KYMRIAH, Tisagenlecleucel Form

Tisagenlecleucel (Kymriah™) is a CD19-directed, genetically modified, autologous T-cell immunotherapy. FDA Approved Indication(s) Kymriah is 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 large B-cell lymphoma (LBCL) 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 • Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy^
Limitation(s) of use: Kymriah is not indicated for treatment of patients with primary central nervous system (CNS) lymphoma.* ____

• Efficacy of Kymriah for the treatment of LBCL has not been established in patients with active CNS disease (see Appendix D). ^ 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 trials.
  Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
  All requests reviewed under this policy require medical director review. It is the policy of health plans affiliated with Centene Corporation® that Kymriah is medically necessary when the following criteria are met:
  I. Initial Approval Criteria
  A. Acute Lymphoblastic Leukemia (must meet all): Only for initial treatment dose; subsequent doses will not be covered.

  1. Diagnosis of B-cell precursor ALL;
  2. Prescribed by or in consultation with an oncologist or hematologist;
  3. Age ≤ 25 years;
  4. Documentation of CD19 tumor expression;
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  CLINICAL POLICY Tisagenlecleucel

  5. Recent (within the last 30 days) documentation of one of the following (a or b): a. Absolute lymphocyte count (ALC) ≥ 500/µL;
     b. CD3 (T-cells) cell count of ≥ 150/μL if ALC < 500/µL;
  6. Request meets one of the following (a, b, c, or d): a. Disease is refractory, defined as failure to achieve a complete response following induction therapy with ≥ 2 cycles of standard chemotherapy regimen (primary refractory) or after 1 cycle of standard chemotherapy for relapsed leukemia (chemorefractory);
     b. Member has had ≥ 2 relapses; c. Disease is relapsed or refractory, Philadelphia chromosome positive (Ph+): member has received 2 lines of chemotherapy that included 2 tyrosine kinase inhibitors (e.g., imatinib, Sprycel®, Tasigna®, Bosulif®, Iclusig®); *Prior authorization may be required for tyrosine kinase inhibitors d. Member has relapsed following allogeneic stem cell transplantation (SCT) and must be ≥ 6 months from SCT at the time of Kymriah infusion;
  7. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma®, Carvykti™, Breyanzi™, Tecartus®, Yescarta™);
  8. Kymriah is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Tecartus, Yescarta);
  9. Dose does not exceed (a or b): a. Weight ≤ 50 kg: 5.0 x 106 chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight; b. Weight > 50 kg: 2.5 x 108 CAR-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) B. Large B-Cell Lymphoma (must meet all): Only for initial treatment dose; subsequent doses will not be covered.
  10. Diagnosis of one of the following LBCL (a–g); a. DLBCL; b. Primary mediastinal large b cell lymphoma (PMBCL); c. Transformed follicular lymphoma (TFL) to DLBCL; d. Transformed nodal marginal zone lymphoma (MZL) to DLBCL; e. High-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma) or high-grade B-cell lymphomas, not otherwise specified; f. Monomorphic post-transplant lymphoproliferative disorders (B-cell type); g. HIV-related DLBCL, primary effusion lymphoma, and HHV8-positive DLBCL;
  11. Prescribed by or in consultation with an oncologist or hematologist;
  12. Age ≥ 18 years;
  13. Recent (within the last 30 days) ALC ≥ 300/µL;
  14. Disease is refractory or member has relapsed after ≥ 2 lines of systemic therapy that includes rituximab and one anthracycline-containing regimen (e.g., doxorubicin); Prior authorization may be required for rituximab
  15. Member does not have active or primary CNS disease (see Appendix D);
  16. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Tecartus, Yescarta); Page 2 of 12

  CLINICAL POLICY Tisagenlecleucel

  8. Kymriah is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Tecartus, Yescarta);
  9. Dose does not exceed 6.0 x 108 CAR-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) C. Follicular Lymphoma (must meet all): Only for initial treatment dose; subsequent doses will not be covered.
  10. Diagnosis of FL grade 1, 2, or 3a;
  11. Prescribed by or in consultation with an oncologist or hematologist;
  12. Age ≥ 18 years;
  13. Request meets one of the following (a or b): a. Disease is relapsed/refractory after ≥ 2 lines of systemic therapy that includes a combination of an anti-CD20 monoclonal antibody (e.g., rituximab or Gazyva®) and an alkylating agent (e.g., bendamustine, cyclophosphamide, chlorambucil); Prior authorization may be required
      b. Member has relapsed following autologous SCT;
  14. Member does not have active CNS involvement by malignancy;
  15. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Tecartus, Yescarta);
  16. Kymriah is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Tecartus, Yescarta);
  17. Dose does not exceed a single administration of 6 x 108 CAR-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) D. Other diagnoses/indications (must meet 1 or 2):
  18. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
  19. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
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  CLINICAL POLICY Tisagenlecleucel II. Continued Therapy A. All Indications in Section I

