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  • CLASSES

    Chimeric Antigen Receptor (CAR) T-Cell Therapy

    BOXED WARNING

    Cytokine release syndrome, infection

    Cytokine release syndrome (CRS) has been reported with tisagenlecleucel; some cases were fatal or life-threatening. Do not administer tisagenlecleucel in patients with active infection or inflammatory disorders. Delay the tisagenlecleucel infusion in patients who have unresolved serious adverse reactions from preceding chemotherapy (e.g., pulmonary or cardiac reactions or hypotension), active graft-versus-host disease (GVHD), or worsening leukemia burden following lymphocyte depleting chemotherapy. Confirm that 2 doses of tocilizumab are available at the facility site prior to the tisagenlecleucel infusion. Monitor patients for signs and symptoms of CRS 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility, then monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. CRS may be associated with hepatic, renal, and cardiac dysfunction and coagulopathy. Management of CRS may include hospitalization, supportive care (e.g., oxygen, fluids, high-dose vasopressors), medical management (e.g., tocilizumab and corticosteroids), and mechanical ventilation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Administer tocilizumab in patients who develop severe or life-threatening CRS. Patients with B-cell acute lymphoblastic leukemia and a high tumor burden (i.e., greater than 50% blasts in the bone marrow), an active uncontrolled infection, or active GVHD may be at increased risk of developing severe CRS.

    Driving or operating machinery, encephalopathy, neurotoxicity, seizures

    Severe and life-threatening neurotoxicity (e.g., encephalopathy, seizures) has been reported with tisagenlecleucel therapy; most cases occurred within 8 weeks of the tisagenlecleucel infusion. Neurologic events may occur with cytokine release syndrome. Monitor patients for signs and symptoms of neurotoxicity including 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility; administer supportive care as indicated. Advise patients to avoid driving or operating machinery or performing other dangerous duties for 8 weeks after the tisagenlecleucel infusion due to the risk of neurological toxicity.

    DEA CLASS

    Rx

    DESCRIPTION

    CD19-directed chimeric antigen receptor (CAR) T-cell therapy
    Used in patients aged up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia and in adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy
    Cytokine release syndrome and severe neurotoxicity have been reported

    COMMON BRAND NAMES

    KYMRIAH

    HOW SUPPLIED

    KYMRIAH/Tisagenlecleucel Intravenous Inj Susp

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    NOTE: Tisagenlecleucel has been designated as an orphan drug by the FDA for the treatment of ALL.
    For the treatment of B-cell precursor ALL that is refractory or in second or later relapse.
    Intravenous dosage
    Adults 25 years and younger, Adolescents, Children, Infants, and Neonates

    For patients weighing greater than 50 kg, infuse a single dose of 0.1 to 2.5 X 108 CAR-positive viable T-cells (non-weight based). For patients weighing 50 kg or less, infuse a single dose of 0.2 to 5 X 106 CAR-positive viable T-cells per kg of body weight. Administer tisagenlecleucel at 2 to 14 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (30 mg/m2 IV daily for 4 days) plus cyclophosphamide (500 mg/m2 IV daily for 2 doses starting with the first fludarabine dose). The 3-month complete remission (CR) rate (CR + CR with incomplete hematologic recovery (CRi) rate) was 83% in 63 evaluable patients with relapsed or refractory B-cell ALL who received a single infusion of tisagenlecleucel in a nonrandomized, phase II trial (the B2202 trial). The CR rate was 63%; the CRi rate was 19%. At a median follow-up time of 4.8 months from response, the median time to CR/CRi onset was 29 days and the median duration of CR/CRi was not reached (range, 1.2 to greater than 14.1 months). Additionally, 12% of patients who achieved a CR/CRi underwent a subsequent stem-cell transplant (SCT). In this trial, leukapheresis was performed per institutional guidelines. Following leukapheresis and T-cell collection, most patients received bridging chemotherapy and all patients had lymphocyte depletion with fludarabine and cyclophosphamide. The median patient age in this study was 12 years (range, 3 to 23 years); 30 patients had received 1 prior SCT and 5 patients had received 2 prior SCT.

