Chimeric Antigen Receptor (CAR)-T Cell Therapy Policy Number: PG0460 ADVANTAGE | ELITE | HMO Last Review: 08/25/2021

INDIVIDUAL MARKETPLACE | PROMEDICA MEDICARE PLAN | PPO

GUIDELINES  This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder terms, conditions, exclusions and limitations contract. It does not constitute a contract or guarantee regarding coverage or reimbursement/payment. Self-Insured group specific policy will supersede this general policy when group supplementary plan document or individual plan decision directs otherwise.  Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards.  This medical policy is solely for guiding medical necessity and explaining correct procedure reporting used to assist in making coverage decisions and administering benefits.

SCOPE X Professional X Facility

DESCRIPTION The spontaneous regression of certain cancers (eg, renal cell carcinoma, melanoma) supports the idea that a patient’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunotherapies designed to stimulate a patient’s own immune system

A rapidly emerging immunotherapy approach is called adoptive cell transfer (ACT) which involves collecting and using patients’ own immune cells to treat their cancers with genetically engineered cells. Adoptive immunotherapy is a method of activating lymphocytes and/or other types of cells for the treatment of cancer and other diseases. The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, two methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions. The most advanced type of ACT is called CAR-T cell therapy. Autologous immunotherapy with CD-19, specifically CAR-T therapy, uses a patient’s own immune system to fight certain types of cancers, B-cell hematological malignancies (leukemia and lymphoma). T cells are extracted and separated out through a blood draw called apheresis or leukapheresis. The T cells are then sent to a manufacturing site where using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs. While the cells are being re-engineered, the patient receives low doses of “lymphodepleting” chemotherapy to help prepare the body for the programmed CAR-T cells. The reprogrammed cells are then re-infused into the body, similar to an autologous stem cell transplant procedure. The procedure is performed only on an acute care setting, to closely monitor for complications and if appropriate immediately transition to inpatient care. After the Car-T cells have been infused back in the body the cells multiply and spread throughout to find and attack specific cells. Participants must be monitored closely for side effects including but not limited to: Cytokine Release Syndrome (CRS) and neurotoxicity. The clinical regimen is consistent with the National Comprehensive Cancer Network (NCCN) guidance for the treatment of patients with CAR T-cell therapy and applicable guidelines established by the U.S. Food & Drug Administration (FDA) in effect on the date of infusion.

CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY Due to difficulties in expanding innate TILs, genetic modification techniques have been harnessed to decorate propagated T cells with engineered chimeric antigen receptors (CARs) that are composed of several functional components: a tumor antigen-targeting single chain variable fragment (scVF) (eg, anti-CD19), a hinge region, a T-

PG0460 – 08/25/2021 cell activation domain (eg, CD3), and one or more costimulatory domains (eg, CD28, 4-1 BB). Viral vector genetic modification approaches (eg, retroviral, lentiviral) have traditionally been used to transfect T cells with CAR genes.

The U.S. Food and Drug Administration has approved two adoptive immunotherapy treatments, Kymriah™ (tisagenlecleucel) and Yescarta™ (axicabtagene ciloleucel). The FDA has approved them for people of certain ages who have specific types of cancer.

POLICY HMO, PPO, Individual Marketplace, Elite/ProMedica Medicare Plan, Advantage Prior authorization review and approval is required for every request for intravenous infusion of Chimeric Antigen Receptor (CAR)-T Cell Therapy [including, but not limited to, tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), brexucabtagene autoleucel (Tecartus), and idecabtagene vicleucel (Abecma)]. Please refer to Prescription Drug Benefits/Prior Authorizations. https://www.paramounthealthcare.com/services/providers/prior-authorization-criteria/magellan- mrx

Chimeric Antigen Receptor (CAR)-T Cell Therapy, including, but not limited to, tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), brexucabtagene autoleucel (Tecartus), and idecabtagene vicleucel (Abecma), will continue to be billed to the medical benefit.

Medical Policy PG0430 Kymriah™ (tisagenlecleucel) (Q2042) and PG0431 Yescarta® (axicabtagene ciloleucel) (Q2041) has been Retired from the Medical Policy Prior Authorization and relocated under Magellan MRx/Pharmacy Prior Authorization.

