Medicare Advantage

Medical Policy

Title:

Chimeric Antigen Receptor (CAR) Therapy

Policy #:

MA08.093k

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
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
Tisagenlecleucel	Kymriah	Acute lymphoblastic leukemia (ALL; young adult and pediatric)

MEDICALLY NECESSARY

AXICABTAGENE CILOLEUCEL (YESCARTA®)
B-Cell Lymphomas

Diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, acquired immunodeficiency syndrome (AIDS)-related DLBCL, primary effusion lymphoma, human herpesvirus 8 (HHV8)-positive DLBCL
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of relapsed or refractory (R/R) DLBCL, R/R primary mediastinal large B-cell lymphoma, R/R high-grade B-cell lymphoma with or without MYC and B-cell lymphoma (BCL)2 and/or BCL6 rearrangement, R/R AIDS-related DLBCL, R/R primary effusion lymphoma, or HHV8-positive DLBCL, not otherwise specified who have received, at a minimum, an anti-cluster of differentiation (CD)20 monoclonal antibody (i.e., rituximab) (unless the tumor is CD20 negative) and an anthracycline (i.e., 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 B-cell lymphomas used as one of the following:

Additional therapy for R/R disease >12 months after completion of first-line therapy 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 <12 months after completion of first-line therapy
Treatment (if anti-CD19 chimeric antigen receptor [CAR] T-cell therapy [i.e., 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

The individual does not have clinically significant active systemic infection or inflammatory disorder including, but not limited to, hepatitis B; hepatitis C; human immunodeficiency virus (HIV) infection; presence of fungal, bacterial, viral, or other infection that is uncontrolled
The individual does not have primary central nervous system (CNS) lymphoma or malignancy
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 (FL grade 1 to 2), nodal marginal zone lymphoma (MZL)

Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R FL (grade 1 to 2) or R/R nodal MZL when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of B-cell lymphomas 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
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.

Gastric and non-gastric mucosa-associated lymphoid tissue (MALT) lymphoma (non-cutaneous)

Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R gastric MALT lymphoma or R/R non-gastric MALT lymphoma (non-cutaneous) when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of B-cell lymphomas used as third-line and subsequent therapy (if not previously given) for relapsed, refractory, or progressive disease in individuals with indications for treatment after two or more prior chemoimmunotherapy regimens
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
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.

Splenic marginal zone lymphoma (MZL)
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R splenic MZL when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of splenic MZL used as third-line and subsequent therapy (if not previously given) for disease recurrence in individuals with indications for treatment after two or more prior chemoimmunotherapy regimens
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
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 to diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL), nodal marginal zone lymphoma (MZL)
Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered for the autologous treatment of R/R histologic transformation to DLBCL from FL (individual must have chemorefractory disease after transformation to DLBCL) or nodal MZL when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of B-cell lymphomas used as third-line and subsequent therapy (if anti-CD19 CAR T-cell therapy [i.e., 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 [i.e., mitoxantrone]-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 (PTLD) (B-cell type)
Axicabtagene ciloleucel (Yescarta) 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 risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of monomorphic PTLD (B-cell type) used as one of the following:

Additional therapy for R/R disease >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 <12 months after completion of initial treatment with chemoimmunotherapy
Treatment (if anti-CD19 CAR T-cell therapy [i.e., 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 a history of prior CAR T-cell therapy or prior gene therapy
The individual is 18 years or older at the time of infusion.