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: Tisagenlecleucel is not indicated for use in patients with primary central nervous system lymphoma.
    For the treatment of relapsed or refractory large B-cell lymphoma (e.g., high grade B-cell lymphoma, DLBCL not otherwise specified, and DLBCL arising from follicular lymphoma) after 2 or more lines of systemic therapy.
    NOTE: Tisagenlecleucel has been designated as an orphan drug by the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).
    Intravenous dosage
    Adults

    0.6 to 6 X 108 CAR-positive viable T-cells infused as a single-dose which may be suspended in 1 or more patient-specific infusion bag(s). Administer tisagenlecleucel at 2 to 11 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (25 mg/m2 IV daily for 3 days) plus cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine); alternative therapy consists of bendamustine (90 mg/m2 IV daily for 2 days) for patients who experienced grade 4 hemorrhagic cystitis with prior cyclophosphamide administration or had resistance to a previous cyclophosphamide-containing regimen. Lymphocyte depletion therapy may be omitted in patients who have a white blood cell count of 1 X 109 cells/L or less within 1 week prior to the tisagenlecleucel infusion.[62282] The best overall response rate was 52% following a single infusion of tisagenlecleucel in 93 adult patients with relapsed or refractory DLBCL included in the efficacy analysis who received 2 or more lines of prior chemotherapy (including rituximab and an anthracycline) and had a relapse following autologous hematopoietic stem-cell transplantation (HSCT) or were ineligible for a HSCT in a nonrandomized, phase 2a trial (the JULIET trial). In these patients, the complete response rate was 40% and the partial response rate was 12%. The median progression-free survival time had not been reached at the time of analysis; the overall survival (OS) time was 12 months and the estimated 12-month OS rate was 45%. Most patients (92%) received bridging therapy prior to the tisagenlecleucel infusion; additionally, 93% of patients received lymphocyte depletion therapy.[64320]

    MAXIMUM DOSAGE

    Adults

    Diffuse Large B-cell Lymphoma
    Adults 18 years and older: 6 X 108 CAR-positive viable T-cells.
    Acute Lymphocytic Leukemia
    Older than 25 years: Safety and Efficacy not established.
    25 years or younger:
    Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
    50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

    Geriatric

    6 X 108 CAR-positive viable T-cells.

    Adolescents

    Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
    50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

    Children

    Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
    50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

    Infants

    5 X 106 CAR-positive viable T-cells per kg.

    Neonates

    5 X 106 CAR-positive viable T-cells per kg.

    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: Employ universal precautions in handling leukapheresis material or tisagenlecleucel; follow local biosafety guidelines applicable for disposal of such products.

    Injectable Administration

    Visually inspect the contents of the infusion bag(s) for any breaks or cracks and the thawed infusion bag for any visible cell clumps prior to administration. Do not infuse the contents if the bag is compromised or if clumps do not disperse after thawing and gentle mixing and call Novartis at 1-844-4KYMRIAH.

    Intravenous Administration

    Tisagenlecleucel is for autologous and intravenous use.
    Each dose of tisagenlecleucel is suspended in 1 to 3 patient-specific infusion bag(s); the total infusion bag volume ranges from 10 to 50 mL.
    Each dose is patient specific; see the Certificate of Analysis for the actual number of chimeric antigen receptor (CAR)-positive T-cells in the product.
    Verify the number of bags received for the dose; see the Certificate of Conformance.
    Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
    Coordinate the timing of the tisagenlecleucel 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 a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion; avoid the prophylactic use of corticosteroids.
     
