Axicabtagene Ciloleucel

B-Cell Lymphoma

B-Cell Lymphoma Indicated for adults with relapsed or refractory large B-cell lymphoma after ?2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, 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 axicabtagene ciloleucel Confirm availability of axicabtagene ciloleucel prior to starting lymphodepleting chemotherapy Lymphodepleting chemotherapy 3 doses of fludarabine and cyclophosphamide infused IV on the fifth, fourth, and third day before infusion of axicabtagene ciloleucel Fludarabine 30 mg/m² IV qDay for 3 days Cyclophosphamide 500 mg/m² IV qDay for 3 days starting with the first dose of fludarabine Premedication Premedicate with acetaminophen 650 mg PO and diphenhydramine 12.5 mg IV or PO ~1 hr before axicabtagene ciloleucel infusion Avoid prophylactic use of systemic corticosteroids at all times (may interfere with axicabtagene ciloleucel activity), except in the case of a life-threatening emergency Axicabtagene ciloleucel IV infusion Administer after completing lymphodepleting chemotherapy Dosing of axicabtagene is based on the number of chimeric antigen receptor (CAR)-positive viable T cells Target dose is 2 x 10^6 CAR-positive viable T cells/kg body weight, not to exceed 2 x 10^8 CAR-positive viable T cells Administer autologously prepared, weight-based IV infusion for individual patient within 30 minutes by either gravity or peristaltic pump Do not use a leukocyte-depleting filter

No clinically important differences in safety or effectiveness were observed between patients aged 65 years and older and younger patients.

IV Preparation Confirm infusion time in advance, and adjust start time for thaw so that axicabtagene is available for infusion when recipient is ready Confirm patient identity prior to preparation, and match the patient's identity with the patient identifiers on the axicabtagene infusion bag; axicabtagene 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 Kite at 1-844-454-KITE Place infusion bag inside a second, sterile bag as per local guidelines 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 Gently mix the contents of the bag to disperse clumps of cellular material; if visible cell clumps remain, continue to gently mix the contents of the bag Do not wash, spin down, and/or resuspend axicabtagene ciloleucel in new media prior to infusion Once thawed, stored at room temperature (20-25°C) for up to 3 hr IV Administration For autologous use only Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period Do not use a leukodepleting filter Central venous access is recommended for the infusion Prime tubing with 0.9% NaCl prior to infusion Infuse entire contents of the bag within 30 minutes by either gravity or a peristaltic pump Thawed infusion bag is stable at room temperature for up to 3 hr Gently agitate the product bag during infusion to prevent cell clumping After completing infusion, rinse tubing with 0.9% NaCl at the same infusion rate to ensure all product is delivered

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Axicabtagene Ciloleucel. Do not administer Axicabtagene Ciloleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Axicabtagene Ciloleucel, including concurrently with CRS or after CRS resolution. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including Axicabtagene Ciloleucel. Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion. Serious Infections: Monitor patients for signs and symptoms of infection; treat appropriately. Prolonged Cytopenias: Patients may exhibit Grade 3 or higher cytopenias for several weeks following Axicabtagene Ciloleucel infusion. Secondary Malignancies: T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including Axicabtagene Ciloleucel. In the event that a secondary malignancy occurs after treatment with Axicabtagene Ciloleucel. Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks. after receiving Axicabtagene Ciloleucel. Monitor for neurologic toxicities after treatment with Axicabtagene Ciloleucel. Provide supportive care and/or corticosteroids, as needed. Monitor complete blood counts. Monitor and provide replacement therapy of hypogammaglobulinemia.

Not Classi Pregnancy Data are not available in pregnant women 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 Therefore, axicabtagene ciloleucel is not recommended for women who are pregnant, and pregnancy after infusion should be discussed with the treating physician 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 axicabtagene ciloleucel 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

>10% Any Grade Cytokine release syndrome (94%) Fever (86%) Tachycardia (57%) Encephalopathy (57%) Hypotension (57%) Fatigue (46%) Headache (45%) Decreased appetite (44%) Chills (40%) Diarrhea (38%) Nausea (34%) Hypoxia (32%) Tremor (31%) Cough (30%) Vomiting (26%) Infections, pathogen unspecified (26%) Constipation (23%) Arrhythmia (23%) Dizziness (21%) Edema (19%) Motor dysfunction (19%) Dyspnea (19%) Aphasia (18%) Pain in extremity (17%) Delirium (17%) Weight decreased (16%) Hypogammaglobulinemia (15%) Back pain (15%) Hypertension (15%) Abdominal pain (14%) Muscle pain (14%) Pleural effusion (13%) Renal insufficiency (12%) Dry mouth (11%) Dehydration (11%) >10% Grades 3-4 Lymphopenia (100%) Leukopenia (96%) Neutropenia (93%) Anemia (66%) Thrombocytopenia (58%) Hypophosphatemia (50%) Encephalopathy (29%) Hyponatremia (19%) Fever (16%) Infections, pathogen unspecified (16%) Hypotension (15%) Cytokine release syndrome (13%) Hyperuricemia (13%) Direct bilirubin increased (13%) Hypoxia (11%) 1-10% Any Grade Arthralgia (10%) Thrombosis (10%) Pulmonary edema (9%) Rash (9%) Cardiac failure (6%) Ataxia (6%) Fungal infections (5%) Cardiac arrest (4%) Seizure (4%) Capillary leak syndrome (3%) Coagulopathy (2%) Dyscalculia (2%) Myoclonus (2%) Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%) Hypersensitivity (1%) 1-10% Grades 3-4 Hypokalemia (10%) Increased ALT (10%) Bacterial infections (9%) Arrhythmia (7%) Aphasia (6%) Delirium (6%) Hypertension (6%) Renal insufficiency, grades 3-4 (5%) Diarrhea, grades 3-4 (4%) Viral infections (3%) Fatigue (3%) Dehydration (3%) Dyspnea (3%) Tachycardia (2%) Decreased appetite (2%) Pain in extremity (2%) Tremor (2%) Pleural effusion (2%) Vomiting (1%) Abdominal pain (1%) Edema (1%) Motor dysfunction (1%) Back pain (1%) Muscle pain (1%) Headache (1%) Dizziness (1%) Thrombosis (1%)

CD19-directed genetically modified autologous T cell immunotherapy that involves reengineering a patient’s own T cells to express a chimeric antigen receptor (CAR) to identify and bind to CD19-expressing malignant and normal B cells Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta costimulatory domains activate downstream signaling cascades that lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines This cascade of events leads to killing of CD19-expressing cells