COVERAGE CRITERIA HMO, PPO, Individual Marketplace, Elite/ProMedica Medicare Plan, Advantage CAR T-cell therapies are adoptive immuno-therapies in which T-cells are removed from the body and genetically engineered to recognize cancer cells that express an antigen receptor protein, such as CD-19 or B-cell maturation antigen (BCMA). They are known as “CAR-T cells”. The harvest and reinfusion of the T-cells is a complex procedure requiring precise scheduling and coordination of resources.

Chimeric Antigen Receptor (CAR) T-cell Therapies: • axicabtagene ciloleucel (Yescarta) (Q2041) • brexucabtagene autoleucel (Tecartus) (C9073) (Q2053) • lisocabtagene maraleucel (Breyanzi) (C9076) • tisagenlecleucel (Kymriah) (Q2042) • idecabtagene vicleucel (Abecma) (C9399)

 Health care facilities that dispense and administer these chimeric antigen receptor (CAR) T therapies must be enrolled and comply with the risk evaluation and mitigation strategy (REMS) requirements.  Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer these CAR T therapies are trained to manage cytokine release syndrome (CRS) and neurologic toxicities (NT).  Administration of CAR T-cell therapy can result in CRS which may cause fatal or life-threatening reactions.  There are multiple CAR T-cell therapies undergoing study for the treatment of several different types of cancers. Most of these therapies are still in early stages of development. Further study is necessary to determine whether they are safe and effective.  CAR T-cell therapy is not coverable for repeated doses and is not coverable if a patient has previously received prior CAR T-cell therapy [including, but not limited to, tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), brexucabtagene autoleucel (Tecartus), and idecabtagene vicleucel (Abecma)].

Regulatory Status

PG0460 – 08/25/2021  On August 30, 2017, tisagenlecleucel (Kymriah) was approved by the FDA for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.  On May 1, 2018, tisagenlecleucel (Kymriah) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.  On October 18, 2017, axicabtagene ciloleucel (Yescarta) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.  Tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel and lisocabtagene maraleucel have a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.  Tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus) and lisocabtagene maraleucel (Breyanz) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS, Yescarta REMS, and Tecartus REMS, respectively. The requirements for the REMS components are as follows: o Health care facilities that dispense and administer tisagenlecleucel, axicabtagene ciloleucel, or brexucabtagene autoleucel must be enrolled and comply with the REMS requirements. o Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after tisagenlecleucel, axicabtagene ciloleucel, or brexucabtagene autoleucel infusion, if needed for treatment of cytokine release syndrome. o Certified health care facilities must ensure that health care providers who prescribe, dispense or administer tisagenlecleucel, axicabtagene ciloleucel, or brexucabtagene autoleucel are trained to manage cytokine release syndrome and neurologic toxicities.  On July 24, 2020, the Food and Drug Administration approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma  On February 5, 2021, lisocabtagene maraleucel (Breyanzi) was approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Coverage is provided in the following conditions: Axicabtagene Ciloleucel (Yescarta)  Patient does not have a clinically significant active systemic infection or inflammatory disorder; and  Patient has not received live vaccines within 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel treatment, and will not receive live vaccines until immune recovery following treatment; and  Patient has been screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); and  Prophylaxis for infection has been followed according to local guidelines; and  Healthcare facility has enrolled in the Yescarta and Tecartus REMS Program and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities; and  Patient has not received prior CAR-T therapy; and  Patient has not received prior anti-CD19 therapy, (e.g., blinatumomab, etc.) Or patient previously received anti-CD19 therapy and re-biopsy indicates CD-10 positive disease; and  Used as single agent therapy (not applicable to lymphodepleting or additional chemotherapy while awaiting manufacture); and  Patient did not receive prior allogenic hematopoietic stem cell transplantation (HSCT); and  Patient aged 18 years or greater; and  Patient has an ECOG performance status of 0-1; and