    Preparation
    Match the patient's identity with the patient identifiers on the infusion bag(s).
    Put the infusion bag inside a second, sterile bag to protect against leaks and port contamination.
    Thaw each infusion bag one at a time at 37 degrees Celsius (C) using either a water bath or dry thaw method; once there is no visible ice in the infusion bag, remove it from the thawing device immediately.
    If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag has been safely administered.
    Do not wash, spin down, and/or resuspend tisagenlecleucel in new media prior to infusion.
    If visible cell clumps remain after thawing, gently mix the contents of the bag to allow the clumps of cellular material to disperse.
    Storage of thawed infusion bag: once the product is at room temperature (20 to 25 degrees C), administer within 30 minutes.
     
    Intravenous (IV) Infusion
    Confirm the patient’s identity with the patient identifiers on the infusion bag(s).
    Prime the tubing with normal saline prior to the infusion.
    Administer as an IV infusion at a rate of 10 mL to 20 mL per minute until infusion bag is empty; adjust this rate as appropriate for smaller children and smaller volumes.
    Do not use a leukocyte-depleting filter.
    Rinse the infusion bag with 10 mL to 30 mL of normal saline; maintain a closed tubing system to assure as many cells as possible are infused into the patient.
    Cells from all of the bag(s) must be infused to complete a single dose.

    STORAGE

    KYMRIAH:
    - See package insert for detailed storage information
    - Store at or below -184 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Cytokine release syndrome, infection

    Cytokine release syndrome (CRS) has been reported with tisagenlecleucel; some cases were fatal or life-threatening. Do not administer tisagenlecleucel in patients with active infection or inflammatory disorders. Delay the tisagenlecleucel infusion in patients who have unresolved serious adverse reactions from preceding chemotherapy (e.g., pulmonary or cardiac reactions or hypotension), active graft-versus-host disease (GVHD), or worsening leukemia burden following lymphocyte depleting chemotherapy. Confirm that 2 doses of tocilizumab are available at the facility site prior to the tisagenlecleucel infusion. Monitor patients for signs and symptoms of CRS 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility, then monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. CRS may be associated with hepatic, renal, and cardiac dysfunction and coagulopathy. Management of CRS may include hospitalization, supportive care (e.g., oxygen, fluids, high-dose vasopressors), medical management (e.g., tocilizumab and corticosteroids), and mechanical ventilation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Administer tocilizumab in patients who develop severe or life-threatening CRS. Patients with B-cell acute lymphoblastic leukemia and a high tumor burden (i.e., greater than 50% blasts in the bone marrow), an active uncontrolled infection, or active GVHD may be at increased risk of developing severe CRS.

    Driving or operating machinery, encephalopathy, neurotoxicity, seizures

    Severe and life-threatening neurotoxicity (e.g., encephalopathy, seizures) has been reported with tisagenlecleucel therapy; most cases occurred within 8 weeks of the tisagenlecleucel infusion. Neurologic events may occur with cytokine release syndrome. Monitor patients for signs and symptoms of neurotoxicity including 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility; administer supportive care as indicated. Advise patients to avoid driving or operating machinery or performing other dangerous duties for 8 weeks after the tisagenlecleucel infusion due to the risk of neurological toxicity.

    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 on the management of these toxicities. Tisagenlecleucel administration also requires a specialized care setting that is enrolled in the KYMRIAH 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 tisagenlecleucel infusion).

    Neutropenia, thrombocytopenia

    Prolonged neutropenia and thrombocytopenia have been reported following tisagenlecleucel therapy; prolonged neutropenia may increase the risk of infection. Monitor complete blood counts regularly until hematologic recovery. The use of myeloid growth factors, especially granulocyte macrophage colony-stimulating factor, is not recommended within 3 weeks after the tisagenlecleucel infusion or until cytokine release syndrome has resolved.

