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Chimeric Antigen Receptor (CART) Therapy: Yescarta Tecartus, Breyanzi, Kymriah and Aucatzyl
08.01.43q

Policy

​The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

INDEX OF MEDICALLY NECESSARY INDICATIONS
 
This policy addresses numerous medically necessary indications for the use of axicabtagene ciloleucel (Yescarta®), brexucabtagene autoleucel (Tecartus®), lisocabtagene maraleucel (Breyanzi®), tisagenlecleucel (Kymriah®), and obecabtagene autoleucel (Aucatzyl®) listed in order of appearance within the Policy section. Please see below for the specific medical necessity criteria. (NOTE: Experimental/Investigational section below must also be reviewed.)​

Product name​Brand nameIndication
Axicabtagene ciloleucelYescarta®
  • B-cell lymphoma ​(BCL)
  • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)​
Brexucabtagene autoleucelTecartus®
  • Mantle cell lymphoma (MCL)
  • Acute lymphoblastic leukemia (ALL)
Lisocabtagene maraleucelBreyanzi®
  • B-cell lymphoma ​(BCL)
  • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
TisagenlecleucelKymriah®​
  • Acute lymphoblastic leukemia (ALL; young adult and pediatric)
  • ​B-cell lymphoma (BCL)
  • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)​​​​​
​Obecabtagene autoleucel ​
​Aucatzyl®​
  • ​Acute lymphoblastic leukemia (ALL)​

 

MEDICALLY NECESSARY


The following general criteria must be met for all chimeric antigen receptor T-cell (CAR-T) therapy indications unless otherwise specified:​ 

  • The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; human immunodeficiency virus (HIV) infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled. 
  • The individual does not have primary central nervous system (CNS) lymphoma or malignancy.
    • Note: Secondary CNS involvement is permitted only for lisocabtagene maraleucel (Breyanzi).
  • The individual does not have a history of prior CAR-T therapy or prior gene therapy.
  • The individual is 18 years or older at time of infusion (unless pediatric indication is explicitly specified, e.g., tisagenlecleucel (Kymriah)​.

AXICABTAGENE CILOLEUCEL (YESCARTA)

B-Cell Lymphomas​

Axicabtagene ciloleucel (Yescarta) is considered medically necessary for the autologous treatment of relapsed or refractory (R/R) B-cell lymphomas in individuals who have previously received at least one anti-CD20 monoclonal antibody (e.g., rituximab), unless the tumor is CD20-negative, and an anthracycline-based chemotherapy regimen (e.g., doxorubicin) when all the criteria above AND the following are met:


Diagnosis of one of the following subtypes:

  • Diffuse large B-cell lymphoma (DLBCL)
  • High-grade B-cell lymphoma (double/triple-hit) with MYC and BCL2 and/or BCL6 rearrangements
  • Primary mediastinal large B-cell lymphoma (PMBCL)
  • Acquired immunodeficiency syndrome (AIDS)/HIV-related DLBCL
  • Primary effusion lymphoma
  • Human herpesvirus 8 (HHV8)-positive DLBCL​
  • Plasmablastic lymphoma  

AND

  • Used as one of the following:
    • Additional therapy for relapsed disease greater than ​12 months after completion of first-line therapy in individuals who have partial response following second-line therapy (National Comprehensive Cancer Network [NCCN] preferred) 
    • Additional therapy for individuals for relapsed disease less than 12 months after completion of first-line chemoimmunotherapy or primary refractory disease (partial response, no response, or progression) 
    • Third-line and subsequent therapy for disease in second relapse or greater in individuals with partial response, relapse, or progressive disease following therapy for R/R disease (NCCN preferred)

Diagnosis of R/R follicular lymphoma (FL): grade 1 to 2, marginal zone lymphoma (MZL)*

  • Used as third-line and subsequent therapy for partial response, no response, relapsed, or progressive disease in individuals with indications for treatment (NCCN preferred).
*Includes extranodal MZL of the stomach (formerly gastric mucosa–associated lymphoid tissue [MALT]), extranodal MZL of nongastric sites (noncutaneous) (formerly ​nongastric MALT), nodal MZL, and splenic MZL.


Diagnosis of R/R histologic transformation of indolent lymphomas to DLBCL

  • For example: from FL [individual must have chemorefractory disease after transformation to DLBCL or nodal MZL]) AND
  • Used as one of the following:
    • Additional therapy in individuals who have received multiple lines of prior therapies including two or more chemoimmunotherapy regimens for indolent or transformed disease with one anthracycline-based regimen [e.g., doxorubicin], unless contraindicated)  
    • Additional therapy for transformed disease following partial response, no response, or progressive disease after initial treatment with anthracycline-based regimens (e.g., doxorubicin)

Diagnosis of R/R monomorphic post-transplant lymphoproliferative disorder (PTLD)

  • Used as one of the following:
    • Additional therapy for R/R disease greater than 12 months after completion of initial treatment with chemoimmunotherapy in individuals who have partial response following second-line chemoimmunotherapy.
    • Additional therapy for individuals with primary refractory disease (partial response, no response, or progression) or relapsed disease less than 12 months after completion of initial treatment with chemoimmunotherapy.
    • Third-line and subsequent therapy for disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred).

Diagnosis of R/R pediatric aggressive mature BCL (primary mediastinal large BCL)

  • Used as consolidation/additional therapy if partial response achieved after therapy for R/R disease (after use of two or more chemoimmunotherapy regimens).​

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) 


Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of histologic (Richter) transformation to DLBCL (including del(17p)/TP53 mutation) when all the general criteria above AND either of the following criteria are met:

  • Untreated CLL or clonally unrelated disease at initial diagnosis
    • Additional therapy for partial response, refractory disease, or progression while on treatment with chemoimmunotherapy regimens after at least one prior systemic therapy regimen
  • Previously treated CLL and clonally related or clonal relation unknown
    • Additional therapy for partial response, refractory disease, or progression while on treatment with non-chemoimmunotherapy regimens other than CAR-T therapy or chemoimmunotherapy regimens

LISOCABTAGENE MARALEUCEL (BREYANZI​)
B-Cell Lymphomas​

Lisocabtagene maraleucel (Breyanzi) is considered medically necessary for the autologous treatment of R/R B-cell lymphomas, when the general criteria above and following criteria are met:

Diagnosis of one of the following subtypes

  • DLBCL
  • High-grade B-cell lymphoma (double/triple-hit) with MYC and BCL2 and/or BCL6 rearrangements
  • Primary mediastinal large B-cell lymphoma
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Follicular lymphoma (grade 3B) 
  • AIDS/HIV-related DLBCL or plasmablastic lymphoma 
  • Primary effusion lymphoma
  • HHV8-positive DLBCL, not otherwise specified 

AND

  • ​​Used as one of the following:
    • ​Second-line therapy for R/R disease greater than 12 months after completion of first-line therapy if no intention to proceed to transplant (NCCN preferred) or are not eligible for HSCT due to comorbidities or age 
    • Additional therapy for R/R disease greater than 12 months after completion of first-line therapy (with no intention to proceed to transplant [or are not eligible for HSCT due to comorbidities or age] in individuals with DLBCL or primary mediastinal large BCL only) in individuals with intention to proceed to transplant who have partial response following second-line therapy 
    • Additional therapy for individuals with primary refractory disease (partial response, no response, or progression) or relapsed disease less than 12 months after completion of first-line therapy 
    • Third-line and subsequent therapy for disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred) 

​Diagnosis of R/R FL (grade 1 to 2)

  • Third-line and subsequent therapy (if not previously given) for partial response, no response, relapsed, or progressive disease

Diagnosis of R/R MCL

  • Used in one of the following regimens:
    • Third and subsequent-line therapy in individuals who have received prior covalent Bruton tyrosine kinase (cBTKi) inhibitor (e.g.,ibrutinib, acalabrutinib) resulting in one of the following: 
      • No response or progressive disease following second-line therapy with cBTKi or other continuous treatment regimens (e.g., lenalidomide and rituximab)
      • Partial response, no response, or progressive disease following second-line therapy with fixed-duration regimens
      • Relapsed or progressive disease (relapse #2 or greater) if not previously given

Diagnosis of R/R histologic transformation of indolent lymphomas to DLBCL*

  • Third-line and subsequent therapy for individuals who have received multiple prior lines of therapies including at least two chemoimmunotherapy regimens for indolent or transformed disease (individuals should have received at least one anthracycline [e.g., doxorubicin] or anthracenedione [e.g., mitoxantrone]-based regimen, unless contraindicated) (NCCN preferred) 

*For example: FL and MZL (includes extranodal MZL of the stomach [formerly gastric MALT], extranodal MZL of nongastric sites [noncutaneous; formerly nongastric MALT], nodal MZL, and splenic MZL.


