Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Chimeric Antigen Receptor (CAR) Therapy

Policy #:08.01.43d

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, 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. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

TISAGENLECLEUCEL (KYMRIAH)

B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Tisagenlecleucel (Kymriah) is considered medically necessary and, therefore, covered for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) when all of the following criteria are met:
  • Confirmed diagnosis of CD19-positive B-cell precursor ALL in individuals 25 years and younger with refractory disease or 2 or more relapses and one of the following subtypes:
    • Philadelphia chromosome-negative disease, or
    • Philadelphia chromosome-positive disease and failure of 2 tyrosine kinase inhibitors (e.g., dasatinib [Sprycel®], imatinib [Gleevec®], ponatinib [Iclusig®])
  • Individual does not have an active infection or inflammatory disorder
  • Individual has not received prior CAR treatment (i.e., tisagenlecleucel, axicabtagene ciloleucel)

LARGE B-CELL LYMPHOMA
Tisagenlecleucel (Kymriah™) is considered medically necessary and, therefore, covered for the treatment of relapsed or refractory large B-cell lymphoma when all of the following criteria are met:
  • Diagnosis of one of the following types of relapsed or refractory large B-cell lymphoma after failure of 2 or more lines of systemic therapy (e.g., RCHOP- rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone):
    • diffuse large B-cell lymphoma (DLBCL) not otherwise specified
    • primary mediastinal large B-cell lymphoma
    • high grade B-cell lymphomas
    • DLBCL arising from follicular lymphoma
  • Individual is 18 years or older
  • Individual does not have clinically significant active systemic infection
  • Individual does not have primary central nervous system lymphoma
  • Individual has not received prior CAR treatment (i.e., tisagenlecleucel, axicabtagene ciloleucel)

AXICABTAGENE CILOLEUCEL (YESCARTA)

Axicabtagene ciloleucel (Yescarta) is considered medically necessary and, therefore, covered when all of the following criteria are met:
  • Diagnosis of one of the following types of relapsed or refractory large B-cell lymphoma after failure of 2 or more lines of systemic therapy (e.g., RCHOP- rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone):
    • AIDS-related diffuse large B-cell lymphoma (DLBCL)
    • DLBCL arising from follicular lymphoma
    • DLBCL not otherwise specified
    • HHV8-positive DLBCL, not otherwise specified
    • monomorphic post-transplant lymphoproliferative disorders (PTLD), B-cell type
    • primary mediastinal large B-cell lymphoma
    • high grade B-cell lymphoma
  • Individual is 18 years or older
  • Individual does not have clinically significant active systemic infection
  • Individual does not have primary central nervous system lymphoma
  • Individual has not received prior CAR treatment (i.e., tisagenlecleucel, axicabtagene ciloleucel)

EXPERIMENTAL/INVESTIGATIONAL

All other uses for tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) 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.

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

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

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™) has been established for the treatment of relapsed or refractory B-cell ALL; the safety and effectiveness of tisagenlecleucel (Kymriah™) has not been established for the treatment of relapsed or refractory diffuse large B-cell lymphoma.

Axicabtagene ciloleucel (Yescarta) was approved by the FDA on October 18, 2017 for the treatment of adult individuals 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, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. The safety and effectiveness of Axicabtagene ciloleucel (Yescarta™) in the pediatric population has not been established.

DOSING GUIDELINES

B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Tisagenlecleucel (Kymriah™)

Lymphodepleting chemotherapy: Fludarabine 30mg/m2 intravenous (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.

LARGE B-CELL LYMPHOMA
Axicabtagene ciloleucel (Yescarta)

Lymphodepleting chemotherapy: Cyclophosphamide 500mg/m2 IV and fludarabine 30mg/m2 IV on the fifth, fourth, and third day before axicabtagene ciloleucel (Yescarta™) infusion.

