Medicare Advantage

Medical Policy

Notification

Chimeric Antigen Receptor (CAR) Therapy

Notification Issue Date: N/A

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

Medical Policy Bulletin

Title:

Chimeric Antigen Receptor (CAR) Therapy

Policy #:

MA08.093p

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®),

ciltacabtagene

autoleucel (

Carvykti®),

idecabtagene

vicleucel (

Abecma®),

lisocabtagene

maraleucel (

Breyanzi®), and

tisagenlecleucel (

Kymriah®) 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 name	Indication
Axicabtagene ciloleucel	Yescarta®	B-cell lymphoma (BCL)
Brexucabtagene autoleucel	Tecartus®	Mantle cell lymphoma (MCL) Acute lymphoblastic leukemia (ALL)
Ciltacabtagene autoleucel	Carvykti®	Multiple myeloma (MM)
Idecabtagene vicleucel	Abecma®	Multiple myeloma (MM)
Lisocabtagene maraleucel	Breyanzi®	B-cell lymphoma (BCL) Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Tisagenlecleucel	Kymriah®	Acute lymphoblastic leukemia (ALL; young adult and pediatric) B-cell lymphoma (BCL)

MEDICALLY NECESSARY

AXICABTAGENE CILOLEUCEL (YESCARTA)
B-Cell Lymphomas

Diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, acquired immunodeficiency syndrome/human immunodeficiency virus-related diffuse large B-cell lymphoma, primary effusion lymphoma, human herpesvirus 8-positive diffuse large B-cell lymphoma
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), R/R primary mediastinal large B-cell lymphoma (BCL), R/R high-grade BCL with or without MYC and BCL2 and/or BCL6 rearrangement, R/R acquired immunodeficiency syndrome (AIDS)/human immunodeficiency virus (HIV)-related DLBCL, R/R primary effusion lymphoma, or human herpesvirus 8 (HHV8)-positive DLBCL, not otherwise specified, who have received, at a minimum, an anti–cluster of differentiation (CD)20 monoclonal antibody (e.g., rituximab) (unless the tumor is CD20 negative) and an anthracycline (e.g., doxorubicin)-containing chemotherapy regimen, when administered at healthcare facilities enrolled in the US Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of R/R BCLs
Used as one of the following:

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
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 (if anti-CD19 chimeric antigen receptor [CAR] T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) of disease in second relapse or greater in individuals with partial response, relapse, or progressive disease following therapy for R/R disease (National Comprehensive Cancer Network [NCCN] preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; 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
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Follicular lymphoma (grade 1 to 2), marginal zone lymphoma*

Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R follicular lymphoma (FL; grade 1 to 2) or R/R marginal zone lymphoma* (MZL) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of one of the above types of R/R BCLs
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)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

*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.

Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma (e.g., from follicular lymphoma, nodal marginal zone lymphoma)

Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R histologic transformation of indolent lymphomas to DLBCL (e.g., from FL [individual must have chemorefractory disease after transformation to DLBCL] or nodal MZL) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of one of the above types of R/R BCLs
Used as additional therapy (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) in individuals who are candidates for additional therapy and have received multiple lines of prior therapies including two or more chemoimmunotherapy regimens for indolent or transformed disease (individuals should have received at least one anthracycline [e.g., doxorubicin] -based regimen, unless contraindicated)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Monomorphic post-transplant lymphoproliferative disorder (B-cell type)
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R monomorphic post-transplant lymphoproliferative disorder (PTLD) (B-cell type) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of R/R monomorphic PTLD (B-cell type)
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 (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] not previously given) of disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Pediatric aggressive mature B-cell lymphoma (primary mediastinal large B-cell lymphoma)
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R pediatric aggressive mature BCL (primary mediastinal large BCL) when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

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 2 or more chemoimmunotherapy regimens) (NCCN preferred)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy

BREXUCABTAGENE AUTOLEUCEL (TECARTUS)
Mantle cell lymphoma

Brexucabtagene autoleucel (Tecartus) is considered medically necessary and, therefore, covered for the autologous treatment for R/R mantle cell lymphoma (MCL) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis R/R MCL
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 non–time-limited regimens (e.g., lenalidomide and rituximab)
Partial response, no response, or progressive disease following second-line therapy with time-limited regimens
Relapsed or progressive disease (relapse #2 or greater) if not previously given

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

B-Cell Precursor Acute lymphoblastic leukemia

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 administered at healthcare facilities enrolled in the FDA REMS, 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 clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
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)

The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

CILTACABTAGENE AUTOLEUCEL (CARVYKTI)
Multiple myeloma

Ciltacabtagene autoleucel (Carvykti) is considered medically necessary and, therefore, covered for the autologous treatment for R/R multiple myeloma (MM) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following are met:

Diagnosis of late relapse or progressive MM
The individual has been treated with one of the following regimens:

One prior line of therapy including all of the following (NCCN preferred):

