YESCARTA

Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell gene therapy. It is CD19-directed immunotherapy that works by using a patient's own genetically altered immune cells to kill B-cell cancer cells in the blood. Axicabtagene ciloleucel is indicated for use after 2 or more lines of systemic therapy in adult patients with relapsed or refractory large B-cell lymphoma (LBL; e.g., 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) or lymphoma. Axicabtagene ciloleucel is also indicated in adults with LBL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. It is not indicated for the treatment of patients with primary central nervous system lymphoma. Cytokine release syndrome and severe neurotoxicity have been reported. Axicabtagene ciloleucel is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS. Information for this program enrollment is available at www.YescartaTecartusREMS.com or 1-844-454-5483.

General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Axicabtagene ciloleucel may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling axicabtagene ciloleucel; follow local biosafety guidelines applicable for disposal.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.

Route-Specific Administration

Injectable Administration
Visually inspect the contents of the infusion bag for any breaks or cracks before thawing. Do not infuse the contents if the bag is compromised; follow local guidelines or call Kite Pharma at 1-844-454-5483.
Intravenous Administration
-Axicabtagene ciloleucel is for autologous and intravenous use.
-Each dose of axicabtagene ciloleucel contains a maximum of 2 X 108 CAR-positive viable T-cells suspended in a single patient-specific infusion bag; the total infusion bag volume is approximately 68 mL.
-Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
-Coordinate the timing of the axicabtagene ciloleucel thaw and infusion; confirm the infusion time in advance, and adjust the start time for thaw so that the recipient will be ready.
-Premedicate patients with acetaminophen and diphenhydramine approximately 1 hour prior to the infusion; avoid corticosteroids use except in the case of a life-threatening emergency.
Preparation
-Match the patient's identity with the patient identifiers on the cassette; do not remove the product bag from the cassette if the patient-specific label does not match the intended recipient.
-Remove the product bag from the cassette; verify that the patient information on the cassette label matches the bag label.
-Put the infusion bag inside a second, sterile bag to protect against leaks and port contamination.
-Thaw the infusion bag at 37 degrees Celsius (C) using either a water bath or dry thaw method; once there is no visible ice in the infusion bag, gently mix the contents of the bag to allow the clumps of cellular material to disperse.
-If visible cell clumps remain, continue to gently mix the contents of the bag; small clumps of cellular material should disperse with gentle manual mixing.
-Do not wash, spin down, and/or re-suspend axicabtagene ciloleucel in new medium prior to infusion.
-Storage: After thawing, the product may be stored at room temperature (20 to 25 degrees C) for up to 3 hours.

Intravenous (IV) Infusion
-Confirm the patient's identity with the patient identifiers on the infusion bag.
-Prime the tubing with normal saline prior to the infusion; do not use a leukocyte-depleting filter.
-Administer as an IV infusion within 30 minutes via gravity or a peristaltic pump until the infusion bag is empty.
-Gently agitate the product bag during the infusion to prevent cell clumping.
-Rinse the tubing with normal saline at the same infusion rate to ensure all product contents are delivered.

Hypotension including orthostatic hypotension (47% to 57%; grade 3 or higher, 4% to 15%), tachycardia/sinus tachycardia (43% to 57%; grade 3 or higher, 1% to 2%), arrhythmia (14% to 23%; grade 3 or higher, 2% to 7%), hypertension (9% to 15%; grade 3 or higher, 6% or less), heart failure (1% to 6%), and cardiac arrest (4% or less) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term arrhythmia includes atrial fibrillation, atrial flutter, AV block, right bundle-branch block, bradycardia, QT prolongation on electrocardiogram (ECG), T-wave inversion on ECG, irregular heart rate, extrasystoles, ventricular tachycardia, supraventricular tachycardia (SVT), and ventricular arrhythmia.

