Tisagenlecleucel

Tisagenlecleucel is used for: Acute Lymphoblastic Leukemia, Large B-Cell Lymphoma,

Acute Lymphoblastic Leukemia CD19-directed genetically modified autologous T-cell immunotherapy indicated for young adults aged <25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by IV infusion of tisagenlecleucel Lymphodepleting chemotherapy Fludarabine 30 mg/m² IV qDay for 4 days PLUS Cyclophosphamide 500 mg/m² IV qDay for 2 days starting with the first dose of fludarabine Tisagenlecleucel IV infusion Administer 2-14 days after completing lymphodepleting chemotherapy Premedicate with acetaminophen and diphenhydramine (see Administration) <50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg Infuse autologously prepared, weight-based IV for individual patient at 10-20 mL/min Do not use a leukocyte-depleting filter Adjust infusion rate as appropriate for smaller children and smaller volumes Large B-Cell Lymphoma Indicated for adults with relapsed or refractory large B-cell lymphoma (r/rDLBCL) after ?2 lines of systemic therapy including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by IV infusion of tisagenlecleucel Lymphodepleting chemotherapy Lymphodepleting chemotherapy may be omitted if WBC count ?1 x 10^9/L within 1 week before tisagenlecleucel infusion Fludarabine 25 mg/m² IV qDay for 3 days PLUS Cyclophosphamide 250 mg/m² IV qDay for 3 days starting with the first dose of fludarabine Alternate lymphodepleting chemotherapy Bendamustine 90 mg/m² IV qDay for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen Tisagenlecleucel IV infusion Administer 2-11 days after completing lymphodepleting chemotherapy Premedicate with acetaminophen and diphenhydramine 0.6-6 x 10^8 CAR-positive viable T cells/kg

Acute Lymphoblastic Leukemia CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged <25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by IV infusion of tisagenlecleucel Lymphodepleting chemotherapy Fludarabine 30 mg/m² IV qDay for 4 days PLUS Cyclophosphamide 500 mg/m² IV qDay for 2 days starting with the first dose of fludarabine Tisagenlecleucel IV infusion Administer 2-14 days after completing lymphodepleting chemotherapy Premedicate with acetaminophen and diphenhydramine (see Administration) <50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg Infuse autologously prepared, weight-based IV for individual patient at 10-20 mL/min Do not use a leukocyte-depleting filter Adjust infusion rate as appropriate for smaller children and smaller volumes

IV Preparation Confirm infusion time in advance, and adjust start time for thaw so that tisagenlecleucel is available for infusion when recipient is ready Ensure 2 doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period; premedicate patient; see Dosing Confirm patient identity prior to preparation, match the patient's identity with the patient identifiers on the tisagenlecleucel infusion bag; tisagenlecleucel is for autologous use only Inspect the infusion bag for any breaks or cracks before thawing; if bag is compromised, do not infuse the contents; contact Novartis at 1-844-4KYMRIAH Place infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination; thaw infusion bag 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 thawed, stored at room temperature (20-25°C) for up to 30 minutes Do not wash, spin down, and/or resuspend tisagenlecleucel in new media prior to infusion; inspect contents of the thawed infusion bag for any visible cell clump; 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 tisagenlecleucel if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised; IV Administration Premedication Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine ~30-60 minutes before tisagenlecleucel infusion Do not use corticosteroids at any time except in the case of a life-threatening emergency Tisagenlecleucel infusion Administer IV infusion at 10-20 mL/min, adjusted as appropriate for smaller children and smaller volume Infusion bag volume ranges from 10-50 mL Do not use a leukocyte-depleting filter; prime tubing prior to infusion with 0.9% NaCl Infuse all contents of the infusion bag; rinse infusion bag with 10-30 mL 0.9% NaCl while maintaining a closed tubing system to assure as many cells as possible are infused into the patient Follow local biosafety guidelines applicable for handling and disposal of such products

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment in a majority of patients (see Black Box Warnings and Adverse Effects) Neurological toxicities, which may be severe or life-threatening, can occur following treatment (see Black Box Warnings) Available only through a restricted access program (see Black Box Warnings) Allergic reactions may occur during infusion; serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) or dextran 40 in the product Serious infections, including life-threatening or fatal infections, reported; before administering, infection prophylaxis for neutropenia should follow local guidelines; monitor for signs and symptoms of infection after treatment and treat appropriately Viral reactivation can occur; hepatitis B virus (HBV) reactivation can result in fulminant hepatitis, hepatic failure, and death; perform screening for HBV, hepatitis C virus (HCV), and HIV in accordance with clinical guidelines before collection of cells for manufacturing. Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission (CR); monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines Secondary malignancies or recurrence of leukemia may occur; monitor patient life-long for secondary malignancies Owing to the potential for neurological events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following treatment; advise patients to refrain from driving and engaging in hazardous occupations or activities HIV and the lentivirus used to make tisagenlecleucel have limited, short spans of identical genetic material (RNA); therefore, some commercial HIV nucleic acid test (NAT) tests may yield false-positive results in patients who have received tisagenlecleucel.

