Tisagenlecleucel (Kymriah) Form

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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Important note: Unless otherwise indicated, medical policies will apply to all lines of business. Medical necessity as defined by this policy does not ensure the benefit is covered. This medical policy does not replace existing federal or state rules and regulations for the applicable service or supply. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan documents. See the member plan specific benefit plan document for a complete description of plan benefits, exclusions, limitations, and conditions of coverage. In the event of a discrepancy, the plan document always supersedes the information in this policy.

SERVICE: Tisagenlecleucel (Kymriah®) PRIOR AUTHORIZATION: Required POLICY: Please review the plan’s EOC (Evidence of Coverage) or Summary Plan Description (SPD) for details. For Medicare plans, please refer to Medicare NCD 110.24 Chimeric Antigen Receptor (CAR) T-cell Therapy For Medicaid plans, please confirm coverage as outlined in the Texas Medicaid Provider Procedures Manual | TMHP (TMPPM). Texas Mandate HB154 is applicable for Medicaid plans.
Baylor Scott & White Health Plan (BSWHP) may consider tisagenlecleucel (Kymriah®) medically necessary when documentation is submitted showing ALL of the following criteria are met:
Universal Criteria Applied to All Requests

1. Tisagenlecleucel is prescribed by or in consultation with a board-certified hematologist or oncologist; AND
2. Tisagenlecleucel will be dosed and administered according to FDA approved labeling; AND
3. Tisagenlecleucel will be used as monotherapy; AND
4. Member has been assessed by a hematologist/oncologist to be an appropriate candidate for apheresis; AND
5. Member has documentation of CD-19 tumor expression; AND
6. Member has had no prior treatment with CAR T-cell immunotherapy (e.g., axicabtagene, brexucabtagene, liscabtagene, obecabtagene); AND
7. If the member has received prior treatment with anti-CD19 (e.g., tafasitamab, loncastuximab, blinatumomab) therapy the member’s repeat biopsy indicates CD-19 positive disease; AND
8. Member does NOT have any of the following: a. Active hepatitis B (HBs AG-positive), active hepatitis C, HIV infection, or uncontrolled infection b. Active central nervous system (CNS) malignancy involvement with presence of lymphoblasts (i.e., WBC ≥ 5 cells/mcl in the cerebral spinal fluid)

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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Indication Specific Criteria B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) specific criteria:

1. Member meets all universal criteria; AND
2. Member is 25 years or younger; AND
3. Member has a Karnofsky or Lansky performance score ≥ 50% or an Eastern Cooperative Oncology Group (ECOG) performance score of 0-3; AND
4. Member has a diagnosis of B-cell precursor acute lymphoblastic leukemia (B-ALL); AND

5. If the member has Philadelphia chromosome (Ph)-negative disease the member has one of the following: a. 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) b. Second or greater bone marrow relapse

   AND

6. If the member has Philadelphia chromosome (Ph)-positive disease the member has one of the following: a. Contraindication, intolerance, or has failed two prior lines of tyrosine kinase inhibitor (TKI)

   therapy (e.g., imatinib, dasatinib, ponatinib, etc.)
   b. Any bone marrow relapse after allogeneic stem cell transplantation (SCT) B-cell Lymphoma specific criteria:

7. Member meets all universal criteria; AND
8. Member is 18 years or older; AND
9. Member has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; AND

10. The member has one of the following: a. Diffuse large B-cell lymphoma (DLBCL) not otherwise specified b. High grade B-cell lymphoma c. DLBCL arising from follicular lymphoma d. Follicular lymphoma (FL)

    AND

11. Tisagenlecleucel will be used as third-line or subsequent therapy BSWHP considers only ONE treatment per lifetime is medically necessary as repeat administration of tisagenlecleucel (Kymriah®) is experimental and investigational because the effectiveness of this strategy has not been established. BSWHP considers tisagenlecleucel (Kymriah®) for the treatment of all other indications to be experimental and investigational because the effectiveness of this strategy has not been established.

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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All requests will be reviewed by both a clinical pharmacist and a medical director. BACKGROUND: Tisagenlecleucel (Kymriah®) KYMRIAH is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of: • Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. • Adult patients 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, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Limitations of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. • Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Mechanism of Action Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy (containing human cells modified with a lentivirus) in which a patient's T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. CD3 zeta is a critical component for initiating T-cell activation and antitumor activity, while 4-1BB enhances expansion and persistence of tisagenlecleucel. After binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel cells. Tisagenlecleucel is prepared from the patient's peripheral blood cells obtained via leukapheresis. B-cell Precursor Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia is a malignant disorder of lymphoid progenitor cells characterized by uncontrolled proliferation and accumulation of immature lymphoblasts in the bone marrow and peripheral blood. B-cell precursor ALL is the most common subtype in children and adolescents, but it also occurs in adults. Relapsed or refractory disease following multiple lines of therapy is associated with poor outcomes and limited curative options. Tisagenlecleucel produced an high overall remission rate in the single-arm ELIANA study of children and young adults. One dose of tisagenlecleucel produced an overall remission rate of 81% (60% complete remission, 21% complete remission with incomplete hematologic recovery) at 3 months in the single-arm ELIANA study of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL; N=75; median age, 11 years; range, 3 to 23 years). Of patients with a