Tisagenlecleucel (Kymriah™)
  • Lymphodepleting chemotherapy: Fludarabine 25 mg/m2 IV daily for 3 days and cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine
  • Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 IV daily for 2 days if the individual experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen
  • Infuse tisagenlecleucel (Kymriah™) 2 to 11 days after completion of the lymphodepleting chemotherapy
  • Lymphodepleting chemotherapy may be omitted if an individual’s white blood cell (WBC) count is less than or equal to 1 x 109/L within 1 week prior to tisagenlecleucel (Kymriah™) infusion

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 2 categories: precursor B cell lymphoblastic leukemia, which account for approximately 70-80% of childhood ALL cases, and precursor T cell lymphoblastic leukemia.

Lymphoma is the most common blood cancer, and is divided into 2 categories: Hodgkin lymphoma and non-Hodgkin lymphoma. Lymphoma occurs when lymphocytes grow abnormally. There are two main types of lymphocytes in the body: B-lymphocytes and T-lymphocytes. Non-Hodgkin lymphoma 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% of all cases.

TISAGENLECLEUCEL (KYMRIAH)

Tisagenlecleucel (Kymriah) is a genetically-modified autologous T-cell immunotherapy. Each dose of tisagenlecleucel (Kymriah) is customized to the individual. The individual's T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a chimeric antigen receptor (CAR). The modified T-cells target and bind to CD19 expressing leukemia cells and eliminates them. Prior to initiating the Kymriah™ infusion, individuals must undergo lymphodepleting chemotherapy to reduce the level of white blood cells and help the body accept the reprogrammed CAR-T cells.

On August 30, 2017, the United States Food and Drug Administration (FDA) approved tisagenlecleucel (Kymriah™) for the treatment of individuals up to 25 years old with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later stage relapse. Efficacy and safety of tisagenlecleucel (Kymriah™) in pediatric individuals with relapsed and refractory B-cell acute lymphoblastic leukemia (ALL) were established in a single-arm, open-label, phase 2 study (ELIANA). The primary outcome of this trial is the overall remission rate within 3 months of infusion of tisagenlecleucel (Kymriah™). Secondary outcomes included duration of remission, overall survival, and safety. Of the 63 individuals infused with tisagenlecleucel (Kymriah™), 52 (83%) achieved complete response and were minimal residual disease (MRD) negative. Duration of remission 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 was not reached by any of the 52 individuals.

On May 1, 2018, the FDA approved tisagenlecleucel (Kymriah™) for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Efficacy and safety of tisagenlecleucel (Kymriah™) were established in a retrospective subgroup analysis of an open-label, single-arm trial (JULIET) of 68 individuals. The study included adults with relapsed or refractory DLBCL who had received 2 or more lines of chemotherapy, including rituximab and anthracycline, or relapsed following autologous hematopoietic stem cell transplantation. Tisagenlecleucel (Kymriah™) was administered as a single infusion, following 2-11 days after completion of lymphodepleting chemotherapy. The complete response (CR) rate and partial response (PR) rate was 32% and 18%, respectively; median duration of response was longer in those with CR compared with PR (not reached vs 3.4 months). Median time to first response was 0.9 months (range, 0.7 to 3.3 months).

AXICABTAGENE CILOLEUCEL (YESCARTA)

On October 18, 2017, the United States Food and Drug Administration approved axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with relapsed or refractory large B-cell lymphoma after 2 or more lines of therapy. Axicabtagene ciloleucel (Yescarta) is the second 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.

Safety and efficacy of axicabtagene ciloleucel (Yescarta™) for the treatment of adult individuals with relapsed or refractory B-cell non-Hodgkin lymphoma were established in a single arm, open-label, multicenter trial (ZUMA-1). Individuals eligible for the trial had refractory disease to the most recent therapy or relapse within 1 year of autologous hematopoietic stem cell transplant. Of the 101 individuals who received the axicabtagene ciloleucel (Yescarta™) infusion, 52 (51%) achieved complete remission and 21 (21%) achieved partial remission. At the median follow up of 7.9 months, individuals in complete remission had not reached the estimated duration of response.