Pregnancy No animal reproductive and developmental toxicity studies have been conducted Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia Pregnant women who have received tisagenlecleucel may have hypogammaglobulinemia; assess immunoglobulin levels in newborns of treated mothers Pregnancy status of females with reproductive potential should be verified; sexually active females of reproductive potential should have a pregnancy test prior to starting treatment Contraception: See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy; limited exposure data available concerning the duration of contraception following treatment with tisagenlecleucel Lactation Unknown if distributed in human breast milk Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Side effects of Tisagenlecleucel : >10% (Pediatric & Young Adults with ALL) Cytokine release syndrome (79%) Cytokine release syndrome, grades 3-4 (49%) Hypogammaglobulinemia (43%) Infection, unspecified pathogen (41%) Pyrexia (40%) Prolonged neutropenia, Day 28 (40%) Febrile neutropenia, grades 3-4 (37%) Decreased appetite (37%) Headache (37%) Encephalopathy (34%) Hypotension (31%) Increased AST, grades 3-4 (28%) Hypokalemia, grades 3-4 (27%) Prolonged thrombocytopenia, Day 28 (27%) Viral infection (26%) Tachycardia (26%) Nausea (26%) Diarrhea (26%) Vomiting (26%) Fatigue (25%) Hypoxia (24%) Acute kidney injury (24%) Hypotension, grades 3-4 (22%) Edema (21%) Cough (21%) Increased ALT, grades 3-4 (21%) Increased bilirubin, grades 3-4 (21%) Delirium (21%) Hypophosphatemia, grades 3-4 (19%) Hypertension (19%) Bacterial infection (19%) Constipation (18%) Viral infection, grades 3-4 (18%) Hypoxia, grades 3-4 (18%) Pain (18%) Prolonged neutropenia, Day 56 (17%) Infection, unspecified pathogen, grades 3-4 (16%) Hypofibrinogenemia with grades 3-4 CRS (16%) Abdominal pain (16%) Pain in extremity (16%) Pulmonary edema (16%) Rash (16%) Decreased appetite, grades 3-4 (15%) Pyrexia, grades 3-4 (15%) Myalgia (15%) Fungal infection (13%) Anxiety (13%) Bacterial infection, grades 3-4 (13%) Acute kidney injury, grades 3-4 (13%) Increased INR (13%) Dyspnea, grades 3-4 (12%) Prolonged thrombocytopenia, Day 56 (12%) Arthralgia (12%) Tachypnea (12%) >10% (Adults with DLBCL) Lymphopenia, grades 3-4 (97%) Neutropenia, grades 3-4 (81%) Leukopenia, grades 3-4 (77%) Cytokine release syndrome (74%) Anemia, grades 3-4 (58%) Thrombocytopenia, grades 3-4 (54%) Infection, unspecified pathogen (42%) Pyrexia (34%) Diarrhea (31%) Nausea (27%) Fatigue (26%) Hypotension (26%) Infection, unspecified pathogen grades 3-4 (25%) Hypophosphatemia (24%) Cytokine release syndrome, grades 3-4 (23%) Edema (23%) Headache (21%) Cough (19%) Dyspnea (18%) Febrile neutropenia, grades 3-4 (17%) Acute kidney injury (17%) Constipation (16%) Encephalopathy (16%) Pain (15%) Hypogammaglobulinemia (14%) Tachycardia (13%) Chills (13%) Decreased appetite (12%) Hypokalemia (12%) Hyponatremia (11%) Decreased weight (11%) Dizziness (11%) Encephalopathy, grades 3-4 (11%) 1-10% (Pediatric & Young Adults with ALL) Sleep disorders (10%) Face edema (10%) Peripheral edema, grades 3-4 (10%) Chills (10%) Fluid overload (10%) Back pain (10%) Pleural effusion (10%) Nasal congestion (10%) Pulmonary edema, grades 3-4 (10%) Encephalopathy, grades 3-4 (10%) Fungal infection, grades 3-4 (7%) Blood and lymphatic system disorders: DIC (9%) Histiocytosis lymphocytic hemophagocytosis (7%) Coagulopathy (6%) Blood creatinine increased (7%) aPTT prolonged (6%) Respiratory, thoracic, and mediastinal disorders: Respiratory distress (6%), respiratory failure (6%), acute RDS (4%) Cardiac disorders: Cardiac arrest (4%), cardiac failure (7%) Metabolism and nutrition disorders: Tumor lysis syndrome (6%) Vascular disorders: Capillary leak syndrome (3%) General disorders and administration site conditions: Multiple organ dysfunction syndrome (3%) Nervous System: Intracranial hemorrhage (1%), seizure (3%) Gastrointestinal disorders: Abdominal compartment syndrome (1%) Immune system disorders: GVHD (1%) 1-10% (Adults with DLBCL) Arthralgia (10%) Hypotension, grades 3-4 (8%) Fatigue, grades 3-4 (7%) Pyrexia, grades 3-4 (6%) Acute kidney injury, grades 3-4 (6%) Dyspnea, grades 3-4 (6%) Hypogammaglobulinemia, grades 3-4 (4%) Appetite decreased, grades 3-4 (4%) Tachycardia, grades 3-4 (3%) Pain, grades 3-4 (3%) Weight decreased, grades 3-4 (3%) Edema, grades 3-4 (2%) Diarrhea, grades 3-4 (1%) Nausea, grades 3-4 (1%) Constipation, grades 3-4 (1%) Dizziness, grades 3-4 (1%)

CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells CAR is composed of a murine single-chain antibody fragment that recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances expansion and persistence of tisagenlecleucel CAR transmits a signal to promote T-cell expansion owing to binding of CD19 expressed cells, activation, target cell elimination, and persistence of tisagenlecleucel cells