Decreased appetite/anorexia (24% to 44%; grade 3 or higher, 2%), diarrhea including colitis and enteritis (29% to 42%; grade 3 or higher, 1% to 4%), nausea (34% to 40%; grade 3 or higher, 2% or less), vomiting (20% to 26%; grade 3 or higher, 1% or less), constipation (20% to 28%), abdominal pain including dyspepsia (14% to 20%; grade 3 or higher, 4% or less), and xerostomia (11% or less) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Hypogammaglobulinemia (14%; grade 3 or higher, 1% or less) and infection (45%; grade 3 or higher, 17%) including grade 3 or higher pathogen unspecified infection (12%), bacterial infection (5%), viral infection (3%), and fungal infection (1%) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel (n = 422) in clinical trials. Other infectious events that were reported with axicabtagene ciloleucel in clinical studies include pneumonia (13% or less) and sepsis (4% or less). Hepatitis B exacerbation/reactivation has also occurred. Monitor patients for signs and symptoms of infection prior to and after the axicabtagene ciloleucel infusion; administer prophylactic antimicrobial therapy and other anti-infective therapy as medically indicated. Additionally, monitor immunoglobulin levels after axicabtagene ciloleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. Disseminated fungal infections (e.g., candida sepsis and aspergillus) and viral reactivation (e.g., human herpes virus-6 (HHV-6) encephalitis and JC virus-related progressive multifocal leukoencephalopathy (PML)) have been reported in patients with immunosuppression. Consider a diagnosis or HHV-6 or PML in immunosuppressed patients with neurologic events; perform a diagnostic evaluation. The term hypogammaglobulinemia includes decreased immunoglobulin D and G levels.

Weight loss was reported in 16% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108).

Dehydration was reported in 11% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108); grade 3 or higher dehydration occurred in 3% of patients.

Delirium (15%; grade 3 or higher, 4% to 6%) and insomnia (10%) were reported in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received axicabtagene ciloleucel (n = 422) in clinical trials. Anxiety was reported in 9% of patients with relapsed or refractory aggressive B-cell NHL who received axicabtagene ciloleucel in a nonrandomized trial (n = 108). Affective disorder occurred in 10% (grade 3 or higher, 1%) of patients with follicular lymphoma who received axicabtagene ciloleucel in another nonrandomized trial (n = 146). The term delirium includes agitation, delusion, disorientation, hallucinations, hyperactivity, irritability, and restlessness. The term affective disorder includes anxiety, depression, impulsive behavior, mania, and panic attack.

Edema was reported in 13% to 23% (grade 3 or higher, 1%) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term edema includes face edema, generalized edema, fluid overload, hypervolemia, local swelling, localized edema, genital edema, peripheral edema, periorbital edema, peripheral swelling, pulmonary edema, and scrotal edema.

Hypoxia including decreased oxygen saturation (21% to 32%; grade 3 or higher, 8% to 11%), cough including upper-airway cough syndrome (25% to 30%; grade 3 or higher, 1% or less), dyspnea (8% to 19%; grade 3 or higher, 3% or less), pleural effusion (13% or less; grade 3 or higher, 2% or less), pulmonary edema (9% or less), nasal congestion (10% or less), and respiratory failure (2% or less) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term dyspnea includes acute respiratory failure, exertional dyspnea, orthopnea, and respiratory distress/respiratory arrest.

Nephrotoxicity, specifically renal insufficiency, was reported in 8% to 12% (grade 3 or higher, 5% or less) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Thrombosis was reported in 7% to 12% (grade 3 or higher, 4% or less) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term thrombosis included deep vein thrombosis, venous thromboembolism, peripheral ischemia, pulmonary embolism, splenic infarction, splenic vein thrombosis, subclavian vein thrombosis, thrombosis in device, and vascular occlusion.

Coagulopathy was reported in 2% to 9% of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Rash was reported in 9% to 19% (grade 3 or higher, 3% or less) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term rash included bullous rash/dermatitis, erythema, pruritus, maculopapular rash, Stevens-Johnson syndrome, and urticaria.

Capillary leak syndrome was reported in 3% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108).

Fatigue was reported in 46% to 52% (grade 3 or higher, 1% to 7%) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. The term fatigue included asthenia, decreased activity, and malaise.

Motor dysfunction occurred in 15% to 19% (grade 3 or higher, 1% to 4%) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials. Other musculoskeletal events that were reported with axicabtagene ciloleucel in clinical studies include musculoskeletal pain (40% or less; grade 3 or higher, 1% or less), extremity pain (17% or less; grade 3 or higher, 2% or less), back pain (15% or less; grade 3 or higher, 1% or less), muscle pain/myalgia (14% or less; grade 3 or higher, 1% or less), arthralgia (10% or less), and muscle injury (1% or less). The term motor dysfunction included involuntary muscle contractions, muscle cramps, spasms, rigidity, strain, twitching, and weakness. The term musculoskeletal pain included arthritis, arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, and extremity pain.