Diagnosis of R/R MZL 

  • Used as third-line and subsequent therapy for individuals who have received multiple prior lines of therapies (individuals may have recieved prior HSCT)
Diagnosis of R/R monomorphic PTLD
  • Used as one of the following: 
    • Second-line therapy for R/R disease greater than 12 months after completion of first-line therapy if no intention to proceed to transplant or are not eligible for HSCT due to comorbidities or age
    • Additional therapy for R/R disease greater than 12 months after completion of initial treatment with chemoimmunotherapy in individuals who have partial response following second-line chemoimmunotherapy 
    • Additional therapy for individuals with primary refractory disease (partial response, no response, or progression) or relapsed disease less than 12 months after completion of first-line therapy 
    • Third-line and subsequent therapy for disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease ​

Diagnosis of R/R pediatric aggressive mature BCL (primary mediastinal BCL)

  • Consolidation/additional therapy if partial response achieved after therapy for R/R disease (after use of two or more chemoimmunotherapy regimens) (NCCN preferred)

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)


Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of CLL and SLL, when the general criteria above AND either following criteria are met:​ 

  • In combination with or without ibrutinib for R/R disease after prior therapy with BTK inhibitor- and ​​venetoclax-based regimens in individuals with CLL/SLL with or without del(17p)/TP53 mutation (NCCN preferred)
  • Histologic (Richter) transformation to DLBCL (including del(17p)/TP53 mutation) when either of the following criteria are met:
    • Untreated CLL or clonally unrelated disease at initial diagnosis
      • Additional therapy for partial response, refractory disease, or progression while on treatment with chemoimmunotherapy regimens after at least one prior systemic therapy regimen
    • Previously treated CLL and clonally related or clonal relation unknown
      • ​Additional therapy for partial response, refractory disease, or progression while on treatment with non-chemoimmunotherapy regimens other than CAR-T therapy or chemoimmunotherapy regimens
​BREXUCABTAGENE AUTOLEUCEL (TECARTUS) 

Mantle Cell Lymphoma (MCL)


Brexucabtagene autoleucel (Tecartus) is considered medically necessary and, therefore, covered for the autologous treatment of R/R MCL when the general criteria above AND the following criteria are met: 

  • ​Used as second-line and subsequent-line therapy for individuals who have received prior covalent Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib) resulting in one of the following:  
    • No response or progressive disease following second-line therapy with covalent BTK inhibitor or other continuous treatment regimens (e.g., lenalidomide and rituximab​)
    • Partial response, no response, or progressive disease following second-line therapy with fixed-duration regimens
    • Relapsed or progressive disease (relapse #2 or greater) if not previously given

Cell Precursor Acute Lymphoblastic Leukemia (B-ALL)


Brexucabtagene autoleucel (Tecartus) is considered medically necessary and, therefore, covered for the autologous treatment for R/R B-cell precursor acute lymphoblastic leukemia (B-ALL) when the general criteria above​ AND all of the following are met: 

  • Used as single-agent therapy when the individual meets one of the following: 
    • R/R Philadelphia chromosome (Ph)-positive B-ALL following therapy that has included tyrosine kinase inhibitors (TKIs) (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) 
    • R/R Ph-negative B-ALL (NCCN preferred) 
  • The individual does not have any of the following:
    • Burkitt lymphoma/leukemia
    • Concomitant genetic syndrome (e.g., Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, other known bone marrow failure syndrome)
    • Grade 2 to 4 graft-versus-host disease (GVHD)

TISAGENLECLEUCEL (KYMRIAH)

B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL)


Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the autologous treatment of ​refractory disease or two or more relapses B-ALL with morphologic bone marrow tumor involvement (five percent or greater lymphoblasts) when the general criteria above​ AND all of the following criteria are met:​

  • Individuals 25 years and younger at the time of infusion and one of the following subtypes: 
    • Ph-negative disease (NCCN​-preferred regimen) 
    • ​​Ph-positive disease following therapy that has included two TKIs (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) 

OR

  • Individuals 18 years and younger​ and one of the following subtypes: 
    • BCR::ABL1-negative (formerly called Ph-negative) disease and refractory or two or more relapses
    • BCR::ABL1-positive (formerly called Ph-positive) disease and TKI (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib)​ intolerant or refractory 
    • BCR::ABL1-positive (formerly called Ph-positive) disease and relapse after ​HSCT

AND

  • The individual does not have any of the following: 
    • Concomitant genetic syndromes associated with bone marrow failure states (e.g., Fanconi anemia; Kostmann syndrome; Shwachman-Diamond syndrome; any other bone marrow syndrome)
    • Burkitt lymphoma/leukemia
    • Grade 2 to 4 GVHD

B-Cell Lymphomas​


Tisagenlecleucel (Kymriah) is considered medically necessary for the autologous treatment of R/R B-cell lymphomas, when the general criteria above​ AND the following criteria are met:

Diagnosis of one of the following subtypes:

  • Diffuse large B-cell lymphoma (DLBCL)
  • High-grade B-cell lymphoma with rearrangement plus rearrangement of BCL2, BCL6, or both genes (double- or triple-hit lymphoma)
  • AIDS/HIV-related DLBCL or plasmablastic lymphoma 
  • Primary effusion lymphoma
  • HHV8-positive DLBCL, not otherwise specified

AND

  • ​Used as one of the following:
    • Third-line and subsequent therapy as additional therapy for R/R disease greater than 12 months after completion of first-line therapy in individuals who have partial response following second-line therapy 
    • Third-line and subsequent therapy as treatment for disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred) ​

Diagnosis of R/R FL (grade 1 to 2)

  • Used as third-line and subsequent therapy (if not previously given) for partial response, no response, relapsed, or progressive disease in individuals with indications for treatment after two or more prior chemoimmunotherapy​regimens ​(NCCN preferred) AND
  • The individual does not have evidence of histologic transformation 

Diagnosis of R/R histologic transformation of indolent lymphomas to DLBCL*

  • Used as third-line and subsequent therapy for individuals who have received multiple prior lines of therapies including at least two chemoimmunotherapy regimens for indolent or transformed disease (individuals should have received at least one ​anthracycline [e.g., doxorubicin] or anthracenedione [e.g., mitoxantrone]-based regimen, unless contraindicated) (NCCN preferred).
*For example: FL, nodal MZL.


Diagnosis of R/R monomorphic posttransplant PTLD

  • Used as one of the following: 
    • Second-line therapy for R/R disease greater than 12 months after completion of first-line therapy with chemoimmunotherapy in individuals who have partial response following second-line chemoimmunotherapy 
    • Third-line and subsequent therapy as for disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred)
Obecabtagene Autoleucel (AUCATZYL​) 

B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL)

Obecabtagene autoleucel (Aucatzyl) is considered medically necessary and, therefore, covered for the autologous treatment of ​R/R B-ALL with morphologic bone marrow tumor involvement (≥5% lymphoblasts) when the general criteria above​ AND the following are met:  

  • Used as single-agent therapy when the individual meets one of the following: 
    • R/R Philadelphia chromosome (​Ph)-positive B-ALL following therapy that has included tyrosine kinase inhibitors (TKIs) (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) 
    • ​R/R Ph-negative B-ALL (NCCN preferred) 
  • The individual does not have any of the following:  ​
    • ​Burkitt lymphoma/leukemia​
    • ​​Grade 2 to 4 GVHD​
    • ​Any prior CD19 directed therapy other than blinatumomab (Blincyto)
    • ​​History of Grade 3 or higher neurotoxicity following blinatumomab (Blincyto) treatment​​

    EXPERIMENTAL/INVESTIGATIONAL

    ​
    All other uses for axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus)​, ​lisocabtagene maraleucel (Breyanzi), tisagenlecleucel (Kymriah) and obecabtagene Autoleucel (Aucatzyl)​ are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

    ​NOT ELIGIBLE FOR SEPARATE REIMBURSEMENT

    The harvesting and preparation of blood-derived T lymphocytes and the receipt and preparation of chimeric antigen receptor T cells are not eligible for separate reimbursement from the CAR-T administration.

    REQUIRED DOCUMENTATION

    The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

    The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.​

    Guidelines

    BLACK BOX WARNINGS

    Refer to the specific manufacturer's prescribing information for any applicable Black Box warnings.​​

    ADEQUATE ORGAN AND BONE MARROW FUNCTION

    Prior to being considered for chimeric antigen receptor (CAR) T therapy, the individual should be assessed for adequate organ and bone marrow function. The following parameters from published peer-reviewed literature may be used for guidance:
    • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
    • Left ventricular ejection fraction of 45 percent or greater
    • Serum creatinine of 1.5 times the upper limit of normal (ULN) or less
    • Estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2 or greater
    • Alanine aminotransferase (ALT) 5 times the ULN or less for age
    • Bilirubin 2.0 mg/dL or less (expect for individuals with Gilbert syndrome whose total bilirubin should be three times the ULN or less and direct bilirubin 1.5 times the ULN or less)
    • Pulmonary reserve of grade 1 or less dyspnea and pulse oximetry of greater than 91 percent on room air
    • Absolute neutrophil count (ANC) greater than 1.000/mm3
    • Absolute lymphocyte count (ALC) 300/mm3 or greater
    • Platelets 50.000/mm3 or greater
    • Hemoglobin (Hgb) greater than 8.0 g/dL
    BENEFIT APPLICATION​

    Subject to the terms and conditions of the applicable benefit contract, axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), lisocabtagene maraleucel (Breyanzi), tisagenlecleucel (Kymriah)​ and obecabtagene autoleucel (Aucatzyl) are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

    US FOOD AND DRUG ADMINISTRATION STATUS

    Axicabtagene ciloleucel (Yescarta) was approved by the US Food and Drug Administration (FDA) on October 18, 2017, for the treatment of adult individuals with relapsed or refractory ​(R/R) large B-cell lymphoma after two or more lines of systemic therapy, 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 (FL). Supplemental approvals for ciloleucel (Yescarta) have since been issued by the FDA.​ The safety and effectiveness of axicabtagene ciloleucel (Yescarta) in the pediatric population has not been established.