BREXUCABTAGENE AUTOLEUCEL (TECARTUS®)
Mantle cell lymphoma (MCL)

Brexucabtagene autoleucel (Tecartus) is considered medically necessary and, therefore, covered for the autologous treatment for relapsed or refractory (R/R) MCL when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

The individual meets both of the following criteria:

The individual has a diagnosis of the relapsed or refractory R/R MCL
As third-line therapy for individuals who have received prior chemoimmunotherapy AND a Bruton tyrosine kinase (BTK) inhibitor i.e., ibrutinib, acalabrutinib) resulting in one of the following:

No response or progressive disease following second-line therapy with BTK inhibitor or other non-time limited regimens (i.e., lenalidomide and rituximab if BTK inhibitors are contraindicated [National Comprehensive Cancer Network {NCCN} preferred])
Partial response, no response or progressive disease following second-line therapy with time-limited regimens (NCCN-preferred option if no response or progressive disease)
Relapsed disease (relapse #2 or greater) following second-line-therapy (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

Acute lymphoblastic leukemia (ALL)

Brexucabtagene autoleucel (Tecartus) is considered medically necessary and, therefore, covered for the autologous treatment for R/R ALL when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following are met:

The individual meets one of the following:

R/R Philadelphia chromosome-positive B-ALL (following therapy that has included tyrosine kinase inhibitors [TKIs] [i.e., bosutinib, dasatinib, imatinib, nilotinib, ponatinib])
R/R Philadelphia chromosome-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’s lymphoma/leukemia
Concomitant genetic syndrome (e.g., Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, other known BM 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 (CARVYKTITM)
Multiple myeloma (MM)

Ciltacabtagene autoleucel (Carvykti) is considered medically necessary and, therefore, covered for the autologous treatment for relapsed or refractory (R/R) MM when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS), and all of the following are met:

The individual has a diagnosis of late relapse or progressive MM
The individual has been treated with four or more prior lines of therapy including all of the following:

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

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) (i.e., belantamab mafodotin, teclistamab, idecabtagene vicleucel [Abecma])
The individual has not undergone allogeneic HSCT
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 (ABECMATM)
Multiple myeloma (MM)

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

The individual has a diagnosis of late relapse or progressive MM
The individual has been treated with four or more prior lines of therapy including all of the following:

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

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 (DLBCL), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma (THRBL), follicular lymphoma (FL grade 3B), acquired immunodeficiency syndrome (AIDS)-related DLBCL, primary effusion lymphoma, human herpesvirus 8 (HHV8)-positive DLBCL
Lisocabtagene maraleucel (Breyanzi) is considered medically necessary and, therefore, covered for the autologous treatment of relapsed or refractory (R/R) DLBCL, R/R high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma), R/R primary mediastinal large B-cell lymphoma, R/R THRBCL, R/R FL grade 3B, R/R AIDS-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 risk evaluation and mitigation strategies (REMS) and all of the following are met:

Diagnosis of one of the above types of B-cell lymphomas used as one of the following:

Additional therapy for R/R disease >12 months after completion of first-line therapy 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 <12 months after completion of first-line therapy
Treatment (if anti-CD19 CAR T-cell therapy [i.e., 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
Treatment for R/R disease to first-line chemoimmunotherapy for individuals who are not eligible for HSCT due to comorbidities or age

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
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 (DLBCL) (e.g., follicular lymphoma [FL], marginal zone lymphoma [MZL])
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 risk evaluation and mitigation strategies (REMS) and all of the following are met:

Diagnosis of one of the above types of B-cell lymphomas used as third-line and subsequent therapy for all subtypes of transformed indolent lymphomas (if anti-CD19 CAR T-cell therapy [i.e., 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 [i.e., doxorubicin] or anthracenedione [i.e., mitoxantrone]-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 active CNS-only involvement by 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 time of infusion

Monomorphic post-tranplant lymphoproliferative disorder (PTLD) (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 risk evaluation and mitigation strategies (REMS) and all of the following are met:

Diagnosis of monomorphic PTLD (B-cell type) when used as one of the following:

Additional therapy for R/R disease >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 <12 months after completion of first-line therapy (i.e., CD20 antibody [i.e., rituximab] and anthracycline [i.e., doxorubicin]-containing agent)
Treatment (if anti-CD19 CAR T-cell therapy [i.e., 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
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 (ALL)

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

Confirmed diagnosis of CD19-positive B-cell precursor ALL with morphologic BM 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:

Philadelphia chromosome (Ph)--negative disease with refractory disease or relapses after two or more TKIs (i.e., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) (NCCN preferred regimen)
Philadelphia chromosome (Ph)--positive disease with refractory disease or relapses after two or more TKIs (i.e., bosutinib, dasatinib, imatinib, nilotinib, ponatinib)

The individual does not have any of the following:

Concomitant genetic syndromes associated with BM failure states (e.g., Fanconi anemia; Kostmann syndrome; Schwachman syndrome; any other BM 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 Acute Lymphoblastic Leukemia (ALL)

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

Confirmed diagnosis of CD19-positive B-cell precursor ALL with morphologic BM tumor involvement (five percent or greater lymphoblasts) in individuals 18 years and younger and one of the following subtypes:

Ph-negative disease with refractory disease or two or more relapses
Ph-positive disease and TKI (i.e., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) intolerant or refractory
Ph-positive disease and relapse after HSCT

The individual does not have any of the following:

Concomitant genetic syndromes associated with BM failure states (e.g., Fanconi anemia; Kostmann syndrome; Schwachman syndrome; any other BM 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 (DLBCL), high-grade B-cell lymphoma, acquired immunodeficiency syndrome (AIDS)-related DLBCL, primary effusion lymphoma, human herpesvirus 8 (HHV8)-positive DLBCL
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 B-cell lymphoma); R/R high-grade B-cell lymphoma with MYC rearrangement plus rearrangement of BCL2, BCL6, or both genes (double- or triple-hit lymphoma); R/R AIDS-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 risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of B-cell lymphomas used as one of the following:

Third-line and subsequent therapy as additional therapy for R/R disease >12 months after completion of first-line therapy in individuals with intention to proceed to transplant who have partial response following second-line therapy
Third-line and subsequent therapy as treatment (if anti-CD19 CAR T-cell therapy [i.e., 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

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 [FL], nodal marginal zone lymphoma [MZL]) to diffuse large B-cell lymphoma (DLBCL)

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 risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of one of the above types of B-cell lymphomas as third-line and subsequent therapy (if anti-CD19 CAR T-cell therapy [i.e., 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 [i.e., mitoxantrone]-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 disorders (PTLD) (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 risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of PTLD (B-cell type) used as one of the following:

Third-line and subsequent therapy as additional therapy for R/R disease >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 [i.e., 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 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 (FL) (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 risk evaluation and mitigation strategies (REMS), and all of the following criteria are met:

Diagnosis of FL (grade 1 to 2) 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
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 (REMS) 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 two 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 x upper limit of normal (ULN) or less
Estimated glomerular filtration rate (eGMR) 60 mL/min/1.73 m2 or greater
Alanine aminotransferase (ALT) 5 x ULN or less for age
Bilirubin 2.0 mg/dl or less (expect for individuals with Gilbert syndrome whose total bilirubin should be 3 x ULN or less and direct bilirubin 1.5 x ULN or less)
Pulmonary reserve of grade 1 or less dyspnea and pulse oximetry of >91 percent on room air
Absolute neutrophil count (ANC) >1.000/mm3
Absolute lymphocyte count (ALC) 300/mm3 or greater
Platelets 50.000/mm3 or greater
Hemoglobin (Hgb) >8.0 g/dl

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 (FDA) STATUS

Axicabtagene ciloleucel (Yescarta) was approved by the 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. The safety and effectiveness of axicabtagene ciloleucel (Yescarta) in the pediatric population has not been established.

Brexucabtagene autoleucel (Tecartus) was approved by the FDA on July 24, 2020 for the treatment of adult individuals with R/R mantle cell lymphoma (MCL). The safety and effectivness of brexucabtagene autoleucel (Tecartus) has 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. 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. 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 500mg/m2 intravenously (IV) and fludarabine 30mg/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 (MCL)

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 (ALL)

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 three 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 x 106 CAR-positive viable T cells per kg body weight with a maximum of 1 x 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 three days. Infuse idecabtagene vicleucel (Abecma) 2 days after completion of lymphodepleting chemotherapy.

