukapheresis to product release (i.e., when the product passed quality testing and was made available to the investigator) was 13 days. Tables 9, 10, and 11 summarize study characteristics, results, and safety data, respectively. As noted in Table 10, axicabtagene ciloleucel therapy led to significant improvements, as compared with standard care, in EFS and response, with the expected level of high-grade toxic effects. In the axicabtagene ciloleucel arm, the estimated median DOR was 28.4 months in patients who achieved CR and 1.6 months (95% CI, 1.4 to 1.9) in patients who achieved a best response of PR. Fifty-five percent of patients randomized to the standard of care arm subsequently received CD19-directed CAR T-cell therapy off protocol. Westin et al (2023) reported results of long term follow-up of the ZUMA-7 trial at a median follow-up of 47.2 months^65, while Elsawy et al (2022) reported patient-reported outcomes assessed by Quality of Life Questionnaire-Core 30.^66, Results showed that treatment with axicabtagene ciloleucel resulted in significantly longer OS than standard of care along with clinically meaningful improvements in QOL.

No major limitations in study relevance, design and conduct limitations were noted.

Table 9. Summary of Key Trial Characteristics

     CAR: chimeric antigen receptor; CNS: central nervous system; CrCl:creatinine clearance; DLBCL: diffuse large B-cell lymphoma; ECOG: European Cooperative Oncology Group; EFS: event free survival; HCT: hematopoietic cell transplantation; IQR: interquartile range; NHL: non-Hodgkin lymphoma.

Table 10. Summary of Key Trial Efficacy Results

     CI: confidence interval; CR: complete response; DOR: duration of response; EFS: event free survival; HR; hazard ratio; NE: not estimable; ORR: objective response rate; OS: overall survival; PR: partial response; PFS: progression free survival. a The objective response rate (ORR) is the sum of complete (CR) and partial (PR) responses and was graded according to 2007 revised International Working Group criteria54, as assessed by the independent review committee. b defined as the time from randomization to the earliest date of disease progression according to the Lugano classification, the commencement of new therapy for lymphoma, death from any cause, or a best response of stable disease up to and including the response on the day 150 assessment after randomization

Table 11. Summary of Key Trial Safety Results

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

Subsection Summary: Axicabtagene Ciloleucel for Large B-Cell Lymphoma

The evidence for use of axicabtagene ciloleucel for relapsed or refractory aggressive DLBCL (including multiple subsets) after 2 or more lines of treatment 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 CRs, and 21% had PRs. However, the observed benefits were offset by a high frequency and severity of adverse reactions. Any grade CRS was observed in 94% patients in the pivotal trial. Long term results with up to 5 years of follow-up showed that treatment with axicabtagene ciloleucel induced long-term survival with no new safety signals in patients with refractory LBCL. Axicabtagene ciloleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma who failed first-line chemoimmuno therapy in the randomized controlled ZUMA-7 trial. Axicabtagene ciloleucel treatment resulted in more than 60% improvement in the primary endpoint of EFS as well as multiple secondary outcomes such as response rate. The expected level of high-grade toxic effects were reported.

Population Reference No. 5

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 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, phosphoinositide 3-kinase (PI3K) inhibitors (e.g., copanlisib, duvelisib, idelalisib, and umbralisib ) and an 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 lymphoma^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 12 and 13. This trial enrolled 146 patients with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. The median time from leukapheresis to product delivery was 17 days (range, 13 to 33) and leukapheresis to product infusion was 27 days (range, 19 to 250 ). All treated patients received infusion on day 0 and were hospitalized until at least day 7. The primary endpoint was the ORR by central review (per Lugano classification).

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. As per the prescribing label, the ORR was 91% and median time to response was 1.0 month (range, 0.8 to 3.1) after a median follow-up of 14.5 months. Results of ZUMA-5 trial were published by Jacobson at el (2022) with a median follow up of 17.5 months.^69, Among 86 patients, ORR was 94% with 79% with CR. Updated results after 24-month follow-up published by Palomba et al (2023) reported durable long-term responses.^70,

No major limitations in study relevance, design and conduct limitations were noted.

Table 12. Summary of Key Trial Characteristics

     CAR: chimeric antigen response; NHL: non-Hodgkin lymphoma. a Of 123 patients who underwent leukapheresis, 120 received axicabtagene ciloleucel. Reasons for not receiving treatment: 3 (ineligible due to thrombocytopenia, 1 went into remission prior to initiating lymphodepletion, and 1 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 13. Summary of Key Trial Efficacy Results

     CI: confidence interval; CR: complete response; CRS: cytokine release syndrome; DOR: duration of response; ITT: intention to treat; NE: not estimable; ORR: objective response rate; PR: partial response. 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.

Section Summary: Axicabtagene Ciloleucel for Follicular Lymphoma

The evidence for axicabtagene ciloleucel for individuals with relapsed or refractory follicular lymphoma consists of 1 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. The primary efficacy analysis demonstrated an ORR of 91% with a 60% rate of CR. At 12 months, 76% remained in remission. Updated results after 24-month follow-up reported durable long-term responses. No notable study limitations were identified.

Population Reference No. 6

Brexucabtagene Autoleucel

Mantle Cell Lymphoma

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 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 MCL.

Interventions

The therapy being considered is brexucabtagene autoleucel. It is an autologous T-cell immunotherapy containing genetically modified autologous anti-CD19-transduced CD3+ cells. By binding to CD19-expressing cancer cells and normal B cells, brexucabtagene autoleucel initiates T-cell activation and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells. 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^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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).^71, 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. 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 14. 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 Bruton’s kinase inhibitor (BTK) inhibitor therapy, and 81% had received ≥3 lines of prior therapies.