  1. Continued therapy will not be authorized as Kymriah is indicated to be dosed one time only. Approval duration: Not applicable B. Other diagnoses/indications (must meet 1 or 2):
  2. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
  3. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     III. Diagnoses/Indications for which coverage is NOT authorized:
     A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. LBCL: Active or primary CNS disease (see Appendix D). IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALC: absolute lymphocyte count ALL: acute lymphoblastic leukemia CAR: chimeric antigen receptor CML: chronic myelogenous leukemia CNS: central nervous system
     CRS: cytokine release syndrome CSF: cerebral spinal fluid
     DLBCL: diffuse large B-cell lymphoma FDA: Food and Drug Administration FL: follicular lymphoma
     LBCL: large B-cell lymphoma MZL: marginal zone lymphoma Ph+: Philadelphia chromosome positive PMBCL: primary mediastinal large B-cell lymphoma r/r: relapsed or refractory REMS: risk evaluation and mitigation strategy SCT: stem cell transplantation TFL: transformed follicular lymphoma WBC: white blood cell Page 4 of 12

  Appendix B: Therapeutic Alternatives
  This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
  Drug Name Dosing Regimen Dose Limit/ Maximum Dose Acute Lymphoblastic Leukemia imatinib mesylate (Gleevec®) Sprycel® (dasatinib) Iclusig® (ponatinib) Tasigna® (nilotinib) Bosulif® (bosutinib) Various combination regimens that may include the following: daunorubicin, doxorubicin, vincristine, dexamethasone, prednisone, pegaspargase, nelarabine, methotrexate, cyclophosphamide, cytarabine, rituximab, 6-mercaptopurine Large B-Cell Lymphoma First-Line Treatment Regimens RCHOP (Rituxan® (rituximab), cyclophosphamide, doxorubicin, vincristine, prednisone) RCEPP (Rituxan® (rituximab), cyclophosphamide, etoposide, prednisone, procarbazine) RCDOP (Rituxan® (rituximab), cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)

• Rituxan® (rituximab) RCEOP (Rituxan (rituximab), cyclophosphamide, etoposide, vincristine, prednisone) Adults: 800 mg/day Pediatrics: 600 mg/day Adults with Ph+ ALL: 600 mg/day Pediatrics with Ph+ ALL: 340 mg/m2/day Ph+ ALL: 140 mg per day Ph+ ALL: 45 mg per day Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg twice per day Ph+ CML: 500 mg per day 600 mg/day Ph- ALL: varies 180 mg/day 45 mg/day
  800 mg/day
  Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 5 of 12

  CLINICAL POLICY Tisagenlecleucel Drug Name Dosing Regimen Varies Varies Varies Dose Limit/ Maximum Dose Varies Varies Varies RGCVP (Rituxan® (rituximab), gemcitabine, cyclophosphamide, vincristine, prednisone) Second-Line Treatment Regimens Bendeka® (bendamustine) ± Rituxan® (rituximab) CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± Rituxan® (rituximab) CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± Rituxan® (rituximab) DA-EPOCH ± Rituxan® (rituximab) GDP (gemcitabine, dexamethasone, cisplatin) ± Rituxan® (rituximab) gemcitabine, dexamethasone, carboplatin ± Rituxan® (rituximab) GemOx (gemcitabine, oxaliplatin) ± Rituxan® (rituximab) gemcitabine, vinorelbine ± Rituxan® (rituximab) lenalidomide ± Rituxan® (rituximab) Rituxan (rituximab) DHAP (dexamethasone, cisplatin, cytarabine) ± Rituxan® (rituximab) DHAX (dexamethasone, cytarabine, oxaliplatin) ± Rituxan® (rituximab) ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± Rituxan® (rituximab) ICE (ifosfamide, carboplatin, etoposide) ± Rituxan® (rituximab) MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± Rituxan® (rituximab) Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 6 of 12

