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    Chimeric Antigen Receptor (CAR) T-Cell Therapy

    BOXED WARNING

    Cytokine release syndrome, infection

    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. 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.

    Driving or operating machinery, encephalopathy, mental status changes, neurotoxicity, seizures

    Severe neurotoxicity (e.g., 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. 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 with continuous cardiac telemetry and pulse oximetry. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis in these patients. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities.

    DEA CLASS

    Rx

    DESCRIPTION

    CD19-directed chimeric antigen receptor (CAR) T-cell therapy
    Used in adult patients with relapsed or refractory large B-cell lymphoma or follicular lymphoma after 2 or more lines of systemic therapy
    Cytokine release syndrome and severe neurotoxicity have been reported

    HOW SUPPLIED

    YESCARTA Intravenous Inj Susp

    DOSAGE & INDICATIONS

    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. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion.[62530] The primary endpoint of investigator-assessed objective response rate was 82% 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 54%. At a median follow-up time of 15.4 months, the median time to response was 1 month (range, 0.8 to 6 months) and the median duration of response was 8.1 months. In 108 patients who received axicabtagene ciloleucel in phase 1 or 2 studies, the median progression-free survival time was 5.8 months and the median overall survival time had not been reached. 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.[63697]

    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. 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).

    MAXIMUM 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.

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    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.

    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.

    STORAGE

    Generic:
    - See package insert for detailed storage information

    CONTRAINDICATIONS / PRECAUTIONS

    Cytokine release syndrome, infection

    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. 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.

    Driving or operating machinery, encephalopathy, mental status changes, neurotoxicity, seizures

    Severe neurotoxicity (e.g., 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. 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 with continuous cardiac telemetry and pulse oximetry. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis in these patients. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities.

    Requires a specialized care setting, requires an experienced clinician

    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).

    Aminoglycoside hypersensitivity

    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

    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.

    Anemia, neutropenia, thrombocytopenia

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

    New primary malignancy

    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

    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.

    Hepatitis B exacerbation, immunosuppression, progressive multifocal leukoencephalopathy

    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 may occur with drugs directed against B cells, such as axicabtagene ciloleucel. Screen all patients for HBV, hepatitis C virus, and HIV prior to cell collection (leukapheresis).

    Fungal infection, viral infection

    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.

    Blood donation

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

    Laboratory test interference

    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

    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.

    Contraception requirements, pregnancy testing, reproductive risk

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 23.0-100.0
    leukopenia / Delayed / 92.0-96.0
    neutropenia / Delayed / 92.0-93.0
    cytokine release syndrome / Rapid / 88.0-88.0
    anemia / Delayed / 30.0-66.0
    thrombocytopenia / Delayed / 35.0-58.0
    hypophosphatemia / Delayed / 25.0-50.0
    encephalopathy / Delayed / 16.0-29.0
    neurotoxicity / Early / 26.0-26.0
    infection / Delayed / 19.0-19.0
    hyponatremia / Delayed / 10.0-19.0
    fever / Early / 8.0-16.0
    hypotension / Rapid / 4.0-15.0
    pleural effusion / Delayed / 0-13.0
    hyperuricemia / Delayed / 10.0-13.0
    elevated hepatic enzymes / Delayed / 13.0-13.0
    thrombosis / Delayed / 10.0-12.0
    hypoxia / Early / 8.0-11.0
    hypokalemia / Delayed / 0-10.0
    hyperbilirubinemia / Delayed / 10.0-10.0
    hyperglycemia / Delayed / 0-10.0
    pulmonary edema / Early / 0-9.0
    hypertension / Early / 6.0-6.0
    heart failure / Delayed / 2.0-6.0
    delirium / Early / 5.0-6.0
    coagulopathy / Delayed / 2.0-6.0
    aphasia / Delayed / 4.0-6.0
    nephrotoxicity / Delayed / 0-5.0
    visual impairment / Early / 0-5.0
    cardiac arrest / Early / 0-4.0
    diarrhea / Early / 1.0-4.0
    seizures / Delayed / 2.0-4.0
    dehydration / Delayed / 3.0-3.0
    dyspnea / Early / 1.0-3.0
    rash / Early / 0-3.0
    capillary leak syndrome / Early / 3.0-3.0
    fatigue / Early / 1.0-3.0
    sinus tachycardia / Rapid / 1.0-2.0
    anorexia / Delayed / 1.0-2.0
    tremor / Early / 1.0-2.0
    abdominal pain / Early / 0-1.0
    vomiting / Early / 1.0-1.0
    hypogammaglobulinemia / Delayed / 0-1.0
    peripheral edema / Delayed / 0-1.0
    edema / Delayed / 1.0-1.0
    myalgia / Early / 0-1.0
    back pain / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    macrophage activation syndrome / Delayed / 1.0-1.0
    headache / Early / 1.0-1.0
    dizziness / Early / 0-1.0
    stroke / Early / 0-1.0
    bradycardia / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    AV block / Early / Incidence not known
    atrial flutter / Early / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    thromboembolism / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    aphonia / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    myelitis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 23.0-28.0
    peripheral neuropathy / Delayed / 12.0-12.0
    hypocalcemia / Delayed / 0-10.0
    ataxia / Delayed / 6.0-10.0
    dysphagia / Delayed / 0-6.0
    paresis / Delayed / 0-2.0
    myoclonia / Delayed / 0-2.0
    antibody formation / Delayed / 0-1.0
    colitis / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    mania / Early / Incidence not known
    hallucinations / Early / Incidence not known
    erythema / Early / Incidence not known
    bullous rash / Early / Incidence not known
    bone pain / Delayed / Incidence not known
    dyskinesia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    loss of consciousness / Rapid / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    bleeding / Early / Incidence not known

    Mild

    nausea / Early / 34.0-40.0
    chills / Rapid / 29.0-40.0
    cough / Delayed / 25.0-30.0
    weight loss / Delayed / 16.0-16.0
    insomnia / Early / 9.0-16.0
    xerostomia / Early / 0-11.0
    nasal congestion / Early / 0-10.0
    arthralgia / Delayed / 0-10.0
    anxiety / Delayed / 0-9.0
    dyspepsia / Early / Incidence not known
    hyperactivity / Early / Incidence not known
    restlessness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    lethargy / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Intravenous Route

    In patients with large B-cell lymphoma, the median anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax level was 205% higher (43.6 vs. 21.2 cells/microliter (microL)) in 73 patients who achieved an objective response compared with 23 patients who were nonresponders in a nonrandomized trial. Additionally, the median anti-CD19 CAR T-cell AUC(0-28 days) value was 251% higher (557.1 vs. 222 days X cells/microL) in responders. 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.