Fever (85% to 93%; grade 3 or higher, 8% to 16%) and chills (28% to 40%; grade 3 or higher, 1% or less) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Grade 3 or higher cytopenias not resolved by day 30 were reported in 39% of patients with relapsed or refractory non-Hodgkin lymphoma following lymphodepleting chemotherapy and axicabtagene ciloleucel (n = 422) in clinical trials; prolonged cytopenias included thrombocytopenia (13%), neutropenia (33%), and anemia (8%). Monitor complete blood counts regularly until hematologic recovery. Grade 3 or 4 cytopenias that developed after axicabtagene ciloleucel therapy included decreased leukocyte count/leukopenia (94% to 96%), decreased neutrophil count/neutropenia (92% to 94%), decreased lymphocyte count/lymphopenia (94% to 96%), decreased hemoglobin level/anemia (32% to 60%), and decreased platelet count/thrombocytopenia (26% to 56%). Additionally, febrile neutropenia was reported following axicabtagene ciloleucel therapy in 36% of patients; it sometimes occurred concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated.

Grade 3 or 4 decreased phosphate level/hypophosphatemia (52% or less), decreased sodium level/hyponatremia (10% to 19%), decreased calcium level/hypocalcemia (10% or less), and decreased potassium level/hypokalemia (11% or less) were reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Grade 3 or 4 hyperuricemia was reported in 13% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108). Additionally, grade 3 or 4 hyperuricemia occurred in 10% of patients with follicular lymphoma who received axicabtagene ciloleucel in another nonrandomized trial (n = 146).

Grade 3 or 4 increased direct bilirubin level/hyperbilirubinemia was reported in 14% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108).

Antibody formation to FMC63, the originating antibody of the anti-CD19 chimeric antigen receptor, was detected at baseline (pre-dose) in 4% of patients with relapsed or refractory large B-cell lymphoma (LBL) in 2 clinical trials. Following the axicabtagene ciloleucel dose, antibody formation was present in 1% of LBL patients who had negative test results at baseline. In another trial in patients with relapsed or refractory follicular lymphoma, antibody formation to FMC63 was present at baseline (pre-dose) in 13% of patients and post-dose in 2% of patients who had negative test results at baseline. A confirmatory cell-based assay demonstrated that all patients who had a positive result using enzyme-linked immunosorbent assay (ELISA) at screening were antibody negative at all time points tested. There is no evidence that the presence of antibodies has an impact on axicabtagene ciloleucel efficacy or its safety profile.

Hypersensitivity reactions including anaphylactoid reactions were reported in 1% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108). Premedicate patients with acetaminophen and diphenhydramine prior to the axicabtagene ciloleucel infusion.

Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) and hypersensitivity was reported in 1% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108).

Cytokine release syndrome (CRS) was reported in 90% (grade 3 or higher, 9%) of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel (n = 422) in clinical trials. Ongoing CRS at the time of death was reported in 5 patients (large B-cell lymphoma, n = 4/276; follicular lymphoma, n = 1/146) who died after receiving axicabtagene ciloleucel. Symptoms of CRS may include fever (85%), hypotension (40%), tachycardia (32%), hypoxia (20%), chills (22%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, heart failure, renal insufficiency, capillary leak syndrome, multiorgan failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Multiple organ dysfunction syndrome occurred in 1% of patients with follicular lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 146). Observe patients closely for signs or symptoms of CRS at least daily for 7 days in a certified healthcare facility following the infusion, and continue monitoring for at least 4 weeks after the infusion. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Patients with mild symptoms (e.g., fever, nausea, fatigue, headache, myalgia, and malaise) may require symptomatic treatment only. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS. The use of prophylactic corticosteroids (dexamethasone 10 mg PO once daily for 3 days starting prior to axicabtagene ciloleucel infusion) resulted in delayed onset and decreased duration of CRS in a cohort of 39 patients with large B-cell lymphoma from a clinical trial. However, patients in this cohort had more severe and longer lasting neurologic toxicities. Therefore, consider the use of prophylactic corticosteroids only after a risk versus benefit assessment taking into account individual patient comorbidities.