Treatment:
Idecabtagene vicleucel (Abecma) target dose is 300 to 460 x 106 CAR-positive T cells.

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

Relapsed or Refractory LBCL after two or more lines of therapy

Treatment:
Lisocabtagene maraleucel (Breyanzi) target dose is 50 to 110 x 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components).

Relapsed or Refractory LBCL after one line of therapy

Treatment:
Lisocabtagene maraleucel (Breyanzi) target dose is 90 to 110 x 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 (FL)

Pre-treatment:

Lymphodepleting chemotherapy: Fludarabine 25 mg/m2 IV daily for three days and cyclophosphamide 250 mg/m2 IV daily for three days starting with the first dose of fludarabine.
Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 IV daily for two 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’s is experiencing significant cytopenia (e.g., white blood cell [WBC] count is less than or equal to 1 x 109/L) within one week prior to tisagenlecleucel (Kymriah) infusion.

Treatment:
Tisagenlecleucel (Kymriah) dose for adult individuals: 0.6 to 6.0 x 108 CAR-positive viable T cells.

Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia (ALL)

Pre-treatment:
Lymphodepleting chemotherapy: Fludarabine 30mg/m2 IV daily for 4 days and cyclophosphamide 500mg/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 x 106 CAR-positive viable T cells per kg body weight
The individual is above 50 kg: dose is 0.1 to 2.5 x 108 CAR-positive viable T cells

Description

Acute lymphoblastic leukemia (ALL) is a rapidly progressing cancer of immature forms of white blood cells (lymphocytes) in the bone marrow and blood. These cancerous cells grow quickly and crowd the bone marrow, preventing it from making normal red blood cells, white blood cells, and platelets. ALL is the most common form of cancer in children and the median age at diagnosis is 15 years old. There are approximately 5970 new cases per year, with 2500-3500 being children, in the United States. Lymphoblastic leukemias are classified in two categories: precursor B cell lymphoblastic leukemia, which accounts for approximately 70-80 percent of childhood ALL cases, and precursor T cell lymphoblastic leukemia.

Lymphoma is the most common blood cancer and is divided into two categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Lymphoma occurs when lymphocytes grow abnormally. There are two main types of lymphocytes in the body: B-lymphocytes and T-lymphocytes. NHL is the most common cancer of the lymphatic system, with over 74,000 cases diagnosed annually in the United States. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for 32 percent of all cases. There are other subtypes of B-cell lymphomas including DLBCL, DLBCL arising from indolent lymphoma (including follicular lymphoma [FL], marginal zone lymphoma [MZL], chronic lymphocytic leukemia [CLL] or small lymphocytic lymphoma), high-grade B-cell lymphoma with rearrangements of MYC and either B-cell lymphoma (BCL)2, BCL6, or both (double-hit or triple-hit lymphoma), primary mediastinal large B-cell lymphoma, FL grade 3B, acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, primary effusion lymphoma, human herpesvirus (HHV)8-positive DLBCL not otherwise specified, post-hematopoietic stem cell transplantation [HSCT] lymphoproliferative disorders (PTLD), and mantle-cell lymphoma (MCL).

Mantle cell lymphoma (MCL) is another subtype of B-cell lymphoma and makes up about five percent of lymphomas. It can be challenging to create a treatment plan for the cancer because it tends to grow faster than slow-growing indolent lymphomas but also does not respond to therapies that are used to treat fast-growing aggressive lymphomas. MCL can be widespread and found in the lymph nodes, bone marrow, and the spleen at diagnosis. MCL is most often found in individuals older than 60 years of age.

Multiple myeloma (MM) is a cancer of the plasma cell which are cells found in the bone marrow that are part of the immune system. The effects of the growing cancer cells can cause a decrease in other components of the blood (red blood cells, white blood cells, platelets), speed up the breakdown of bones by osteoclasts, decrease the number of antibodies in the blood leading to increased infection risk, and also lead to kidney damage or failure. MM is a relatively uncommon cancer. For 2022, the American Cancer Society estimates that there will be 34,470 new cases diagnosed and 12,640 deaths due to the cancer.