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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treatment response, relapse-free survival rate was 80% at 6 months and 59% at 12 months. Event-free survival was 73% at 6 months and 50% at 12 months; median event-free survival was not reached. Overall survival rate was 90% and 75% at 6 months and 12 months, respectively.
B-Cell Lymphoma DLBCL is the most common subtype of non-Hodgkin lymphoma (NHL) in adults, representing an aggressive malignancy of mature B lymphocytes. Despite high initial response rates to chemoimmunotherapy (e.g., R-CHOP), approximately 30–40% of patients relapse or develop refractory disease. Prognosis is poor after failure of second-line therapy, particularly in those ineligible for or relapsing after autologous stem cell transplantation.
The multicenter phase II study (JULIET) evaluated tisagenlecleucel in patients with relapsed/refractory DLBCL (after at least two lines of therapy, including rituximab and an anthracycline) and TFL.121 Patients who had been previously treated with anti-CD19 CAR T-cell therapy or an allogeneic HCT and those with PMBL, or active CNS involvement were excluded. In this study, 115 patients received infusion with tisagenlecleucel. After a median follow-up of 40 months, the best ORR was 53% (39% CR). The median PFS and OS were 3 months and 11 months, respectively. Among the patients who had achieved a CR at 3 months and 6 months, the median PFS and OS were not reached. Follicular Lymphoma (FL) Follicular lymphoma is an indolent, but generally incurable, B-cell non-Hodgkin lymphoma characterized by a relapsing and remitting clinical course. While many patients respond well to initial chemoimmunotherapy, disease relapse is common, and responses tend to shorten with successive therapies. Patients with relapsed or refractory FL after multiple prior lines of treatment have limited options and may develop treatment resistance. The phase II ELARA trial evaluated tisagenlecleucel in patients with relapsed/refractory FL after ≥2 lines of systemic therapy including an anti-CD20 mAb and an alkylating agent or disease relapse after HDT/ASCR.82,83 At a median follow-up of 29 months, among the 94 evaluable patients, the ORR was 86% (68% CR) and the median PFS was not reached.83 The estimated 24-month PFS and OS rates were 57% and 88%, respectively. CODES: Important note: Due to the wide range of applicable diagnosis codes and potential changes to codes, an inclusive list may not be presented, but the following codes may apply. Inclusion of a code in this section does not guarantee that it will be reimbursed, and patient must meet the criteria set forth in the policy language.

CPT Codes: 36511 Therapeutic apheresis; for white blood cells HCPCS Codes: Q2042 - Kymriah (Tisagenlecleucel) S2107 Adoptive immunotherapy i.e., development of specific antitumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment ICD10 codes: C83.30 - C83.39 Diffuse large B-cell lymphoma C85.20 - C85.29 Primary mediastinal large B-cell lymphoma C91.00 - C91.02 Acute lymphoblastic leukemia

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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D47.Z1 Post-transplant lymphoproliferative disorder ICD10 Not covered:

POLICY HISTORY: Status Date Action New 10/22/2020 New policy Update 11/19/2020 Added criteria for prescriber, dosing and administration Update 04/22/2021 Medicaid instructions added. Update 05/27/2021 Removed Oncology Analytics line, added apheresis criteria, reformatted criteria Update 07/22/2021 Added clinician reviewer criteria Update 06/23/2022 Added NCD information Updated 10/27/2022 Removed language with CMS LCD since NCD applies. Removed Texas Mandate HB1584 language from main policy section as the policy is compliant. Minor formatting update. Updated 12/01/2022 Added additional follicular lymphoma criteria Reviewed 10/26/2023 Applied new layout and format. Updated 10/14/2024 Reformatted with Universal and Specific criteria, Updated universal criteria to align exclusion criteria when applicable across CAR-T therapies Updated 09/08/2025 Updated beginning note to align with standard language,
Updated age requirement to align with standard language, Updated prescriber requirement to align with standard language, Removed REMS program requirement,
Updated indication specific title, Updated dosing and administration language to align with standard language,
Updated monotherapy language to align with standard language,
Updated apheresis language to align with standard language, Updated formatting of no prior treatment with CAR T-cell immunotherapy requirement,
Added examples of anti-CD19 therapy, Updated universal exclusion criteria language, Removed the following universal exclusion criteria to align with OncoHealth: Active GVHD, On immunosuppression for autoimmune disorder/transplant, Pregnant, Updated lifetime treatment and experimental and investigational language to align with standard language, Updated background section, Updated citation to AMA format.