Neurotoxicity (78%; grade 3 or higher, 25%) including encephalopathy (50%; grade 3 or higher, 16% to 29%), headache (43%; grade 3 or higher, 1% to 3%), tremor (29%; grade 3 or higher, 1% to 2%), dizziness including syncope and vertigo (21%; grade 3 or higher, 4% or less), and aphasia (17%; grade 3 or higher, 4% to 7%) was reported in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel (n = 422) in clinical trials. Most toxicities occurred within the first 8 weeks after therapy. Fatal and serious cases of cerebral edema and encephalopathy have occurred including prolonged encephalopathy lasting up to 173 days. Neurologic toxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Monitor patients closely for signs or symptoms of neurotoxicity at least daily for 7 days in a certified healthcare facility following the infusion, and continue monitoring for at least 4 weeks after the infusion; administer supportive care and/or corticosteroids as indicated. Monitor patients with grade 2 or higher neurotoxicity with continuous cardiac telemetry and pulse oximetry. Consider starting levetiracetam for seizure prophylaxis in patients who experience any grade neurotoxicity. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities. Other neurotoxicity that was reported with axicabtagene ciloleucel in clinical studies include peripheral neuropathy (12% or less; grade 3 or higher, 2% or less), ataxia (10% or less), seizures (4% or less), dyscalculia (2% or less), myoclonia (2% or less), Hemiparesis/paresis (2% or less), facial paralysis (2% or less), and ischemic stroke (1% or less). The term peripheral neuropathy included allodynia, cervical radiculopathy, hyperesthesia, hypoesthesia, neuralgia, peroneal nerve palsy, sciatica, and paresthesias. The term encephalopathy included agraphia, amnesia, aphonia, apraxia, bradyphrenia, CAR T-cell-related encephalopathy syndrome, cognitive disorder, confusion, depressed level or loss of consciousness, disturbance in attention, hypersomnia, immune effector cell-associated neurotoxicity, leukoencephalopathy, dysarthria, dysgraphia, dyskinesia, lethargy, memory impairment, mental status changes, paranoia, somnolence/drowsiness, speech disorder, and stupor. Spinal cord edema, myelitis, quadriplegia, dysphagia, and status epilepticus were reported in postmarketing surveillance of axicabtagene ciloleucel. The use of prophylactic corticosteroids (dexamethasone 10 mg PO once daily for 3 days starting prior to axicabtagene ciloleucel infusion) resulted in more severe and longer lasting neurologic toxicities in a cohort of 39 patients with large B-cell lymphoma from a clinical trial. Therefore, consider the use of prophylactic corticosteroids only after a risk versus benefit assessment taking into account individual patient comorbidities.

Grade 3 or 4 hyperglycemia occurred in 11% or less of patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Bleeding occurred in 8% of patients with follicular lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 146).

Visual impairment (5% to 7%) and blindness (1% or less) occurred in patients with relapsed or refractory non-Hodgkin lymphoma who received axicabtagene ciloleucel in clinical trials.

Grade 3 or 4 decreased albumin level/hypoalbuminemia was reported in 19% of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel in a nonrandomized trial (n = 108).

Cytokine release syndrome (CRS) has been reported with axicabtagene ciloleucel; some cases were fatal or life-threatening. Do not administer axicabtagene ciloleucel in patients with active infection or inflammatory disorders. The use of prophylactic corticosteroids may delay the onset and decrease the duration of CRS; however, more severe neurologic toxicities or prolongation of neurologic toxicities may occur. Therefore, consider the use of prophylactic corticosteroids only after a risk versus benefit assessment taking into account individual patient comorbidities. Confirm that 2 tocilizumab doses are available at the facility site prior to the axicabtagene ciloleucel infusion. Observe patients closely for signs or symptoms of CRS at least daily for 7 days in a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Patients with mild symptoms (e.g., fever, nausea, fatigue, headache, myalgia, and malaise) may require symptomatic treatment only. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS.

Severe neurotoxicity (e.g., immune effector cell-associated neurotoxicity syndrome (ICANS), encephalopathy, seizures, and cerebral edema) has been reported with axicabtagene ciloleucel therapy; some cases were fatal or life-threatening. Neurologic toxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Most cases of neurotoxicity occurred within 8 weeks of the axicabtagene ciloleucel infusion. Advise patients to avoid driving or operating machinery or performing other dangerous duties for 8 weeks after the axicabtagene ciloleucel infusion due to the risk of neurologic events (e.g., mental status changes, seizures) and altered or decreased consciousness or coordination. Severe neurologic toxicities or prolongation of neurologic toxicities may occur with the use of prophylactic corticosteroids; therefore, consider the use of prophylactic corticosteroids only after a risk versus benefit assessment taking into account individual patient comorbidities. Observe patients closely for signs or symptoms of neurotoxicity at least daily for 7 days in a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Exclude other causes of neurologic symptoms. Administer supportive care and/or corticosteroids as indicated. Monitor patients with grade 2 or higher neurotoxicity/ICANS with continuous cardiac telemetry and pulse oximetry. Consider starting levetiracetam for seizure prophylaxis in patients who experience any grade neurotoxicity. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities.