A proteasome inhibitor (e.g., carfilzomib, ixazomib, bortezomib)
An immunomodulatory agent (e.g., thalidomide, lenalidomide, pomalidomide, cyclophosphamide)
Are refractory to lenalidomide

Three prior lines of therapy (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have known active or prior history of significant CNS disease
The individual does not have a history of prior therapy that is targeted to B-cell maturation antigen (BCMA) (e.g., belantamab mafodotin, teclistamab, idecabtagene vicleucel [Abecma])
The individual has not undergone allogeneic hematopoietic stem cell transplantation (HSCT) within the past 6 months or an autologous HSCT 12 weeks or less before apheresis
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

IDECABTAGENE VICLEUCEL (ABECMA)
Multiple myeloma

Idecabtagene vicleucel (Abecma) is considered medically necessary and, therefore, covered for the autologous treatment for R/R MM when administered at healthcare facilities enrolled in the FDA REMS, and all of the following are met:

Diagnosis of late relapse or progressive MM
The individual has been treated with one of the following regimens:

Two prior lines of therapy including all of the following (NCCN preferred):

A proteasome inhibitor (e.g., carfilzomib, ixazomib, bortezomib)
An immunomodulatory agent (e.g., thalidomide, lenalidomide, pomalidomide, cyclophosphamide)
An anti-CD38 monoclonal antibody (e.g., isatuximab, daratumumab)

At least 3 prior lines of therapy (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have known active or prior history of significant CNS disease
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

LISOCABTAGENE MARALEUCEL (BREYANZI)
B-Cell Lymphomas

Diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma (grade 3B), acquired immunodeficiency syndrome/human immunodeficiency virus-related diffuse large B-cell lymphoma, primary effusion lymphoma, human herpesvirus 8-positive diffuse large B-cell lymphoma
Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R DLBCL, R/R high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma), R/R primary mediastinal large BCL, R/R THRBCL, R/R FL (grade 3B), R/R AIDS/HIV-related DLBCL, R/R primary effusion lymphoma, and R/R HHV8-positive DLBCL, not otherwise specified when administered at healthcare facilities enrolled in the FDA REMS, and all of the following are met:

Diagnosis of one of the above types of R/R B-cell lymphomas
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 (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) of disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

Follicular lymphoma (grade 1 to 2)

Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R FL (grade 1 to 2) when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

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
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

Mantle cell lymphoma

Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R MCL when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

Diagnosis of R/R MCL
Used in one of the following regimens:

As second-line therapy for individuals who are appropriate for aggressive induction therapy and have received prior covalent Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib)
As third and subsequent-line therapy for individuals who are appropriate for less aggressive induction therapy 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

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

Histologic transformation of indolent lymphoma to diffuse large B-cell lymphoma (e.g., follicular lymphoma, marginal zone lymphoma*)
Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R histologic transformation of indolent lymphomas to DLBCL (e.g., FL, MZL*) when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

Diagnosis of one of the above types of R/R BCLs
Used as third-line and subsequent therapy (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) for individuals who are candidates for additional therapy and who have received multiple lines of prior therapies including two or more 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)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

Monomorphic post-transplant lymphoproliferative disorder (B-cell type)
Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R monomorphic PTLD (B-cell type) when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

Diagnosis of R/R monomorphic PTLD (B-cell type)
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
Treatment (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] not previously given) of disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

Pediatric aggressive mature B-cell lymphoma (primary mediastinal large B-cell lymphoma)
Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R pediatric aggressive mature BCL (primary mediastinal large BCL)when administered at healthcare facilities enrolled in the FDA REMS and all of the following are met:

Diagnosis of 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) (NCCN preferred)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) when administered at healthcare facilities enrolled in the FDA REMS and all of the following criteria are met:

Diagnosis of R/R CLL/SLL
Used as either of the following:

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 who have indications for treatment (NCCN preferred)
Additional therapy for treatment of histologic (Richter) transformation to DLBCL (clonally related or unknown clonal status) in individuals with del(17p)/TP53 mutation or who are chemotherapy refractory or unable to receive chemoimmunotherapy

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have active CNS-only involvement by malignancy, but can have secondary CNS involvement
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at time of infusion

TISAGENLECLEUCEL (KYMRIAH)
B-Cell Precursor Acute Lymphoblastic Leukemia

Tisagenlecleucel (Kymriah) as a single-agent therapy is considered medically necessary and, therefore, covered for the autologous treatment of R/R B-ALL when administered at healthcare facilities enrolled in the FDA REMS and all of the following criteria are met:

Confirmed diagnosis of CD19-positive B-ALL with morphologic bone marrow tumor involvement (five percent or greater lymphoblasts) in individuals 25 years and younger at the time of infusion with relapsed or refractory (R/R) disease and one of the following subtypes:

Ph-negative disease with refractory disease or two or more relapses (NCCN preferred regimen)
Ph-positive disease with refractory disease or two or more relapses following therapy that has included two TKIs (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib)

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

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy

Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Tisagenlecleucel (Kymriah), as a single-agent therapy, is considered medically necessary and, therefore, covered for the autologous treatment of R/R pediatric B-ALL when administered at healthcare facilities enrolled in the FDA REMS and all of the following criteria are met:

Confirmed diagnosis of CD19-positive B-ALL with morphologic bone marrow tumor involvement (five percent or greater lymphoblasts) in 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

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

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy

B-Cell Lymphomas

Diffuse large B-cell lymphoma, high-grade B-cell lymphoma, acquired immunodeficiency syndrome/human immunodeficiency virus-related diffuse large B-cell lymphoma, primary effusion lymphoma, human herpesvirus 8-positive diffuse large B-cell lymphoma
Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the autologous treatment of R/R DLBCL (tisagenlecleucel [Kymriah] is not FDA approved for R/R primary mediastinal large BCL); R/R high-grade BCL with MYC rearrangement plus rearrangement of BCL2, BCL6, or both genes (double- or triple-hit lymphoma); R/R AIDS/HIV-related DLBCL; R/R primary effusion lymphoma; or R/R HHV8-positive DLBCL, not otherwise specified when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of one of the above types of R/R BCLs
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 (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) of disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Histologic transformation of indolent lymphomas (e.g., follicular lymphoma, nodal marginal zone lymphoma) to diffuse large B-cell lymphoma

Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the autologous treatment of R/R histologic transformation of indolent lymphomas (e.g., FL, nodal MZL) to DLBCL when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of one of the above types of R/R BCLs
Used as third-line and subsequent therapy (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] was not previously given) in individuals who are candidates for additional therapy and have received multiple lines of prior therapies including two or more chemoimmunotherapy regimens for indolent or transformed disease (individuals should have received at least one anthracycline [i.e., doxorubicin] or anthracenedione [e.g., mitoxantrone]-based regimen, unless contraindicated) (NCCN preferred)
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Monomorphic post-transplant lymphoproliferative disorders (B-cell type)
Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the autologous treatment of R/R monomorphic PTLD (B-cell type) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

Diagnosis of R/R monomorphic PTLD (B-cell type)
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 initial treatment with chemoimmunotherapy in individuals who have partial response following second-line chemoimmunotherapy
Third-line and subsequent therapy as treatment (if anti-CD19 CAR T-cell therapy [e.g., axicabtagene ciloleucel {Yescarta}, brexucabtagene autoleucel {Tecartus}, lisocabtagene maraleucel {Breyanzi}, tisagenlecleucel {Kymriah}] not previously given) of disease in second relapse or greater in individuals with partial response, no response, or progressive disease following therapy for R/R disease (NCCN preferred)

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

Follicular lymphoma (grade 1 to 2)
Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the autologous treatment of R/R FL (grade 1 to 2) when administered at healthcare facilities enrolled in the FDA REMS, and all of the following criteria are met:

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)
The individual does not have evidence of histologic transformation
The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; HIV infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary CNS lymphoma or malignancy
The individual does not have a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion

EXPERIMENTAL/INVESTIGATIONAL

All other uses for

axicabtagene

ciloleucel (

Yescarta),

brexucabtagene

autoleucel (

Tecartus),

ciltacabtagene

autoleucel (

Carvykti),

idecabtagene

vicleucel (

Abecma),

lisocabtagene

maraleucel (

Breyanzi), or

tisagenlecleucel (

Kymriah) 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 CAR-T cells are not eligible for separate reimbursement from the CAR-T cell 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.

RISK EVALUATION AND MITIGATION STRATEGY PROGRAM

Due to the risk of cytokine release syndrome (CRS) and neurological toxicities, axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), ciltacabtagene autoleucel (Carvykti), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), and tisagenlecleucel (Kymriah) are only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The requirements of the REMS include:

Healthcare facilities that dispense and administer axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), ciltacabtagene autoleucel (Carvykti), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), or tisagenlecleucel (Kymriah) must be enrolled in the program.
Certified healthcare facilities must have on-site, immediate access to tocilizumab (Actemra) and ensure that a minimum of two doses are available for each patient for administration within 2 hours after axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), ciltacabtagene autoleucel (Carvykti), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), or tisagenlecleucel (Kymriah) infusion if needed to treat CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), ciltacabtagene autoleucel (Carvykti), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), or tisagenlecleucel (Kymriah) are trained about the management of CRS and neurological toxicities.

ADEQUATE ORGAN AND BONE MARROW FUNCTION

Prior to being considered for 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) five 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 3 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/dlL

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), ciltacabtagene autoleucel (Carvykti), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), or tisagenlecleucel (Kymriah) are covered under the medical benefits of the Company’s Medicare Advantage 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 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 have 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.

Ciltacabtagene autoleucel (Carvykti) was approved by the FDA on February 28, 2022, for the treatment of adult individuals with R/R multiple myeloma (MM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti–cluster of differentiation (CD)38 monoclonal antibody. Supplemental approvals for ciltacabtagene autoleucel (Carvykti) have since been issued by the FDA. The safety and effectiveness of ciltacabtagene autoleucel (Carvykti) in the pediatric population have not been established.