PG0460 – 08/25/2021 Large B-Cell Lymphoma  Patient does not have primary central nervous system lymphoma; and  Patient’s disease is relapsed or refractory defined as a relapse with 1 year after autologous hematopoietic stem cell transplantation (HSCT) or disease refractory to the most recent therapy; and o Patient has Diffuse large B-cell lymphoma (DLBCL) as histologic transformation; and . Patient received two or more prior lines of chemoimmunotherapy which must have included an anthracycline or anthracenedione-based regime, unless contraindicated; and . Patient had Follicular Lymphoma (FL) or Nodal Marginal Zone Lymphoma; and  Patient received multiple lines of prior therapies for indolent or transformed disease; or . Patient had Follicular Lymphoma (FL); and  Patient received minimal or no chemotherapy prior to histologic transformation and had partial response, no response, or progressive disease after treatment; or o Patient has Richter’s transformation of CLL to DLBCL; and . Patient received two or more prior lines of systemic therapy; or . Used for treatment of disease that is in second or greater relapse; or o Patient has AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), or high grade B-cell lymphoma, HHV8- positive diffuse large B-cell lymphoma, not otherwise specified, or monomorphic post-transplant lymphoproliferative disorder (B-cell type); and . Used as additional therapy for patients with intention to proceed to transplant who have partial response following second-line therapy for relapsed or refractory disease; or . Used for treatment of disease that is in second or greater relapse Follicular Lymphoma (FL)  Patient has relapsed or refractory grade 1-2 disease; and  Patient has received two or more prior lines of systemic therapy

Brexucabtagene Autoleucel (Tecartus)  Patient aged 18 years or greater; and  Healthcare facility has enrolled in the YESCARTA & TECARTUS REMS and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities; and  Patient does not have a clinically significant active systemic infection or inflammatory disorder; and  Prophylaxis for infection has been followed according to local guidelines; and  Patient has not received live vaccines within 6 weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel treatment, and will not receive live vaccines until immune recovery following treatment; and  Patient has been screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); and  Used as single agent therapy (not applicable to lymphodepleting or additional chemotherapy while awaiting manufacture); and  Patient did not receive prior allogenic hematopoietic stem cell transplantation (HSCT); and  Patient does not have central nervous system lymphoma, detectable cerebrospinal fluid malignant cells or brain metastasis; and Mantel Cell Lymphoma  Patient’s has relapsed or refractory disease; and  Patient has at least one measurable lesion; and  Patient must have received previous systemic therapy which included at least on agent from each of the following categories: o Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib, acalabrutinib, zanubrutinib) o Anti-CD20 monoclonal antibody (e.g., rituximab) o Anthracycline- Or bendamustine-containing chemotherapy

Idecabtagene Vicleucel (Abecma)  Patient is 18 years of older; and

PG0460 – 08/25/2021  Health care facility has enrolled in the ABECMA REMS Program and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities; and  Patient has not received prior allogeneic hematopoietic stem cell transplant; and  Patient has not received prior CAR-T or B-cell maturation antigen (BCMA) targeted therapy; and  Patient does not have a clinically significant active systemic infection or inflammatory disorder; and  Patient has not received live vaccines within 6 weeks prior to the start of lymphodepleting chemotherapy, during idecabtagene vicleucel treatment, and will not receive live vaccines until immune recovery following treatment; and  Patient has been screened for cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); and  Prophylaxis for infection has been followed according to local institutional guidelines or clinical practice; and  Used as single agent therapy (not applicable to lymphodepleting or additional chemotherapy while awaiting manufacture); and  Patient does not have known central nervous system involvement, including a history or presence of clinically relevant pathology, with myeloma; and  Patient does not have active or a history of plasma cell leukemia; and Multiple Myeloma  Patient has measurable disease, defined as on or more of the following: o Serum M protein ≥ 1.0 g/dL o Urine M protein ≥ 200 mg/24 h o Serum free light chain (FLC) assay; involved FLC ration level ≥ 10 mg/dL (provided serum FLC ratio is abnormal); and  Patient has relapsed or refractory disease; and  Patient has received at least 4 prior therapies, including a proteasome inhibitor (e.g., bortezomib, etc.) an immunomodulatory agent (e.g., lenalidomide, thalidomide, etc.) and an anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab, etc.)