Because of the risk of cytokine release syndrome and neurological toxicities, use requires an experienced clinician with training in the management of these toxicities. Axicabtagene ciloleucel administration also requires a specialized care setting that is enrolled in the YESCARTA and TECARTUS REMS program and can comply with all program requirements (e.g., 2 doses of tocilizumab are available for each patient within 2 hours of the axicabtagene ciloleucel infusion).

Allergic reactions including anaphylaxis may occur with axicabtagene ciloleucel therapy. Premedicate patients with acetaminophen and diphenhydramine prior to the axicabtagene ciloleucel infusion. Reactions may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in the product. Use axicabtagene ciloleucel with caution in patients with a history of DMSO or aminoglycoside hypersensitivity.

Vaccination with live viral vaccines during or following treatment with axicabtagene ciloleucel has not been studied. Live virus vaccination is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel therapy, and until immune recovery after axicabtagene ciloleucel therapy.

Prolonged cytopenias (e.g., anemia, neutropenia, and thrombocytopenia) have been reported following axicabtagene ciloleucel therapy. Monitor complete blood counts regularly until hematologic recovery.

There is a risk of a new primary malignancy with axicabtagene ciloleucel therapy. Life-long monitoring for the development of new primary malignancies is recommended. Report cases of new primary malignancy to Kite at 1-844-454-5483; instructions will be provided regarding patient sample collection for testing.

Hypogammaglobulinemia and B-cell aplasia may occur with axicabtagene ciloleucel therapy. Monitor immunoglobulin levels after axicabtagene ciloleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines.

Viral reactivation including human herpes virus-6 (HHV-6) encephalitis and JC virus-related progressive multifocal leukoencephalopathy (PML) have been reported in patients with immunosuppression who received axicabtagene ciloleucel. Consider a diagnosis or HHV-6 or PML in immunosuppressed patients with neurologic events and perform a diagnostic evaluation. Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death has occurred with drugs directed against B cells, including axicabtagene ciloleucel. Screen all patients for HBV, hepatitis C virus, and HIV and manage per applicable clinical guidelines prior to cell collection (leukapheresis).

Serious infections including bacterial infection, fungal infection, viral infection, and opportunistic infections have been reported with axicabtagene ciloleucel therapy; some cases were life-threatening or fatal. Monitor patients for signs and symptoms of infection prior to and after the axicabtagene ciloleucel infusion; administer prophylactic antimicrobial therapy and other anti-infective therapy as medically indicated. Febrile neutropenia has also been reported following axicabtagene ciloleucel therapy; it may occur concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated.

Patients who receive axicabtagene ciloleucel should avoid cell, organ, tissue, and blood donation.

False-positive HIV test results have been reported in patients who received treatment with chimeric antigen receptor (CAR) T-cell immunotherapy, such as axicabtagene ciloleucel. The use of gammaretroviral or lentiviral vectors to reprogram T-cells as part of CAR T-cell therapy has resulted in laboratory test interference with HIV-1 nucleic acid amplification testing (NAAT). False test results may occur due to vector interference with long terminal repeat (LTR) genomes in HIV NAAT. Alternative testing methods for HIV (e.g., assays that target p24 antigen and anti-HIV-1 antibodies or the integrase gene) should be performed in patients who have received CAR T-cell therapy.

Pregnancy should be avoided by females of reproductive potential during axicabtagene ciloleucel treatment; pregnancy after axicabtagene ciloleucel administration should be discussed with the treating physician. There are no available data with axicabtagene ciloleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if axicabtagene ciloleucel has the potential to be transferred to the fetus. However, based on its mechanism of action, fetal toxicity including B-cell lymphocytopenia may occur if the transduced cells cross the placenta.

Counsel patients about the reproductive risk and contraception requirements during axicabtagene ciloleucel treatment. Sexually active females of reproductive potential should undergo pregnancy testing prior to axicabtagene ciloleucel therapy. See prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive lymphodepleting chemotherapy. There are insufficient data to recommend a duration of contraception following treatment with axicabtagene ciloleucel. There are no data on the effect of axicabtagene ciloleucel on fertility.