Idecabtagene vicleucel (Abecma) was approved by the FDA on March 26, 2021, for the treatment of adult individuals with R/R MM after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Supplemental approvals for idecabtagene vicleucel (Abecma) have since been issued by the FDA. The safety and effectiveness of idecabtagene vicleucel (Abecma) in the pediatric population have not been established.

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 age 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.

DOSING GUIDELINES

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 kg 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 kg 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 kg body weight, with a maximum of 1 × 10⁸ CAR-positive viable T cells.

CILTACABTAGENE AUTOLEUCEL (CARVYKTI)

Pre-treatment:
Lymphodepleting chemotherapy: fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² IV daily for 3 days. Infuse ciltacabtagene autoleucel (Carvykti) 2 to 4 days after completion of lymphodepleting chemotherapy.

Treatment:
Ciltacabtagene autoleucel (Carvykti) dose is 0.5 to 1.0 × 10⁶ CAR-positive viable T cells per kg body weight with a maximum of 1 × 10⁸ CAR-positive viable T cells.

IDECABTAGENE VICLEUCEL (ABECMA)
Pre-treatment:
Lymphodepleting chemotherapy: fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² IV daily for 3 days. Infuse idecabtagene vicleucel (Abecma) 2 days after completion of lymphodepleting chemotherapy.

Treatment:
Idecabtagene vicleucel (Abecma) target dose is 300 to 510 × 10⁶ CAR-positive 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).

Relapsed or Refractory Large B-Cell Lymphoma (including grade 3B Follicular Lymphoma) 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

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 (DLBCL) 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 kg body weight
The individual is above 50 kg: dose is 0.1 to 2.5 × 108 CAR-positive viable T cells

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 versus 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 {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 hematopoietic stem cell transplantation (HSCT).

Multiple myeloma (MM) is also a type of blood cancer, particularly of the plasma cells within the bone marrow. Like leukemia and lymphoma, the cancer affects the immune system of the individual with the malignancy. Like leukemia and lymphoma, treatment includes a combination of chemotherapy, biologicals, radiation therapy, and hematopoietic stem cell transplantation (HSCT).

Chimeric antibody receptor (CAR) T-cell therapy is a method whereby the T cells (a type of white blood cell) are altered in a laboratory in order to have them find and destroy cancer cells or other disease-producing cells. Each dose of CAR T is customized to the individual and their cancer or disease. The individual's T cells are collected during a process called leukapheresis and sent to a manufacturing center where they are genetically modified to include a new 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 CAR T 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 percent (95 percent confidence interval [CI], 73 to 89) with 54 percent achieving a complete remission (CR) and 28 percent achieving a partial remission (PR). At the median follow-up of 7.9 months, individuals in complete remission had not reached the estimated DOR. Grade 3 or higher adverse events occurred in 95 percent of the individuals. Grade 3 or higher cytokine release syndrome (CRS) occurred in 17 percent of individuals and grade 3 or higher neurologic events occurred in 28 percent 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 to 28.8) was also published. The ORR was now 83 percent, with a CR of 58 percent and PR of 25 percent. The median DOR was 11.1 months (95 percent CI, 4 to not estimable). The median PFS was 5.9 months (95 percent CI, 3.3 to 15.0). The median overall survival (OS) was not reached (95 percent 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 CAR T-cell 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 to 22.6). Of 109 individuals who were able to be assessed in the updated analysis, the ORR was 92 percent [95 percent CI, 85 to 97]) with 83 individuals (76 percent) having a CR. At a cutoff of 18 months, the estimated PFS rate was 64.8 percent (95 percent CI, 54.2 to 73.5). DOR was not reached. At the 18-month cutoff, the OS rate was 87.4 percent (95 CI, 79.2 to 92.5). Among all individuals who were transfused with axicabtagene ciloleucel (Yescarta), 147 (99 percent) experienced treatment-emergent adverse events with 128 (86 percent) experiencing grade 3 or higher events. CRS occurred in 121 individuals (82 percent) with grade 3 or higher occurring in 10 individuals (7 percent). Neurological events occurred in 87 individuals (59 percent) with grade 3 or higher occurring in 28 individuals (19 percent). A total of 19 individuals died after transfusion with axicabtagene ciloleucel (Yescarta), but only one death was believed to be due to 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 into 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 percent in the axicabtagene ciloleucel (Yescarta) cohort versus 16 percent in the SOC cohort (hazard ratio [HR] for event/death, 0.40; 95 percent CI, 0.31 to 0.51; P<0.001). The OS rate at 24 months was 61 percent in the axicabtagene ciloleucel (Yescarta) cohort and 52 percent in the SOC cohort. A response occurred in 83 percent of individuals in the axicabtagene ciloleucel (Yescarta) cohort and 50 percent of individuals in the SOC cohort, with a complete response occurring in 65 percent of individuals in the axicabtagene ciloleucel (Yescarta) cohort versus 32 percent in the SOC cohort. Grade 3 or higher adverse events occurred in 91 percent of individuals in the axicabtagene ciloleucel (Yescarta) cohort and 83 percent of the SOC cohort. Grade 3 or higher CRS occurred in six percent and grade 3 or higher neurological event occurred in 21 percent 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 and 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.

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. A total of 74 individuals were enrolled. Brexucabtagene autoleucel (KTE-X19) was manufactured for 71 individuals and administered to 68. The primary efficacy analysis showed that 93 percent (95 percent CI, 84 to 98) had an objective response as assessed by an independent radiologic review committee with 67 percent (95 percent CI, 53 to 78) having a CR. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57 percent of the 60 individuals in the primary efficacy analysis were in remission. At 12 months, the estimated PFS and OS were 61 percent and 83 percent, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94 percent of the individuals) and infections (in 32 percent). Grade 3 or higher CRS and neurologic events occurred in 15 percent and 31 percent 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). A total of 71 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 percent CI, 37.8 to 65.7) and 15 percent 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 percent of individuals, CRS occurred in 89 percent of individuals, and neurological events occurred in 60 percent of individuals. Six of the treated individuals (11 percent) died secondary to grade 5 adverse events, with two of these believed to be treatment related.

CILTACABTAGENE AUTOLEUCEL (CARVYKTI)

On February 28, 2022, the FDA approved ciltacabtagene autoleucel (Carvykti) for the treatment of adult individuals with R/R MM after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Ciltacabtagene autoleucel (Carvykti) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy.

The safety and efficacy of ciltacabtagene autoleucel (Carvykti) for the treatment of adult individuals with MM were evaluated in a single-arm, open-label, multicenter, phase 1b/2 trial (CARTITUDE-1; NCT03548207). Individuals were eligible for treatment if they had a diagnosis of R/R MM and had received three or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. One of the primary endpoints was overall response rates along with safety data. Key secondary endpoints included DOR and PFS. A total of 113 individuals were enrolled in the study and 97 individuals received the ciltacabtagene autoleucel (Carvykti) infusion. The overall response rate was 97 percent (95 percent CI, 91.2 to 99.4 in 94 of 97 individuals). A stringent complete response was achieved by 65 individuals (67 percent). Neither median DOR (95 percent CI, 15.9 to not estimable) nor median PFS (95 percent CI, 16.8 to not estimable) was reached as of the data cut-off (median follow-up, 12.4 months). At 1 year, the PFS was 77 percent (95 percent CI, 66.0 to 84.3) and overall survival rate was 89 percent (95 percent CI, 80.2 to 93.5). All of the transfused individuals experienced an adverse event with hematological adverse events being the most common. CRS occurred in 95 percent (92 of 97) of individuals, but only four percent were grade 3 or 4. Fourteen individuals died during the study, with six of these believed to be treatment related.

The safety and efficacy of ciltacabtagene autoleucel (Carvykti) for the treatment of adult individuals with MM who were refractory to lenalidomide were evaluated in a phase 3, randomized, open-label study (CARTITUDE-4; NCT04181827) versus the provider’s choice of effective standard therapy (pomalidomide, bortezomib, dexamethasone [PVd] or daratumumab, pomalidomide, dexamethasone [DPd]) in individuals who had received 1 to 3 lines of prior therapy that included a proteasome inhibitor and an immunomodulatory drug. The primary endpoint was PFS up to 6 years or death due to any cause, whichever occurred first. Key secondary endpoints included ORR and percentage of individuals with CR or better (stringent CR). A total of 419 individuals were randomized in a 1:1 ratio to treatment with ciltacabtagene autoleucel (Carvykti) or standard therapy. At a median follow-up of 15.9 months, the medium PFS was not reached for the ciltacabtagene autoleucel (Carvykti) cohort versus 11.8 months for the standard therapy cohort (P<0.0001). The ORR was 84.6 percent for the ciltacabtagene autoleucel (Carvykti) cohort versus 67.8 percent for the standard therapy cohort (P<0.0001). The percentage of individuals that experienced a complete response or better in the ciltacabtagene autoleucel (Carvykti) cohort was 74.1 percent versus 22.3 percent for the standard therapy cohort (P<0.0001). Of the individuals in the ciltacabtagene autoleucel (Carvykti) cohort, 76.1 percent experienced CRS; 1.1 percent grade 3 or 4, none grade 5. The percentage of adverse events were similar between the two cohorts.

IDECABTAGENE VICLEUCEL (ABECMA)

On February 28, 2022, the FDA approved idecabtagene vicleucel (Abecma) for the treatment of adult individuals with R/R MM after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Idecabtagene vicleucel (Abecma) is a BCMA-directed genetically modified autologous T-cell immunotherapy.

The safety and efficacy of idecabtagene vicleucel (Abecma) for the treatment of adult individuals with MM were evaluated in a single-arm, open-label, multicenter, phase 2 trial (KarMMa; NCT03361748). Individuals were eligible for treatment if they had a diagnosis of R/R MM and had received three or more previous lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The primary endpoint was an overall response of partial response or better. A key secondary endpoint was the rate of complete response or better. A total of 140 individuals were enrolled with 128 individuals being transfused with target doses of 150 × 10⁶ CAR T cells, 300 × 106 CAR T cells, or 450 × 10⁶ CAR T cells. Ninety-two percent of the individuals had received a prior autologous HSCT. At a median follow-up of 13.3 months (range, 0.2 to 21.2), 94 individuals (73 percent; 95 percent CI, 66 to 81) had a response to the infusion (P<0.001), and 42 individuals (33 percent) had a complete or stringent complete response. The median DOR for any dose was 10.7 months (95 percent CI, 9.0 to 11.3) with a median DOR of 11.3 months (95 percent CI, 10.3 to 11.4) for the 450 × 10⁶ cohort. The median PFS for any dose was 8.8 months (95 percent CI, 5.6 to 11.6) with a PFS of 12.1 months (95 percent CI, 8.8 to 12.3) for the 450 × 106 cohort. All of the individuals who were transfused reported adverse events, with 99 percent (127 of 128) experiencing grade 3 or 4 events that were mostly hematological. Infections occurred in 88 individuals (69 percent). CRS occurred in 107 individuals (84 percent) with most being grade 1 or 2. A total of 44 individuals (34 percent) died during the study period, with four of these believed to be treatment related.

The safety and efficacy of idecabtagene vicleucel (Abecma) for the treatment of adult individuals with R/R MM who had received 2 to 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab, and were refractory to the most recent regimen were evaluated in a phase 3, randomized, open-label study (KarMMa-3; NCT03651128) versus the provider’s choice of effective standard therapy (daratumumab, pomalidomide, dexamethasone [DPd], daratumumab, bortezomib, dexamethasone [DVd], ixazomib, lenalidomide, dexamethasone [Ird], carfilzomib, dexamethasone [Kd], elotuzumab, pomalidomide, dexamethasone [EPd] depending on what treatment the individual had previously received. The primary endpoint was PFS. Key secondary endpoints included ORR and the percentage of individuals who achieved a CR or better (stringent CR). A total of 386 individuals were randomized in a 2:1 ratio to treatment with idecabtagene vicleucel (Abecma) or standard therapy. At a median follow-up of 18.6 months, the median PFS was 13.3 months in the idecabtagene vicleucel (Abecma) cohort versus 4.4 months in the standard treatment cohort (P<0.0001). The ORR was 71 percent for the idecabtagene vicleucel (Abecma) cohort versus 42 percent for the standard therapy cohort (P<0.0001). The percentage of individuals in the idecabtagene vicleucel (Abecma) cohort who achieved CR or better was 98 percent versus 7 percent in the standard therapy cohort. In the idecabtagene vicleucel (Abecma) cohort, 88 percent experienced CRS, with 5 percent being grade 3 or higher. The percentage of adverse events were higher in the idecabtagene vicleucel (Abecma) cohort than in the standard therapy cohort, but were consistent with previous studies. No new safety signals were identified.

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 percent CI, 15.0 to 19.3) an ORR was achieved by 186 individuals (73 percent; 95 percent CI, 66.8 to 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 percent; 95 percent CI, 46.8 to 59.4; P<0.0001). The median DOR was not reached at a median follow-up of 12 months (95 percent CI, 11.2 to 16.7). The median PFS was 6.8 months (95 percent CI, 3.3 to 14.1) after a median follow up of 12.3 months. Median OS was 21.1 months (95 percent CI, 13.3 to not estimable) after a median follow-up of 17.5 months (95 percent CI, 12.9 to 17.8). CRS occurred in 113 individuals (42 percent) with grade 3 or higher occurring in six individuals (two percent). Nine individuals (six percent) 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 (three percent) 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 percent CI, 6.1 to not reached) compared to 2.3 months (95 percent CI, 2.2 to 4.3) for the SOC cohort; P<0.0001. The CRR for the lisocabtagene maraleucel (Breyanzi) cohort was 66 percent (95 percent CI, 56 to 76) versus 39% (95 percent CI, 29 to 50) for the SOC cohort. The ORR in the lisocabtagene maraleucel (Breyanzi) cohort was 85 percent (95 percent CI, 77 to 92) versus 48 percent (95 percent CI, 37 to 59) in the SOC cohort. The most common grade 3 or worse adverse event was neutropenia in 80 percent of the lisocabtagene maraleucel (Breyanzi) cohort and 51 percent of the SOC cohort. Grade 3 CRS occurred in 1 percent, and neurological events occurred in 4 percent 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 percent (95 percent CI, 68 to 89); P<0.0001). At a median follow-up of 13.0 months, the median PFS was 9.03 months (95 percent CI, 4.17 to not reached). At a median follow up of 15.5 months, the median DOR was 12.09 months (95 percent CI, 6.24 to not reached). In the intention-to-treat population, the CRR was 46 percent (95 percent CI, 34 to 58). In this same group, the median EFS was 8.15 months (95 percent CI, 4.37 to 13.34). Median OS was not reached. CRS occurred in 38 percent (one grade 3) of participants and neurological events occurred in 31 percent (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 2 or more lines of therapy for individuals with high-risk features, or after 3 or more lines of therapy for individuals 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 percent. 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 percent experienced grade 3 CRS; none experienced grade 4 or 5. One death from macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS/HLH) was felt 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 2 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 percent. The CR rate was 73.4 percent. At a median of 18 months, the DOR has not been reached. CRS occurred in 58 percent of treated individuals, but only 1 percent was grade 3 with none being grade 4 or 5. Two deaths were felt 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 2 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 percent. The CR rate was 67.6 percent. The median DOR was 13.3 months. CRS was reported in 61 percent of treated individuals with 1 percent being grade 4, and none being grade 3 or 5. Only 1 death was considered to be treatment related.