    Infusion-related reactions

    Allergic reactions including infusion-related reactions have been reported with tisagenlecleucel therapy; serious hypersensitivity reactions (e.g., anaphylactoid reactions) have occurred. Premedicate patients with acetaminophen and an antihistamine prior to the tisagenlecleucel infusion. Monitor for hypersensitivity reactions during the infusion. Reactions may be due to dimethyl sulfoxide (DMSO) or dextran 40 contained in the tisagenlecleucel product.

    New primary malignancy

    There is a risk of new primary malignancy or leukemia recurrence with tisagenlecleucel therapy. Life-long monitoring for the development of new primary malignancies is recommended. Report cases of new primary malignancy to Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH; instructions will be provided regarding patient sample collection for testing.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported with tisagenlecleucel therapy. Institute prophylactic measures to prevent TLS. Monitor patients for signs or symptoms of TLS and treat as clinically appropriate.

    Vaccination

    Vaccination with live viral vaccines during or following treatment with tisagenlecleucel has not been studied. It is not recommended for at least 6 weeks prior to the start of lymphocyte depleting chemotherapy, during tisagenlecleucel therapy, and until immune recovery after tisagenlecleucel therapy.

    Blood donation

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

    Laboratory test interference

    False-positive HIV test results have been reported in patients who received tisagenlecleucel therapy. The use of gammaretroviral or lentiviral vectors to reprogram T-cells as part of chimeric antigen receptor (CAR) T-cell immunotherapy 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.

    Hepatitis, hepatitis B exacerbation

    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 tisagenlecleucel. 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, and viral infection have been reported with tisagenlecleucel therapy; some cases were life-threatening or fatal. Monitor patients for signs and symptoms of infection; administer prophylactic antimicrobial therapy and other anti-infective therapy as clinically appropriate.

    Hypogammaglobulinemia, neonates

    Hypogammaglobulinemia and agammaglobulinemia (immunoglobulin deficiency) have been reported in patients who achieve a complete remission following tisagenlecleucel therapy. Monitor immunoglobulin levels after tisagenlecleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. Assess immunoglobulin levels in neonates who are born to mothers treated with tisagenlecleucel.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during tisagenlecleucel treatment; pregnancy after tisagenlecleucel administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. There are no available data with tisagenlecleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if tisagenlecleucel 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 tisagenlecleucel treatment. It is unknown whether tisagenlecleucel can cause fetal harm if taken during pregnancy, although fetal toxicity is possible based on its mechanism of action. 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 tisagenlecleucel. Pregnancy status of females of reproductive potential should be verified; sexually active females of reproductive potential should undergo pregnancy testing prior to initiation of tisagenlecleucel. Women who become pregnant while receiving tisagenlecleucel should be apprised of the potential hazard to the fetus. There are no data on the effect of tisagenlecleucel on fertility.

