Coverage Policy Manual
Policy #: 2024042
Category: Pharmacy
Initiated: August 2024
Last Review: August 2025
  Lisocabtagene Maraleucel (e.g., Breyanzi)
Description:
Lisocabtagene maraleucel is a chimeric antigen receptor (CAR) T-cell gene therapy. It is CD19-directed immunotherapy that works by using a patient's own genetically altered immune cells to kill B-cell cancer cells in the blood. Lisocabtagene maraleucel is indicated for use in adult patients with relapsed or refractory large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia or small lymphocytic lymphoma. It is not indicated for the treatment of patients with primary central nervous system lymphoma. Lisocabtagene maraleucel has black box warning for cytokine release syndrome, severe neurotoxicity, and new T-cell malignancies (Breyanzi, 2025).
 
REGULATORY STATUS
 
On February 5, 2021, the Food and Drug Administration approved lisocabtagene maraleucel (e.g., Breyanzi) for adults with relapsed or refractory large B-cell lymphoma after one prior therapy.
 
On June 24, 2022, the Food and Drug Administration approved lisocabtagene maraleucel (e.g., Breyanzi) for the treatment of adult patients with 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, who have:
1)Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
2)Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant (HSCT) due to comorbidities or age.
 
On March 14, 2024, the Food and Drug Administration approved lisocabtagene maraleucel (e.g., Breyanzi) for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 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).
 
On May 15, 2024, the Food and Drug Administration approved lisocabtagene maraleucel (e.g., Breyanzi) for adults with relapsed or refractory follicular lymphoma (FL) 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).
 
On May 30, 2024, the Food and Drug Administration approved lisocabtagene maraleucel (e.g., Breyanzi) for adults with relapsed or refractory mantle cell lymphoma (MCL) who have received at least two prior lines of systemic therapy.
 
On June 26, 2025 the Food and Drug Administration approved streamlined patient monitoring requirements and removed REMS program requirement for lisocabtagene maraleucel (e.g., Breyanzi).
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
For coverage criteria prior to August 21, 2024 for Lisocabtagene Maraleucel (e.g., Breyanzi), please email codespecificinquiry@arkbluecross.com for a hardcopy print of the coverage policy.
  
Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.
 
Prior Approval is required for lisocabtagene maraleucel (e.g., Breyanzi).
 
The use of this drug/therapy requires documentation of direct involvement and ordering by a physician with expertise in specified condition and in a center approved for administration of CAR-T or gene product.
 
Effective November 1, 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Lisocabtagene maraleucel (e.g., Breyanzi) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
FDA Labeled Indications:
 
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
 
LARGE B-CELL LYMPHOMA:
 
    1. Individual is 18 years of age or older at the time of infusion; AND
    2. Individual has a histologically confirmed diagnosis of relapsed or refractory, aggressive, diffuse large B-cell lymphoma not otherwise specified (including diffuse large B-cell lymphoma arising from indolent lymphoma); high-grade B-cell lymphoma or primary mediastinal large B-cell lymphoma or follicular lymphoma grade 3B; AND
    3. Individual has treatment resistant disease defined as follows:
        1. Disease refractory to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy including an Anti-CD20 monoclonal body (for example, rituximab) and an anthracycline-containing chemotherapy regimen (Breyanzi, 2025); OR
        2. Disease refractory to or relapsed after first-line chemoimmunotherapy including an Anti-CD20 monoclonal body (for example, rituximab) and an anthracycline-containing chemotherapy regimen and individual is not eligible for hematopoietic stem cell transplantation due to comorbidities or age (Breyanzi, 2025); OR
        3. Relapsed or refractory disease after two or more lines of systemic therapy including an Anti-CD20 monoclonal body (for example, rituximab) and an anthracycline-containing chemotherapy regimen (Breyanzi, 2025); AND
    4. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
    5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
    6. Individual does not have primary central nervous system lymphoma; AND
    7. There is only one administration of lisocabtagene maraleucel per individual per lifetime.
 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) or SMALL LYMPHOCYTIC LYMPHOMA (SLL)
 
    1. Individual is 18 years of age or older at the time of infusion; AND
    2. Individual has a diagnosis of:
        1. Relapsed or refractory Chronic Lymphocytic Leukemia (CLL); OR
        2. Relapsed or refractory Small Lymphocytic Lymphoma (SLL); AND
    3. Individual has received at least two prior lines of therapy including the following:
        1. Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib) or deemed ineligible for BTK therapy; AND
        2. B-cell lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax); AND
    4. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
    5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
    6. Individual does not have primary central nervous system lymphoma; AND
    7. There is only one administration of lisocabtagene maraleucel per individual per lifetime.
 