Results are summarized in Table 15. 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%.^72, 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.^71, The median time to response was 28 days (range, 24 to 92 ) with a median follow-up time for DOR of 8.6 months.^72, 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.^68, Notable AEs of grade 3 or higher were cytopenias (94%), infections (32%), NT (31%), and CRS (15%). Grade 3 NTwas reported in 15 (22%) patients and included encephalopathy, confusional state, and aphasia 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. 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 AEs 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.

Wang et al (2022) reported results of long term follow-up of the ZUMA-2 trial at a median follow-up of 35.6 months.^73,Results showed that treatment with axicabtagene ciloleucel induced durable long-term responses with manageable safety.

No major limitations in study relevance, design and conduct limitations were noted.

Table 14. Summary of Key Trial Characteristics

     BTK: Bruton's tyrosine kinase; CAR: chimeric antigen response; MCL: mantle cell lymphoma.  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. The median time from leukapheresis to the delivery of CAR T-cells in the trial was 16 days. 

Table 15. Summary of Key Trial Efficacy Results

     ADE: adverse drug event; CI: confidence interval; CR: complete response; CRS: cytokine release syndrome; DOR: duration of response; ITT: intention to treat; NE: not estimable; NR; not reached; NT: neurological toxicity; ORR; objective response rate; PR: partial response.

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%). Pivotal 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. Results of long term follow-up at a median follow-up of 35.6 months showed durable long-term responses with manageable safety. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified.

Population Reference No. 7

B-Cell Acute Lymphoblastic Leukemia

Clinical Context and Therapy Purpose

The purpose of brexucabtagene autoleucel is to provide a treatment option that is an alternative to or an improvement on existing therapies in adult patients with relapsed or refractory B-cell ALL.

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 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 CR with induction therapy (ie, failure to eradicate all detectable leukemia cells [<5% blasts] from the bone marrow and blood with subsequent restoration of normal hematopoiesis [>25% marrow cellularity and normal peripheral blood counts]).^42,

Interventions

The therapy being considered is brexucabtagene autoleucel. It is an autologous T-cell immunotherapy containing genetically modified autologous anti-CD19-transduced CD3+ cells. By binding to CD19-expressing cancer cells and normal B cells, brexucabtagene autoleucel initiates T-cell activation and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells. 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

In general, the only curative therapy for relapsed or refractory ALL is allogeneic 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 (eg, blinatumomab, inotuzumab ozogamicin, CAR T-cell therapy), or chemotherapy regimens. All options have a category 2A recommendation in the NCCN guidelines.

Outcomes

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

Objective or overall response rates are typically calculated as the sum of patients achieving CR and CRi. Partial response is not defined for this disease. Response criteria utilizing conventional morphological features are published by the NCCN.

A 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 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 HR for EFS in MRD-negative patients compared with MRD-positive patients of 0.23 (95% 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 (eg, relapse, development of a second neoplasm, or death in remission).

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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, phase 2, single-arm, international, multicenter trial (ZUMA-3), patients that had relapsed or refractory B-precursor ALL with morphological disease in the bone marrow (≥5% blasts) were treated with brexucabtagene autoleucel.^74, Study characteristics and results are summarized in Tables 16 to 18.

Of the 54 patients who were evaluable for efficacy, the median age was 40 years (range, 19 to 84), 61% were male, and 67% were White. At enrollment, 46% had refractory relapse disease, 26% had primary refractory disease, 20% had an untreated second or later relapse, and 7% had a first untreated relapse. Among prior therapies, 43% of patients were previously treated with allogeneic SCT, 46% with blinatumomab, and 22% with inotuzumab. The efficacy was established on the basis of CR within 3 months after infusion and the duration of CR. Twenty-eight (51.9%) of the 54 evaluable patients achieved CR, and with a median follow-up for responders of 7.1 months, the median duration of CR was not reached. The median time to CR was 56 days (range, 25 to 86). All efficacy evaluable patients had potential follow-up for ≥10 months with a median actual follow-up time of 12.3 months (range, 0.3 to 22.1). Fatal adverse reactions occurred in 5% (4/78) of patients including cerebral edema, sepsis, and fungal pneumonia. Of the 4 patients who had fatal adverse reactions: 1 patient with fatal pneumonia had pre-existing pneumonia prior to study enrollment, and 1 patient with fatal sepsis had prolonged cytopenia and immunosuppression from prior therapies and underlying disease. Safety results are summarized in Table 21.

Shah et al (2022) reported results of long term follow-up of the ZUMA-3 trial at a median follow-up of 26.8 months.^75, Results showed that treatment with axicabtagene ciloleucel induced durable long-term responses with manageable safety.

No major limitations in study relevance were noted. Identified design and conduct limitations are summarized in Table 22.

Table 16. Summary of Key Pivotal Trial Characteristics

     ALL: acute lymphoblastic leukemia; allo-SCT: allogeneic stem-cell transplant; CAR: chimeric antigen receptor; CR: complete remission; CRi: complete remission with incomplete hematologic recovery; ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: EuroQOL 5-Dimension; 5-Level; MRD: minimal residual disease; OCR, overall complete remission; OS: overall survival; PROs: patient reported outcomes; VAS: visual analogue scale a Relapsed or refractory disease was defined as primary refractory, first relapse with remission of ≤12 months, relapsed or refractory after ≥2 previous lines of systemic therapy, or relapsed or refractory after allo-SCT b 71 patients were enrolled and leukapheresed; 6 did not receive brexucabtagene autoleucel due to manufacturing failure, 8 were not treated primarily due to adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with brexucabtagene autoleucel, and 1 treated with brexucabtagene autoleucel was inevaluable for efficacy. Among the remaining 54 efficacy-evaluable patients, the median time from leukapheresis to product delivery was 16 days (range, 11 to 39) and the median time from leukapheresis to brexucabtagene autoleucel infusion was 29 days (range, 20 to 60 ). 