  CLINICAL POLICY Tisagenlecleucel Drug Name Dosing Regimen Dose Limit/ Maximum Dose Varies Varies Varies Varies Varies FL First-Line and Second-Line + Subsequent Treatment Regimens bendamustine + (Gazyva® (obinutuzumab) or rituximab) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + (Gazyva® (obinutuzumab) or rituximab) CHOP + Gazyva® (obinutuzumab) or rituximab CVP (cyclophosphamide, vincristine, prednisone) + Gazyva® (obinutuzumab) CVP + Gazyva® (obinutuzumab) or rituximab rituximab ± (lenalidomide, chlorambucil, or cyclophosphamide)
  Varies rituximab
  Gazyva® (obinutuzumab) Varies Zevalin® (ibritumomab tiuxetan) Varies Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Varies Varies Varies Varies Varies Varies Varies Varies Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): cytokine release syndrome (CRS), neurological toxicities Appendix D: General Information
  • Refractory ALL is defined as complete remission not achieved after 2 cycles of standard chemotherapy or 1 cycle of standard chemotherapy due to relapsed leukemia.2 • CRS, including fatal or life-threatening reactions, occurred in patients receiving Kymriah. Do not administer Kymriah to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurological toxicities, which may be severe or life-threatening, can occur following treatment with Kymriah, including concurrently with CRS. Monitor for neurological events after treatment with Kymriah. Provide supportive care as needed.
  • Kymriah is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kymriah REMS.
  • Novartis, the manufacturer of Kymriah, recommends that patients with ALL have an ALC ≥ 500/µL for leukapheresis collection. Patients with an ALC < 500/μL during leukapheresis screening should have had a CD3 (T-cells) cell count of ≥ 150/μL to be eligible for leukapheresis collection. • The JULIET trial in patients with DLBCL excluded patients with an ALC <300/μL. Page 7 of 12

  CLINICAL POLICY Tisagenlecleucel • Patients with active CNS disease were excluded in the ELIANA trial for ALL and the JULIET trial for DLBCL. In the ALL trial, active CNS involvement by malignancy was defined by CNS-3 per NCCN guidelines (WBC ≥ 5/mcL in CSF with presence of lymphoblasts). In the DLBCL trial, active CNS involvement was assessed during screening by CNS symptom assessment to evaluate clinical evidence of CNS disease, CNS brain imaging (MRI/CT) if clinically indicated, and CSF cytology only if there was suspicion of CNS involvement. • NCCN treatment guidelines for ALL state that CNS-directed therapy may include cranial irradiation, intrathecal chemotherapy (e.g., methotrexate, cytarabine, corticosteroids), and/or systemic chemotherapy (e.g., high-dose methotrexate, intermediate or high-dose cytarabine, pegaspargase). For primary DLBCL of the CNS (i.e., primary CNS lymphoma), NCCN treatment guidelines for CNS cancers recommend a high-dose methotrexate induction based regimen or other systemic therapy regimen if patient is unsuitable for or intolerant to high-dose methotrexate. If a complete response is achieved, or complete response unconfirmed, continue with consolidation therapy with high-dose chemotherapy with stem cell rescue, high-dose cytarabine with or without etoposide, low dose whole brain radiation therapy, or continuation with monthly high-dose methotrexate-based regimen. Alternatively, whole brain radiation therapy is recommended if patient is not a candidate for systemic chemotherapy. • NCCN Pediatric ALL treatment guidelines state that Kymriah can be used in relapsed disease that includes medullary and/or extramedullary disease as CAR-T cells have shown activity against extramedullary disease. NCCN defines extramedullary as disease involving the CNS or testes. • Frigault et al. 2019 reported on their institutional experience with 8 secondary CNS lymphoma patients treated with Kymriah. The best response assessed 28 days post- Kymriah infusion in these patients included complete responses (n = 2) and partial response (n = 2). Additionally, two patients died within 30 days of Kymriah infusion, the remaining two patients experienced disease progression. All patients were receiving CNS-directed therapy for refractory disease up until lymphodepletion.
  • Enrollment in the JULIET trial in patients with DLBCL did not require CD19 positive tumor expression. In a subgroup analysis the best overall response rate was comparable between patients with unequivocal CD19 expression (49%, 95% CI 34 to 64, n = 49) and patients with low or negative CD19 expression (50%, 95% CI 29 to 71, n = 24). V. Dosage and Administration
  Indication ALL LBCL FL Dosing Regimen* ≤ 50 kg: 0.2 to 5.0 x 106 CAR- positive viable T cells per kg of body weight IV

  50 kg: 0.1 to 2.5 x 108 CAR- positive viable T cells IV 0.6 to 6.0 x 108 CAR-positive viable T cells IV 0.6 to 6.0 x 108 CAR-positive viable T cells IV Maximum Dose ≤ 50 kg: 5.0 x 106 CAR-positive viable T cells per kg of body weight 50 kg: 2.5 x 108 CAR-positive viable T cells 6.0 x 108 CAR-positive viable T- cells 6.0 x 108 CAR-positive viable T- cells *Kymriah should be administered at a certified healthcare facility Page 8 of 12

  CLINICAL POLICY Tisagenlecleucel VI. Product Availability
  Single-dose unit infusion bag: frozen suspension of genetically modified autologous T-cells labeled for the specific recipient VII.