RISK EVALUATION AND MITIGATION STRATEGY (REMS) PROGRAM

Due to the risk of cytokine release syndrome (CRS) and neurological toxicities, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) are only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The requirements of the REMS include:
  • Healthcare facilities that dispense and administer tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) must be enrolled in the program
  • Certified healthcare facilities must have on-site, immediate access to tocilizumab (Actemra®) and ensure that a minimum of two doses are available for each patient for administration within 2 hours after tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) infusion if needed to treat CRS
  • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) are trained about the management of CRS and neurological toxicities

OFF-LABEL INDICATIONS

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


American Cancer Society. Key Statistics for Non-Hodgkin Lymphoma. 01/04/2018. Available at: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html . Accessed May 30, 2018.

Elsevier’s Clinical Pharmacology Compendium. Kymriah. 05/07/2018. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed May 29, 2018.

Elsevier’s Clinical Pharmacology Compendium. Yescarta. 10/20/2017. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed May 29, 2018.

Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. N Engl J Med 2013; 368:1509-18.

Horton TM, Steuber CP. Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and adolescents. [UpToDate]. Updated 07/10/2017. Available at: https://www.uptodate.com/contents/overview-of-the-presentation-and-diagnosis-of-acute-lymphoblastic-leukemia-in-children-and-adolescents?source=search_result&search=ALL&selectedTitle=1~150 [via subscription only]. Accessed May 29, 2018.

Kymriah (tisagenlecleucel). [prescribing information] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 05/2018. Available at: https://www.hcp.novartis.com/products/kymriah/ . Accessed May 25, 2018.

Lexi-Drugs Compendium. Kymriah. 05/23/2018. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 29, 2018.

Lexi-Drugs Compendium. Yescarta. 05/21/2018. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 29, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Acute Lymphoblastic Leukemia.V.1.2018. [NCCN Web site]. 03/12/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf [via free subscription]. Accessed May 29, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Diffuse Large B-Cell Lymphoma.V.4.2018. [NCCN Web site]. 05/15/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf [via free subscription]. Accessed May 29, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Kymriah. [NCCN Web site]. 2018. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed May 17, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Yescarta. [NCCN Web site]. 2018. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed May 17, 2018.

Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphoytic leukemia. Sci Transl Med 7, 303ra139. 2015.

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

Truven Health Analytics. Micromedex® DrugDex® Compendium. Kymriah. 05/16/2018. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 29, 2018.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Yescarta. 02/19/2018. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 29, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Kymriah™ (tisagenlecleucel) prescribing information, approval letter, REMS documents [FDA Web site]. 05/01/18. Available at: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581222.htm . Accessed May 25, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Yescarta™ (axicabtagene ciloleucel) prescribing information, approval letter, REMS documents [FDA Web site]. 10/18/17. Available at: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581222.htm . Accessed May 25, 2018.

Yescarta (axicabtagene ciloleucel). [prescribing information] Santa Monica, CA: Kite Pharma, Inc.; 2017. Issued 10/2017. Available at: https://www.yescarta.com/ . Accessed May 24, 2018.



Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


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 viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

Q2042 Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References

Attachment A: Chimeric Antigen Receptor (CAR) Therapy
Description: ICD-10 CODES AND NARRATIVES




Policy History

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

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

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

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

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

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

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

The following HCPCS codes have been added to this policy:
Q2041 Axicabtagene ciloleucel, up to 200 million autologous anti-cd19 car t cells, including leukapheresis and dose preparation procedures, per infusion

08.01.43a
01/01/2018This policy has been identified for the HCPCS code update, effective 01/01/2018.

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

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

This new policy has been issued to communicate the Company's coverage position for tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™).
Version Effective Date: 01/01/2019
Version Issued Date: 01/02/2019
Version Reissued Date: N/A

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