Table 17. Summary of Key Pivotal Trial Efficacy Results

     CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete blood count recovery; NE, not estimable; OCR, overall complete remission. a Of the 71 patients that were enrolled (and leukapheresed), 57 patients received lymphodepleting chemotherapy, and 55 patients received brexucabtagene autoleucel. Fifty-four patients were included in the efficacy evaluable population. + Indicates a censored value.

Table 18. Summary of Key Trial Safety Results

     AE: adverse event; CRS: cytokine release syndrome; NT: neurological toxicity. 1 CRS was graded according to the Lee Criteria53,

Subsection Summary: Brexucabtagene Autoleucel for B-Cell Acute Lymphoblastic Leukemia

The evidence for use of brexucabtagene autoleucel for CD19+ relapsed or refractory B-cell ALL in adult patients includes a single-arm prospective trial in which 52% (28 of 54) of patients achieved complete remission. Results of long term analysis at a median follow-up of 26.8 months showed durable long-term responses with manageable safety. The observed benefits must be balanced with a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (89%) of the patients and approximately 24% had CRS at grade 3 or higher.

Population Reference No. 8

Lisocabtagene Maraleucel

Large B-Cell Lymphoma

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 large B-cell lymphomas.

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 large B-cell lymphomas. 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,

Interventions

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 (ie, 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 lymphoma^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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

Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Therapy

The approval of lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND).^76, The primary end point was the percentage of patients with treatment–emergent AEs and the ORR (complete or partial response) based on assessment by the independent review committee according to the Lugano classification. Tables 19 and 20 summarize study characteristics and results, respectively. 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. 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. Data on health-related quality of life and symptoms were reported by Patrick et al (2021). Clinically meaningful improvement was observed in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire scores for global health status/QOL.^77,

Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% (122/268) of patients receiving lisocabtagene maraleucel, with grade ≥3 CRS (Lee grading system^53,) 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). Median duration of CRS was 5 days (range, 1 to 30) in all patients, including those who died or had CRS ongoing at time of death. No major limitations in study relevance were noted.

Relapsed or Refractory Large B-Cell Lymphoma After One Line of Therapy

The approval of lisocabtagene maraleucel after 1 prior therapy was based on the results of an open-label, multicenter, phase 3 TRANSFORM study^78,79, and 1 single arm, open-label trial (PILOT) which enrolled transplant-eligible individuals.^80, The primary endpoint of TRANSFORM trial was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. The median age of enrolled patients was 59 years (range 18 to 75 years). More than half of the patients (55%) were diagnosed with DLBCL NOS, 23% with high-grade B-cell lymphoma, 10% with primary mediastinal large B-cell lymphoma, and 8% with DLBCL arising from indolent lymphoma. Primary refractory disease to last therapy was present in 73% of the patients and 27% had relapsed disease within 12 months of achieving complete response(CR) to first-line therapy. Table 19 and 20 summarize study characteristics and results respectively. Of 92 trial participants randomized to lisocabtagene maraleucel, 89 (97%) received it. The median time from leukapheresis to product availability was 26 days (range: 19 to 84 days), and the median time from leukapheresis to product infusion was 36 days (range: 25 to 91 days). Results reported significant improvement in median event-free survival in the lisocabtagene maraleucel (10.1 months) compared with the standard-of-care group (2.3 months); stratified hazard ratio 0.35; 95% CI 0.23 to 0.53; stratified Cox proportional hazards model one-sided p<0.0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the lisocabtagene maraleucel group vs 46 [51%] of 91 patients in the standard-of-care group), anemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs 3 [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the lisocabtagene maraleucel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the lisocabtagene maraleucel and 44 (48%) in the standard-of-care group.^81,

In the PILOT study, the primary endpoint was the ORR based on an independent review committee according to the Lugano 2014 criteria. Of 74 individuals who underwent leukapheresis, 61 (82%) received lisocabtagene maraleucel; 1 (1.4%) received CAR-positive T cells that did not meet the product specifications (manufacturing failure) and 12 (16%) did not receive CAR-positive T cells for other reasons. The median age was 74 years, 61% were male, 89% were white, 3% were Asian, and 2% were Black. Diagnoses included de novo DLBCL NOS (51%), high-grade B-cell lymphoma (33%), and DLBCL arising from follicular lymphoma (15%). Of these patients, 53% had primary refractory disease, 23% had relapse within 12 months of completing first-line therapy, and 25% had relapse >12 months after first-line therapy. Table 19 and 20 summarize study characteristics and results respectively. The median time to CR was 1 month (range 0.8 to 6.9 months). Median on-study follow-up was 12.3 months. The ORR was 80% (95% CI 68 to 89; p<.0001).^80,81,

Table 19. Summary of Key Trial Characteristics

     a HGBCL with gene arrangements in MYC and either BCL2, BCL6, or both. b 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).

     AST: aspartate aminotransferase; ALT: alanine aminotransferase; 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); HSCT: hemopoietic stem cell transplant; HGBCL, high-grade B-cell lymphoma; IRC: independent review committee; LBCL: large B-cell lymphoma; LVEF: left ventricular ejection fraction; 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

     CI: confidence interval; CR: complete response; DOR: duration of response; EFS: event-free survival;ORR : objective response rate; OS: overall survival; PR: partial response; PFS: progression free survival. a The objective response (OR) is the sum of complete (CR) and partial (PR) responses and were graded according to 2014 Lugano criteria55, as assessed by the independent review committee. b EFS is defined as time from randomization to the earliest date of disease progression or relapse, death from any cause, failure to achieve CR or PR by 9 weeks post-randomization, or start of new lymphoma therapy due to efficacy concerns. 

Subsection Summary: Lisocabtagene Maraleucel for Relapsed or Refractory 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). The primary efficacy analysis demonstrated an ORR of 73% with a 54% 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) in all patients, including those who died or had CRS ongoing at time of death. Lisocabtagene maraleucel was also evaluated for the treatment of adults with relapsed or refractory large B-cell lymphoma after 1 prior therapy in the randomized controlled TRANSFORM trial and single-arm PILOT study. The primary endpoint of EFS in the lisocabtagene maraleucel treated arm was superior to standard therapy (10.1 versus 2.3 months; HR= 0.35) in the TRANSFORM trial. The primary endpoint of overall response was 80% in the PILOT trial that enrolled transplant-ineligible patients with relapsed or refractory LBCL after 1 line of chemoimmunotherapy. No notable study limitations were identified.

Population Reference No. 9

Follicular Lymphoma

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 relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy.

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 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 options for patients who have had multiple relapses or have refractory follicular lymphoma include lenalidomide, phosphoinositide 3-kinase (PI3K) inhibitors (e.g., copanlisib, duvelisib, idelalisib, and umbralisib) and an 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 lymphoma^54,or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND-FL).^82, The primary endpoint was the percentage of patients who achieve ORR (complete or partial response) based on assessment by the independent review committee according to the Lugano classification. Tables 21 and 22 summarize study characteristics and results, respectively. The median age was 63 years (range, 23 to 80), 62% were male, ECOG performance status was 0 in 63% and 1 in 37% of patients. Patients were heavily pretreated and had aggressive disease. The median number of prior systemic therapies was 3 (range: 2 to 10), with 46% receiving 2 prior lines, 22% receiving 3 prior lines and 32% receiving ≥4 prior lines. Twenty-nine percent of patients had prior autologous HSCT. Eighty-nine percentage patients had Stage III-IV disease at study entry, 29% had bulky disease, 64% had progression within 6 months of the most recent regimen, and 50% had progression within 24 months of initial diagnosis. The primary efficacy analysis demonstrated an ORR of 96% with a 73% rate of CR among 94 patients evaluable for efficacy. The median DOR was not reached. Of the 69 patients who achieved a CR, 88% had remission lasting at least 12 months and 83% had remission lasting at least 18 months.

Safety data included 107 adult patients. Serious adverse reactions occurred in 26% of patients. The most common nonlaboratory serious adverse reactions (>2%) were CRS, aphasia, febrile neutropenia, fever, and tremor. The most common nonlaboratory adverse reactions (≥20%) were CRS, headache, musculoskeletal pain, fatigue, constipation, and fever.

Table 21. Summary of Key Trial Characteristics

     a Of 114 patients who underwent leukapheresis, 107 received lisocabtagene maraleucel and the median dose administered was 100.02 x 106 CAR-positive viable T-cells (range: 93.4 to 109.2 x 106 CAR-positive viable T cells). CI: confidence interval; CR: complete response; CrCl: creatinine clearance; DOR: duration of response; ECOG : Eastern Cooperative Oncology Group; IRC: independent review committee; ORR: objective response rate; OS: overall survival; PET: positron emission tomography; PFS: progression free survival.

Table 22. Summary of Key Trial Efficacy Results

     CI: confidence interval; CR: complete response; DOR: duration of response; ORR : objective response rate; PR: partial response  a The objective response (OR) is the sum of complete (CR) and partial (PR) responses and were graded according to 2014 Lugano criteria55, as assessed by the independent review committee.

Section Summary: Lisocabtagene Maraleucel for Follicular Lymphoma

The evidence for lisocabtagene maraleucel for individuals with relapsed or refractory follicular lymphoma consists of a one single-arm study. The TRANSCEND-FL 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. The primary interim efficacy analysis demonstrated an ORR of 96% with a 73% rate of CR. The median DOR was not reached. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified.

Population Reference No. 10

Relapsed or Refractory Chronic Lymphocytic Lymphoma or Small Lymphocytic Lymphoma

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 relapsed or refractory chronic lymphocytic lymphoma (CLL) or small lymphocytic lymphoma (SLL).

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 CLL/SLL 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 a BTK inhibitor and a BCL-2 inhibitor.

Interventions

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 options for patients with multiply relapsed/refractory CLL/SLL with prior exposure to both a BTK inhibitor and B-cell lymphoma 2 (BCL-2) inhibitor is individualized. Available options have not been directly compared in a clinical trial, and a choice depends on prior response, comorbidities, and access to cellular therapies.

Outcomes

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

Efficacy was based on ORR (including CR and PR) and DOR as determined by an IRC using 2018 International Workshop CLL (iwCLL) criteria.^83, Responses are categorized as complete, partial, or progressive.

As mentioned in a previous section of this document, the severity of CAR-T therapy mediated CRS and NT is assessed by ASTCT criteria.^43,44,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. 1. • 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 AEs, 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 lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND-CLL).^84,The primary endpoint was the percentage of patients who achieve ORR (complete or partial response) based on assessment by the independent review committee according to the 2018 International Workshop CLL criteria.

Tables 23 and 24 summarize study characteristics and results, respectively. The median age was 63 years (range, 23 to 80), 62% were male, ECOG performance status was 0 in 63% and 1 in 37% of patients. Nineteen of 84 patients were not evaluable for efficacy (13 patients did not have baseline disease assessments performed after completion of bridging therapy, 1 patient lacked measurable disease, and 5 had Richter’s transformation). Of the 65 efficacy-evaluable patients, the median age was 66 years, 68% were male and 80% were White. Two-percent were Hispanic and 89% were non-Hispanic. Eighty-three percent of patients had at least one high risk genetic attribute including 43% del(17p), 45% TP53 mutation, 45% unmutated IGHV, and 62% with complex karyotype. Fifty-one percent of the patients had bulky disease. The median number of prior therapies was 5 (range: 2 to 12). All 65 patients were exposed to a BTK inhibitor, of which 88% were refractory, 1.5% were relapsed, and 11% were intolerant. Of 65 patients who received a BCL-2 inhibitor, 92% were refractory, none relapsed, and 6% were intolerant. A total of 83% had disease refractory to last therapy. The primary efficacy analysis demonstrated an ORR of 45% with a 20% rate of CR among 65 patients evaluable for efficacy. The median DOR was 35.3 months. Of the 13 patients who achieved a CR, 100% had remission lasting at least 12 months and 88% had remission lasting at least 18 months.

Safety data included 89 adult patients. Serious adverse reactions occurred in 60% of patients. The most common nonlaboratory serious adverse reactions (>2%) were CRS, encephalopathy, febrile neutropenia, pneumonia, hemorrhage, fever, renal failure, aphasia, abdominal pain, delirium, tumor lysis syndrome, upper respiratory tract infection, and hemophagocytic lymphohistiocytosis [IEC-HS]. Fatal adverse reactions occurred in 1.1% of patients.

Table 23. Summary of Key Trial Characteristics

     a MRD negative status defined as less than one CLL cell per 104 leukocytes using ClonoSEQ, a next generation sequencing assay at any time post infusion. b Of 113 patients who underwent leukapheresis, 94 received lisocabtagene maraleucel. Of the 94, 84 received lisocabtagene maraleucel at 90 to 111 × 106 CAR-positive T cells and 10 received a cell-dose outside of this dose range; 3 received CAR-positive T cells that did not meet the product specifications (manufacturing failure); and 16 other patients did not receive lisocabtagene maraleucel for other reasons. Nineteen of 84 patients were not evaluable for efficacy (13 patients did not have baseline disease assessments performed after completion of bridging therapy, 1 patient lacked measurable disease, and 5 had Richter’s transformation) CI: confidence interval; CLL: chronic lymphocytic leukemia; CR: complete response; CrCl: creatinine clearance; DOR: duration of response; ECOG : Eastern Cooperative Oncology Group; IRC: independent review committee; ORR: objective response rate; OS: overall survival; PET: positron emission tomography; PFS: progression free survival; SLL: small lymphocytic lymphoma. 

Table 24. Summary of Key Trial Efficacy Results

     CI: confidence interval; CR: complete response; DOR: duration of response; ORR : objective response rate; PR: partial response; MRD: minimal residual disease  a The objective response (OR) is the sum of complete (CR) and partial (PR) responses and were graded according to 2018 International Workshop CLL (iwCLL) criteria.83,

Section Summary: Lisocabtagene Maraleucel for Relapsed or Refractory Chronic Lymphocytic Lymphoma or Small Lymphocytic Lymphoma

The evidence for lisocabtagene maraleucel for individuals with relapsed or refractory chronic lymphocytic lymphoma or small lymphocytic lymphoma consists of a one single-arm study. The TRANSCEND-CLL study enrolled adult patients with relapsed refractory CLL/SLL after 2 or more lines of systemic therapy, including including an BTK inhibitor and a BCL-2 inhibitor. The primary interim efficacy analysis demonstrated an ORR of 45% with a 20% rate of CR. The median DOR was 30.5 months. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment.

Population Reference No. 11

Mantle Cell Lymphoma

Clinical Context and Therapy Purpose

The purpose of lisocabtagene maraleucel in adult patients who have relapsed or refractory MCL is to provide a treatment option that is an improvement on existing therapies.

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 MCL.

Interventions

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

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^54, or Lugano criteria^55, 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 NT is assessed by ASTCT criteria.^43,44,

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 AEs, 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 an open-label, phase 1 study (TRANSCEND-MCL).^85,

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. Of the 71 patients, data for 68 patients were included in the primary efficacy analysis who received at least 2 prior lines of therapy including a BTK inhibitor, had PET-positive disease at study baseline or after bridging therapy, received conforming product in the intended dose range, and had at least 6 months of follow up from the date of first response and are summarized in Table 25 and 26.

The median age was 69 years; 75% were male, ECOG performance status was 0 in 57% and 1 in 43% of patients; 87% were White. The median number of prior therapies was 3 (range: 2 to 11), 32% had received prior HSCT, 29% had blastoid morphology and 10% had CNS lymphoma involvement at baseline. All 68 patients were exposed to BTK inhibitor, of which 56% were refractory, defined as any response to prior BTK inhibitor that was less than PR. Both the median time to first response (CR or PR) and the median time to first CR were 1 month (range: 0.7 to 3 months). The median DOR was 13.3 months. Of the 46 patients who achieved a CR, 58% had remission lasting at least 12 months and 48% had remission lasting at least 18 months.

Safety data included 88 adult patients. Serious adverse reactions occurred in 53% of patients.The most common nonlaboratory serious adverse reactions (>2%) were CRS, confusional state, fever, encephalopathy, mental status changes, pleural effusion, upper respiratory tract infection, and decreased appetite. Fatal adverse reactions occurred in 4.5% of patients.

No major limitations in study relevance, design and conduct limitations were noted.

Table 25. Summary of Key Trial Characteristics

     BTK: Bruton's tyrosine kinase; CR: complete response; CrCl: creatinine clearance; DOR: duration of response; ECOG : Eastern Cooperative Oncology Group; IRC: independent review committee; ORR: objective response rate; MCL: mantle cell lymphoma. a Of 89 patients who underwent leukapheresis, 71 received lisocabtagene maraleucel and the median dose administered was 99.8 x 106 CAR-positive viable T cells (range: 90 to 103 x 106 CAR-positive viable T cells). 