Chimeric antibody receptor T-cell (CAR T) therapy is a method whereby the T cells (a type of white blood cell) are altered in a lab 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 a new gene that contains a chimeric antigen receptor (CAR). The modified T-cells target and bind to a specific protein on the surface of the antigen causing the cancer or disease and help the individual’s own immune system to help destroy the target. Prior to initiating the CAR T infusion, individuals must 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 2 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). Some of the 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], 73-89) 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 felt 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 six 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. Some of the secondary endpoints were 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 worse 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 felt 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 randomized 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 end point of the trial was event-free survival (EFS) based on assessment by a blinded central reviewer. Some secondary endpoints were 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 acute lymphoblastic leukemia (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, has a first relapse after a remission that lasted one 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 felt 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. Important secondary endpoints were 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 was 12.4 months). At one 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 felt to be treatment related.

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 secondary end point 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 x 106 CAR T cells, 300 x 106 CAR T cells, or 450 x 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 x 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 x 106 cohort. All of the individuals who were transfused reported adverse events with 99 percent (127 of 128) experiencing grade 3 or 4 events which were mostly hematological. Infections occurred in 88 individuals (69 percent). CRS occurred in 107 individuals (84 percent) and was mostly graded as 1 or 2. A total of 44 individuals (34 percent) died during the study period with four of these felt to be treatment related.

LISOCABTAGENE MARALEUCEL (BREYANZI)

On February 5, 2021, the FDA approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with R/R large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and FL grade 3B. Lisocabtagene maraleucel (Breyanzi) is a CD19-directed genetically modified autologous T cell immunotherapy. During the lisocabtagene maraleucel (Breyanzi) manufacturing process, CD8+ and CD4+ T cells are selected from leukapheresis material and then independently activated, transduced, and expanded. Both of these are then infused into the individual.

The safety and efficacy of lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with large B-cell lymphoma 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 x 106 CAR T cells (one or two doses), 100 x 106 CAR T cells, or 150 x 106 CAR T cells and 25 individuals received an infusion of a non-conforming 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 worse 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 x 106 CAR T cells. A total of 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 elibible for autologous HSCT. This 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 2 cohorts. One cohort received a standard of care (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 1 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 (95percnet 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.

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). 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 three 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 six months and 59 percent (95 percent CI, 41 to 73) at 12 months. The rate of EFS at six 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 six 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 felt 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 felt 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 2 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. 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 three 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. 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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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.

Tisagenlecleucel (Kymriah^®). [prescribing information] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 03/2022. Available at: https://www.novartis.com/us-en/sites/novartis_us/files/kymriah.pdf. Accessed July 31, 2022.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Axicabtagene ciloleucel (Yescarta^®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 04/01/2022. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel. Accessed July 31, 2022.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Brexucabtagene autoleucel (Tecartus^®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 10/01/2021. Available at:
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel. Accessed July 31, 2022.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Ciltacabtagene autoleucel (Carvykti^TM). Prescribing information, approval letter, REMS documents. [FDA Web site]. 02/28/2022. Available at: https://www.fda.gov/vaccines-blood-biologics/carvykti. Accessed July 31, 2022.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Idecabtagene vicleucel (Abecma^TM). Prescribing information, approval letter, REMS documents. [FDA Web site]. 03/26/2021. Available at: https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel. Accessed July 31, 2022.

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US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Tisagenlecleucel (Kymriah^®). Prescribing information, approval letter, REMS documents. [FDA Web site]. 06/11/2021. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel. Accessed July 31, 2022.

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Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

0540T

NOT ELIGIBLE FOR SEPARATE REIMBURSEMENT
0537T, 0538T, 0539T

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 460 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

Version Effective Date:

10/31/2022

Version Issued Date: