KYMRIAH

KYMRIAH (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells that are genetically modified using a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR). The CAR is comprised of a murine single-chain antibody fragment (scFv) specific for CD19, followed by a CD8 hinge and transmembrane region that is fused to the intracellular signaling domains for 4-1BB (CD137) and CD3 zeta. KYMRIAH is prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, then transduced with the lentiviral vector containing the anti-CD19 CAR transgene and activated with anti-CD3/CD28 antibody coated beads. The transduced T cells are expanded in cell culture, washed, and formulated into a suspension, which then is cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag(s). The product is thawed prior to administration [see Dosage and Administration (2.2), How Supplied/Storage and Handling (16)] . The thawed product is a colorless to slightly yellow suspension of cells. In addition to T cells, other cell populations, including monocytes, NK cells, and B cells, may be present. The formulation contains 31.25% (v/v) of Plasma-Lyte A, 31.25% (v/v) of 5% Dextrose/0.45% sodium chloride, 10% Dextran 40 (LMD)/5% Dextrose, 20% (v/v) of 25% Human Serum Albumin (HSA), and 7.5% (v/v) dimethyl sulfoxide (DMSO). Pediatric and Young Adult r/r B-cell ALL: A single dose of KYMRIAH may contain up to 2.5 x 10 8 CAR-positive viable T cells provided in one to three patient-specific infusion bag(s). Based on the patient’s weight reported at the time of leukapheresis, one of two possible dose ranges will be prepared for the patient: For patients 50 kg or less: 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight. For patients above 50 kg: 0.1 to 2.5 x 10 8 CAR-positive viable T cells. Adult r/r DLBCL and r/r FL: A single dose of KYMRIAH may contain 0.6 to 6.0 x 10 8 CAR-positive viable T cells provided in one to three patient-specific infusion bag(s). The actual number of CAR-positive T cells in the product is reported on the Certificate of Analysis (CoA) that is shipped with KYMRIAH. The volume of CAR-positive viable T cells in an infusion bag ranges from 10 mL to 50 mL.

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy 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. ( 1.1 ) 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. Limitations of Use : KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. ( 1.2 ) Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. 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 trial(s). ( 1.3 ) 1.1 Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia KYMRIAH is indicated for 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. 1.2 Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma KYMRIAH is indicated for 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. Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. 1.3 Adult Relapsed or Refractory Follicular Lymphoma KYMRIAH is indicated for treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

For autologous use only. For intravenous use only. Administer a lymphodepleting regimen if needed before infusion of KYMRIAH. ( 2.2) Do NOT use a leukodepleting filter. ( 2.2 ) Verify the patient’s identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and an H1-antihistamine. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.1 ) Dosing of KYMRIAH is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. Pediatric and Young Adult B-cell ALL (up to 25 years of age) • For patients 50 kg or less, administer 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight intravenously. ( 2.1 ) • For patients above 50 kg, administer 0.1 to 2.5 x 10 8 total CAR-positive viable T cells (non-weight based) intravenously. ( 2.1 ) Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma • Administer 0.6 to 6.0 x 10 8 CAR-positive viable T cells intravenously. ( 2.1 ) Note: The patient identifier number may be preceded by the letters DIN or Aph ID. Figure 1. KYMRIAH Infusion Bag 2.1 Recommended Dose For autologous use only. For intravenous use only. Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. Based on the patient weight reported at the time of leukapheresis: - Patients 50 kg or less: administer 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight. - Patients above 50 kg: administer 0.1 to 2.5 x 10 8 CAR-positive viable T cells. Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. - For adult patients: administer 0.6 to 6.0 x 10 8 CAR-positive viable T cells. 2.2 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 (5.1)]. 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. 2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)] . Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1 (Lee et al., 2014). Alternative CRS management strategies may be implemented based on appropriate institutional or academic guidelines. Table 1. CRS Grading and Management Guidance a Lee et al., 2014. b Santomasso et al., 2021. c Refer to tocilizumab Prescribing Information for details. d Alternative therapy includes anti-cytokine and anti-T cell therapies as per institutional policy and published guidelines such as (but not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, and ATG. CRS grade a Symptomatic treatment Tocilizumab Corticosteroids Grade 1 Mild symptoms requiring symptomatic treatment only (e.g., low grade fever, fatigue, anorexia, etc.) Exclude other causes (e.g., infection) and treat specific symptoms (e.g., with antipyretics, antiemetics, analgesics, etc.) In patients with persistent (> 3 days) or refractory fever, consider managing as Grade 2 CRS b . Not applicable Grade 2 Symptoms require and respond to moderate intervention Oxygen requirement < 40% or Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed. Administer tocilizumab c intravenously over 1 hour: - 8 mg/kg (max. 800 mg) if body weight ≥ 30 kg - 12 mg/kg if body weight < 30 kg If no improvement after first dose, repeat every 8 hours (limit to a maximum of 3 dosages in 24-hour period; maximum total of 4 doses). If no improvement within 24 hours of tocilizumab, administer a daily dose of 2 mg/kg/day methylprednisolone intravenously (or equivalent) until vasopressor and oxygen no longer needed, then taper. If not improving, manage as appropriate grade below. Grade 3 Symptoms require and respond to aggressive intervention Oxygen requirement ≥ 40% or Hypotension requiring high dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis High-flow oxygen Intravenous fluids, and high-dose or multiple vasopressors Treat other organ toxicities as per local guidelines. Per Grade 2 If not improving, consider alternative therapy d . Per Grade 2 If not improving, manage as Grade 4. Grade 4 Life-threatening symptoms Requirement for ventilator support or Grade 4 organ toxicity (excluding transaminitis) Mechanical ventilation Intravenous fluids and high-dose vasopressor(s) Treat other organ toxicities as per local guidelines. Per Grade 2 If not improving, consider alternative therapy d . Administer methylprednisolone 1,000 mg intravenously one to two times per day for 3 days. If not improving, consider methylprednisolone 1,000 mg intravenously two to three times a day or alternate therapy d . Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. Neurologic Toxicities Patients should be monitored for neurologic toxicities, including ICANS, following KYMRIAH infusion, particularly during and after resolution of CRS. Identify neurologic toxicities based on clinical presentation. Evaluate for and treat other causes of neurological symptoms. Consider non-sedating seizure prophylaxis (e.g., levetiracetam) for patients at higher risk of seizure, such as those with seizure history, CNS disease, concerning EEG findings, or neoplastic brain lesions. If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Alternative neurologic toxicities management strategies may be implemented based on appropriate institutional, academic, or consensus guidelines. Table 2. Guidance for Grading and Management of ICANS a ASTCT criteria for grading NT (Lee et al., 2019); NCI CTCAE criteria for grading NT used in clinical trials. b ICE Assessment Tool: (1) Orientation: orientation to year, month, city, and hospital: 4 points. (2) Naming: ability to name three objects (e.g., point to clock, pen, and button): 3 points. (3) Following commands: ability to follow simple commands (e.g., show me 2 fingers or close your eyes and stick out your tongue): 1 point. (4) Writing: ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point. (5) Attention: ability to count backward from 100 by 10: 1 point. c Santomasso et. al., 2021. d Alternate therapy may include anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone (50 mg) plus methotrexate (12 mg). * A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as Grade 4 ICANS if unarousable. ICANS grade a No concurrent CRS Concurrent CRS Grade 1 ICE score b : 7-9 with no depressed level of consciousness Offer supportive care with intravenous hydration and aspiration precautions. Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Caution with repeated tocilizumab doses in patients with ICANS. Consider adding corticosteroids to tocilizumab past the first dose c . Grade 2 ICE score b : 3-6 and/or Mild somnolence awaking to voice Supportive care as above. Consider dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours) until the event is Grade 1 or less. If improving, taper corticosteroids. Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. If refractory to tocilizumab past the first dose, administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours) until the event is Grade 1 or less, then taper corticosteroids. Grade 3 ICE score b : 0-2 * and/or Depressed level of consciousness awakening only to tactile stimulus and/or Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging Administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours). Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours). Continue corticosteroids until the event is Grade 1 or less, then taper corticosteroids. If not improving, manage as Grade 4. Grade 4 ICE score b : 0 * (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or Diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing’s triad Consider mechanical ventilation for airway protection. Administer high-dose methylprednisolone intravenously 1,000 mg one to two times per day for 3 days. If not improving, consider 1,000 mg of methylprednisolone two to three times per day or alternate therapy d . Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines. Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Administer methylprednisolone 1,000 mg intravenously one to two times per day for 3 days. If not improving, consider methylprednisolone 1,000 mg intravenously two to three times per day or alternate therapy d . Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines.

None. None. ( 4 )

Pediatric and Young Adult B-cell ALL (up to 25 years of age): The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury. ( 6.1 ) Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, hemorrhage, dyspnea, and headache. ( 6.1 ) Adult Relapsed or Refractory Follicular Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogens unspecified, fatigue, musculoskeletal pain, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in the WARNINGS AND PRECAUTIONS and in this section reflect exposure to KYMRIAH in three non-randomized, single-arm studies in which 79 pediatric and young adult patients with relapsed/refractory (r/r) B-cell ALL (Study 1: CCTL019B2202), 115 adults with r/r diffuse large B-cell lymphoma (Study 2: CCTL019C2201), and 97 adults with r/r follicular lymphoma (Study 3: CCTL019E2202) received a single dose of CAR-positive viable T cells. Pediatric and Young Adult r/r B-cell Acute Lymphoblastic Leukemia (ALL) (up to 25 years of age) Based on a recommended dose which was weight-based, all 79 patients in the Study 1 received a single intravenous dose of KYMRIAH [see Clinical Studies (14.1)] . The most common adverse reactions (> 20%) were CRS (77%), infections-pathogen unspecified (57%), hypogammaglobulinemia (53%), fever (42%), decreased appetite (38%), viral infectious disorders (38%), headache (35%), febrile neutropenia (34%), hemorrhage (32%), musculoskeletal pain (32%), vomiting (32%), encephalopathy (30%), bacterial infectious disorders (29%), diarrhea (29%), hypotension (29%), cough (27%), nausea (27%), pain (25%), hypoxia (25%), tachycardia (24%), edema (23%), fatigue (23%), and acute kidney injury (22%). The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 3. Table 3. Adverse Reactions in ≥ 10% of Pediatric and Young Adults Patients with r/r B-cell ALL in Study 1 (N = 79) a Includes multiple related composite terms. b Encephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms. c Dyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure. Adverse reaction All Grades (%) Grades 3 or higher (%) Blood and lymphatic system disorders Febrile neutropenia 34 34 Cardiac disorders Tachycardia a 24 4 Gastrointestinal disorders Vomiting 32 1 Diarrhea 29 1 Nausea 27 3 Abdominal pain a 18 3 Constipation 18 0 General disorders and administration site conditions Fever 42 13 Pain a 25 3 Fatigue a 23 0 Edema a 23 8 Immune system disorders Cytokine release syndrome 77 48 Hypogammaglobulinemia a 53 13 Infections and infestations Infections-pathogen unspecified 57 27 Viral infectious disorders 37 22 Bacterial infectious disorders 29 16 Fungal infectious disorders 15 9 Metabolism and nutrition disorders Decreased appetite 38 15 Hypocalcemia 20 6 Hyperferritinemia a 10 3 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 32 4 Arthralgia 14 1 Nervous system disorders Headache a 35 3 Encephalopathy b 30 9 Psychiatric disorders Delirium a 19 4 Anxiety 17 3 Sleep disorder a 11 0 Renal and urinary disorders Acute kidney injury a 22 14 Respiratory, thoracic and mediastinal disorders Cough a 27 0 Hypoxia 25 20 Dyspnea c 19 14 Pulmonary edema 15 9 Nasal congestion 11 0 Oropharyngeal pain 10 0 Pleural effusion 10 4 Tachypnea 10 5 Skin and subcutaneous tissue disorders Rash a 18 1 Vascular disorders Hemorrhage a 32 10 Hypotension 29 20 Hypertension 19 5 Other clinically important adverse reactions which occurred in <10% of patients include the following: Blood and lymphatic system disorders: coagulopathy (6%), hemophagocytic lymphohistiocytosis (6%), pancytopenia (3%) Cardiac disorders: cardiac failure (9%), arrhythmia (4%) Eye disorders: visual impairment (3%) Gastrointestinal disorders: abdominal distention (4%), ascites (4%), stomatitis (4%), abdominal compartment syndrome (1%), dry mouth (1%) General disorders and administration site conditions: chills (9%), asthenia (4%), influenza-like illness (3%), multiple organ dysfunction syndrome (3%) Immune system disorders: infusion related reaction (6%), graft versus host disease (3%) Investigations: prothrombin time prolonged (4%), fibrin D dimer increased (3%), weight decreased (3%) Metabolism and nutrition disorders: tumor lysis syndrome (6%), hypercalcemia (4%) Nervous system disorders: tremor (8%), seizure (6%), dizziness (5%), peripheral neuropathy (4%), speech disorder (3%), motor dysfunction (1%), neuralgia (1%) Respiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (4%), lung infiltration (1%) Skin and subcutaneous tissue disorders: pruritus (9%), erythema (6%), hyperhidrosis (4%), night sweats (1%) Vascular disorders: capillary leak syndrome (3%), thrombosis (3%), flushing (1%) Laboratory Abnormalities Table 4. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Pediatric and Young Adult Patients with r/r B-cell ALL in Study 1 (N = 79) a CTCAE = Common Terminology Criteria for Adverse Events version 4.03. Laboratory abnormality Grade 3 or 4 a (%) Hematology Blood fibrinogen decreased 11 Biochemistry Aspartate aminotransferase increased 29 Hypokalemia 28 Alanine aminotransferase increased 22 Hypophosphatemia 20 Hyperbilirubinemia 19 Hyperglycemia 13 All patients experienced neutropenia, anemia and thrombocytopenia. See Table 5 for the incidences of ≥ Grade 3 prolonged thrombocytopenia and prolonged neutropenia in responding patients. Table 5. Prolonged Cytopenias Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL a ≥ Grade 3 observed within 14 days after Day 28 or Day 56 in responding patients. Prolonged cytopenia N = 52 (%) N = 52 (%) Day 28 Day 56 Prolonged neutropenia a 40 17 Prolonged thrombocytopenia a 27 12 Adult r/r Diffuse Large B-cell Lymphoma (DLBCL) In Study 2, 115 adults with r/r DLBCL received a single intravenous dose of KYMRIAH [see Clinical Studies (14.2)] . The most common adverse reactions (incidence > 20%) were CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, bleeding episodes, dyspnea, and headache. The study population characteristics were median age of 56 years (range, 22 to 76 years), 80% DLBCL; a median of 3 prior lines of therapy (range, 1 to 6), 49% had a prior autologous hematopoietic stem cell transplantation, and 32% had received prior radiation therapy. One hundred seven patients (93%) received lymphodepleting chemotherapy prior to KYMRIAH, which included fludarabine (n = 85) or bendamustine (n = 22). The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 6 below. Table 6. Adverse Reactions Reported in ≥ 10% of Adult Patients with r/r DLBCL in Study 2 (N = 115) a Includes multiple related composite terms. b Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, metabolic encephalopathy and thinking abnormal. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms. c Peripheral neuropathy includes paraesthesia, hypoaesthesia, hyperaesthesia, peripheral sensory neuropathy, neuropathy peripheral, cranial nerve paralysis, demyelinating polyneuropathy, Horner’s syndrome, polyneuropathy, and sciatica. d Dizziness includes dizziness, presyncope, and syncope. e Dyspnea includes dyspnea, dyspnea exertional, respiratory distress, and respiratory failure. Adverse reaction All Grades (%) Grades 3 or higher (%) Blood and lymphatic system disorders Febrile neutropenia 17 17 Cardiac disorders Tachycardia a 13 3 Arrhythmia a 10 5 Gastrointestinal disorders Diarrhea 31 1 Nausea 29 1 Constipation 17 1 Abdominal pain a 10 2 General disorders and administration site conditions Fever 35 5 Fatigue a 27 6 Edema a 27 3 Pain a 14 3 Chills 12 0 Immune system disorders Cytokine release syndrome 74 23 Hypogammaglobulinemia a 17 6 Infections and infestations Infections-pathogen unspecified 48 26 Bacterial infectious disorders 17 8 Fungal infectious disorders 11 5 Viral infectious disorders 11 2 Investigations Weight decreased 12 4 Metabolism and nutrition disorders Decreased appetite 14 4 Musculoskeletal and connective tissue disorders Arthralgia 14 0 Musculoskeletal pain a 13 1 Nervous system disorders Headache a 21 1 Encephalopathy b 16 11 Peripheral neuropathy c 12 3 Dizziness d 12 2 Psychiatric disorders Anxiety 10 1 Sleep disorder a 10 0 Renal and urinary disorders Acute kidney injury a 17 6 Respiratory, thoracic and mediastinal disorders Dyspnea e 21 6 Cough a 17 0 Skin and subcutaneous tissue disorders Rash a 11 0 Vascular disorders Hypotension a 25 9 Hemorrhage a 22 8 Other clinically important adverse reactions which occurred in <10% of patients include the following: Blood and lymphatic system disorders: pancytopenia (3%), hemophagocytic lymphohistiocytosis (2%), B-cell aplasia (1%) Cardiac disorders: cardiac failure (1%) Eye disorders: visual impairment (6%) Gastrointestinal disorders: vomiting (9%), stomatitis (6%), dry mouth (5%), abdominal distension (4%), ascites (3%) General disorders and administration site conditions: influenza-like illness (9%), asthenia (7%), multiple organ dysfunction syndrome (3%) Immune system disorders: infusion related reaction (3%) Investigations: fibrin D dimer increased (4%) Metabolism and nutrition disorders: hypocalcemia (5%), hypercalcemia (4%), hyperferritinemia (4%), tumor lysis syndrome (2%) Musculoskeletal and connective tissue disorders: myalgia (5%) Nervous system disorders: motor dysfunction (6%), tremor (6%), speech disorder (4%), neuralgia (3%), seizure (3%), ataxia (2%), ischemic cerebral infarction (1%) Psychiatric disorders: delirium (5%) Respiratory, thoracic, and mediastinal disorders: hypoxia (8%), oropharyngeal pain (8%), pleural effusion (5%), nasal congestion (4%), pulmonary edema (3%), tachypnea (3%) Skin and subcutaneous tissue disorders: night sweats (5%), pruritus (4%), hyperhidrosis (4%), erythema (2%) Vascular disorders: thrombosis (6%), hypertension (4%), capillary leak syndrome (1%) Laboratory Abnormalities Table 7. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Adult r/r DLBCL Patients in Study 2 (N = 115) a CTCAE = Common Terminology Criteria for Adverse Events version 4.03. Laboratory parameter Grade 3 or 4 a (%) Hematology Lymphopenia 95 Neutropenia 82 Leukopenia 78 Anemia 59 Thrombocytopenia 56 Biochemistry Hypophosphatemia 24 Hypokalemia 13 Adult r/r Follicular Lymphoma (FL) The safety of KYMRIAH was evaluated in Study 3, a trial that included 97 patients with r/r FL who received a single intravenous dose of KYMRIAH [see Clinical Studies (14.3)] . Patients with a history of CNS disorders or autoimmune disease requiring systemic immunosuppression were ineligible. The median age was 57 years (range, 29 to 73 years), 34% were female, 75% were White, 13% were Asian, and 1% were Black or African American. The most common adverse reactions (incidence > 20%) were CRS, infections-pathogen unspecified, fatigue, musculoskeletal pain, headache, and diarrhea. The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 8 below. Table 8. Adverse Reactions Reported in ≥ 10% of Adult Patients with r/r FL in Study 3 (N = 97) a Includes multiple related composite terms. b Includes one case of progressive multifocal leukoencephalopathy due to John Cunningham virus reactivation. Adverse reaction All Grades (%) Grades 3 or higher (%) Blood and lymphatic system disorders Febrile neutropenia 13 13 Gastrointestinal disorders Diarrhea 24 2 Nausea 16 2 Constipation 16 0 Abdominal pain a 10 1 General disorders and administration site conditions Fatigue a 27 3 Fever 19 1 Immune system disorders Cytokine release syndrome 53 0 Hypogammaglobulinemia a 18 1 Infections and infestations Infections-pathogen unspecified 38 12 Viral infectious disorders b 18 5 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 25 1 Arthralgia 10 0 Nervous system disorders Headache a 25 2 Respiratory, thoracic and mediastinal disorders Cough a 19 0 Skin and subcutaneous tissue disorders Rash a 10 0 Other clinically important adverse reactions which occurred in <10% of patients include the following: Blood and lymphatic system disorders: pancytopenia (3%), hemolysis (2%), coagulopathy (2%) Cardiac disorders: tachycardia (2%), arrhythmia (4%) Eye disorders: visual impairment, blindness (preexisting progressive blindness, which initiated prior to start of lymphodepleting chemotherapy, further worsened after KYMRIAH infusion), vision blurred (4%) Gastrointestinal disorders: vomiting (9%), stomatitis (4%), abdominal distension (2%), dry mouth (2%) General disorders and administration site conditions: edema (9%), pain (8%), chills (6%) Immune system disorders: infusion related reaction (3%), graft versus host disease (1%), hemophagocytic lymphohistiocytosis (1%) Infections and infestations: bacterial infectious disorders (7%), fungal infectious disorders (2%) Investigations: weight decreased (7%) Metabolism and nutrition disorders: decreased appetite (8%), tumor lysis syndrome (2%) Nervous system disorders: dizziness (8%), motor dysfunction (9%), peripheral neuropathy (7%), immune effector cell-associated neurotoxicity syndrome (4%), encephalopathy (3%), tremor (3%) Psychiatric disorders: sleep disorder (6%), anxiety (2%), delirium (1%) Renal and urinary disorder: acute kidney injury (4%) Respiratory, thoracic, and mediastinal disorders: dyspnea (8%), pleural effusion (6%), oropharyngeal pain (5%), nasal congestion (2%), rhinorrhea (2%) Skin and subcutaneous tissue disorders: pruritus (9%), night sweats (3%), erythema (2%), hyperhidrosis (1%) Vascular disorders: hypotension (9%), hemorrhage (6%), hypertension (5%), thrombosis (1%) Laboratory Abnormalities Table 9. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Adult Patients with r/r FL Patients in Study 3 (N = 97 * ) a CTCAE = Common Terminology Criteria for Adverse Events version 4.03. * Evaluable population (n = 91 to 97) for each laboratory value included number of patients who had both baseline (before KYMRIAH infusion) and at least one post-KYMRIAH infusion on-study laboratory value available. Laboratory abnormality Grade 3 or 4 a (%) Hematology Neutropenia 63 Leukopenia 40 Thrombocytopenia 21 Anemia 20 Lymphopenia 19 Biochemistry Hypophosphatemia 12 6.2 Postmarketing Experience Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse events have been identified during postmarketing use of KYMRIAH. Immune system disorders: Anaphylactic reaction Neoplasms: T cell malignancies Infections and infestations: Progressive multifocal leukoencephalopathy Eye disorders: Blindness

HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false-positive results in patients who have received KYMRIAH.