Table 26. Summary of Key Trial Efficacy Results

     CI: confidence interval; CR: complete response; DOR: duration of response; ORR; objective response rate; PR: partial response.

Section Summary: Lisocabtagene Maraleucel for Relapsed or Refractory Mantle Cell Lymphoma

The evidence for lisocabtagene maraleucel for individuals with relapsed or refractory MCL consists of one phase 1 single-arm study. The TRANSCEND-MCL study enrolled adult patients with relapsed refractory MCL who were heavily pre-treated. Of the 71 patients enrolled, results were reported for 68 evaluable patients with a median follow-up of 16.1 months. The primary efficacy analysis demonstrated an ORR of 85% with a 68% rate of CR. The median DOR was 13.3 months. Fifty-one percent of patients remained in remission at 12 months. 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. Results of long term follow-up at a median follow-up of 35.6 months showed durable long-term responses with manageable safety. In the absence of a RCT, it is difficult to draw comparisons with currently available salvage treatment. No notable study limitations were identified.

Supplemental Information

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 Institute for Health and Care Excellence

Tisagenlecleucel

On May 15, 2024, the National Institute for Health and Care Excellence (NICE) issued a technology appraisal guidance [TA975] on tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in people aged 25 years and under.^86,Treatment with tisagenlecleucel is recommended as an option for treating relapsed or refractory B-cell ALL that is

• relapsed after a transplant, or

• relapsed for a second or later time, or

• refractory

On November 29, 2023, the NICE issued issued a technology appraisal guidance [TA933] and stated that it is unable to make a recommendation on tisagenlecleucel (Kymriah) for treating relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies because Novartis did not provide a complete evidence submission.^87,

Axicabtagene Ciloleucel

On February 28, 2023, the NICE issued a technology appraisal guidance [TA872] on axicabtagene ciloleucel for treating DLBCL and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies^88,. Treatment with axicabtagene ciloleucel is recommended as an option for treating DLBCL and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. The committee concluded that axicabtagene ciloleucel would be positioned as a treatment option for people whose disease:

• did not respond after 2 systemic therapies, or

• has relapsed after 1 systemic therapy, and who have had chemotherapy and an autologous stem cell transplant but whose disease has then relapsed again, or

• has relapsed after 1 systemic therapy, and who would have been able to have an autologous stem cell transplant as part of a second treatment, but whose disease does not respond to salvage chemotherapy

On June 7, 2023, the NICE issued a technology appraisal [TA895] guidance on axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy. ^89, Treatment with axicabtagene ciloleucel is recommended as an option for treating diffuse large B‑cell lymphoma in adults if the conditions in the managed access agreement are followed. Relapsed or refractory was defined as follows:

• Refractory disease is defined as progressive disease as the best response to 1st line standard chemo-immunotherapy or stable disease as the best response after at least 4 cycles of 1st line standard chemo-immunotherapy or a partial response as the best response after at least 6 cycles of 1st line standard chemo-immunotherapy with biopsy-proven residual disease or a partial response with biopsy-proven progressive disease within 12 months or less from completion of treatment.

• Relapsed disease is defined as disease that was in complete remission following 1st line standard chemo-immunotherapy and has been followed by a biopsy-proven disease relapse within 12 months or less from completion of treatment

On June 7, 2023, the NICE issued a technology appraisal guidance [TA894] on axicabtagene ciloleucel for treating relapsed or refractory follicular lymphoma.^90,Axicabtagene ciloleucel is not recommended, within its marketing authorisation, for treating relapsed or refractory follicular lymphoma after 3 or more systemic treatments in adults. The committee made these recommendations because the clinical evidence is from a small study that suggests that axicabtagene ciloleucel increases the amount of time people have before their condition gets worse and how long they live, but it is uncertain by how much. Axicabtagene ciloleucel does not meet NICE's criteria to be considered a life-extending treatment at the end of life. This is because people having standard treatments for relapsed or refractory follicular lymphoma after 3 or more systemic treatments are likely to live longer than 2 years.

Brexucabtagene Autoleucel

On February 24, 2021 the NICE issued a technology appraisal guidance [TA677] on brexucabtagene autoleucel for treating relapsed or refractory mantle cell lymphoma (MCL).^91, Treatment with brexucabtagene autoleucel is recommended as an option for relapsed or refractory MCL in adults who have previously had a Bruton's TKI. It is only recommended if the conditions in the managed access agreement are followed. Relapsed or refractory was defined as follows:

• Refractory disease is defined as being either progressive disease as the best response to the last line of systemic therapy or stable disease as the best response after at least 2 cycles of the last line of therapy with stable disease duration lasting no longer than 6 months from the last dose of the last line of systemic therapy

• Relapsed disease is defined as disease that responded partially or completely to the last line of therapy and has since progressed

On June 7, 2023 the NICE issued a technology appraisal guidance [TA893] on brexucabtagene autoleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over. ^92,Treatment with brexucabtagene autoleucel is recommended as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people 26 years and over. It is only recommended if the conditions in the managed access agreement are followed. Relapsed or refractory was defined as follows:

• The patient fulfils one of the following clinical scenarios relating to the definition of relapsed or refractory ALL.