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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REFERENCES:

The following scientific references were utilized in the formulation of this medical policy. BSWHP will continue to review clinical evidence related to this policy and may modify it at a later date based upon the evolution of the published clinical evidence. Should additional scientific studies become available, and they are not included in the list, please forward the reference(s) to BSWHP so the information can be reviewed by the Medical Coverage Policy Committee (MCPC) and the Quality Improvement Committee (QIC) to determine if a modification of the policy is in order.

1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Brentjens RJ. Are chimeric antigen receptor T cells ready for prime time? Clin Adv Hematol Oncol. 2016;14(1):17-19.
3. Brudno JN, Somerville RP, Shi V, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34(10):1112-1121.
4. Children’s Hospital of Philadelphia (CHOP). What to expect: CAR T-cell therapy process. 2017. Available at: http://www.chop.edu/centers-programs/cancer-immunotherapy-program/your-experience. Accessed August 8, 2017.
5. Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. 2017;45(2):e124-e131.
6. Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322-3331.
7. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-4190.
8. Harris DT, Kranz DM. Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors. Trends Pharmacol Sci. 2016;37(3):220-230.
9. Hettle R, Corbett M, Hinde S, et al. The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal. Health Technol Assess. 2017;21(7):1-204.
10. Holzinger A, Barden M, Abken H. The growing world of CAR T cell trials: a systematic review. Cancer Immunol Immunother. 2016;65(12):1433-1450.
11. Ikeda H. T-cell adoptive immunotherapy using tumor-infiltrating T cells and genetically engineered TCR-T cells. Int Immunol. 2016;28(7):349-353.
12. Inman S. Juno accelerates development of JCAR017, halts JCAR015. March 2, 2017. Available at: http://www.onclive.com/web-exclusives/juno-accelerates-development-of-jcar017-halts-jcar015. Accessed August 8, 2017.
13. Kebriaei P, Singh H, Huls MH, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363-3376.
14. Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35(16):1803-1813.
15. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517-528.
16. Leukemia and Lymphoma Society (LLS). Chimeric antigen receptor (CAR) T-cell therapy. 2017. Available at: https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy. Accessed August 8, 2017.
17. Locke FL, Davila ML. Regulatory challenges and considerations for the clinical application of CAR-T cell anti-cancer therapy. Expert Opin Biol Ther. 2017;17(6):659-661.

MEDICAL COVERAGE POLICY SERVICE: Tisagenlecleucel (Kymriah®) Policy Number: 279 Effective Date: 11/1/2025 Last Review: 9/8/2025 Next Review: 9/8/2026

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18. Lymphoma Research Foundation (LRF). Diffuse large B-cell lymphoma (DLBCL). 2016. Available at: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300153. Accessed August 8, 2017.
19. Martin A, Morgan E, Hijiya N. Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments. Paediatr Drugs. 2012;14(6):377-387.
20. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.
21. Maus MV, Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. J Immunother Cancer. 2017;5:36.
22. Pan J, Yang JF, Deng BP, et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia. 2017. Epub ahead of print May 15, 2017. Available at: http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2017145a.html?foxtrotcallback=true. Accessed August 8, 2017.
23. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914-921.
24. Rose S. DLBCL responds well to anti-CD19 CAR therapy. Cancer Discov. 2017;7(3):241-242.
25. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32.
26. Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123-2138.
27. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.
28. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19- specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017. Epub ahead of print July 17, 2017. Available at: http://ascopubs.org/doi/abs/10.1200/JCO.2017.72.8519. Accessed August 8, 2017.
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30. Zhang T, Cao L, Xie J, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget. 2015;6(32):33961-33971.
31. Maude SL, Laetsch TW, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448.

32. Riviere I, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. [In press].

    Note: Health Maintenance Organization (HMO) products are offered through Scott and White Health Plan dba Baylor Scott & White Health Plan, and Scott & White Care Plans dba Baylor Scott & White Care Plan. Insured PPO and EPO products are offered through Baylor Scott & White Insurance Company. Scott and White Health Plan dba Baylor Scott & White Health Plan serves as a third-party administrator for self-funded employer-sponsored plans. Baylor Scott & White Care Plan and Baylor Scott & White Insurance Company are wholly owned subsidiaries of Scott and White Health Plan. These companies are referred to collectively in this document as Baylor Scott & White Health Plan. RightCare STAR Medicaid is offered through Scott and White Health Plan in the Central Texas Medicaid Rural Service Area (MRSA); FirstCare STAR is offered through SHA LLC dba FirstCare Health Plans (FirstCare) in the Lubbock and West MRSAs; and FirstCare CHIP is offered through FirstCare in the Lubbock Service Area.