FOLLICULAR LYMPHOMA
 
    1. Individual is 18 years of age or older at the time of infusion; AND
    2. Individual has a diagnosis of relapsed or refractory follicular lymphoma; AND
    3. Individual has received at least two prior lines of therapy including the following:
        1. Anti-CD20 antibody (e.g., rituximab); AND
        2. Alkylating agent (e.g., bendamustine); AND
    4. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
    5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
    6. Individual does not have primary central nervous system lymphoma; AND
    7. There is only one administration of lisocabtagene maraleucel per individual per lifetime.
 
MANTLE CELL LYMPHOMA (MCL)
 
    1. Individual is 18 years of age or older at the time of infusion; AND
    2. Individual has a diagnosis of relapsed or refractory mantle cell lymphoma; AND
    3. Individual has received at least two prior lines of therapy including a Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib) or deemed ineligible for BTK therapy; AND
    4. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
    5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
    6. Individual does not have primary central nervous system lymphoma; AND
    7. There is only one administration of lisocabtagene maraleucel per individual per lifetime.
 
Off-label Indications:
 
The use of this drug for off-label indications not listed below is subject to policy 2000030.
 
    1. Individual meets one of the following options (A&B or C&D):
        1. Individual is 18 years of age or younger (NCCN 2A); AND  
        2. Individual is diagnosed with Pediatric Aggressive Mature B-Cell Lymphomas- Primary Mediastinal Large B-cell lymphoma (NCCN 2A); OR
        3. Individual is 18 years of age or older; AND
        4. Individual has a histologically confirmed diagnosis of one of the following:
            1. Monomorphic Post-Transplant Lymphoproliferative (B-cell type) Disorders (PTLD) (NCCN 2A); OR
            2. HIV-related B cell Lymphomas (NCCN 2A); OR
            3. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NCCN 1, 2A); AND
    2. Individual is using in one of the following ways:
        1. Relapsed or refractory disease after receiving two or more lines of systemic therapy (which may or may not include therapy supported by autologous stem cell transplant), including all of the following:
            1. An anthracycline-containing chemotherapy regimen; AND
            2. For CD20-positive disease, anti-CD20 monoclonal antibody, such as rituximab; OR
        2. Relapsed or refractory disease (less than or equal to 12 months) after first-line rituximab and anthracycline-based chemotherapy (Breyanzi 2025); AND
        3.  Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
        4. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
        5. There is only one administration of lisocabtagene maraleucel per individual per lifetime.
 
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)]. The use of this drug for off-label indications not listed above is subject to policy 2000030.
 
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, 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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Lisocabtagene maraleucel (e.g., Breyanzi) for the treatment of any indication or circumstance not described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals with contracts without primary coverage criteria, lisocabtagene maraleucel (e.g., Breyanzi) for any indication or circumstance not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The repeat treatment of lisocabtagene maraleucel (e.g., Breyanzi) for the treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mantle cell lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals without primary coverage criteria, the repeat treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mantle cell lymphoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Lisocabtagene maraleucel (e.g., Breyanzi) after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals without primary coverage criteria, the use of lisocabtagene maraleucel (e.g., Breyanzi) after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
POLICY GUIDELINES
Relapsed or refractory disease is defined as disease progression after the last regimen or failure to achieve a partial remission or complete remission to the last regimen.
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, lisocabtagene maraleucel (e.g., Breyanzi) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication below.
 