    Brexucabtagene autoleucel (Tecartus) was approved by the FDA on July 24, 2020, for the treatment of adult individuals with R/R mantle cell lymphoma (MCL).​ Supplemental approvals for brexucabtagene autoleucel (Tecartus) have since been issued by the FDA. The safety and effectiveness of brexucabtagene autoleucel (Tecartus) have not been established in pediatric individuals MCL.

    ​Lisocabtagene maraleucel (Breyanzi) was approved by the FDA on February 5, 2021, for the treatment of adult individuals with R/R large B-cell lymphoma after two 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 FL grade 3B. Supplemental approvals for lisocabtagene maraleucel (Breyanzi) have since been issued by the FDA. The safety and effectiveness of lisocabtagene maraleucel (Breyanzi) in the pediatric population have not been established.

    Tisagenlecleucel (Kymriah) was approved by the FDA on August 30, 2017, for the treatment of individuals up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Supplemental approvals for tisagenlecleucel (Kymriah) have since been issued by the FDA. In the pediatric population, the safety and effectiveness of tisagenlecleucel (Kymriah) have been established for the treatment of R/R B-cell ALL. The safety and effectiveness of tisagenlecleucel (Kymriah) have not been established for the treatment of R/R DLBCL in pediatric individuals.​

    Obecabtagene autoleucel (Aucatzyl) was approved by the FDA on November 8, 2024, for the treatment of adults with relapsed or refractory B-cell precursor, acute lymphoblastic leukemia (ALL). Safety and effectiveness have not been established in pediatric individuals.​

    DOSING GUIDELINES 
    *There is a dosing limit of 1 treatment course per lifetime*

    AXICABTAGENE CILOLEUCEL (YESCARTA)
    Pre-treatment:
    Lymphodepleting chemotherapy: cyclophosphamide 500 mg/m2 intravenously (IV) and fludarabine 30 mg/m2 IV on the fifth, fourth, and third day before axicabtagene ciloleucel (Yescarta) infusion.

    Treatment:
    Axicabtagene ciloleucel (Yescarta) target dose is 2 × 106 chimeric antigen receptor (CAR​)-positive viable T cells per kilogram body weight, with a maximum of 2 × 108 CAR-positive viable T cells.​

    BREXUCABTAGENE AUTOLEUCEL (TECARTUS)
    Mantle Cell Lymphoma

    Pre-treatment: 
    Lymphodepleting chemotherapy: cyclophosphamide 500 mg/m2 IV and fludarabine 30 mg/m2 IV on each of the fifth, fourth, and third days before infusion of brexucabtagene autoleucel (Tecartus).​

    Treatment:
    Brexucabtagene autoleucel (Tecartus) dose is 2 × 106 CAR-positive viable T cells per kilogram body weight, with a maximum of 2 × 108 CAR-positive viable T cells.

    Acute Lymphoblastic Leukemia

    Pre-treatment: 
    Lymphodepleting chemotherapy: fludarabine 25 mg/m2 IV on each of the fourth, third, and second days and cyclophosphamide 900 mg/m2 IV on the second day before infusion of brexucabtagene autoleucel (Tecartus).​

    Treatment:
    Brexucabtagene autoleucel (Tecartus) dose is 1 × 106 CAR-positive viable T cells per kilogram body weight, with a maximum of 1 × 108 CAR-positive viable T cells.

    LISOCABTAGENE MARALEUCEL (BREYANZI)
    Pre-treatment: 
    Lymphodepleting chemotherapy: fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 IV daily for 3 days. Infuse lisocabtagene maraleucel (Breyanzi) 2 to 7 days after completion of lymphodepleting chemotherapy.

    Relapsed or Refractory Large B-Cell Lymphoma ​(including grade 3B Follicular Lymphoma)​ 
    After One Line of Therapy:
    Treatment:
    Lisocabtagene maraleucel (Breyanzi) target dose is 90 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components).

    After Two or More Lines of Therapy:
    Treatment:
    Lisocabtagene maraleucel (Breyanzi) target dose is 50 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components).

    Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Follicular Lymphoma (grades 1 to 2), Mantle Cell Lymphoma, Marginal Zone Lymphoma 
     
    Treatment:
    Lisocabtagene maraleucel (Breyanzi) target dose is 90 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable​ T cells of the CD8 and CD4 components)​

    TISAGENLECLEUCEL (KYMRIAH)
    Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma (grade 1 to 2) 

    Pre-treatment:
    • Lymphodepleting chemotherapy: Fludarabine 25 mg/m2 IV daily for 3 days and cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine.
    • Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 IV daily for 2 days if the individual experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide-containing regimen.
    • Infuse tisagenlecleucel (Kymriah) 2 to 11 days (R/R DLBCL) or 2 to 6 days (R/R FL) after completion of the lymphodepleting chemotherapy.
    • Lymphodepleting chemotherapy may be omitted if an individual is experiencing significant cytopenia (e.g., white blood cell ​[WBC​] count is less than 1 × 109/L​) within 1 week prior to tisagenlecleucel (Kymriah) infusion.
    Treatment:
    Tisagenlecleucel (Kymriah) dose for adult individuals: 0.6 to 6.0 × 108 CAR-positive viable T cells.

    Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia​

    Pre-treatment:
    Lymphodepleting chemotherapy: Fludarabine 30 mg/m2 IV daily for 4 days and cyclophosphamide 500 mg/m2 IV daily for 2 days starting with the first dose of fludarabine. Infuse tisagenlecleucel (Kymriah) 2 to 14 days after completion of lymphodepleting chemotherapy.

    Treatment:
    Tisagenlecleucel (Kymriah)​ dose is based on the individual's weight reported at the time of leukapheresis: 
    • The individual is 50 kg or less: dose is 0.2 to 5.0 × 106 CAR-positive viable T cells per kilogram body weight
    • The individual is above 50 kg: dose is 0.1 to 2.5 ×​ 108 CAR-positive viable T cells​

    AUCATZYL (OBECABTAGENE AUTOLEUCEL)

    B-ALL


    Pretreatment: fludarabine for 4 days and cyclophosphamide for 2 days.


    Treatment: Total dose: 410 × 106 CD19 chimeric antigen receptor (CAR)–positive viable T cells administered as a split dose infusion on day 1 (3 days +/- 1 day) and day 10 (±2 days).​

    Description

    Leukemia is a type of blood cancer of the bone marrow and blood-forming cells. The result is the production of abnormal blood cells, mostly the white blood cells. Leukemia is divided into several types based on the speed of growth and the types of cells the cancer starts in (myeloid cells vs lymphoid cells). Fast-growing leukemias are considered to be acute. Slower growing leukemias are considered to be chronic. The classifications of leukemias include acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). ALL and AML are the two most common types of leukemia found in children. AML and CLL are the two most common types of leukemia found in adults. Treatment includes a combination of chemotherapy, biologicals, radiation therapy, and hematopoietic stem cell transplantation (HSCT).

     

    Lymphoma is also a blood cancer, but is a cancer of the lymphatic system. Lymphomas account for approximately half of all blood cancers that occur yearly. Lymphomas are divided into two categories: Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs). NHLs are differentiated as being T-cell lymphomas or B-cell lymphomas (BCLs). The majority of NHLs are BCLs and can be categorized as either high-grade cancers that grow quickly or low-grade cancers that grow slowly. The list of BCLs is numerous and includes diffuse large B-cell lymphoma (DLBCL), primary mediastinal BCL, follicular lymphoma (FL), small lymphocytic lymphoma (SLL; this type of cancer is so closely related to CLL that they are treated the same), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL; these include extranodal marginal zone BCL [also known as mucosa-associated lymphoid tissue lymphoma or MALT; can either be gastric or non-gastric], nodal marginal zone BCL, or splenic marginal zone BCL). Like leukemias, treatment includes a combination of chemotherapy, biologicals, radiation therapy, and HSCT.

     

    ​Axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), lisocabtagene maraleucel (Breyanzi), tisagenlecleucel (Kymriah),​ and obecabtagene autoleucel (Aucatzyl) are all autologous, cluster of differentiation (CD)19-directed chimeric antigen receptor T-cell (CART) therapies. CART therapy is a method whereby the T cells (a type of white blood cell) are altered in a laboratory to enable them to find and destroy cancer cells or other disease-producing cells. Each dose of CART is customized to the individual and their cancer or disease. The individual's T cells are collected during a process called leukapheresis; the cells are then sent to a manufacturing center where they are genetically modified to include a new chimerica antigen receptor (CAR) gene. The modified T cells target and bind to the specific protein on the surface of the antigen causing the cancer or disease and trigger the individual’s own immune system to help destroy the target. Prior to initiating the CART infusion, individuals undergo lymphodepleting​ chemotherapy to reduce the level of white blood cells and help the body accept the reprogrammed CAR T cells.


    AXICABTAGENE CILOLEUCEL (YESCARTA)

    On October 18, 2017, the US Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of therapy. Axicabtagene ciloleucel (Yescarta) is the second cluster of differentiation (CD​)19-directed genetically modified autologous T-cell immunotherapy available in the United States. Like tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta) is customized to the individual after the T cells are harvested. The T cells are genetically modified to express a chimeric antigen receptor that targets CD19-expressing cells.

    The safety and efficacy of axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with R/R B-cell NHL were evaluated in a single arm, open-label, multicenter trial, phase 1/2 trial (ZUMA-1; NCT02348216). Individuals eligible for the trial had refractory disease to the most recent therapy or relapse within 1 year of autologous HSCT. The primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DOR) and safety data. Of the 101 individuals who received the axicabtagene ciloleucel (Yescarta) infusion, the ORR was 82% (95% confidence interval [CI], 73–89) with 54% achieving a complete remission (CR) and 28% achieving a partial remission (PR). At the median follow-up of 7.9 months, individuals in CR had not reached the estimated DOR. Grade 3 or higher adverse events occurred in 95% of the individuals. Grade 3 or higher cytokine-release syndrome (CRS) occurred in 17% of individuals and grade 3 or higher neurologic events occurred in 28% of individuals. There were four deaths, two of which were believed to be related to the infusion. A long-term follow-up for a median of 27.1 months (range, 25.7–28.8) was also published. The ORR was now 83%, with a CR of 58% and PR of 25%. The median DOR was 11.1 months (95% CI, 4 to not estimable). The median PFS was 5.9 months (95% CI, 3.3–15.0). The median overall survival (OS) was not reached (95% CI, 12.8 to not estimable). No participants were lost to follow-up.

    The safety and efficacy of axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with R/R indolent NHL, including FL and MZL, were evaluated in a single-arm, open-label, multicenter, phase 2 trial (ZUMA-5; NCT03105336). Individuals eligible for the trial had indolent NHL, including FL and nodal or extranodal MZL, that was R/R after two or more previous lines of therapy. Exclusion criteria included autologous HSCT within the previous 6 months, previous allogeneic HSCT, previous CD19-targeted therapy, or previous CART therapy. Disease assessments via positron emission tomography–computed tomography (PET-CT) or CT were performed by the investigators and an independent review committee. The primary endpoint of the trial was ORR. Key secondary endpoints included DOR, PFS, OS, and safety. A total of 153 individuals underwent leukapheresis and 148 were transfused with axicabtagene ciloleucel (Yescarta). The median follow-up was 17.5 months (range, 14.1–22.6). Of 109 individuals who were able to be assessed in the updated analysis, the ORR was 92% [95% CI, 85–97]) with 83 individuals (76%) having a CR. At a cutoff of 18 months, the estimated PFS rate was 64.8% (95% CI, 54.2–73.5). DOR was not reached. At the 18-month cutoff, the OS rate was 87.4% (95% CI, 79.2–92.5). Among all individuals who were transfused with axicabtagene ciloleucel (Yescarta), 147 (99%) experienced treatment-emergent adverse events with 128 (86%) experiencing grade 3 or higher events. CRS occurred in 121 individuals (82%) with grade 3 or higher occurring in 10 individuals (7%). Neurological events occurred in 87 individuals (59%) with grade 3 or higher occurring in 28 individuals (19%). Nineteen individuals died after transfusion with axicabtagene ciloleucel (Yescarta), but only one death was believed to be caused by the infusion.

    The safety and efficacy of axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with R/R large B-cell lymphoma versus standard of care (SOC) were evaluated in a randomized, open-label, multicenter, phase 3 trial (ZUMA-7; NCT03391466). Individuals with large B-cell lymphoma that had become R/R after no more than 12 months after receiving first-line chemoimmunotherapy were randomly assigned in a 1:1 ratio to receive either axicabtagene ciloleucel (Yescarta) or SOC therapy (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy; if the individual responded to the chemoimmunotherapy, they received high-dose chemotherapy and autologous HSCT). The primary endpoint of the trial was event-free survival (EFS) based on assessment by a blinded central reviewer. Key secondary endpoints included OS and response to the treatment. In the trial, 180 individuals were randomly assigned to the axicabtagene ciloleucel (Yescarta) cohort and 179 individuals into the SOC cohort. At a median follow-up of 24.9 months, the median EFS in the axicabtagene ciloleucel (Yescarta) cohort was 8.3 months versus 2.0 months in the SOC cohort. The 24-month EFS was 41% in the axicabtagene ciloleucel (Yescarta) cohort versus 16% in the SOC cohort (hazard ratio [HR] for event/death, 0.40; 95% CI, 0.31–0.51; P<0.001). The OS rate at 24 months was 61% in the axicabtagene ciloleucel (Yescarta) cohort and 52% in the SOC cohort. A response occurred in 83% of individuals in the axicabtagene ciloleucel (Yescarta) cohort and 50% of individuals in the SOC cohort, with a complete response occurring in 65% of individuals in the axicabtagene ciloleucel (Yescarta) cohort versus 32% in the SOC cohort. Grade 3 or higher adverse events occurred in 91% of individuals in the axicabtagene ciloleucel (Yescarta) cohort and 83% of the SOC cohort. Grade 3 or higher CRS occurred in 6% and grade 3 or higher neurological event occurred in 21% of individuals receiving axicabtagene ciloleucel (Yescarta), but no deaths related to either CRS or neurologic events were reported.

    BREXUCABTAGENE AUTOLEUCEL (TECARTUS)

    On July 24, 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for the treatment of adult individuals with R/R MCL. Brexucabtagene autoleucel (Tecartus) is a CD19-directed genetically modified autologous T-cell immunotherapy that is customized to the individual after the T cells are harvested. The T cells are genetically modified to express a chimeric antigen receptor that targets CD19-expressing cells.

    The safety and efficacy of brexucabtagene autoleucel (Tecartus) for the treatment of adult individuals with R/R MCL, who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase (BTK) inhibitor (ibrutinib or acalabrutinib), were evaluated in a single-arm, open-label, multicenter phase 2 trial (ZUMA-2; NCT02601313). Eligible individuals had disease progression after their last regimen or refractory disease to their most recent therapy. Seventy-four individuals were enrolled. Brexucabtagene autoleucel (KTE-X19) was manufactured for 71 individuals and administered to 68. The primary efficacy analysis showed that 93% (95% CI, 84–98) had an objective response as assessed by an independent radiologic review committee, with 67% (95% CI, 53–78) having a CR. At a median follow-up of 12.3 months (range, 7.0–32.3), 57% of the 60 individuals in the primary efficacy analysis were in remission.​ At 12 months, the estimated PFS and OS were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the individuals) and infections (in 32%). Grade 3 or higher CRS and neurologic events occurred in 15% and 31%​ of individuals, respectively; none were fatal.

    The safety and efficacy of brexucabtagene autoleucel (Tecartus) for the treatment of adult individuals with ALL were evaluated in a single-arm, open-label, multicenter, phase 1/2 trial (ZUMA-3; NCT02614066). Individuals were eligible for treatment if they had primary refractory ALL, had a first relapse after a remission that lasted 1 year or less, had R/R ALL after second- or higher line of therapy, or R/R ALL 100 days or more after allogeneic HSCT). Seventy-one individuals were enrolled. Brexucabtagene autoleucel (KTE-X19) was manufactured for 65 individuals and administered to 55. The primary endpoint was the rate of overall CR or CR with incomplete hematological recovery by central assessment. Fifty-six percent of the individuals achieved a CR (95% CI, 37.8–65.7) and 15% of the individuals achieved a CR with incomplete hematological recovery. Median OS was 18.2 months in the treated individuals and was not reached in individuals who responded to the treatment. All the treated individuals experienced at least one adverse event. Grade 3 or higher cytopenia occurred in 76% of individuals, CRS occurred in 89% of individuals, and neurological events occurred in 60% of individuals. Six of the treated individuals (11%) died secondary to grade 5 adverse events, with two of these believed to be treatment related.    

    LISOCABTAGENE MARALEUCEL (BREYANZI)

    On February 5, 2021, the FDA approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with R/R large B-cell lymphoma after two 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 FL grade 3B. Lisocabtagene maraleucel (Breyanzi) is a CD19-directed genetically modified autologous T-cell immunotherapy. During the lisocabtagene maraleucel (Breyanzi) manufacturing process, CD8+ and CD4+ T cells are selected from leukapheresis material and then independently activated, transduced, and expanded. Both of these are then infused into the individual.

    The safety and efficacy of lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with R/R large B-cell lymphoma after two or more lines of systemic therapy were evaluated in a single-arm, open-label, multicenter phase 1 trial (TRANSCEND-NHL-001; NCT02631044). Primary endpoints were ORR assessed by an independent review committee, adverse events, and dose-limiting toxicities. A total of 344 individuals underwent leukapheresis, with 269 individuals being transfused with target doses of 50 ×106 CAR T cells (one or two doses), 100 × 106 CAR T cells, or 150 × 106 CAR T cells and 25 individuals received an infusion of a nonconforming CAR T-cell product (i.e., one component did not meet criteria). At a median follow-up of 18.8 months (95% CI, 15.0–19.3) an ORR was achieved by 186 individuals (73%; 95% CI, 66.8–78.0; P<0.0001) in the efficacy-evaluable set (256 individuals who had received the infusion and had PET-positive disease) with a CR being achieved in 136 individuals (53%; 95% CI, 46.8–59.4; P<0.0001). The median DOR was not reached at a median follow-up of 12 months (95% CI, 11.2 to 16.7). The median PFS was 6.8 months (95% CI, 3.3 to 14.1) after a median follow up of 12.3 months. Median OS was 21.1 months (95% CI, 13.3 to not estimable) after a median follow-up of 17.5 months (95% CI, 12.9–​​​​17.8). CRS occurred in 113 individuals (42%) with grade 3 or higher occurring in six individuals (2%). Nine individuals (6%) experienced a dose-limiting toxicity including one individual who died from diffuse alveolar damage after receiving a dose of 50 × 106 CAR T cells. Seven individuals (3%) of the total individuals who were infused died from treatment-emergent events.