  • the patient has primary refractory disease i.e. did not achieve a complete remission after 2 cycles of standard chemotherapy for newly diagnosed ALL or,

  • the patient has a bone marrow relapse after allogeneic stem cell transplantation in 1st remission and is at least 3 months since allogeneic SCT with no active Graft versus Host Disease (GVHD) requiring systemic therapy or,

  • the patient has a bone marrow relapse after allogeneic stem cell transplantation in 2nd remission and is at least 3 months since allogeneic SCT with no GvHD requiring systemic therapy or,

  • the patient is in 1st bone marrow relapse following a remission lasting 12 months or less (not had SCT) or,

  • the patient is refractory to or has relapsed after 2nd or more line chemotherapy/monoclonal antibody (not had SCT) or,

  • relapsed disease and ineligible for allogeneic SCT due to comorbid disease (but still fit enough for CAR-T cell therapy with brexucabtagene autoleucel) or contraindicated to allogeneic SCT conditioning or lack of a suitable donor.

Lisocabtagene Maraleucel

On July 10, 2024, the NICE issued issued a technology appraisal guidance [TA987] and stated that it is unable to make a recommendation on lisocabtagene maraleucel (Breyanzi) for treating relapsed or refractory aggressive B-cell non-Hodgkin lymphoma in adults because Celgene did not provide a complete evidence submission.^92,

As of September 3, 2024, as per the NICE website, the technology appraisal guidance "Lisocabtagene maraleucel for treating relapsed or refractory aggressive B-cell non-Hodgkin lymphoma after 1 systemic treatment [ID3869]" is currently under development with no listed date for completion.

As of September 3, 2024, as per the NICE website, the technology appraisal guidance "Lisocabtagene maraleucel for treating relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma [ID6174]" is currently under development with no listed date for completion.

National Comprehensive Cancer Network

Acute Lymphoblastic Leukemia

Current National Comprehensive Cancer Network (NCCN) guidelines^i,ii for ALL (v. 2.2024)^42, 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 National Comprehensive Cancer Network (NCCN) guidelines^i.ii for ALL (v. 2.2024)^42, recommend (category 2A) brexucabtagene autoleucel as a treatment option for relapsed or refractory

• Philadelphia chromosome-positive adolescent and young adult patients with refractory disease OR ≥2 relapses and failure of tyrosine kinase inhibitors.

• Philadelphia chromosome-negative adolescent and young adult patients with refractory disease OR ≥2 relapses.

B-Cell Lymphoma

Current NCCN guidelines^i.ii for B-cell lymphoma (v.3.2024)^40, recommend:

• axicabtagene ciloleucel, lisocabtagene maraleucel and tisagenlecleucel (category 2A) as a third-line treatment and subsequent therapy for follicular lymphoma.

• axicabtagene ciloleucel (category 2A) as a third-line treatment and subsequent therapy for marginal zone lymphomas.

• brexucabtagene autoleuce and lisocabtagene maraleucel (category 2A) as a second-line treatment and subsequent therapy for mantle cell lymphoma.

• axicabtagene ciloleucel and lisocabtagene maraleucel (category 1) as a second-line treatment for relapsed disease <12 months or primary refractory diffuse large B-Cell lymphoma.

• lisocabtagene maraleucel (category 2A) as a second-line treatment for diffuse large B-Cell lymphoma when there is no intention to proceed to transplant.

• axicabtagene ciloleucel, lisocabtagene maraleucel and tisagenlecleucel (category 2A) as a third-line treatment and subsequent therapy for diffuse large B-Cell lymphoma.

• axicabtagene ciloleucel, lisocabtagene maraleucel and tisagenlecleucel (category 2A) as a treatment for histologic transformation of indolent lymphomas to diffuse large B-Cell lymphoma after multiple lines of prior therapies that includes ≥2 of chemoimmunotherapy regimens for indolent or transformed disease.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Current NCCN guidelines ^i.ii for chronic lymphocytic leukemia/small lymphocytic lymphoma (v.1.2025)^93, recommend lisocabtagene maraleucel (category 2A) as a treatment option for relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma after prior therapy with BTK inhibitor and venetoclax-based regimens.

ⁱ Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (v. 2.2024) and B-Cell Lymphomas (v 3.2024).
© National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 2, 2024. 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.

Medicare National Coverage

Decision Summary:

1. The Centers for Medicare & Medicaid Services (CMS) covers autologous treatment for cancer with T-cells expressing at least one chimeric antigen receptor (CAR) when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) and used for a medically accepted indication as defined at Social Security Act section 1861(t)(2) i.e., is used for either an FDA-approved indication (according to the FDA-approved label for that product), or for other uses when the product has been FDA-approved and the use is supported in one or more CMS-approved compendia.

2. The use of non-FDA-approved autologous T-cells expressing at least one CAR is non-covered. Autologous treatment for cancer with T-cells expressing at least one CAR is non-covered when the requirements in Section A are not met.

3. This policy continues coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 27.

Table 27. Summary of Key Trials

    NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial. b Trial has completed accrual and preliminary results in efficacy-evaluable patients (n = 37) have been published.94,

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. Available at https://www.govinfo.gov/content/pkg/FR-2020-05-29/pdf/2020-10122.pdf Accessed Sep 10, 2023.
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 Sep 10, 2023.
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. PI3Kδ 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 3.2024. August 26, 2024; https://www.nccn.org/professionals/physician/gls/pdf/b-cell.pdf. Accessed October 2, 2024.
41. Sander B, Campo E, Hsi ED. Chronic lymphocytic leukaemia/small lymphocytic lymphoma and mantle cell lymphoma: from early lesions to transformation. Virchows Arch. Jan 2023; 482(1): 131-145. PMID 36454275
42. National Comprehensive Cancer Network (NCCN). Acute Lymphoblastic Leukemia. Version 2.2024. July 19, 2024; https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed Sep 26, 2024.
43. 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
44. 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 Sep 10, 2023.
45. 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
46. Laetsch TW, Maude SL, Rives S, et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. Mar 20 2023; 41(9): 1664-1669. PMID 36399695
47. Laetsch TW, Myers GD, Baruchel A, et al. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. Dec 2019; 20(12): 1710-1718. PMID 31606419
48. Bishop MR, Dickinson M, Purtill D, et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. Feb 17 2022; 386(7): 629-639. PMID 34904798
49. 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
50. 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
51. Leahy AB, Newman H, Li Y, et al. CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials. Lancet Haematol. Oct 2021; 8(10): e711-e722. PMID 34560014
52. Levine JE, Grupp SA, Pulsipher MA, et al. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. Aug 2021; 9(8). PMID 34353848
53. 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
54. 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
55. 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
56. 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
57. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. Oct 2021; 22(10): 1403-1415. PMID 34516954
58. Maziarz RT, Waller EK, Jaeger U, et al. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. Feb 25 2020; 4(4): 629-637. PMID 32074277
59. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. Feb 2022; 28(2): 325-332. PMID 34921238
60. Dreyling M, Fowler NH, Dickinson M, et al. Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update. Blood. Apr 25 2024; 143(17): 1713-1725. PMID 38194692
61. Prescribing Label: Kymriah (tisagenlecleucel) suspension for intravenous infusion. Initial Approval 2017 Available at https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf Accessed Sep 10, 2023.
62. 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
63. Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. May 11 2023; 141(19): 2307-2315. PMID 36821768
64. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. Feb 17 2022; 386(7): 640-654. PMID 34891224
65. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. Jul 13 2023; 389(2): 148-157. PMID 37272527
66. Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. Nov 24 2022; 140(21): 2248-2260. PMID 35839452
67. Prescribing Label: Yescarta (axicabtagene ciloleucel) suspension for intravenous infusion. 2017; Available at https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf Accessed Sep 10, 2023.
68. 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
69. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. Jan 2022; 23(1): 91-103. PMID 34895487
70. Palomba ML, Ghione P, Patel AR, et al. A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma. Expert Rev Anticancer Ther. Feb 2023; 23(2): 199-206. PMID 36723678
71. 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
72. Prescribing Label: Tecartus (brexucabtagene autoleucel) suspension for intravenous infusion. Initial Approval 2020 Available at https://www.gilead.com/-/media/files/pdfs/medicines/oncology/tecartus/tecartus-pi.pdf Accessed on Sep 10, 2023.
73. Wang Y, Jain P, Locke FL, et al. Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. J Clin Oncol. May 10 2023; 41(14): 2594-2606. PMID 36753699
74. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. Aug 07 2021; 398(10299): 491-502. PMID 34097852
75. Shah BD, Ghobadi A, Oluwole OO, et al. Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. J Hematol Oncol. Dec 10 2022; 15(1): 170. PMID 36494725
76. 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
77. Patrick DL, Powers A, Jun MP, et al. Effect of lisocabtagene maraleucel on HRQoL and symptom severity in relapsed/refractory large B-cell lymphoma. Blood Adv. Apr 27 2021; 5(8): 2245-2255. PMID 33904895
78. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. Jun 18 2022; 399(10343): 2294-2308. PMID 35717989
79. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. Apr 06 2023; 141(14): 1675-1684. PMID 36542826
80. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. Aug 2022; 23(8): 1066-1077. PMID 35839786
81. Prescribing label: Breyanzi (lisocabtagene maraleucel) suspension for intravenous infusion. Initial Approval 2021 Available at https://packageinserts.bms.com/pi/pi_breyanzi.pdf Accessed Sep 10, 2023.
82. Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. Aug 2024; 30(8): 2199-2207. PMID 38830991
83. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. Jun 21 2018; 131(25): 2745-2760. PMID 29540348
84. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. Aug 19 2023; 402(10402): 641-654. PMID 37295445
85. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene Maraleucel in Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis of the Mantle Cell Lymphoma Cohort From TRANSCEND NHL 001, a Phase I Multicenter Seamless Design Study. J Clin Oncol. Apr 01 2024; 42(10): 1146-1157. PMID 38072625
86. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA975]: Tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukemia in people aged 25 years and under. Published: 15 May 2024. Available at https://www.nice.org.uk/guidance/TA975/chapter/1-Recommendations. Accessed on Sep 2, 2024.
87. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA933]: Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies. Published: 29 November 2023. Available at https://www.nice.org.uk/guidance/ta933. Accessed on Sep 3, 2024.
88. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA872]: Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. Published: 28 February 2023. Available at https://www.nice.org.uk/guidance/ta872/chapter/1-Recommendation. Accessed on Sep 4, 2024.
89. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA895]: Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy. Published: 7 June 2024. Available at https://www.nice.org.uk/guidance/ta895. Accessed on Sep 6, 2024.
90. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA894]: Axicabtagene ciloleucel for treating relapsed or refractory follicular lymphoma. Published: 7 June 2024. Available at https://www.nice.org.uk/guidance/ta894/chapter/1-Recommendations. Accessed on Sep 5, 2024.
91. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA677]: Brexucabtagene autoleucel for treating relapsed or refractory mantle cell lymphoma. Published: 24 February 2021. Available at https://www.nice.org.uk/guidance/ta677 Accessed on Sep 7, 2024.
92. National Institute for Health and Care Excellence Technology Appraisal Guidance [TA893]: Brexucabtagene autoleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over. Published: 7 June 2023. Available at https://www.nice.org.uk/guidance/ta893 Accessed on Sep 8, 2024.
93. National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 1.2025. October 1, 2024; https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed October 3, 2024.
94. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. Apr 2022; 28(4): 735-742. PMID 35314842

Codes

Applicable Modifiers

N/A

Policy History