NON-HODGKIN LYMPHOMA:
    • The recommended dose for lisocabtagene maraleucel for individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma after two or more lines of therapy is 20 to 110 x 1 million CAR-positive viable T cells.
 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) or SMALL LYMPHOCYTIC LYMPHOMA (SLL):
    • The recommended dose for lisocabtagene maraleucel for individuals with CLL or SLL is 90 to 110 ×1 million CAR-positive viable T cells as single intravenous infusion.
 
FOLLICULAR LYMPHOMA:
    • The recommended dose for lisocabtagene maraleucel for individuals with FL is 90 to 110 ×1 million CAR-positive viable T cells as single intravenous infusion.
 
MANTLE CELL LYMPHOMA (MCL):
    • The recommended dose for lisocabtagene maraleucel for individuals with MCL is 90 to 110 x 1 million CAR-positive viable T cells as single intravenous infusion.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Effective August 21, 2024 to October 31, 2025
 
Prior Approval is required for lisocabtagene maraleucel (e.g., Breyanzi.
 
The initial use of this drug requires documentation of direct physician (MD/OD) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.
 
Effective August 21, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Lisocabtagene maraleucel as a one-time, single administration treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following conditions:
 
1. NON-HODGKIN LYMPHOMA:
a. Individual is 18 years of age or older at the time of infusion; AND
b. Individual has a histologically confirmed diagnosis of *relapsed or refractory, aggressive, diffuse large B-cell lymphoma not otherwise specified (including diffuse large B-cell lymphoma arising from indolent lymphoma); high-grade B-cell lymphoma or primary mediastinal large B-cell lymphoma or follicular lymphoma grade 3B; AND
c. Individual has received adequate prior therapy including ALL of the following:
i. Anti-CD20 monoclonal antibody for CD20-positive tumor; AND
ii. Anthracycline-containing chemotherapy regimen; AND
iii. For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemo refractory disease after transformation to diffuse large B-cell lymphoma; AND
d. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
f. Individual does not have primary central nervous system lymphoma; AND
g. There is only one administration of lisocabtagene maraleucel per individual per lifetime; AND
h. Must be dosed in accordance with the FDA label; OR
 
2. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) or SMALL LYMPHOCYTIC LYMPHOMA (SLL):
a. Individual is 18 years of age or older at the time of infusion; AND
b. Individual has a diagnosis of:
i. *Relapsed or refractory Chronic Lymphocytic Leukemia (CLL); OR
ii. *Relapsed or refractory Small Lymphocytic Lymphoma (SLL); AND
c. Individual has received at least two prior lines of therapy including the following:
i. Bruton tyrosine kinase (BTK) inhibitor or deemed ineligible for BTK therapy; AND
ii. B-cell lymphoma 2 (BCL-2) inhibitor; AND
d. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
f. Individual does not have primary central nervous system lymphoma; AND
g. There is only one administration of lisocabtagene maraleucel per individual per lifetime; AND
h. Must be dosed in accordance with the FDA label; OR
 
3. FOLLICULAR LYMPHOMA:
a. Individual is 18 years of age or older at the time of infusion; AND
b. Individual has a diagnosis of *relapsed or refractory follicular lymphoma; AND
c. Individual has received at least two prior lines of therapy including the following:
i. Anti-CD20 antibody; AND
ii. Alkylating agent; AND
d. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
f. Individual does not have primary central nervous system lymphoma; AND
g. There is only one administration of lisocabtagene maraleucel per individual per lifetime; AND
h. Must be dosed in accordance with the FDA label; OR
 
4. MANTLE CELL LYMPHOMA (MCL):
a. Individual is 18 years of age or older at the time of infusion; AND
b. Individual has a diagnosis of *relapsed or refractory mantle cell lymphoma; AND
c. Individual has received at least two prior lines of therapy including a Bruton tyrosine kinase (BTK) inhibitor or deemed ineligible for BTK therapy; AND
d. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
f. Individual does not have primary central nervous system lymphoma; AND
g. There is only one administration of lisocabtagene maraleucel per individual per lifetime; AND
h. Must be dosed in accordance with the FDA label.
 