    On June 24, 2022, the FDA approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with refractory large B-cell lymphoma to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy who were eligible for autologous HSCT. This approval was based on a randomized, parallel-group, open-label, multicenter phase 3 trial (TRANSFORM; NCT03575351). A total of 184 individuals were divided 1:1 into two cohorts. One cohort received a SOC regimen, and the other cohort received lisocabtagene maraleucel (Breyanzi). The primary endpoint was EFS. Secondary endpoints were CRR, PFS, OS, ORR, DOR, and adverse events. At the interim data analysis, the median EFS for the lisocabtagene maraleucel (Breyanzi)​ cohort was 10.1 months (95% CI, 6.1 to not reached) compared to 2.3 months (95% CI, 2.2–4.3) for the SOC cohort; P<0.0001. The CRR for the lisocabtagene maraleucel (Breyanzi)​​ cohort was 66% (95% CI, 56–76) versus 39% (95% CI, 29–50) for the SOC cohort. The ORR in the lisocabtagene maraleucel (Breyanzi)​​ cohort was 85% (95% CI, 77–92) versus 48% (95% CI, 37–​59) in the SOC cohort. The most common grade 3 or worse adverse event was neutropenia in 80% of the lisocabtagene maraleucel (Breyanzi)​ cohort and 51% of the SOC cohort. Grade 3 CRS occurred in 1%, and neurological events occurred in 4% of individuals treated with lisocabtagene maraleucel (Breyanzi)​. There were no treatment-related deaths in the lisocabtagene maraleucel (Breyanzi)​ cohort and one treatment-related death in the SOC cohort.

    The safety and efficacy of lisocabtagene maraleucel (Breyanzi)​ in adult individuals with R/R large B-cell lymphoma after first-line treatment and who were ineligible for HSCT (based on age, performance status, and/or comorbidities) were studied in TRANSCEND-PILOT (NCT03483103). This was a single-arm, open-label, multicenter phase 2 study that enrolled 61 participants. The primary endpoint was ORR. The secondary endpoints were CRR, DOR, PFS, EFS, OS, and adverse events. The ORR was 80% (95% CI, 68–89); ​P<0.0001). At a median follow-up of 13.0 months, the median PFS was 9.03 months (95% CI, 4.17 to not reached). At a median follow up of 15.5 months, the median DOR was 12.09 months (95% CI, 6.24 to not reached). In the intention-to-treat population, the CRR was 46% (95% CI, 34–58). In this same group, the median EFS was 8.15 months (95% CI, 4.37–13.34). Median OS was not reached. CRS occurred in 38% (one grade 3) of participants and neurological events occurred in 31% (three grade 3) of individuals. There were no grade 4 events and no deaths.

    The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R CLL or SLL after two or more lines of therapy for individuals with high-risk features, or after three or more lines of therapy for individ​uals with standard-risk features was studied in a phase 1/2 open-label study (TRANSCEND CLL 004; NCT03331198). The individuals were required to have received a Bruton tyrosine kinase (BTK) inhibitor and a BCL2 inhibitor as part of their prior therapy. The phase 1 portion of the study was the dose-finding portion of the study that determined the dose of lisocabtagene maraleucel (Breyanzi) that would be used in the phase 2 portion of the study. The primary endpoint of the phase 2 portion of the study was the ORR or remission at 24 months. Key secondary endpoints were DOR, PFS, and OS. Of the 113 individuals who underwent leukapheresis, 94 received lisocabtagene maraleucel (Breyanzi). The ORR was 45%. The median DOR was 35.3 months. The median PFS was 11.9 months. The median OS was 30.3 months. In individuals who received lisocabtagene maraleucel (Breyanzi), 9% experienced grade 3 CRS; none experienced grade 4 or 5. One death from macrophage activation syndrome–hemophagocytic lymphohistiocytosis (MAS/HLH) was believed to be related to treatment. There was a higher incidence of CRS and neurological events in treated individuals, which is consistent with other studies in individuals with CLL.

    The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R FL after two or more lines of therapy were studied in a phase 2 open label study (TRANSCEND FL; NCT04245839). The individuals were required to have received an anti-CD20 and alkylating agent as part of their prior therapy. The primary endpoint was ORR. Key secondary endpoints included the percentage of CRs and DOR. Of the 114 individuals who underwent leukapheresis, 107 received lisocabtagene maraleucel (Breyanzi). The ORR was 95.7%. The CR rate was 73.4%. At a median of 18 months, the DOR has not been reached. CRS occurred in 58% of treated individuals, but only 1% was grade 3 with none being grade 4 or 5. Two deaths were believed to be treatment related. One was from MAS/HLH, and the other was due to progressive multifocal leukoencephalopathy after the 90-day treatment-emergent period.

    ​ 

    The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R MCL after two or more lines of therapy was studied in a phase 1 open label study (TRANSCEND-NHL 001, MCL cohort; NCT NCT02631044). The individuals were required to have received an alkylating agent, a BTK inhibitor, and either rituximab or other CD20-targeted agent as part of their prior therapy. A key primary endpoint included ORR at 24 months. Key secondary endpoints included percentage of CRs and DOR. Of the 89 individuals who underwent leukapheresis, 71 received lisocabtagene maraleucel (Breyanzi). The ORR was 85.3%. The CR rate was 67.6%. The median DOR was 13.3 months. CRS was reported in 61% of treated individuals with 1% being grade 4, and none being grade 3 or 5. Only one death was considered to be treatment related. 


    The trial evaluating lisocabtagene maraleucel (Breyanzi) in R/R marginal zone lymphoma (MZL) was the TRANSCEND FL‑MZL Cohort, registered as NCT04245839. This was an open-label, multicenter, single-arm Phase II study in adults with MZL who had relapsed after two or more lines of systemic therapy or after a hematopoietic stem cell transplant. Participants underwent leukapheresis to collect T cells, received lymphodepleting chemotherapy (fludarabine + cyclophosphamide), then a single infusion of lisocabtagene maraleucel (Breyanzi) 2 to 7 days later. Of the 77 leukapheresed individuals, 66 received the planned infusion. The ORR was 95.5%, with 62.1% achieving a CR on imaging. Responses were durable, with median follow-up of 21.6 months, and DOR was not reached.​ ​​


    TISAGENLECLEUCEL (KYMRIAH)

    On August 30, 2017, the FDA approved tisagenlecleucel (Kymriah) for the treatment of individuals up to 25 years old with B-cell precursor ALL that is refractory or in second- or later stage relapse. Tisagenlecleucel (Kymriah) is a CD19-directed genetically modified autologous T-cell immunotherapy.

    The efficacy and safety of tisagenlecleucel (Kymriah) in pediatric and young adult individuals with R/R B-cell ALL were evaluated in a single-arm, open-label, multicenter, phase 2 study (ELIANA; NCT02435849). Enrolled individuals had to have received at least one prior line of therapy. ​The primary outcome of this trial is the ORR within 3 months of infusion of tisagenlecleucel (Kymriah). Secondary outcomes included DOR, EFS, OS, and safety. Of 92 individuals who were enrolled, 75 received an infusion. Of the 75 individuals infused with tisagenlecleucel (Kymriah) and who had at least 3 months of follow-up, the ORR was 81% (95% CI, 71–89) with 45 individuals (60%) achieving CR and 16 individuals (21%) having CR with incomplete hematologic recovery and all of them were minimal residual disease (MRD) negative. DOR was defined as the time since onset of CR to relapse or death due to underlying cancer, whichever is earlier. A median duration of remission DOR was not reached by any of the 61 individuals who achieved a CR or CR with incomplete hematologic recovery. The rate of relapse-free survival was 80% (95% CI, 65–89) at 6 months and 59% (95% CI, 41–73) at 12 months. The rate of EFS at 6 months was 73% (95% CI, 60–82) and at 12 months was 50% (95% CI, 35–64) with median EFS not being achieved. The rate of OS for all 75 individuals who received an infusion was 90% (95% CI, 81–95) at 6 months and 76% (95% CI, 63–86) at 12 months. Of the 75 individuals who received an infusion, 71 (95%) experienced an adverse event that was believed to be related to the infusion. CRS occurred in 77% of the individuals who received an infusion, and neurologic events occurred in 40%. Nineteen individuals died after receiving an infusion, but only three of the deaths were believed to be caused by the infusion.

    On May 1, 2018, the FDA approved tisagenlecleucel (Kymriah) for the treatment of adults with R/R DLBCL after at least two prior lines of therapy. The efficacy and safety of tisagenlecleucel (Kymriah) were evaluated in an open-label, single-arm multicenter, Phase 2 trial (JULIET; NCT02445248). The study included adults with R/R DLBCL who had received two or more lines of chemotherapy, including rituximab and anthracycline, or were ineligible for autologous HSCT or had relapsed following autologous HSCT. The primary endpoint was ORR. Key secondary endpoints included DOR, OS, and safety data. A total of 165 individuals were enrolled and 111 received an infusion. Of the 93 individuals in the efficacy analysis set (individuals who had received an infusion and who were able to be followed for at least 3 months after), the ORR was 52% (95% CI, 41–62) with 40% obtaining a CR and 12% a PR. The median DOR was not reached (95% CI, 10 months to not estimable). The estimated rate of PFS at 12 months was 83%. The median OS among individuals who had received an infusion was 12 months (95% CI, 7 months to not reached). The percentage of individuals who received an infusion who experienced grade 3 or higher CRS was 22%. The percentage of these individuals who experienced a neurologic event of grade 3 or higher was 12%. Although three individuals died after receiving an infusion, none of these were due to the infusion but were from disease progression. 

    On May 27, 2022, the FDA approved tisagenlecleucel (Kymriah) for the treatment of adults with R/R FL after two or more lines of systemic therapy. This indication was approved under accelerated approval and continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials. The efficacy and safety of tisagenlecleucel (Kymriah) were evaluated in an open-label, single-arm multicenter, Phase 2 trial (ELARA; NCT03568461). The study included 98 adults with R/R FL grades 1 to 2 who had previously received two or more lines of treatment or had relapsed after autologous HSCT. Individuals were not eligible for the study if they had previously undergone allogeneic HSCT or had active CNS malignancy. The primary endpoint was CRR. Key secondary endpoints included ORR, DOR, PFS, OS, and safety. Based on interim data, the CRR was 69.1% (95% CI, 58.8–78.3). The ORR was 86.2% (95% CI, 77.5–92.4). The data for the other secondary endpoints has not matured yet. At the time of the publication of the data, the rate of CRS was 48.5% (with none grade 3 or higher) and the rate of neurological events was 37.1% (3% were grade 3 or higher). There have not been any treatment-related deaths. 

    Aucatzyl (obecabtagene autoleucel)


    The Phase 1b/2 FELIX trial (NCT04404660) was an open‑label, multicenter, single‑arm study evaluating Aucatzyl (obecabtagene autoleucel) in adults with relapsed or refractory B‑cell acute lymphoblastic leukemia (ALL).​ Participants received a lymphodepleting chemotherapy regimen, followed by a bone marrow burden–adjusted split dose totaling 410 × 10⁶ CD19-positive CAR T cells on Day 1 and Day 10 (±2 days). Among the 94 efficacy-evaluable participants in the pivotal cohort, 55% achieved CR, and the overall remission rate (CR or CR with incomplete hematologic recovery) was 77%. The median duration of response was 14.1 months.​​​
    ​​
    OFF-LABEL INDICATIONS

    There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.​​

    References

    Autolus Inc. Aucatzyl (obecabtagene autoleucel) suspension for intravenous infusion. Prescribing Information. Gaithersburg, MD: Autolus; revised November 2024.

    Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicenter seamless design study. Lancet. 2020;396(10254):839-852.

    American Cancer Society. CAR T-cell therapy and its side effects. [American Cancer Society Web site]. 11/11/2024. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html. Accessed November 26, 2025.

    American Cancer Society. Key Statistics for Non-Hodgkin Lymphoma. [American Cancer Society Web site]. 01/17/2024. Available at: https://www.cancer.org/can​cer/non-hodgkin-lymphoma/about/key-statistics.html. Accessed November 26, 2025.

    American Cancer Society. Leukemia. [American Cancer Society Web site]. Available at: https://www.cancer.org/cancer/types/leukemia.html. Accessed November 26, 2025.

    American Cancer Society. Lymphoma. [American Cancer Society Web site]. Available at:  https://www.cancer.org/cancer/types/lymphoma.html. Accessed November 26, 2025.

    American Cancer Society. Types of B-Cell lymphoma. [American Cancer Society Web site]. 02/15/2024. Available at: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html. Accessed November 26, 2025.

    American Hospital Formulary Service (AHFS). Axicabtagene ciloleucel (Yescarta®). AHFS Drug Information 2024. [UpToDate Lexidrug Web site]. 11/13/25. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025.

    American Hospital Formulary Service (AHFS). Brexucabtagene autoleucel (Tecartus®). AHFS Drug Information 2024. [UpToDate Lexidrug Web site]. 11/13/25​. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025.

    American Hospital Formulary Service (AHFS). Lisocabtagene maraleucel (Breyanzi®). AHFS Drug Information 2024. [UpToDate Lexidrug Web site]. 11/13/25​. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025.

    American Hospital Formulary Service (AHFS). Tisagenlecleucel (Kymriah®). AHFS Drug Information 2024. [UpToDate Lexidrug Web site]. 11/13/25​​. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025​.

    American Society of Hematology. Leukemia. [American Society of Hematology Web site]. Available at: https://www.hematology.org/education/patients/blood-cancers/leukemia. Accessed November 26, 2025​.

    American Society of Hematology. Lymphoma. [American Society of Hematology Web site]. Available at: https://www.hematology.org/education/patients/blood-cancers/lymphoma. Accessed November 26, 2025​.

    Axicabtagene ciloleucel (Yescarta®). [prescribing information]. Santa Monica, CA​: Kite Pharma, Inc; 06/2024. Available at: https://www.yescarta.com/. Accessed November 26, 2025​.

    Brexucabtagene autoleucel (Tecartus®). [prescribing information]. Santa Monica, CA​: Kite Pharma, Inc.; 06/2024. Available at: https://www.tecartus.com/. Accessed November 26, 2025​.

    ClinicalTrial.gov. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). ClinicalTrials.gov Identifier: NCT03105336. First Posted: April 7, 2017. Last Update Posted: September 4, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. A study evaluating the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (ZUMA-3). ClinicalTrials.gov Identifier: NCT02614066. First Posted: November 25, 2015. Last Update Posted: November 19, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. A study to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (TRANSFORM). ClinicalTrials.gov Identifier: NCT03575351. First Posted: July 2, 2018. Last Update Posted: November 15, 2023. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND FL). ClinicalTrials.gov Identifier: NCT04245839. First Posted: January 29, 2020. Last Update Posted: October 16, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Efficacy and safety of tisagenlecleucel in adult patients with refractory or relapsed follicular lymphoma (ELARA). ClinicalTrials.gov Identifier: NCT03568461. First Posted: June 26, 2018. Last Update Posted: November 19, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Lisocabtagene maraleucel (JCAR017) as second-line therapy (TRANSCEND-PILOT-017006). ClinicalTrials.gov Identifier: NCT03483103. First Posted: March 30, 2018. Last Update Posted: December 20, 2023. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study evaluating safety and efficacy of JCAR017 in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ClinicalTrials.gov Identifier: NCT03331198. First Posted: November 6, 2017. Last Update Posted: November 7, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study evaluating the safety and efficacy of KTE-C19 in adult participants with refractory aggressive non-Hodgkin lymphoma (ZUMA-1). ClinicalTrials.gov Identifier: NCT02348216. First Posted: January 28, 2015. Last Update Posted: June 4, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study evaluating the safety and pharmacokinetics of JCAR017 in B-cell non-Hodgkin lymphoma (TRANSCENT-NHL-001). ClinicalTrials.gov Identifier: NCT02631044. First Posted: December 15, 2015. Last Update Posted: June 27, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ​ClinicalTrial.gov. Study of efficacy of axicabtagene ciloleucel compared to standard of care therapy in patients with relapsed/refractory diffuse large B cell lymphoma (ZUMA-7). ClinicalTrials.gov Identifier: NCT03391466. First Posted: January 5, 2018. Last Update Posted: September 19, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study of efficacy and safety of CTL019 in adult DLBCL patients (JULIET). ClinicalTrials.gov Identifier: NCT02445248. First Posted: May 15, 2015. Last Update Posted: April 18, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study of efficacy and safety of CTL019 in pediatric ALL patients (ELIANA). ClinicalTrials.gov Identifier: NCT02435849. First Posted: May 6, 2015. Last Update Posted: February 13, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    ClinicalTrial.gov. Study of brexucabtagene autoleucel (KTE-X19) in participants with relapsed/refractory mantle cell lymphoma (Cohort 1 and Cohort 2) (ZUMA-2). ClinicalTrials.gov Identifier: NCT02601313. First Posted: November 10, 2015. Last Update Posted: February 12, 2024. Available at: https://clinicaltrials.gov/. Accessed November 26, 2025​.

    Elsevier's Clinical Pharmacology Compendium. Axicabtagene ciloleucel (Yescarta®). [Clinical Key Web site]. 09/25/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 26, 2025​.

    Elsevier's Clinical Pharmacology Compendium. Brexucabtagene autoleucel (Tecartus®). [Clinical Key Web site]. 09/25/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 26, 2025​.

    Elsevier's Clinical Pharmacology Compendium. Lisocabtagene maraleucel (Breyanzi®). [Clinical Key Web site]. 09/25/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 26, 2025​.

    Elsevier's Clinical Pharmacology Compendium. Tisagenlecleucel (Kymriah®). [Clinical Key Web site]. 09/25/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 26, 2025​.

    Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022;28(2):325-332.

    Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. N Engl J Med. 2013;368(16):1509-1518.

    Horton TM, Aster JC. Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children. [UpToDate]. 06/08/2022. Available at: https://www.uptodate.com/contents/overview-of-the-clinical-presentation-and-diagnosis-of-acute-lymphoblastic-leukemia-lymphoma-in-children?search=Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 [via subscription only]. Accessed November 26, 2025​.

    Idecabtagene vicleucel (Abecma®). [prescribing information]. Summit, NJ: Bristol-Myers Squibb; 07/2024. Available at: https://www.abecma.com/. Accessed November 26, 2025​.

    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. 2022;23(1):91-103.

    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. 2022;399(10343):2294-2308.

    Lisocabtagene maraleucel (Breyanzi®). [prescribing information]. Bothell, WA: Juno Therapeutics, Inc; 05/2024. Available at: https://www.breyanzi.com/. Accessed November 26, 2025​.

    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. 2019;20(1):31-42.

    Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654.

    Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448.

    Merative Micromedex® DRUGDEX® (electronic version). Axicabtagene ciloleucel (Yescarta®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/20/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 26, 2025​.

    Merative Micromedex® DRUGDEX® (electronic version). Brexucabtagene autoleucel (Tecartus®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/20/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 26, 2025​.

    Merative Micromedex® DRUGDEX® (electronic version). Lisocabtagene maraleucel (Breyanzi®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/20/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 26, 2025​.

    Merative Micromedex® DRUGDEX® (electronic version). Tisagenlecleucel (Kymriah®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/20/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 26, 2025​.

    Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024;30(8):2199-2207.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Acute Lymphoblastic Leukemia V2.2025. [NCCN Web site]. 06/27/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf [via free subscription]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - B-Cell Lymphomas  V3.2025. [NCCN Web site]. 08/18/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf [via free subscription]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V1.2026. [NCCN Web site]. 10/10/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Pediatric Acute Lymphoblastic Leukemia V1.2026. [NCCN Web site]. 08/11/2025​. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Pediatric Aggressive Mature B-Cell Lymphomas V2.2025. [NCCN Web site]. 04/28/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_b-cell.pdf. [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Axicabtagene ciloleucel (Yescarta®). Available at: https://www.nccn.org/professionals/drug_compendium/content/content/ [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Brexucabtagene autoleucel (Tecartus®)​. Available at: https://www.nccn.org/professionals/drug_compendium/content/content/ [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Lisocabtagene maraleucel (Breyanzi®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed November 26, 2025​.

    National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Tisagenlecleucel (Kymriah®). Available at: https://www.nccn.org/professionals/drug_compendium/content/content/ [via subscription only]. Accessed November 26, 2025​.

    Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.

    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. 2015;7(303):303ra139.

    Roddie C, Sandhu KS, Tholouli E, Logan AC, Shaughnessy P, Barba P, Ghobadi A, et al. Obecabtagene Autoleucel in Adults With B-Cell Acute Lymphoblastic Leukemia. N Engl J Med. 2024;391(23):2219-2230. doi:10.1056/NEJMoa2406526.​

    Schuster SJ, Bishop MR, Tam CS, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma [abstract]. Blood. 2017;130:Abstract 577.

    Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.

    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. 2021;22(10):1403-1415.

    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. 2022;23(8):1066-1077.

    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. 2021;398(10299):491-502.

    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. 2023;402(10402):641-654.

    Tisagenlecleucel (Kymriah®). [prescribing information] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 06/2025. Available at: https://www.us.kymriah.com/​. Accessed November 26, 2025​.

    UpToDate® LexidrugTM. Axicabtagene ciloleucel (Yescarta®). [UpToDate Lexidrug Web site]. 11/14/25. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025​.​

    UpToDate® LexidrugTM. Brexucabtagene autoleucel (Tecartus®)​. [UpToDate Lexidrug Web site]. 11/3/25. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025​.

    UpToDate® LexidrugTM. Lisocabtagene maraleucel (Breyanzi®). [UpToDate Lexidrug Web site]. 11/17/25​. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025​.

    UpToDate® LexidrugTM. Tisagenlecleucel (Kymriah®). [UpToDate Lexidrug Web site]. 11/12/25. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 26, 2025​.

    US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Axicabtagene ciloleucel (Yescarta®​). Prescribing information, approval letter, REMS documents. [FDA Web site]. 10/2025. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel. Accessed November 26, 2025​.

    US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Brexucabtagene autoleucel (Tecartus®)​. Prescribing information, approval letter, REMS documents. [FDA Web site]. 10/2025. Available at:
    https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel. Accessed November 26, 2025​.

    US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Lisocabtagene maraleucel (Breyanzi®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 12/2025. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel. Accessed December 08, 2025​.

    US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Tisagenlecleucel (Kymriah®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 06/2025. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel. Accessed November 26, 2025​.​

    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. 2020;382(14):1331-1342.​​

    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. 2024;42(10):1146-1157.

    Coding

    CPT Procedure Code Number(s)
    MEDICALLY NECESSARY

    38228

    NOT ELIGIBLE FOR SEPARATE REIMBURSEMENT

    38225, 38226, 38227
    ICD - 10 Procedure Code Number(s)
    N/A​
    ICD - 10 Diagnosis Code Number(s)

    Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy. ​

    HCPCS Level II Code Number(s)

    Q2041Axicabtagene ciloleucel, up to 200 million autologous anti-CD19 CAR positive T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
    Q2042Tisagenlecleucel, up to 600 million CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
    Q2053Brexucabtagene autoleucel, up to 200 million autologous anti-CD19 CAR positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
    Q2054Lisocabtagene maraleucel, up to 110 million autologous anti-CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
    Q2058Obecabtagene autoleucel, 10 up to 400 million CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per infusion​



    Revenue Code Number(s)
    N/A



    Coding and Billing Requirements

    Policy History

    Revisions From 08.01.43q:

    02/09/2026

    This version of the policy will become effective 02/09/2026​. 


    Information for the following drugs (Abecma and Carvykti) now resides in the following separate CART drug policy titled:

    • Chimeric Antigen Receptor (CART) Therapy: Carvykti® & Abecma®​​

    ​The title of the policy was changed as follows:
    FROM:  Chimeric Antigen Receptor (CAR) Therapy
    TO: Chimeric Antigen Receptor (CART) Therapy: Yescarta Tecartus, Breyanzi, Kymriah and Aucatzyl ​


    The following indication has been added in accordance with National Comprehensive Cancer Network (NCCN):

    • Yescarta® and Kymriah®---Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

    The following product has been added, which was FDA approved 11/08/2024:

    • Aucatzyl (obecatagene autoleucel)

    The following indications have been revised in accordance with NCCN:

    • Yescarta® - addition of subtype plasmablastic lymphoma;  additional therapy for transformed disease following partial response, no response, or progressive disease after initial treatment with anthracycline-based regimens (e.g., doxorubicin) 
    • Breyanzi® - addition of subtype plasmablastic lymphoma;   CLL/SLL - In combination with or without ibrutinib; criteria for Histologic (Richter) transformation to DLBCL (including del(17p)/TP53 mutation)
    • Kymriah® - addition of subtype plasmablastic lymphoma
    The following HCPCS code for Aucatzyl (obecatagene autoleucel)​ has been added to this policy as medically necessary:​
    • ​Q2058 Obecabtagene autoleucel, 10 up to 400 million CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per infusion​


    Revisions From 08.01.43p:

    02/24/2025This version of the policy will become effective 02/24/2025.

    The following policy criteria have been added to the policy in alignment with the National Comprehensive Cancer Network compendium accessed 11/20/2024:
    Lisocabtagene maraleucel (Breyanzi): follicular lymphoma (grade 1 to 2)
    Lisocabtagene maraleucel (Breyanzi): mantle cell lymphoma
    Lisocabtagene maraleucel (Breyanzi): chronic lymphocytic leukemia/small lymphocytic lymphoma

    The following policy criteria have been revised in alignment with NCCN compendium:
    Axicabtagene ciloleucel (Yescarta)
    Brexucabtagene autoleucel (Tecartus)
    Ciltacabtagene autoleucel (Carvykti)
    Idecabtagene vicleucel (Abecma)
    Lisocabtagene maraleucel (Breyanzi)
    Tisagenlecleucel (Kymriah)

    All of the ICD-10 CM codes have been removed from this policy, since they are informational. Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.​


    Revisions From 08.01.43o:

    01/01/2025This version of the policy will become effective 01/01/2025.

    Inclusion of a policy in a Code Update memo does not imply that a full review of
    the policy was completed at this time.

    The following CPT codes have been added to this policy:
    38225 Chimeric antigen receptor T-cell therapy; harvesting of T lymphocytes 
    38226 Chimeric antigen receptor T-cell therapy; preparation of T lymphocytes
    38227 Receipt and preparation of cells for Chimeric antigen receptor T-cell therapy​ 
    38228 Autologous CAR-T cell administration 

    The following CPT codes have been removed from ​this policy:
    0537T Chimeric antigen receptor t-cell (car-t) therapy; harvesting of blood-derived t lymphocytes for development of genetically modified autologous car-t cells, per day
    0538T Chimeric antigen receptor t-cell (car-t) therapy; preparation of blood-derived t lymphocytes for transportation (eg, cryopreservation, storage)
    0539T Chimeric antigen receptor t-cell (car-t) therapy; receipt and preparation of car-t cells for administration
    0540T Chimeric antigen receptor t-cell (car-t) therapy; car-t cell administration, autologous​


    Revisions From 08.01.43n:

    10/01/2024This version of the policy will become effective 10/01/2024.

    Inclusion of a policy in a Code Update memo does not imply that a full review of
    the policy was completed at this time.

    The following ICD-10 code has been added to Attachment A of this policy:
    C83.398  Diffuse large B-cell lymphoma of other extranodal and solid organ site

    The following ICD-10 codes have been removed from Attachment A of ​this policy:
    C83.39    Diffuse large B-cell lymphoma, extranodal and solid organ sites
    C88.4      Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]​


    Revisions From 08.01.43m:

    07/01/2024

    This version of the policy will become effective 07/01/2024.