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 1 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 percent (95 percent CI, 71 to 89) with 45 individuals (60 percent) achieving CR and 16 individuals (21 percent) 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 complete remission 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 percent (95 percent CI, 65 to 89) at 6 months and 59 percent (95 percent CI, 41 to 73) at 12 months. The rate of EFS at 6 months was 73 percent (95 percent CI, 60 to 82) and at 12 months was 50 percent (95 percent CI, 35 to 64) with median EFS not being achieved. The rate of OS for all 75 individuals who received an infusion was 90 percent (95 percent CI, 81 to 95) at 6 months and 76 percent (95 percent CI, 63 to 86) at 12 months. Of the 75 individuals who received an infusion, 71 (95 percent) experienced an adverse event that was believed to be related to the infusion. CRS occurred in 77 percent of the individuals who received an infusion, and neurologic events occurred in 40 percent. A total of 19 individuals died after receiving an infusion, but only three were believed to be due to 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 percent (95 percent CI, 41 to 62) with 40 percent obtaining a CR and 12 percent a PR. The median DOR was not reached (95 percent CI, 10 months to not estimable). The estimated rate of PFS at 12 months was 83 percent. The median OS among individuals who had received an infusion was 12 months (95 percent CI, 7 months to not reached). The percentage of individuals who received an infusion who experienced grade 3 or higher CRS was 22 percent. The percentage of these individuals who experienced a neurologic event of grade 3 or higher was 12 percent. Although 3 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 percent (95 percent CI, 58.8 to 78.3). The ORR was 86.2 percent (95 percent CI, 77.5 to 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 percent (with none grade 3 or higher) and the rate of neurological events was 37.1 percent (3 percent were grade 3 or higher). There have not been any treatment-related deaths.

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.

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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 20, 2024.

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 20, 2024.

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 20, 2024.

ClinicalTrial.gov. Efficacy and safety study of bb2121 in subjects with relapsed and refractory multiple myeloma (KarMMa). ClinicalTrials.gov Identifier: NCT03361748. First Posted: December 5, 2017. Last Update Posted: February 1, 2024. Available at: https://clinicaltrials.gov/. Accessed November 20, 2024.

ClinicalTrial.gov. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). ClinicalTrials.gov Identifier: NCT03651128. First Posted: August 29, 2018. Last Update Posted: December 15, 2022. Available at: https://clinicaltrials.gov/. Accessed November 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

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 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Axicabtagene ciloleucel (Yescarta®). [Clinical Key Web site]. 10/04/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Brexucabtagene autoleucel (Tecartus®). [Clinical Key Web site]. 10/04/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Ciltacabtagene autoleucel (Carvykti®). [Clinical Key Web site]. 10/04/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Idecabtagene vicleucel (Abecma®). [Clinical Key Web site]. 10/04/2023. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Lisocabtagene maraleucel (Breyanzi®). [Clinical Key Web site]. 06/13/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

Elsevier's Clinical Pharmacology Compendium. Tisagenlecleucel (Kymriah®). [Clinical Key Web site]. 10/04/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 20, 2024.

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 20, 2024.

Idecabtagene vicleucel (Abecma®). [prescribing information]. Summit, NJ: Bristol-Myers Squibb; 07/2024. Available at: https://www.abecma.com/. Accessed November 20, 2024.

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 20, 2024.

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. 10/21/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

Merative Micromedex® DRUGDEX® (electronic version). Brexucabtagene autoleucel (Tecartus®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 10/21/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

Merative Micromedex® DRUGDEX® (electronic version). Ciltacabtagene autoleucel (Carvykti®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 10/07/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

Merative Micromedex® DRUGDEX® (electronic version). Idecabtagene vicleucel (Abecma®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 10/28/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

Merative Micromedex® DRUGDEX® (electronic version). Lisocabtagene maraleucel (Breyanzi®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/28/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

Merative Micromedex® DRUGDEX® (electronic version). Tisagenlecleucel (Kymriah®). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 11/06/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2024.

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.

Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Acute Lymphoblastic Leukemia V2.2024. [NCCN Web site]. 07/19/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf [via free subscription]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - B-Cell Lymphomas V3.2024. [NCCN Web site]. 08/26/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf [via free subscription]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V1.2025. [NCCN Web site]. 10/01/2024. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. [via subscription only]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Multiple Myeloma V1.2025. [NCCN Web site]. 09/17/2024. Available from: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. [via subscription only]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Pediatric Acute Lymphoblastic Leukemia V1.2025. [NCCN Web site]. 08/28/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. [via subscription only]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Pediatric Aggressive Mature B-Cell Lymphomas V2.2024. [NCCN Web site]. 09/03/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_b-cell.pdf. [via subscription only]. Accessed November 20, 2024.

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 20, 2024.

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 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Ciltacabtagene autoleucel (Carvykti®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed November 20, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Idecabtagene vicleucel (Abecma®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed November 20, 2024.

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 20, 2024.

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 20, 2024.

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.

Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cell or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014.

San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347.

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; 06/2024. Available at: https://www.us.kymriah.com/. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Axicabtagene ciloleucel (Yescarta®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Brexucabtagene autoleucel (Tecartus®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Ciltacabtagene autoleucel (Carvykti®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Idecabtagene vicleucel (Abecma®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Lisocabtagene maraleucel (Breyanzi®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

UpToDate® Lexidrug^TM. Tisagenlecleucel (Kymriah®). [UpToDate Lexidrug Web site]. 11/06/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Axicabtagene ciloleucel (Yescarta®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 06/12/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Brexucabtagene autoleucel (Tecartus®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 06/12/2024. Available at:
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Ciltacabtagene autoleucel (Carvykti®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 04/05/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/carvykti. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Idecabtagene vicleucel (Abecma®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 04/04/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Lisocabtagene maraleucel (Breyanzi®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 05/30/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel. Accessed November 20, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Tisagenlecleucel (Kymriah®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 08/16/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel. Accessed November 20, 2024.

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)

See Attachment A.

HCPCS Level II Code Number(s)

Q2041	Axicabtagene ciloleucel, up to 200 million autologous anti-CD19 CAR positive T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2042	Tisagenlecleucel, up to 600 million CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2053	Brexucabtagene autoleucel, up to 200 million autologous anti-CD19 CAR positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2054	Lisocabtagene maraleucel, up to 110 million autologous anti-CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2055	Idecabtagene vicleucel, up to 510 million autologous b-cell maturation antigen (bcma) directed car-positive t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2056	Ciltacabtagene autoleucel, up to 100 million autologous b-cell maturation antigen (bcma) directed car-positive t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.093p:

02/24/2025

This 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 MA08.093o:

01/01/2025

This 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 MA08.093n:

10/01/2024

This 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 MA08.093m:

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 MA08.093l:

01/01/2024	Effective 01/01/2024, this policy applies to New Jersey Medicare Advantage (MA) lines of business.
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]

01/01/2024

Effective 01/01/2024, this policy applies to New Jersey Medicare Advantage (MA) lines of business.

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 MA08.093k:

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:

The following codes have been removed from this policy:

C9098, Z92.850

Revisions From MA08.093j:

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

Revisions From MA08.093i:

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 MA08.093h:

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 MA08.093g:

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 MA08.093f:

01/01/2021

This version of the policy is effective 01/01/2021.

As of January 1, 2021, providers should submit claims directly to the Independence Medicare Advantage plan for Chimeric Antigen Receptor (CAR) Therapy. Claims for dates of service on or after January 1, 2021 should no longer be submitted to the local Medicare Administrative Contractor (MAC) for this service.

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

MEDICALLY NECESSARY

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

HCPCS Level II Code Numbers and Narratives were added

Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2042 Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

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 MA08.093e:

01/01/2019

This version of the policy is effective 01/01/2019.

This policy has been updated to communicate coverage and reimbursement for CAR-T Cell Therapy for the Company’s Medicare Advantage members will be processed through the local Medicare Administrative Contractor (MAC), as this therapy has been identified as meeting Medicare's the significant cost threshold.

The following CPT codes have been added to this policy:
0537T, 0538T, 0539T, 0540T

All ICD-10 CM codes have been deleted from Attachment A of this policy.

Revisions From MA08.093d:

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 MA08.093c:

07/30/2018

This 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 MA08.093b:

04/01/2018

This 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 MA08.093a:

01/01/2018

This 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 MA08.093:

11/29/2017

New policy number MA08.093 was issued as a result of of a new FDA approval of tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™).

This version of the policy will become effective 11/29/2017.

This new policy has been developed to communicate the Company’s coverage criteria for tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™).

Version Effective Date:

02/24/2025

Version Issued Date:

02/24/2025

Version Reissued Date:

N/A

Medicare Advantage

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Medical Policy Bulletin

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Description

References

Coding

CPT Procedure Code Number(s)

ICD - 10 Procedure Code Number(s)

ICD - 10 Diagnosis Code Number(s)

HCPCS Level II Code Number(s)

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MPMiscCodesNarrativesPub​

Coding and Billing Requirements

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MPMiscCodesNarrativesPub