Lisocabtagene Maraleucel (Breyanzi)  Patient does not have a clinically significant active systemic infection or inflammatory disorder; and  Patient has not received live vaccines within 6 weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel treatment, and will not receive live vaccines until immune recovery following treatment; and  Patient has been screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); and  Prophylaxis for infection has been followed according to local guidelines; and  Healthcare facility has enrolled in the BREYANZI REMS Program and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities; and  Patient has not received prior CAR-T therapy; and  Patient has not received prior anti-CD19 therapy, (e.g., tafasitamab, etc.) OR patient previously received anti- CD19 therapy and re-biopsy indicates CD-19 positive disease; and  Used as single agent therapy (not applicable to lymphodepleting or additional chemotherapy while awaiting manufacture); and  Patient is 18 years or older; and  Patient does not have primary central nervous system lymphoma; and Large B-Cell Lymphoma  Patient has relapsed or refractory disease after at least two lines of systemic therapy Or After autologous hematopoietic stem cell transplantation (HSCT); and  Patient has a diagnosis of diffuse large B cell lymphoma (SLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma; high-grade B-cell lymphoma; primary mediastinal B-cell lymphoma (PMBCL); follicular lymphoma Grade 3B; and  Patient received previous treatment with an anthracycline and CD20-targeted agent

PG0460 – 08/25/2021

Tisagenlecleucel (Kymriah)  Patient does not have an active infection or inflammatory disorder; and  Patient has not received live vaccines with 6 weeks prior to the start of lymphodepleting chemotherapy and will not receive live vaccines until immune recovery following Kymriah treatment; and  Patient has been screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); and  Prophylaxis for infection has been followed according to local guidelines; and  Healthcare facility has enrolled in the Kymriah REMS Program and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities; and  Patient has not received prior CAR-T therapy; and  Patient has not received prior anti-CD19 therapy, (e.g., blinatumomab, etc.) OR patient previously received anti-CD19 therapy and re-biopsy indicates CD-19 positive disease; and  Used as single agent therapy (not applicable to lymphodepleting or bridging chemotherapy); and  Patient has a life expectancy > 12 weeks; and B-Cell Precursor Acute Lymphoblastic Leukemia (ALL)  Patient aged 3 to 25 years; and  Patient’s disease is refractory or in second or later relapse defines as one of the following: o Second or greater bone marrow (BM) relapse; or o Any BM relapse after allogenic stem cell transplantation (SCT); or o Primary refractory (not achieving a complete response after 2 cycles of standard chemotherapy) or chemorefractory (not achieving a complete response after 1 cycle of standard chemotherapy for relapsed disease); or o Patients with Philadelphia chromosome (Ph)-positive disease have a contraindication, intolerance, or have failed two prior lines of tyrosine kinase inhibitor (TKI) therapy (e.g, imatinib, dasatinib, ponatinib, etc.); or o Patient has a performance status (Karnofsky/Lansky) ≥ 50 Large B-Cell Lymphoma  Patient aged 18 years or greater; and  Patient has an ECOG performance status of 0-1; and  Patient does not have primary central nervous system lymphoma; and  Patient’s disease is relapsed or refractory; and o Patient has Diffuse large B-cell lymphoma (DLBCL) as histologic transformation; and . Patient received two or more prior lines of chemoimmunotherapy which must have included an anthracycline or anthracenedione-based regimen, unless contraindicated; and . Patient has Follicular Lymphoma (FL) or Nodal Marginal Zone Lymphoma; and  Patient received multiple line of prior therapies for indolent or transformed disease; or . Patient had Follicular Lymphoma (FL); and  Patient received minimal or no chemotherapy prior to histologic transformation and had partial response, no response, or progressive disease after treatment; or o Patient has Richter’s transformation of CLL to DLBCL; and . Patient received two or more prior lines of systemic therapy; or . Used for treatment of disease that is in second or greater relapse; or o Patient has diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, HHVS-positive diffuse large B-cell lymphoma, not otherwise specified, high-grade B-cell lymphomas, or monomorphic post- transplant lymphoproliferative disorder (B-cell type); and . Used as additional therapy for patients with intention to proceed to transplant who have a partial response following second-line therapy for relapsed or refractor disease; or . Used for treatment of disease that is in second or greater relapse

Boxed Warning Axicabtagene Ciloleucel (Yescarta)

PG0460 – 08/25/2021 WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES  Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. Do not administer axicabtagene ciloleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.  Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.  Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

Brexucabtagene Autoleucel (Tecartus) WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES  Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.  Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.  Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

Idecabtagene Vicleucel (Abecma) WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA  Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with Abecma. Do not administer Abecma to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.  Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with Abecma, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with Abecma. Provide supportive care and/or corticosteroids as needed.  Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life- threatening reactions, occurred in patients following treatment with Abecma. HLH/MAS can occur with CRS or neurologic toxicities.  Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with Abecma.  Abecma is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS)

Lisocabtagene Maraleucel (Breyanzi) WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES  Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Breyanzi. Do not administer Breyanzi to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.  Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Breyanzi, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with Breyanzi. Provide supportive care and/or corticosteroids as needed.  Breyanzi is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.

Tisagenlecleucel (Kymriah) WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES  Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving tisagenlecleucel. Do not administer tisagenlecleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

PG0460 – 08/25/2021  Neurological toxicities, which may be severe or life-threatening, can occur following treatment with tisagenlecleucel, including concurrently with CRS. Monitor for neurological events after treatment with tisagenlecleucel. Provide supportive care as needed.  Tisagenlecleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

CODING/BILLING INFORMATION The inclusion or exclusion of a code in this section does not necessarily indicate coverage. Codes referenced in this clinical policy are for informational purposes only. Codes that are covered may have selection criteria that must be met. Payment for supplies may be included in payment for other services rendered. HCPCS CODES C9073 Brexucabtagene autoleucel, up to 200 million autologous anti-CD19 CAR positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose (eff 1/1/21 and deleted 4/1/21) C9076 Lisocabtagene maraleucel, up to 110 million autologous anti-CD19 CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose (new code effective 7/1/21) C9399 Unclassified drugs or biologicals Q2040 Tisagenlecleucel, up to 250 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per infusion (deleted 1/1/2019) Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-CD19 CAR positive T cells, including leukapheresis and dose preparation procedures, per therapeutic dose. (Use this code for Yescarta) Q2042 Tisagenlecleucel, up to 600 million CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per therapeutic dose. (Use this code for Kymriah) Q2053 Brexucabtagene autoleucel, up to 200 million autologous anti-cd19 car positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose (new eff 4/1/21) S2107 Adoptive immunotherapy i.e. development of specific anti-tumor reactivity (e.g. tumor infiltrating lymphocyte therapy) per course of treatment Non-Covered These codes are not separately reimbursable 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 (new code effective 1/1/19) 0538T Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage) (new code effective 1/1/19) 0539T Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration (new code effective 1/1/19) 0540T Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous (new code effective 1/1/19)

Paramount reserves the right to review and revise our policies periodically when necessary. When there is an update, we will publish the most current policy to https://www.paramounthealthcare.com/services/providers/medical-policies/ .

REVISION HISTORY EXPLANATION ORIGINALEFFECTIVE DATE: 11/01/2019 Date Explanation & Changes  Created Medical Policy for Adoptive Immunotherapy, as a medical policy 10/17/19 reference/communication to refer the provider to the Pharmacy Prior Authorization area. https://www.paramounthealthcare.com/services/providers/prior-authorization-criteria/magellan-mrx 12/08/2020  Medical Policy placed on the new Paramount Medial Policy Format  Changed medical policy name from Adoptive Immunotherapy CAR-T Cell Therapy 08/25/2021 KYMRIAH OR YESCARTA to Chimeric Antigen Receptor (CAR)-T Cell Therapy

PG0460 – 08/25/2021  Revised documentation supporting Kymriah and Yescarta, along with adding Tecartus, Breyanzi and Abecma  Policy updated to reflect most current clinical evidence

REFERENCES/RESOURCES Centers for Medicare and Medicaid Services, CMS Manual System and other CMS publications and services

Ohio Department of Medicaid

American Medical Association, Current Procedural Terminology (CPT®) and associated publications and services

Centers for Medicare and Medicaid Services, Healthcare Common Procedure Coding System, HCPCS Release and Code Sets

U.S. Preventive Services Task Force, http://www.uspreventiveservicestaskforce.org/ Industry Standard Review

Hayes, Inc.

Industry Standard Review

PG0460 – 08/25/2021