*Relapsed or refractory disease is defined as disease progression after last regimen or failure to achieve a partial remission or complete remission to the last regimen.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
NON-HODGKIN LYMPHOMA:
    • The recommended dose for lisocabtagene maraleucel for individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma after two or more lines of therapy is 20 to 110 x 1 million CAR-positive viable T cells.
 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) or SMALL LYMPHOCYTIC LYMPHOMA (SLL):
    • The recommended dose for lisocabtagene maraleucel for individuals with CLL or SLL is 90 to 110 ×1 million CAR-positive viable T cells as single intravenous infusion.
 
FOLLICULAR LYMPHOMA:
    • The recommended dose for lisocabtagene maraleucel for individuals with FL is 90 to 110 ×1 million CAR-positive viable T cells as single intravenous infusion.
 
MANTLE CELL LYMPHOMA (MCL):
    • The recommended dose for lisocabtagene maraleucel for individuals with MCL is 90 to 110 x 1 million CAR-positive viable T cells as single intravenous infusion.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Lisocabtagene maraleucel for the treatment of any indication or circumstance not described above does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals with contracts without primary coverage criteria, lisocabtagene maraleucel for any indication or circumstance not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The repeat treatment of lisocabtagene maraleucel for the treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mantle cell lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals without primary coverage criteria, the repeat treatment of individuals with relapsed or refractory aggressive types of non-Hodgkin lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mantle cell lymphoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Lisocabtagene maraleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy for any indication or circumstance does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For individuals without primary coverage criteria, the use of lisocabtagene maraleucel after administration of tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
 
 
Rationale:
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.
 
Lisocabtagene Maraleucel
 
The approval of lisocabtagene maraleucel was based on the results of 1 single arm, open-label trial (TRANSCEND) [Abramson, et al. 2020]. Trial participants were required to have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 lines of systemic therapy or auto-HSCT. Of 299 patients who received leukapheresis, 15% (n=44) did not receive CAR-positive T-cells either due to manufacturing failures (n=2), death (n=29), disease complications (n=6), or other reasons (n=7). Of the 255 patients who received treatment, 192 were evaluable for efficacy. Twelve were not evaluable due to absence of positron emission tomography (PET) positive disease at study baseline or after bridging therapy and 51 (17%) either received CAR T-cells outside of the intended dose range (n=26) or received CAR T-cells that did not meet product specifications (manufacturing failures; n=25). The primary end point was the percentage of patients with treatment–emergent adverse events and the ORR (complete or partial response).
 
The primary endpoint was the objective response, defined as the proportion of patients who achieved a best overall response of CR or PR, based on assessment by the independent review committee according to the Lugano classification. The median age was 63 (range, 18 to 86) years including older subpopulations (≥65 years, 42%; ≥75 years, 10%). Patients were heavily pretreated and had aggressive disease. Of these patients, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior HCT, and 2.6% had CNS involvement. The primary efficacy analysis demonstrated an ORR of 73% with a 55% rate of CR among 192 patients evaluable for efficacy. The median DOR was 16.7 months. Response durations were longer in patients who achieved a CR, as compared to patients with a best response of a PR (Table 17). Of the 104 patients who achieved a CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months.
 
Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% (122/268) of patients receiving lisocabtagene maraleucel, with ≥ Grade 3 CRS (Lee grading system, Lee et al 2014) in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. Cytokine release syndrome resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death. No major limitations in study relevance were noted
 
SUMMARY OF EVIDENCE
 
Lisocabtagene Maraleucel
 
For individuals who are adults with relapsed or refractory DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma); high-grade B-cell lymphoma or primary mediastinal large B-cell lymphoma or follicular lymphoma grade 3B who receive lisocabtagene maraleucel, the evidence includes a single-arm prospective trial (TRANSCEND). Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. In 299 patients who underwent leukapheresis, therapy was successfully administered to 255 (85%). Of these, 192 were evaluable for efficacy. Twelve were not evaluable due to absence of PET positive disease at study baseline or after bridging therapy and 51 (17%) either received CAR T-cells outside of the intended dose range (n=26) or received CAR T-cells that did not meet product specifications (manufacturing failures; n=25). The primary efficacy analysis demonstrated an ORR of 73% with a 55% rate of CR. The median DOR was 16.7 months. Response durations were longer in patients who achieved a CR, as compared to patients with a best response of a PR. Of the 104 patients who achieved a CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months. Cytokine release syndrome, including fatal or life-threatening reactions, occurred in 46% of patients including ≥ Grade 3 CRS in 4% of patients. The median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death. No notable study limitations were identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
 
