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Tisagenlecleucel is a genetically modified autologous cellular immunotherapy comprised of chimeric antigen receptor (CAR) T-cells specific to CD19, a cell surface protein found on normal and malignant B-cells. It is a customized treatment that is prepared using an individual patient’s own T-cells. Steps for preparing tisagenlecleucel include: collecting a patient’s immune cells from blood via leukapheresis; sending the cells to a manufacturing facility; genetically modifying the patient’s T-cells to produce CD19-specific CARs on their surface; expanding the number of CAR T-cells; returning the cells to the treatment facility; and infusing the CAR T-cells back into the patient. This process takes about 2 weeks. Patients typically receive lymphodepleting chemotherapy prior to intravenous infusion of tisagenlecleucel. Once infused, the CAR T-cells selectively target and bind to CD19-expressing B-cells, thereby promoting T-cell expansion and activation, B-cell depletion, and persistence of the CAR T-cells.

The U.S. Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah™) for the following indications:

• 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. The recommended dose is 0.2 to 5.0 x 10⁶ CAR-positive viable T cells per kg of body weight for patients 50 kg or less, and 0.1 to 2.5 x 10⁸ CAR-positive viable T cells for patients above 50 kg.
• 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, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Tisagenlecleucel is not indicated for treatment of patients with primary central nervous system lymphoma. The recommended dose is 0.6 to 6.0 x 10⁸ CAR-positive viable T cells.

Severe and life-threatening adverse reactions have occurred in patients receiving tisagenlecleucel, including cytokine release syndrome and neurological toxicities. Due to these safety concerns, the FDA regulates tisagenlecleucel through a restricted distribution program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS. Under the REMS, only certified healthcare facilities can administer tisagenlecleucel. The prescribing information for tisagenlecleucel also includes a black box warning.

I.   Tisagenlecleucel may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • B-Cell Precursor Acute Lymphoblastic Leukemia (ALL)
    1. Diagnosis of B-cell precursor acute lymphoblastic leukemia (ALL); AND
    2. Age 25 years or younger; AND
    3. Laboratory-confirmed CD19 tumor expression; AND
    4. Disease is refractory or in second or later relapse, as defined by ONE of the following:
       • Second or greater bone marrow relapse; OR
       • Any bone marrow relapse after allogeneic stem cell transplantation (SCT) and must be ≥6 months from SCT at the time of tisagenlecleucel infusion; OR
       • Primary refractory as defined by not achieving a complete response after 2 cycles of a standard chemotherapy regimen or chemorefractory as defined by not achieving a complete response after 1 cycle of standard chemotherapy for relapsed leukemia; OR
       • Patients with Philadelphia chromosome-positive ALL who are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated; OR
  • Large B-Cell Lymphoma
    1. Diagnosis of ANY of the following large B-cell lymphomas:
       • Diffuse large B-cell lymphoma (DLBCL) not otherwise specified; OR
       • Primary mediastinal large B-cell lymphoma; OR
       • High-grade B-cell lymphoma; OR
       • DLBCL arising from follicular lymphoma (FL) (i.e., transformed FL); OR
       • DLBCL arising from nodal marginal zone lymphoma; OR
       • AIDS-Related DLBCL; OR
       • Human herpesvirus 8 (HHV8)-positive DLBCL, not otherwise specified; OR
       • Monomorphic post-transplant lymphoproliferative disorder (B-cell type); AND
    2. Age 18 years or older; AND
    3. Disease is refractory or relapsed after TWO or more lines of systemic therapy. Examples include the following:
       • No response to last line of therapy, defined by progressive disease as best response to most recent therapy regimen; OR
       • No response to last line of therapy, defined by stable disease as best response to most recent therapy with duration ≤6 months from last dose of therapy; OR
       • Disease progression or relapsed ≤12 months post-autologous stem cell transplantation (ASCT); OR
       • If salvage therapy is given post-ASCT, no response to or relapsed after the last line of therapy; AND
    4. Patient must have received adequate prior therapy, including ALL of the following:
       • An anthracycline-containing chemotherapy regimen; AND
       • Anti-CD20 monoclonal antibody (e.g., rituximab) unless tumor is CD20-negative; AND
       • For patients with transformed FL, prior chemotherapy for FL with chemorefractory disease after transformation to DLBCL; AND
• Not previously treated with chimeric antigen receptor (CAR) T-cell therapy; AND
• No FDA labeled contraindications to tisagenlecleucel; AND
• Screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection; AND
• Does not have ANY of the following:
  • Active infection;
  • Active graft versus host disease;
  • Inflammatory disorders;
  • High pre-infusion tumor burden (>50% blasts in bone marrow);
  • Uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy;
  • Unresolved serious adverse reactions from preceding chemotherapies, including pulmonary toxicity, cardiac toxicity, or hypotension;
  • Primary central nervous system lymphoma; 
  • Active central nervous system involvement by malignancy; AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

II.  All other uses of tisagenlecleucel are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Table. FDA-Labeled Contraindications

Documentation Submission

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization, when prior authorization is required. In addition, the following documentation must also be submitted:

1. Clinical notes describing the diagnosis and clinical features of the diagnosis.
2. For patients with B-cell precursor ALL, laboratory results for CD19 tumor expression.
3. Laboratory results for HBV, HCV, and HIV screening.
4. Clinical notes describing current and past treatments for the diagnosis, including response to the treatments.
5. For commercial health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).