Tisagenlecleucel

Three (6%) patients required 3 dosages of tocilizumab, 4 (8%) patients required 2 dosages and 8 (16%) patients required single dose of tocilizumab. Two (4%) patients received corticosteroids in addition to tocilizumab. Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred.

CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden [see Dosage and Administration] .

Administration Preparing Patient for KYMRIAH Administration with Lymphodepletion - Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen. Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia Lymphodepleting chemotherapy: Fludarabine (30 mg/m 2 intravenously daily for 4 days) and cyclophosphamide (500 mg/m 2 intravenously daily for 2 days starting with the first dose of fludarabine).

Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy. Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and r/r Follicular Lymphoma

Lymphodepleting chemotherapy: Fludarabine (25 mg/m 2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m 2 intravenously daily for 3 days starting with the first dose of fludarabine).

Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m 2 intravenously daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen.

Infuse KYMRIAH 2 to 11 days (r/r DLBCL) or 2 to 6 days (r/r FL) after completion of the lymphodepleting chemotherapy.

Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count is less than 1 x 10 9 /L within 1 week prior to KYMRIAH infusion. Preparation of KYMRIAH for Infusion and Administration Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and Precautions].

A KYMRIAH dose may be contained in one to three cryopreserved patient specific infusion bag(s). Verify the number of bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA). Coordinate the timing of thaw of KYMRIAH and infusion in the following manner. Confirm the infusion time in advance, and adjust the start time for thaw so that KYMRIAH is available for infusion when the recipient is ready.

If more than one bag has been received for the treatment dose, thaw 1 bag at a time. Wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered. Preparation of KYMRIAH for Infusion 1. Confirm 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. Avoid prophylactic use of systemic corticosteroids, as it may interfere with the activity of KYMRIAH. 3. Confirm patient identity: Prior to KYMRIAH preparation, match the patient's identity with the patient identifiers on each KYMRIAH infusion bag(s).

KYMRIAH is for autologous use only. Employ universal precautions to avoid potential transmission of infectious diseases when handling the product. Note: The patient identifier number may be preceded by the letters DIN or Aph ID. Figure 1. KYMRIAH Infusion Bag 4. Inspect the infusion bag(s) for any breaks or cracks prior to thawing.

If a bag is compromised, do not infuse the contents. Call Novartis at 1-844-4KYMRIAH. 5. Place the infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination. 6. Thaw each infusion bag one at a time at 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag.

Remove bag from thawing device immediately; do not store product bag at 37°C. Once the infusion bag has been thawed and is at room temperature ( 20°C to 25°C ), it should be infused within 30 minutes. Do not wash, spin down, and/or resuspend KYMRIAH in new media prior to infusion. 7. Inspect the contents of the thawed infusion bag for any visible cell clumps.

If visible cell clumps remain, gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse KYMRIAH if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised. Call Novartis at 1-844-4KYMRIAH. Administration of KYMRIAH 8.

Confirm the patient’s identity with the patient identifiers on the infusion bag. 9. Administer KYMRIAH as an intravenous infusion at 10 mL to 20 mL per minute, adjusted as appropriate for smaller children and smaller volumes. The volume in the infusion bag ranges from 10 mL to 50 mL. Do NOT use a leukocyte-depleting filter.

If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered. - Prime the tubing prior to infusion with sodium chloride 9 mg/mL (0.9%) solution for injection. - Infuse all contents of the infusion bag. - Rinse the infusion bag with 10 mL to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection while maintaining a closed tubing system to assure as many cells as possible are infused into the patient. - Cells from all the bag(s) must be infused to complete a single dose.

KYMRIAH contains human cells genetically modified with a lentivirus. Follow local biosafety guidelines applicable for handling and disposal of such products. Monitoring - Monitor patients daily during the first week following KYMRIAH infusion for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.1, 5.2)] . - Instruct patients to remain within proximity of a healthcare facility for at least 2 weeks following infusion. - Advise patients to avoid driving for at least 2 weeks following infusion.