It is not known if axicabtagene ciloleucel is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for axicabtagene ciloleucel and any potential adverse effects on the breast-fed infant from axicabtagene ciloleucel or from the underlying maternal condition.

For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: Axicabtagene ciloleucel has been designated an orphan drug by the FDA for the treatment of NHL including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma.
-for the treatment of relapsed or refractory large B-cell lymphoma (e.g., 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) following 2 or more lines of systemic therapy:
Intravenous dosage:
Adults: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 12.5 mg IV or PO approximately 1 hour prior to the axicabtagene ciloleucel infusion; consider prophylactic corticosteroid use following a risk versus benefit assessment. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The primary endpoint of investigator-assessed objective response rate was 83% in 101 evaluable patients with relapsed or refractory DLBCL (n = 77), primary mediastinal large B-cell lymphoma (n = 8), or transformed follicular lymphoma (n = 16) who received a single infusion of axicabtagene ciloleucel in a multicenter, phase 2 trial (the ZUMA-1 trial). The complete response rate was 58% and the median duration of response was 11.1 months. At a median follow-up time of 63.1 (range, 58.9 to 68.4) months, the median progression-free survival (PFS) and overall survival (OS) times were 5.9 months and 25.8 months, respectively. The estimated 5-year PFS and OS rates were 31.8% and 42.6%, respectively. Following leukapheresis and T-cell collection, all patients had lymphocyte depletion with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (500 mg/m2 IV daily for 3 doses); each was given on the fifth, fourth, and third day prior to the axicabtagene ciloleucel infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. In this study, 85% of patients had stage III or IV disease, 77% of patients had disease resistant to second-line or later therapies, and 69% of patients had received at least 3 prior therapies.
-for the treatment of relapsed or refractory large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy:
Intravenous dosage:
Adults: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 12.5 mg IV or PO approximately 1 hour prior to the axicabtagene ciloleucel infusion; consider prophylactic corticosteroid use following a risk versus benefit assessment. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The median event-free survival (primary endpoint; 8.3 months vs. 2 months; hazard ratio (HR) = 0.4; 95% CI, 0.31 to 0.51; p less than 0.001) and progression-free survival (14.7 months vs. 3.7 months; HR = 0.49; 95% CI, 0.37 to 0.65) times were significantly improved in transplant-eligible patients with relapsed or refractory LBCL who received second-line therapy with axicabtagene ciloleucel compared with 2 or 3 cycles of investigator-selected standard care in a randomized, phase 3 (ZUMA-7) trial (n = 359; median follow-up time, 24.9 months). At a median follow-up of 47.2 (range, 39.8 to 60) months, the median overall survival time was not reached in the axicabtagene ciloleucel arm and 31.1 months in the standard care arm (HR = 0.73; 95% CI, 0.54 to 0.98). Of note, 102 patients (57%) who had disease progression or lack of response in the standard care group received subsequent cellular immunotherapy outside the protocol; 79 out of 102 of these patients (77.5%) received subsequent axicabtagene ciloleucel. Following leukapheresis and T-cell collection, patient who received axicabtagene ciloleucel had lymphocyte depletion with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (500 mg/m2 IV daily for 3 doses); each was given on the fifth, fourth, and third day prior to the axicabtagene ciloleucel infusion. Optional bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was limited to glucocorticoids only. In this trial, patients (median age, 59 years; range, 21 to 81 years) had LBCL that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy (including an anti-CD20 monoclonal antibody and anthracycline-containing regimen). Investigator-selected standard care consisted of protocol-defined, platinum-based, chemoimmunotherapy.
-for the treatment of relapsed or refractory follicular lymphoma following 2 or more lines of systemic therapy:
Intravenous dosage:
Adults: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 12.5 mg IV or PO approximately 1 hour prior to the axicabtagene ciloleucel infusion; consider prophylactic corticosteroid use following a risk versus benefit assessment. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The primary endpoint of investigator-assessed objective response rate was 91% in 81 patients with relapsed or refractory follicular lymphoma who received a single infusion of axicabtagene ciloleucel in a multicenter, phase 2 trial (the ZUMA-5 trial). The complete response rate was 60%. At a median follow-up time of 14.5 months, the median time to response was 1 month (range, 0.8 to 3.1 months) and the median duration of response was not estimable (range, 0 to more than 25 months). Following leukapheresis and T-cell collection, all patients had lymphocyte depletion with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (500 mg/m2 IV daily for 3 doses); each was given on the fifth, fourth, and third day prior to the axicabtagene ciloleucel infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was given in 1 patient. In this study, patients (median age, 62 years; range, 34 to 79 years) had received a median of 3 prior therapies (range, 2 to 9 therapies).

Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity

Cytokine Release Syndrome (CRS) (without concurrent neurologic toxicity)
NOTE: For grade 2 or higher toxicity, administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg); repeat tocilizumab 8 mg/kg IV every 8 hours as needed in patients show no clinical improvement in CRS signs and symptoms. Discontinue tocilizumab in patients who are improving. Do not exceed 3 doses in a 24-hour period or a maximum of 4 doses total.
Grade 1 toxicity (only requiring symptomatic treatment symptoms including fever, nausea, fatigue, headache, myalgia, and malaise): If there is no improvement within 24 hours considering starting tocilizumab. Administer dexamethasone 10 mg IV once if there is no improvement after 3 days.
Grade 2 toxicity (i.e., symptoms require and respond to moderate intervention, oxygen requirement less than 40% FiO2, hypotension responsive to fluids or a low-dose of 1 vasopressor agent, or grade 2 organ toxicity): Start dexamethasone 10 mg IV once daily. If the toxicity is improving, manage like grade 1 CRS toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; quickly taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 3 or 4 CRS toxicity.
Grade 3 toxicity (i.e., symptoms require and respond to aggressive intervention, oxygen requirement of 40% FiO2 or greater, hypotension requiring high-dose or multiple vasopressor agents, grade 3 organ toxicity, or grade 4 transaminitis): Administer dexamethasone 10 mg IV three times daily. If the toxicity is improving, manage like grade 1 or 2 CRS toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; quickly taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 4 CRS toxicity.
Grade 4 toxicity (i.e., life-threatening symptoms, requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or grade 4 organ toxicity (excluding transaminitis): Administer methylprednisolone 1,000 mg IV once daily for 3 days. If the toxicity is improving, manage like grade 1 to 3 CRS toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; taper corticosteroids as clinically appropriate. If the toxicity is not improving, consider increasing the methylprednisolone dosage to 1,000 mg IV twice or three times daily or alternate therapy such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, immunoglobulin (IVIG), and antithymocyte globulin (ATG) therapy.

Neurologic Toxicity/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) without Concurrent CRS
NOTE: Consider seizure prophylaxis with levetiracetam 750 mg IV/PO twice daily in patients who develop any grade neurotoxicity.
Grade 1 toxicity: Administer dexamethasone 10 mg IV once. If there is no improvement after 2 days, give repeat dexamethasone 10 mg IV once.
Grade 2 toxicity: Administer dexamethasone 10 mg IV four times daily. If the toxicity is improving, continue corticosteroids until the toxicity resolves to grade 1 or less; quickly taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 3 or 4 toxicity.
Grade 3 toxicity: Administer methylprednisolone 1,000 mg IV once daily. If the toxicity is improving, manage like grade 1 or 2 toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 4 toxicity.
Grade 4 toxicity: Administer methylprednisolone 1,000 mg IV twice daily. If the toxicity is improving, manage like grade 1 to 3 toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; taper corticosteroids as clinically appropriate. If the toxicity is not improving, consider increasing the methylprednisolone dosage to 1,000 mg IV three times daily or alternate therapy such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, and ATG therapy.

Neurologic Toxicity/ICANS with Concurrent CRS
NOTE: Consider seizure prophylaxis with levetiracetam 750 mg IV/PO twice daily in patients who develop any grade neurotoxicity. For grade 2 or higher CRS, administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg); repeat tocilizumab 8 mg/kg IV every 8 hours in patients show no clinical improvement in CRS signs and symptoms. Discontinue tocilizumab in patients who are improving. Do not exceed 3 doses in a 24-hour period or a maximum of 4 doses total.
Grade 1 toxicity: If there is no improvement within 24 hours considering starting tocilizumab. Administer dexamethasone 10 mg IV once. If there is no improvement after 2 day, give repeat dexamethasone 10 mg IV once.
Grade 2 toxicity: Administer dexamethasone 10 mg IV four times daily. If the toxicity is improving, continue corticosteroids until the toxicity resolves to grade 1 or less; quickly taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 3 or 4 toxicity.
Grade 3 toxicity: Administer methylprednisolone 1,000 mg IV once daily. If the toxicity is improving, manage like grade 1 or 2 toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; taper corticosteroids as clinically appropriate. If the toxicity is not improving, manage like grade 4 toxicity.
Grade 4 toxicity: Administer methylprednisolone 1,000 mg IV twice daily. If the toxicity is improving, manage like grade 1 to 3 toxicity and continue corticosteroids until the toxicity resolves to grade 1 or less; taper corticosteroids as clinically appropriate. If the toxicity is not improving, consider increasing the methylprednisolone dosage to 1,000 mg IV three times daily or alternate therapy such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, and ATG therapy.

