a. Requirements of the KYMRIAH REMS Program have been met:
i. Healthcare facility that dispense and administer drug must be enrolled and comply with the REMS requirements. Certified healthcare facility must have on-site, immediate access to tocilizumab and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after Kymriah^TM infusion, if needed for treatment of CRS.
ii. Certified healthcare facility must ensure that healthcare provider who prescribed, dispensed, or administered Kymriah™ are trained about the management of CRS and neurological toxicities.
b. Member does not have any unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active inflammatory disorders, active graft versus host disease (GVHD), or worsening of leukemia burden, including active central nervous system (CNS) malignancy involvement (i.e. white blood cell (WBC) count greater than or equal to 5 cells/mcl in the cerebral spinal fluid (CSF) with presence of lymphoblasts).
c. Member has been screened for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
d. Prophylaxis for infection has been followed according to local guidelines
e. Vaccination with live vaccines will not to be administered for at least 2 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah™ treatment, and until immune recovery following treatment with Kymriah™ .
f. Myeloid growth factors, including GM-CSF, will not to be administered during the first 3 weeks after Kymriah™ infusion or until CRS has resolved.
g. Member will to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for 8 weeks after drug administration.
h. Kymriah will be used as single agent therapy (not applicable to lymphodepleting or bridging chemotherapy)
i. Member has not received prior CAR treatment

• Treatment of B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse that meet ALL of the following:
  a. Member has CD19-positive, B-cell precursor acute lymphoblastic leukemia (ALL)
  b. Disease is refractory or in second or later relapse defined as ONE of the following:
  i. Second or greater bone marrow (BM) relapse
  ii. Any BM relapse after allogeneic stem cell transplantation (SCT)
  iii. 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)
  iv. Patients with Philadelphia chromosome (Ph)-positive disease have a contraindication, intolerance, or have failed two prior lines of tyrosine kinase inhibitor (TKI) therapy (e.g., imatinib, dasatinib, ponatinib, etc.)
  v. Patient is not eligible for allogeneic SCT
  c. Member aged < 26 years

· Treatment of 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, that meet ALL of the following:
a. Member age of at least 18 years old
b. ECOG performance status of 0 or 1
c. Disease is relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT

[INFORMATIONAL NOTE:
In the pivotal clinical trials for Kymriah (tisagenlecleucel), patients were excluded from the study and receiving the requested agent if they had any of the following:
· Treatment with any prior gene therapy product
· Treatment with any prior anti-CD19 therapy (e.g. blinatumomab)
· Active CNS involvement by malignancy

Per NCCN Guidelines for Ph-Positive ALL, standard treatment recommendations for adolescent and young adult patients with Ph-positive ALL consist of an induction therapy, maintenance therapy, and consolidation therapy. Induction therapy is comprised of multi-agent chemotherapy or corticosteroids (e.g. regimen of daunorubicin, vincristine, prednisone, and pegaspargase with or without methotrexate or cyclophosphamide) combined with a TKI. Treatment regimens should include adequate CNS prophylaxis for all patients. It is important to adhere to the treatment regiments for a given protocol in its entirety, from induction to consolidation/delayed intensification to maintenance therapy. Thereafter, maintenance therapy with a TKI, with or without monthly pulses of vincristine/prednisone, is recommended. Although optimal duration of post-transplant or maintenance TKI is unknown, the minimum suggested duration is 1 year. Then, for patients without a donor, consolidation therapy after a CR should comprise a continuation of multi-agent chemotherapy combined with a TKI. These patients should continue to receive post-consolidation maintenance therapy with a regimen that includes a TKI. Weekly methotrexate and daily 6-MP may be added to the maintenance regimen, as tolerated. But, these doses of these antimetabolite agents may need to be reduced in the setting of hepatotoxicity or myelosuppression.

The CD19 antigen is a pan-B cell marker that can be expressed on the surface of leukemia cells in patients with ALL and NHL, which makes it an immunotherapy target for anti-CD19 treatment. Anti-CD19 therapy targets the CD19 antigen on the surface of B cells and B-cell tumors and causes lysis of the CD19 cell.]

· Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL):
a. One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by infusion of Kymriah^TM
b. Kymriah^TM is administered as a single-dose unit containing chimeric antigen receptor (CAR)-positive viable T cells based on the patient weight reported at the time of leukapheresis. Dosing of Kymriah™ is to include either of the following:
i. For patients 50 kg or less: administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight, OR
ii. For patients above 50 kg: administer 0.1 to 2.5 x 108 CAR-positive viable T cells
c. Lymphodepleting chemotherapy is administered, which consists of both of the following:
i. Fludarabine (30 mg/m2 intravenous daily for 4 days), AND
ii. Cyclophosphamide (500 mg/m2 intravenous daily for 2 days starting with the first dose of fludarabine).
d. Kymriah™ is administered 2 to 14 days after completion of the lymphodepleting chemotherapy.
e. After administration of Kymriah™ , signs and symptoms of Cytokine Release Syndrome (CRS) and other neurological toxicities should be monitored and supportive care should be provided as appropriate.
f. Kymriah will be approved for 60 days duration. A maximum of one dose per lifetime will apply.
· Adult Relapsed or Refractory (r/r) Diffuse Large B-cell lymphoma (DLBCL)
a. One treatment course consists of fludarabine and cyclophosphamide, or bendamustine, lymphodepleting chemotherapy followed by infusion of Kymriah^TM.
b. Kymriah^TM is administered as a single-dose unit containing chimeric antigen receptor (CAR)-positive viable T cells. For adult patients, administer 0.6 to 6.0 x 108 CAR-positive viable T cellsDosing of Kymriah™ is to include either of the following:
c. Lymphodepleting chemotherapy is administered, which consists of all of the following:
i. Fludarabine (25 mg/m2 i.v. daily for 3 days), AND
ii. Cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine), AND
iii. If a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen, alternate lymphodepleting chemotherapy with bendamustine (90 mg/m2 IV daily for 2 days) may be used
iv. Lymphodepleting chemotherapy may be omitted if a patient’s white blood cell (WBC) count is less than or equal to 1 x 109 /L within 1 week prior to Kymriah infusion.
d. Kymriah™ is administered 2 to 11 days after completion of the lymphodepleting chemotherapy.
e. After administration of Kymriah™ , signs and symptoms of Cytokine Release Syndrome (CRS) and other neurological toxicities should be monitored and supportive care should be provided as appropriate.
f. Kymriah will be approved for 60 days duration. A maximum of one dose per lifetime will apply.

[INFORMATIONAL NOTE: As per Novartis, which is the drug manufacturer, tisagenlecleucel (Kymriah^TM) suspension for intravenous infusion is a novel immunocellular therapy and a one-time treatment that uses a patient's own T cells to fight cancer. The registration trial (ELIANA) for tisagenlecleucel (Kymriah^TM) was a Phase II, single arm, multicenter trial evaluating the efficacy and safety in pediatric patients with relapsed and refractory B-cell acute lymphoblastic leukemia. Tisagenlecleucel dose was administered via a single IV infusion of 2.0 - 5.0 x 10⁶ CAR-positive viable T cells per kg body weight (for patients ≤50 kg) and 1.0 - 2.5 x 10⁸ CAR-positive viable T cells (for patients > 50 kg. No patients in the ELIANA trial have been reinfused with Kymriah.

Based on the FDA approved prescribing information, the following is stated in regards to dosing and administration of tisagenlecleucel (Kymriah^TM):
Preparation for Infusion:
1. Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period.
2. Premedicate patient with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to KYMRIAH infusion. Do not use corticosteroids at any time except in the case of a life-threatening emergency.

Based on FDA prescribing information, cytokine release syndrome (CRS) should be identified based on clinical presentation. If CRS is suspected, manage according to the recommendations in Table 1.]

Table 1. Treatment of CRS CRS Severity	Management
Prodromal Syndrome: Low-grade fever, fatigue, anorexia	Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support.
Overt CRS (one or more of the following): − High fever − Hypoxia − Mild hypotension	Administer antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors as needed.
Severe or Life-Threatening CRS (one or more of the following): − Hemodynamic instability despite intravenous fluids and vasopressor support − Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation − Rapid clinical deterioration	Administer high dose or multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed. Administer tocilizumab - Patient weight less than 30 kg: 12 mg/kg intravenously over 1 hour - Patient weight greater than or equal to 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose 800 mg)
Resistant CRS: No clinical improvement in 12 to 18 hours, or worsening at any time, despite prior management.	Administer multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed. Administer methylprednisolone 2 mg/kg as an initial dose, then 2 mg/kg per day until vasopressors and high-flow oxygen are no longer needed, then taper quickly. If no response to steroids within 24 hours, repeat the administration of tocilizumab at - Patient weight less than 30 kg: 12 mg/kg intravenously over 1 hour - Patient weight greater than or equal to 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose 800 mg) If no response to the second dose of tocilizumab within 24 hours, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS.

• As a single-agent therapy for
  • Relapsed/refractory Philadelphia chromosome-positive B-ALL in patients < 26 years and with refractory disease or ≥ 2 relapses and failure of 2 TKIs (tyrosine-kinase inhibitors)
  • Relapsed/refractory Philadelphia chromosome-negative B-ALL in patients < 26 years and with refractory disease or ≥ 2 relapses

• Treatment of histologic transformation to diffuse large B-cell lymphoma (DLBCL) in patients who have received
  • Minimal or no chemotherapy prior to histologic transformation to DLBCL and have partial response, no response, or progressive disease after treatment with ≥2 chemoimmunotherapy regimens which included at least one anthracycline or anthracenedione-based regimen, unless contraindicated
  • Multiple lines of prior therapies (not including axicabtagene ciloleucel or tisagenlecleucel) for indolent or transformed disease (only after treatment with ≥2 chemoimmunotherapy regimens which included at least one anthracycline or anthracenedione-based regimen, unless contraindicated)

• Used for diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma as
  • Additional therapy for patients with intention to proceed to transplant who have partial response following second-line therapy for relapsed or refractory disease
  • Treatment (if tisagenlecleucel or axicabtagene ciloleucel was not previously given) of disease in second relapse or greater in patients with partial response, no response, or progressive disease following therapy for relapsed or refractory disease

• Used for 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 as
  • Additional therapy for patients with intention to proceed to transplant who have partial response following second-line therapy for relapsed or refractory disease
  • Treatment (if tisagenlecleucel or axicabtagene ciloleucel was not previously given) of disease in second relapse or greater in patients with partial response, no response, or progressive disease following therapy for relapsed or refractory disease

• Used for relapsed AIDS-related diffuse large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma, not otherwise specific (NOS) as
  • Additional therapy for patients with intention to proceed to transplant who have partial response following second-line therapy for relapsed or refractory disease
  • Treatment (if not previously given) of disease in second relapse or greater in patients with partial response, no response, or progressive disease following therapy for relapsed or refractory disease

• Treatment for monomorphic PTLD (B-cell type) as
  • Additional therapy for patients with intention to proceed to transplant who have partial response following second-line chemoimmunotherapy for relapsed or refractory disease
  • Treatment of disease in second relapse or greater (if not previously given)

• Preferred therapy (if anti-CD19 CAR T-cell therapy was not previously given) for patients who have received multiple lines of prior therapies including ≥2 chemoimmunotherapy regimens for indolent or transformed disease (patients should have received at least one anthracycline or anthracenedione-based regimen, unless contraindicated)

• Single-agent therapy for
• Additional therapy for patients with intention to proceed to transplant who have partial response following second-line chemoimmunotherapy for relapsed or refractory disease
  • relapsed/refractory Ph-negative B-ALL that is refractory or ≥2 relapses
  • relapsed/refractory Ph-positive TKI intolerant/refractory B-ALL or relapse post-HSCT

	PET-CT (Metabolic response)	CT (Radiologic response)
Lymph nodes and extralymphatic sites	Score 4 or 5 on PET Five Point Scale (5-PS) with reduced uptake compared with baseline No new progressive lesions At interim, these findings suggest responding disease At end of treatment, these findings indicate residual disease	All of the following: ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sites When a lesion is too small to measure on CT, assign 5 mm × 5 mm as the default value When no longer visible, 0 × 0 mm For a node >5 mm × 5 mm, but smaller than normal, use actual measurement for calculation
Non-measured lesion	Not applicable	Absent/normal, regressed, but no increase
Organ enlargement	Not applicable	Spleen must have regressed by >50% in length beyond normal
New lesions	None	None
Bone marrow	Residual uptake higher than uptake in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in the marrow in the context of a nodal response, consideration should be given to further evaluation with MRI or biopsy, or an interval scan	Not applicable

________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Tisagenlecleucel (Kymriah)
Kymriah (Tisagenlecleucel)

References:
1. Kymriah™ [Package Insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. May 2018.

2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 2.2017. August 2017.

3. FDA Approved Vaccines, Blood & Biologics. KYMRIAH. Available at: https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm573706.htm. Accessed September 2017.

4. FDA Press Release. FDA approval brings first gene therapy to the United States. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. Accessed September 2017.

5. Micromedex® Healthcare Series. n.d. Thomson Healthcare, Greenwood Village, CO. September 2017. http://www.thomsonhc.com.

6. Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia. J Clin Oncol. 2014 Nov 10. pii: JCO.2014.56.3247.

7. ClinicalTrials.gov. Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL (ELIANA). July 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02435849. Accessed September 2017.

8. ClinicalTrials.gov. Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients. July 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02228096. Accessed September 2017.

9. Maude SL et al. Efficacy and Safety of CTL019 in the First US Phase II Multicenter Trial in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis. Blood. 2016 128:2801.

10. Maude SL, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. ASCO Meeting Abstracts. 2016;34(15 suppl):3011.

11. Grupp SA, Frey NV, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce significant in vivo proliferation, complete responses and long-term persistence without GVHD in children and adults with relapsed refractory ALL [abstract]. Blood 2013; 122: Abstract 67.

12. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 125646. Tisagenlecleucel. Novartis Pharmaceuticals Corporation.

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