    Breast-feeding

    Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for tisagenlecleucel and any potential adverse effects on the breast-fed infant from tisagenlecleucel or from the underlying maternal condition. It is not known whether tisagenlecleucel is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    cytokine release syndrome / Rapid / 74.0-79.0
    infection / Delayed / 33.0-33.0
    elevated hepatic enzymes / Delayed / 0-28.0
    hypokalemia / Delayed / 12.0-27.0
    anuria / Delayed / 0-24.0
    renal tubular necrosis / Delayed / 0-24.0
    nephrotoxicity / Delayed / 17.0-24.0
    azotemia / Delayed / 0-24.0
    renal failure (unspecified) / Delayed / 0-24.0
    hypophosphatemia / Delayed / 19.0-24.0
    hypotension / Rapid / 8.0-22.0
    neurotoxicity / Early / 18.0-21.0
    hyperbilirubinemia / Delayed / 0-21.0
    hypoxia / Early / 0-18.0
    pulmonary edema / Early / 3.0-16.0
    anorexia / Delayed / 4.0-15.0
    fever / Early / 6.0-15.0
    dyspnea / Early / 6.0-12.0
    impaired cognition / Early / 0-11.0
    drowsiness / Early / 0-11.0
    encephalopathy / Delayed / 10.0-11.0
    lethargy / Early / 0-11.0
    memory impairment / Delayed / 0-11.0
    pleural effusion / Delayed / 5.0-10.0
    disseminated intravascular coagulation (DIC) / Delayed / 3.0-9.0
    heart failure / Delayed / 0-7.0
    malaise / Early / 0-7.0
    fatigue / Early / 0-7.0
    thrombosis / Delayed / 3.0-7.0
    pulmonary embolism / Delayed / 0-7.0
    visual impairment / Early / 3.0-7.0
    tumor lysis syndrome (TLS) / Delayed / 1.0-6.0
    hypertension / Early / 0-6.0
    atrial fibrillation / Early / 0-6.0
    tachypnea / Early / 0-6.0
    coagulopathy / Delayed / 6.0-6.0
    hallucinations / Early / 0-4.0
    agitation / Early / 0-4.0
    restlessness / Early / 0-4.0
    delirium / Early / 0-4.0
    irritability / Delayed / 0-4.0
    cardiac arrest / Early / 0-4.0
    sinus tachycardia / Rapid / 3.0-4.0
    acute respiratory distress syndrome (ARDS) / Early / 0-4.0
    headache / Early / 0-3.0
    migraine / Early / 0-3.0
    seizures / Delayed / 3.0-3.0
    anxiety / Delayed / 0-3.0
    capillary leak syndrome / Early / 1.0-3.0
    nausea / Early / 1.0-3.0
    abdominal pain / Early / 3.0-3.0
    back pain / Delayed / 0-3.0
    edema / Delayed / 2.0-3.0
    weight loss / Delayed / 0-3.0
    pancytopenia / Delayed / 0-2.0
    dizziness / Early / 0-1.0
    syncope / Early / 0-1.0
    stroke / Early / 0-1.0
    diarrhea / Early / 1.0-1.0
    vomiting / Early / 0-1.0
    constipation / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    graft-versus-host disease (GVHD) / Delayed / 1.0-1.0
    peripheral edema / Delayed / 0-1.0
    intracranial bleeding / Delayed / 1.0-1.0
    rash / Early / 0-1.0
    maculopapular rash / Early / 0-1.0

    Moderate

    neutropenia / Delayed / 81.0-100.0
    anemia / Delayed / 58.0-100.0
    thrombocytopenia / Delayed / 54.0-100.0
    antibody formation / Delayed / 86.0-91.4
    prolonged bleeding time / Delayed / 0-13.0
    hyponatremia / Delayed / 0-11.0
    hyperesthesia / Delayed / 0-8.0
    peripheral neuropathy / Delayed / 4.0-8.0
    blurred vision / Early / 0-7.0
    myopathy / Delayed / 0-6.0
    supraventricular tachycardia (SVT) / Early / 0-6.0
    respiratory depression / Rapid / 0-6.0
    contact dermatitis / Delayed / 0-4.0
    aphasia / Delayed / 0-3.0
    dysarthria / Delayed / 0-3.0
    ataxia / Delayed / 0-2.0
    fecal incontinence / Early / 0-1.0
    lymphopenia / Delayed / 94.0
    leukopenia / Delayed / 77.0

    Mild

    cough / Delayed / 19.0-21.0
    myalgia / Early / 7.0-15.0
    chills / Rapid / 10.0-13.0
    nightmares / Early / 0-10.0
    insomnia / Early / 0-10.0
    nasal congestion / Early / 0-10.0
    tremor / Early / 7.0-9.0
    paresthesias / Delayed / 0-8.0
    hypoesthesia / Delayed / 0-8.0
    asthenia / Delayed / 0-7.0
    muscle cramps / Delayed / 0-6.0

    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 tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. 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 tisagenlecleucel treatment; pregnancy after tisagenlecleucel administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. There are no available data with tisagenlecleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if tisagenlecleucel 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.

    Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for tisagenlecleucel and any potential adverse effects on the breast-fed infant from tisagenlecleucel or from the underlying maternal condition. It is not known whether tisagenlecleucel is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Tisagenlecleucel 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 extracellular domain of tisagenlecleucel is a murine monoclonal antibody that targets human CD19. The intracellular domain, CD3-zeta, initiates T-cell activation and mediates antitumor activity; the 4-1BB (CD137) costimulatory domain promotes antitumor activity and enhances proliferation of CAR T-cells. The binding of CAR to CD19 activates tisagenlecleucel 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, a lentiviral vector encodes the CAR molecule via transduction; the vector enters the cell and becomes integrated into the chromosomes of T cells and directs transcription of the tisagenlecleucel CAR.
    To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis; enriched by counterflow centrifugal elutriation; activated by using antibody-coated beads; incubated with a viral vector encoding the CD19 CAR; expanded to large numbers in a bioreactor culture system; and then washed, concentrated, and cryopreserved.

    PHARMACOKINETICS

    Tisagenlecleucel is administered intravenously. It was measurable beyond 2 years in the blood and bone marrow in patients with acute lymphoblastic leukemia (ALL) and was found in peripheral blood for up to 18 months and in the bone marrow for up to 9 months in patients with diffuse large B-cell lymphoma (DLBCL) who achieved a complete response. Blood to bone marrow partitioning indicates high distribution to the bone marrow. In patients with ALL, tisagenlecleucel distribution in bone marrow was 44% of that present in blood at day 28; at months 3 and 6, tisagenlecleucel distribution in the bone marrow was 67% and 69%, respectively. In ALL patients, the geometric mean half-life was 16.8 days (coefficient of variance, (CV), 155.9%) in responding patients (n = 54) and 2.52 days (CV, 171.9%) in nonresponding patients (n = 3). In DLBCL patients, the geometric mean half-life was 45.3 days (CV, 157.7%) in responding patients (n = 21) and 13.6 days (CV, 167%) in nonresponding patients (n = 22).

    Intravenous Route

    After IV administration, tisagenlecleucel exhibits an initial rapid expansion followed by a bi-exponential decline. The Cmax and AUC(0 to 28 days) values were approximately 2-fold higher in CR/Cri patients compared with nonresponding patients. In patients with ALL, the geometric mean Cmax in responding patients (n = 61) was 34,700 copies/mcg (CV, 155.4%), reached at a median Tmax of 9.91 days (range, 0.008 to 27 days); the geometric mean AUC(0 to 28 days) in responding patients was 318,000 copies/mcg X day (CV, 177.8%). Concentrations were lower in ALL patients who did not respond, with a geometric mean Cmax (n = 7) of 20,000 copies/mcg (CV, 71.6%), median Tmax of 20 days (range, 0.03 to 62.7 days), and geometric mean AUC (n = 6) of 156,000 copies/mcg X day (CV, 99.4%). Seven patients had an early Tmax (less than 0.03 days); however, this may represent the amount of transgene present in the catheter from which the sample was collected rather than being representative of the true maximal expansion. In patients with DLBCL, the geometric mean Cmax in responding patients (n = 33) was 5,210 copies/mcg (CV, 256.5%), reached at a median Tmax of 9.83 days (range, 5.73 to 16.8 days); the geometric mean AUC(0 to 28 days) in responding patients was 582,000 copies/mcg X day (CV, 165.1%). Concentrations were higher in DLBCL patients who did not respond, with a geometric mean Cmax (n = 32) of 6,450 copies/mcg (CV, 408.2%), median Tmax of 8.39 days (range, 3.04 days to 27.7 days), and geometric mean AUC (n = 25) of 75,800 copies/mcg X day (CV, 292.3%). The median Tmax for the expansion of transgene levels in peripheral blood occurred at 9 to 10 days in both responding and non-responding patients.