Maximum Dosage Limits:
-Adults
2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose.
-Geriatric
2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose.
-Adolescents
Safety and Efficacy not established.
-Children
Safety and Efficacy not established.
-Infants
Safety and Efficacy not established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.

Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel therapy, and prior to immune recovery following treatment with axicabtagene ciloleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.

SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell therapy that works by redirecting T-cells to target the CD19 antigen on B-cells in patients with hematologic malignancies. The domains, CD28 and CD3-zeta, activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. The binding of CAR to CD19 activates axicabtagene ciloleucel and promotes cell expansion and differentiation and triggers the lysis of CD19-positive cells.
This immunotherapy involves removing, genetically modifying, and then re-infusing a patient's own T-cells. During the manufacturing process, the cells are genetically modified using retroviral transduction to express a CAR comprised of a murine anti-CD19 single chain variable fragment linked to CD28 and CD3-zeta co-stimulatory domains.
To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis; enriched; activated with anti-CD3 antibody in the presence of IL-2; transduced with the replication incompetent retroviral vector containing the anti-CD19 CAR transgene; expanded to large numbers in a cell culture; and then washed, formulated into a suspension, and cryopreserved.

Axicabtagene ciloleucel is administered intravenously. The number of anti-CD19 chimeric antigen receptor (CAR) T-cells in blood correlated with objective response in evaluable patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma who received axicabtagene ciloleucel (n = 96) in a nonrandomized trial. The time to peak anti-CD19 CAR T-cell levels occurred within 7 to 14 days following the axicabtagene ciloleucel infusion.
Pharmacodynamics: Peak levels of cytokines and chemokines (e.g., IL-6, IL-8, IL-10, IL-15, TNF-alpha, IFN-gamma, and sIL2R-alpha) were observed within 14 days of the axicabtagene ciloleucel infusion; these levels typically returned to baseline within 28 days.


-Route-Specific Pharmacokinetics
Intravenous Route
In patients with large B-cell lymphoma (LBL), the median anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax and AUC(0-28 days) values were 205% (43.6 vs. 21.2 cells/microliter (microL)) and 251% (557.1 vs. 222 days X cells/microL) higher, respectively, in 73 patients who achieved an objective response compared (responders) with 23 patients who were nonresponders in a nonrandomized trial. Additionally, patients with LBL had median anti-CD19 CAR T cell Cmax and AUC(0-28 days) values that were 275% (28.9 vs. 10.5 cells/microL) and 418% (292.9 vs. 70.1 days X cells/microL) higher, respectively, in 142 responders compared with 20 nonresponders in another clinical trial. In patients with follicular lymphoma, the median anti-CD19 CAR T-cell Cmax level was 40.1 cells/microL in 74 patients who achieved an objective response and 46 cells/microL in 7 patients who were nonresponders in a nonrandomized trial; the median anti-CD19 CAR T-cell AUC(0-28 days) values were 465.8 and 404.5 days X cells/microL, respectively.


-Special Populations
Geriatric
Age (range, 21 to 80 years) had no significant impact on axicabtagene ciloleucel AUC(0-28 days) or Cmax values.

Gender Differences
Gender had no significant impact on axicabtagene ciloleucel AUC(0-28 days) or Cmax values.

Other
Immunosuppressive therapy
The anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax and AUC(0-28 days) values were 232% and 262% higher, respectively, in patients who received tocilizumab to treat cytokine release syndrome or neurologic toxicity (n = 44) compared with patients who did not receive tocilizumab (n = 57) in a nonrandomized trial. Additionally, the anti-CD19 CAR T-cell Cmax and AUC(0-28 days) values were 155% and 217% higher, respectively, in patients who received corticosteroids (n = 26) compared with patients who did not receive corticosteroids (n = 75).