    Inclusion of a policy in a Code Update memo does not imply that a full review of
    the policy was completed at this time.
    ​
    The following HCPCS code has been revised in this policy:​

    Q2055​


    Revisions From 08.01.43l:

    10/23/2023
    		This version of the policy will become effective 10/23/2023

    The following indication has been added to this policy for axicabtagene ciloleucel (Yescarta) and lisocabtagene maraleucel (Breyanzi) in accordance with National Comprehensive Cancer Network (NCCN) compendium (accessed 08/20/2023) and guideline:
    Pediatric Aggressive Mature B-Cell Lymphomas (V1.2023; 04/04/2023)

    The following policy criteria have been revised in accordance with NCCN compendium (accessed 08/20/2023):
    Axicabtagene ciloleucel (Yescarta)
    Brexucabtagene autoleucel (Tecartus)
    Ciltacabtagene autoleucel (Carvykti)
    Lisocabtagene maraleucel (Breyanzi)
    Tisagenlecleucel (Kymriah)
    ​
    The following codes have been ​added to this policy under Yescarta, Breyanzi, and Kymriah:​
    C85.80 Other specified types of non-Hodgkin lymphoma, unspecified site
    C85.81 Other specified types of non-Hodgkin lymphoma, lymph nodes of head, face, and neck
    C85.82 Other specified types of non-Hodgkin lymphoma, intrathoracic lymph nodes
    C85.83 Other specified types of non-Hodgkin lymphoma, intra-abdominal lymph nodes
    C85.84 Other specified types of non-Hodgkin lymphoma, lymph nodes of axilla and upper limb
    C85.85 Other specified types of non-Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
    C85.86 Other specified types of non-Hodgkin lymphoma, intrapelvic lymph nodes
    C85.88 Other specified types of non-Hodgkin lymphoma, lymph nodes of multiple sites
    C85.89 Other specified types of non-Hodgkin lymphoma, extranodal and solid organ sites

    The following code has been     ​added to this policy under Breyanzi and Kymriah​:​
    C85.87 Other specified types of non-Hodgkin lymphoma, spleen

    The following code has been     ​added to this policy under Breyanzi:
    C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]​

    Revisions From 08.01.43k:
    10/31/2022
    		​This version of the policy will become effective 10/31/2022. 

    The following policy criteria have been added to this policy:

    Criteria for axicabtagene ciloleucel (Yescarta) in accordance with US Food and Drug Administration (FDA) labeling (04/01/2022) and National Comprehensive Cancer Network (NCCN) compendium (accessed 07/31/2022)

    Criteria for brexucabtagene autoleucel (Tecartus) in accordance with FDA labeling (10/01/2021) and NCCN

    Criteria for ciltacabtagene autoleucel (Carvykti) in accordance with FDA labeling (02/28/2022) and NCCN

    Criteria for idecabtagene vicleucel (Abecma) in accordance with FDA labeling (03/26/2021) and NCCN
    Criteria for lisocabtagene maraleucel (Breyanzi) in accordance with FDA labeling (06/24/2022) and NCCN
    Criteria for tisagenlecleucel (Kymriah) in accordance with FDA labeling (05/27/2022) and NCCN


    The following policy criteria have been revised:​

    Criteria for axicabtagene ciloleucel (Yescarta) in accordance with FDA labeling and NCCN 

    Criteria for brexucabtagene autoleucel (Tecartus) in accordance with FDA labeling and NCCN

    Criteria for tisagenlecleucel (Kymriah) in accordance with FDA labeling and NCCN​


    The following codes have been ​added to this policy:

    C82.00, C82.01, C82.02, C82.03, C82.04, C82.05, C82.06, C82.07, C82.08, C82.09, C82.10, C82.11, C82.12, C82.13, C82.14, C82.15, C82.16, C82.17, C82.18, C82.19, C82.40, C82.41, C82.42, C82.43, C82.44, C82.45, C82.46, C82.47, C82.48, C82.49, C83.00, C83.01, C83.02, C83.03, C83.04, C83.05, C83.06, C83.07, C83.08, C83.30, C83.31, C83.32, C83.33, C83.34, C83.35, C83.36, C83.37, C83.38, C83.39, C83.80, C83.81, C83.82, C83.83, C83.84, C83.85, C83.86, C83.87, C83.88, C83.89, C85.10, C85.11, C85.12, C85.13, C85.14, C85.15, C85.16, C85.17, C85.18, C85.19, C85.20, C85.21, C85.22, C85.23, C85.24, C85.25, C85.26, C85.27, C85.28, C85.29, C85.87, C88.4, C90.00, C90.02, C91.00, C91.02, D47.Z1, Q2056


    The following codes have been removed from this policy:

    C9098, Z92.850​

    ​Revisions From 08.01.43j:
    01/01/2022

    This version of the policy is a result of code updates effective 01/01/2022. 

    Following procedure code was added:

    Q2055


    Following procedure code was deleted:

    C9081​


    Revision from 08.01.43i:

    10/01/2021

    This version of the policy is a result of code updates effective 10/01/2021. 

    Procedure code C9076 was deleted.

    Procedure codes were added:

    C9081
    Q2054
     
    The following diagnosis code was added: Z92.850.


    Revisions From 08.01.43h:

    07/01/2021

    This version ​of the policy is effective as of 07/01/2021, and is in place due to a code update that resulted in pocedure code C9076 being added to this policy.


    -- Code J3590​ was also added to this policy.


    Revisions from 08.01.43g:

    04/01/2021

    This version of the policy is effective as of 04/01/2021, and is in place due to coding updates.

     

    • Procedure code C9073 was deleted from this policy.
    • Procedure code Q2053 was added to this policy.


    Revisions From 08.01.43f:

    01/01/2021

    This version of the policy will become effective 01/01/2021​​
    ​
    This policy has been updated to communicate the coverage criteria for chimeric antigen receptor (CAR) therapy (tisagenlecleucel [Kymriah™], axicabtagene ciloleucel [Yescarta™], brexucabtagene autoleucel [Tecartus™]), in accordance with the US Food and Drug Administration (FDA) prescribing information and the National Comprehensive Cancer Network (NCCN) Compendia.

    The following ICD-10 CM codes have been added to this policy:

    C83.10  Mantle cell lymphoma, unspecified site                                  

    C83.11  Mantle cell lymphoma, lymph nodes of head, face, and neck                                              

    C83.12  Mantle cell lymphoma, intrathoracic lymph nodes                                                    

    C83.13  Mantle cell lymphoma, intra-abdominal lymph nodes                                              

    C83.14  Mantle cell lymphoma, lymph nodes of axilla and upper limb                                              

    C83.15  Mantle cell lymphoma, lymph nodes of inguinal region and lower limb                                                 

    C83.16  Mantle cell lymphoma, intrapelvic lymph nodes                                                        

    C83.17  Mantle cell lymphoma, spleen                                             

    C83.18  Mantle cell lymphoma, lymph nodes of multiple sites                                              

    C83.19  Mantle cell lymphoma, extranodal and solid organ sites        

    C88.4    Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]

    Coding table was updated 
    CPT procedure code numbers and narratives have been added to this policy​:

    0540T Chimeric antigen receptor t-cell (car-t) therapy; car-t cell administration, autologous

     

    NOT ELIGIBLE FOR SEPARATE REIMBURSEMENT

    0537T Chimeric antigen receptor t-cell (car-t) therapy; harvesting of blood-derived t lymphocytes for development of genetically modified autologous car-t cells, per day

    0538T Chimeric antigen receptor t-cell (car-t) therapy; preparation of blood-derived t lymphocytes for transportation (eg, cryopreservation, storage)

    0539T Chimeric antigen receptor t-cell (car-t) therapy; receipt and preparation of car-t cells for administration

    THE FOLLOWING CODES ARE USED TO REPRESENT (brexucabtagene autoleucel) TECARTUS

    C9073 Brexucabtagene autoleucel, up to 200 million autologous anti-cd19 car positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose​

    Revisions From 08.01.43e:
    12/09/2019This version of the policy will become effective 12/09/2019.

    This policy has been updated to communicate the coverage criteria for chimeric antigen receptor (CAR) therapy (tisagenlecleucel [Kymriah™] and axicabtagene ciloleucel [Yescarta™]), in accordance with the US Food and Drug Administration (FDA) prescribing information and the National Comprehensive Cancer Network (NCCN) Compendia. ​

    The following ICD-10 CM code has been added to this policy:
    D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)

    Revisions From 08.01.43d:
    01/01/2019 This policy has been identified for the CPT/HCPCS code update, effective 01/01/2019.

    The following HCPCS code has been added to this policy:
    Q2042 Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

    The following HCPCS code has been termed from this policy:
    Q2040 Tisagenlecleucel, up to 250 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per infusion

    The following HCPCS codes has been revised in this policy:
    FROM: Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car t cells, including leukapheresis and dose preparation procedures, per infusion
    TO: Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

    Revisions From 08.01.43c:
    07/30/2018This version of the policy will become effective 07/30/2018.

    This policy has been updated in consideration of revisions within the US Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia for Axicabtagene ciloleucel (Yescarta™) and Tisagenlecleucel (Kymriah™), including the new coverage criteria for Tisagenlecleucel (Kymriah™) for relapsed or refractory large B-cell lymphoma.

    Revisions From 08.01.43b:
    04/01/2018This policy has been identified for the HCPCS code update, effective 04/01/2018.

    The following HCPCS codes have been added to this policy:
    Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car t cells, including leukapheresis and dose preparation procedures, per infusion
    ​
    Revisions From 08.01.43a:
    01/01/2018This policy has been identified for the HCPCS code update, effective 01/01/2018.

    The following HCPCS codes have been added to this policy:
    Q2040 Tisagenlecleucel, up to 250 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per infusion

    Revisions From 08.01.43:
    11/29/2017This version of the policy will become effective 11/29/2017.

    This new policy has been issued to communicate the Company's co​verage position for tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™). 

    2/9/2026
    2/9/2026
    08.01.43
    Medical Policy Bulletin
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