2024 Update
Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis).
 
A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure.
An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839. (Morschhauser F, Dahiya S, Palomba ML, et.al., 2024)
 
Patients with relapsed/refractory (R/R) MCL after ≥two lines of previous therapy, including a Bruton tyrosine kinase inhibitor (BTKi), an alkylating agent, and a CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level (DL) of 50 × 106 (DL1) or 100 × 106 (DL2) chimeric antigen receptor-positive T cells. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria.
Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of previous lines of therapy was three (1-11) with 30% receiving ≥five previous lines of therapy, 73% of patients were age 65 years and older, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary CNS lymphoma. Median (range) on-study follow-up was 16.1 months (0.4-60.5). In the efficacy set (n = 83; DL1 + DL2), ORR was 83.1% (95% CI, 73.3 to 90.5) and complete response (CR) rate was 72.3% (95% CI, 61.4 to 81.6). Median duration of response was 15.7 months (95% CI, 6.2 to 24.0) and progression-free survival was 15.3 months (95% CI, 6.6 to 24.9). Most common grade ≥3 treatment-emergent AEs were neutropenia (56%), anemia (37.5%), and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurologic events (NEs) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%.
 
Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated R/R MCL, including those with high-risk, aggressive disease. (Wang M, Siddiqi T, Gordon LI, et.al., 2024)
 
2025 Update
The FDA approved label updates for liso-cel reduce certain patient monitoring requirements and remove the Risk Evaluation and Mitigation Strategy (REMS) program that had been in place since product was initially approved. The changes include reduced driving restrictions (from 8 weeks to 2 weeks post-treatment) and reduced requirement to stay within proximity of a healthcare facility following infusion of CAR-T reduced from 4 weeks to 3 weeks. The FDA has also approved removal of the REMS requirement from liso-cel product label. A REMS program is often required to help mitigate known or potential risks associated with new drugs or therapies. The FDA has since determined that the established management guidelines and extensive experience of the medical hematology/oncology community are sufficient to diagnose and manage the risks of side effects, including cytokine release syndrome (CRS) and neurologic toxicities (NTs), without a REMS. This change is likely to help accelerate cell therapy into the community center setting.
CPT/HCPCS:
Q2054Lisocabtagene maraleucel, up to 110 million autologous anti-cd19 car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
References: Abramson JS, Palomba ML, Gordon LI, et al.(2020) 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

Breuamzi(2024) package insert Bristol-Meyers Squibb Company, Summit, NJ. 2024

Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P.(2024) Health-related qual of life in pat with triple-class exposed relapsed and refractory mult myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Mar;11(3): e216-e227. doi: 10.1016/S2352-3026(24)00005-X. Erratum in: Lancet Haematol. 2024 May;11(5): e319. doi: 10.1016/S2352-3026(24)00080-2. PMID: 38423700.

Wang M, Siddiqi T, Gordon LI, Kamdar M, Lunning M, Hirayama AV, Abramson JS, Arnason J, Ghosh N, Mehta A, Andreadis C, Solomon SR, Kostic A, Dehner C, Espinola R, Peng L, Ogasawara K, Chattin A, Eliason L, Palomba ML.(2024) 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. 2024 Apr 1;42(10):1146-1157. doi: 10.1200/JCO.23.02214. Epub 2023 Dec 10. PMID: 38072625.

Web(2024) Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024 Jun 3. doi: 10.1038/s41591-024-02986-9. Epub ahead of print. Erratum in: Nat Med. 2024 Jul 9. doi: 10.1038/s41591-024-03175-4. PMID: 38830991.
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