The Plan

Members who have certain types of treatment-resistant lymphoma or leukemia may be eligible for coverage of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell treatment involves genetically modifying a patient’s white blood cells to specifically target the cancer cells in the body. This type of therapy is also known as adoptive immunotherapy.

The process starts by filtering the white blood cells from the patient’s blood. The filtered cells are then genetically modified to target the tumor receptors and expanded to a greater quantity. The patient’s existing immune system is then depleted, often with chemotherapy, prior to infusion in order to allow for a more effective environment for the CAR T-cells to function.

As there are potentially serious side effects, treatment should only be performed when the benefits outweigh the risks, under the care of a licensed physician and in an inpatient facility that is certified to administer CAR T-cell therapy. The facility must provide adequate inpatient monitoring during the infusion or extremely close outpatient monitoring with transplant or CAR T-cell experience. The facility must also have at least two doses of tocilizumab immediately available should a severe adverse reaction occur. Patients are also expected to be available and within appropriate proximity of the treatment location to be monitored for 4 weeks after treatment. Kymriah can only be accessed at specific treatment centers. To obtain more information, contact the REMS Call Center at 1-844-459-6742 or visit https://www.kymriah-rems.com/.

This guideline does not address adoptive T-cell therapy for metastatic prostate cancer: Sipuleucel-T (Provenge™). For sipuleucel-T (Provenge™), please review the criteria outlined in MCG Sipuleucel-T (A-0661).

Definitions:

• Allogeneic Stem Cell Transplant is a treatment where donor stem cells are harvested and transferred into patients with cancer or disorders (after their own immune system has been depleted using chemotherapy or total body irradiation) to repopulate their entire bone marrow with healthy cells.
• Autologous Stem Cell Transplant is similar to allogeneic stem cell transfer, except the patient’s own stem cells are used instead of a matched donor.
• B-cell lymphomas refer to a group of non-Hodgkin’s lymphomas developing from cancerous white blood cells (specifically B-lymphocytes), often involving lymph nodes or other extranodal tissues. This group of lymphomas includes, but is not limited to, the following:
  • Burkitt lymphoma
  • Diffuse large B-cell lymphoma (DLBCL)
  • Primary mediastinal B-cell lymphoma (PMBCL)
  • Mantle cell lymphoma
  • Marginal zone lymphomas
  • Transformed follicular lymphoma
• CAR T-cell or Chimeric Antigen Receptor T-cell therapy is a type of adoptive immunotherapy where a patient’s white blood cells (specifically T-lymphocytes) are genetically engineered to specifically target the receptors on the cancer cells (CD19 receptor in the case of B-cell lymphomas and leukemias), B-cell maturation antigen (BCMA) or prostatic acid phosphatase (PAP) in the case of prostate cancer).
• CAR-T cell-related encephalopathy syndrome (CRES) is another inflammatory immune response that can occur with CAR-T treatment and is treated in the same way as CRS.
• Cytokine release syndrome (CRS) is an inflammatory immune response that may occur with CAR T-cell treatment. It often manifests as fever, hypotension, nausea, and other symptoms, and is an emergent condition that may require prompt treatment with tocilizumab (treatment binds to and inhibits IL-6 to reduce inflammatory and immune excessive response) and/or corticosteroids.
• ECOG score (Eastern Cooperative Oncology Group) is a measure of a patient’s general well-being and ability to participate in activities of daily living. The score ranges from 0 (fully active with restrictions) to 5 (dead) and is available at https://ecog-acrin.org/resources/ecog-performance-status.
• Leukemia refers to a type of malignancy affecting the bone marrow and circulating cells in the bloodstream. Acute lymphoid leukemia (ALL) is one example.
• Metastatic Castrate-Resistant Prostate Cancer is prostate cancer that has metastasized or spread outside of the pelvis. Castrate-resistant refers to the state of the cancer not responding to medications or systemic agents that typically inhibit progression by blocking hormonal signals.
• Relapsed refers to a lymphoma or leukemia that had previously responded to treatment with remission, but has returned after a period since the last treatment.
• Refractory refers to a lymphoma or leukemia that has not responded, has progressed, or has not achieved remission.

Medical Necessity Criteria for Authorization

The Plan considers KYMRIAH® (tisagenlecleucel) medically necessary when ALL the following criteria are met:

1. Prescribed by or in consultation with a hematologist-oncologist; AND
2. Documented evidence of ALL of the following:

2. The member is scheduled for and can safely undergo lymphodepleting therapy (including chemotherapy and/or total body irradiation) before CAR T-cell treatment; AND
3. Documented evidence of ALL of the following:
   1. The healthcare facility administering Kymriah is enrolled and adheres to the Kymriah REMS (Risk Evaluation and Mitigation Strategy), which includes:
      1. Immediate, on-site availability of tocilizumab; AND
      2. Provision of a minimum of two tocilizumab doses per patient, ensuring administration within 2 hours after Kymriah infusion if required for cytokine release syndrome treatment; AND
      3. Healthcare providers involved in prescribing, dispensing, or administering Kymriah are trained in managing cytokine release syndrome and neurological side effects; AND
   2. The member has undergone screening and does NOT have any of the following:
      1. Active Central Nervous System (CNS) involvement by malignancy; OR
      2. Active uncontrolled infection or inflammatory disorders; OR
      3. Active or latent hepatitis B; OR
      4. Active hepatitis C; OR
      5. NOTE: history of hepatitis B or C is acceptable if the viral load is currently non-detectable.
      6. A positive Human Immunodeficiency Virus (HIV) test; OR
      7. In patients with a history of allogeneic stem cell transplantation, active graft vs. host disease (GVHD); OR
      8. Previous treatment with Kymriah or any other CD19-targeted CAR T-cell therapy; AND
4. No contraindications (listed in "Experimental or Investigational / Not Medically Necessary" exclusions) are present; AND
5. The member meets the medical necessity criteria for the applicable indication listed below:

Acute lymphoblastic leukemia, relapsed or refractory

The Plan considers KYMRIAH® (tisagenlecleucel) medically necessary when the member has documented evidence of BOTH of the following:

1. CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL); AND
2. Characterized by ONE of the following:
   1. Is less than 18 years of age AND has documented evidence of ONE of the following:
      1. Philadelphia chromosome-negative B-ALL that is refractory or in second or later relapse (≥ 2 relapses); OR
      2. Philadelphia (Ph) chromosome-negative or Ph-like B-ALL that is minimal residual disease positive (MRD+) after consolidation therapy; OR
   2. Philadelphia chromosome-positive B-ALL AND ONE of the following:
      1. Refractory to at least TWO tyrosine kinase inhibitors (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib), unless contraindicated/intolerant; OR
      2. Relapse post-hematopoietic stem cell transplant (HSCT); OR
      3. With less than complete response or MRD+ at end of consolidation therapy; OR
3. Is 18 to 25 years of age with B-ALL that is refractory or in second or later relapse (≥ 2 relapses) AND documented evidence of ONE of the following:
   1. Philadelphia chromosome-negative B-ALL; OR
   2. Philadelphia chromosome-positive B-ALL AND failure of 2 tyrosine kinase inhibitors (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib), unless contraindicated/intolerant.

B-Cell Lymphomas

B-cell Lymphomas, relapsed or refractory

The Plan considers KYMRIAH® (tisagenlecleucel) medically necessary when the member has documented evidence of ALL of the following:

1. The member is 18 years of age or older; AND
2. ONE of the following CD19-positive relapsed or refractory large B-cell lymphoma:
   • AIDS-related B-cell lymphoma; OR
   • Diffuse large B-cell lymphoma; OR
   • HHV-8 associated B-cell lymphoma; OR
   • Monomorphic post-transplant lymphoproliferative disorder (B-cell type); OR
   • Other high-grade B-cell lymphoma; OR
   • Transformed follicular lymphoma (into an aggressive large B-cell lymphoma); OR
   • Transformed nodal marginal zone lymphoma (into diffuse large B-cell lymphoma); AND
3. The member has received prior treatment with at least TWO prior lines of systemic therapy:
   • For members with CD20-positive tumors, previous chemoimmunotherapy regimens must have included an anti-CD20 monoclonal antibody (e.g., Rituxan or rituximab biosimilars), unless contraindicated; and
   • For diffuse large B-cell lymphoma arising from follicular lymphoma OR nodal marginal zone lymphoma - documented evidence of BOTH of the following:
     1. The two lines of therapy have been given after malignant transformation; OR
     2. Chemoimmunotherapy regimens included at least one anthracycline or anthracenedione-based regimen, unless contraindicated.

Follicular lymphoma, relapsed or refractory

The Plan considers KYMRIAH® (tisagenlecleucel) medically necessary when the member has documented evidence of BOTH of the following:

1. The member is 18 years of age or older; AND
2. Follicular lymphoma characterized by ONE of the following:
   • Refractory to a second line or later line of systemic therapy (including an anti-CD20 antibody and an alkylating agent); OR
   • Relapsed within 6 months after completion of a second line or later line of systemic therapy; OR
   • Relapsed during or within six months after completion of an anti-CD20 antibody maintenance therapy following at least two lines of therapy;

Relapsed after autologous hematopoietic stem cell transplant (HSCT).

Length of Stay

Initial Inpatient Admission

Up to 7 days

Extension Stay Criteria

Additional inpatient hospital days after 7 days are medically necessary when:

1. Patient has cytokine release syndrome (CRS); OR
2. Patient has neurotoxicity, CAR-T Related Encephalopathy Syndrome (CRES); OR
3. Patient has developed any adverse reaction continuing after infusion that include, but are not limited to, fever, hypoxia, hypotension, tachycardia, hypersensitive reactions, hypogammaglobulinemia, infections-pathogen unspecified, bleeding episodes, diarrhea, nausea, vomiting, headache, acute kidney injury, edema, and delirium; OR
4. Patient is not stable for discharge, as outlined in the general recovery course and discharge criteria in MCG General Recovery Care > Problem Oriented General Recovery Guidelines >Medical Oncology GRG (PG-ONC).

Experimental or Investigational / Not Medically Necessary

CAR T-cell therapy for any other indication is considered experimental, investigational, or unproven. Non-covered indications and contraindications include, but are not limited to, the following:

• Any lymphoma subtype not mentioned above, including primary CNS lymphoma and Mantle cell lymphoma; OR
• Any leukemia subtype except acute lymphoid leukemia (ALL); OR
• Any other cancer type or condition not included in the Clinical Indications criteria above; OR
• Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and/or a MYC translocation); OR
• When any other newly diagnosed malignancy or other malignancy that is under active treatment or not currently in remission is present; OR
• Patients with an ECOG score of 3-4, as the efficacy and evidence for use in patients with poor performance status is limited; OR
• Any of the following contraindications:
  • Active HIV; or
  • Active, severe systemic infection including but not limited to those currently requiring IV antibiotics; or
  • Current pregnancy; or
  • Hepatitis B or Hepatitis C with detectable viral load; or
  • Live vaccination within 6 weeks of planned treatment date; or
  • Uncontrolled central nervous system disease, including but not limited to brain metastases, positive CSF disease, seizure disorder, dementia, history of stroke, cerebellar disease, or autoimmune CNS disease.