lisocabtagene maraleucel (Rx)

Brand and Other Names:Breyanzi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, suspension

  • A single dose contains 50-110 x 106 CAR-positive viable T cells, consisting of CD8 and CD4 components, with each component supplied separately in single-dose vials
  • More than 1 vial of each of the CD8 component and/or CD4 component may be needed to achieve the dose
  • Each vial contains 6.9-322 x 106 CAR-positive viable T cells in 4.6 mL cell suspension (1.5-70 x 106 T cells/mL)
  • Check Rlease for Infusion (RFI) Certificate for specific content

B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell immunotherapy (Anti-CD19) indicated for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapies, including DLBCL not otherwise specified (arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3 B

One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of lisocabtagene maraleucel

Confirm availability of lisocabtagene maraleucel before starting lymphodepleting chemotherapy

Pretreatment - Lymphodepleting chemotherapy

  • Administer lymphodepleting chemotherapy before infusing lisocabtagene maraleucel
  • Fludarabine 30 mg/m2 IV plus cyclophosphamide 500 mg/m2 IV qDay for 3 days
  • Infuse lisocabtagene maraleucel 2-7 days after completing lymphodepleting chemotherapy
  • Delay lisocabtagene maraleucel infusion if patient has unresolved serious adverse events from lymphodepleting chemotherapy, active uncontrolled infection, or active graft-versus-host disease (GVHD)

Premedication

  • Premedicate with acetaminophen 650 mg PO and diphenhydramine 25-50 mg PO/IV (or other H1 antihistamine) ~30-60 minutes before CAR T-cell infusion
  • Avoid prophylactic use of systemic corticosteroids at all times (may interfere with CAR T-cell activity), except in the case of a life-threatening emergency

Lisocabtagene maraleucel IV infusion

  • For autologous use only; administer 2-7 days after completing lymphodepleting chemotherapy
  • Dose based on the number of CAR-positive viable T-cells per vial
  • A single dose contains 50-110 x 106 CAR-positive viable T-cells (consisting of 1:1 CAR-positive viable T-cells of the CD8 and CD4 components)
  • Each component supplied separately in 1-4 single-dose vials

Dosage Modifications

Cytokine release syndrome (CRS) management

NOTE: If corticosteroids are initiated, continue for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper

  • Grade 1
    • Symptoms: Fever
    • <72 hr after CAR T-cell infusion: Consider 8 mg/kg IV over 1 hr, not to exceed 800 mg; may also consider dexamethasone 10 mg IV q24hr
    • ≥72 hr: Treat symptomatically
  • Grade 2
    • Symptoms require and respond to moderate intervention; oxygen requirement <40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity
    • Administer tocilizumab 8 mg/kg IV infused over 1 hr; not to exceed 800 mg
    • Repeat tocilizumab q8hr as needed if not responsive to IV fluids or increasing supplemental oxygen; not to exceed 3 doses in a 24-hr period or 4 doses in total; after 2 doses of tocilizumab, consider alternant immunosuppressants
    • If improving, discontinue tocilizumab
    • If <72 hr: Dexamethasone 10 mg IV q12-24hr
    • If ≥72 hr: Consider dexamethasone at above dose
    • No improvement within 24 hr or rapid progression: Repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20 mg IV q6-12hr); if no improvement on maximized dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed
  • Grade 3
    • Symptoms require aggressive intervention; oxygen requirement ≥40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis
    • Tocilizumab administration per Grade 2; if improving, discontinue
    • Corticosteroid dose as for Grade 2; taper if improving or manage as Grade 2 if not improving
  • Grade 4
    • Life-threatening symptoms; requires ventilator support, continuous venovenous hemodialysis, or Grade 4 organ toxicity (excluding transaminitis)
    • Tocilizumab administration per Grade 2; if improving, discontinue
    • Corticosteroid dose as for Grade 2; taper if improving or manage as Grade 2 if not improving

Neurologic toxicity grading and management

  • Grade 1
    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
    • <72 hr: Consider dexamethasone 10 mg IV q12-24hr for 2-3 days
    • ≥72 hr: Observe
  • Grade 2
    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
    • Dexamethasone 10 mg IV q12hr for 2-3 days, or longer for persistent symptoms; consider taper for total steroid exposure >3 days
    • If no improvement after 24 hr or worsening of neurologic toxicity, increase dexamethasone to up to 20 mg IV q6hr
    • If no improvement after another 24 hr, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg QID; taper within 7 days)
  • Grade 3
    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
    • Dexamethasone 10-20 mg IV q8-12
    • Steroids not recommended for isolated Grade 3 headaches
    • If no improvement after 24 hr or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2)
    • If cerebral edema suspected, consider hyperventilation and hyperosmolar therapy; administer high-dose methylprednisolone 1-2 g IV q24hr prn; taper as clinically indicated and cyclophosphamide 1.5 g/m2
  • Grade 4
    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
    • Dexamethasone 20 mg IV q6hr
    • If no improvement after 24 hr or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2)
    • If cerebral edema suspected, consider hyperventilation and hyperosmolar therapy; give high-dose methylprednisolone and cyclophosphamide (dose and frequency as per Grade 3)

Dosing Considerations

Limitation of use: Not indicated for treatment primary CNS lymphoma

Administer at a certified healthcare facility

Monitor for signs/symptoms of CRS and neurologic toxicities at least daily for 7 days following infusion

Instruct patients to remain within proximity of the certified healthcare facility at least 4 weeks following infusion

Verify pregnancy status of females with reproductive potential

Safety and efficacy not established

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Interactions

Interaction Checker

and lisocabtagene maraleucel

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Fatigue (48%)
            • Cytokine release syndrome (46%)
            • Musculoskeletal pain (37%)
            • Nausea (33%)
            • Hypogammaglobulinemia (32%)
            • Headache (30%)
            • Encephalopathy (29%)
            • Infections (29%)
            • Decreased appetite (28%)
            • Diarrhea (26%)
            • Hypotension (26%)
            • Tachycardia (25%)
            • Dizziness (24%)
            • Constipation (23%)
            • Cough (23%)
            • Abdominal pain (21%)
            • Vomiting (21%)
            • Edema (21%)
            • Tremor (16%)
            • Fever (16%)
            • Dyspnea (16%)
            • Insomnia (14%)
            • Hypertension (14%)
            • Bacterial infections (13%)
            • Upper respiratory tract infection (13%)
            • Rash (13%)
            • Chills (12%)
            • Peripheral neuropathy (11%)
            • Renal failure (11%)

            Grade >3

            • Neutropenia (76%)
            • Thrombocytopenia (39%)
            • Anemia (23%)
            • Infections (16%)
            • Hypofibrinogenemia (15%)
            • Hypophosphatemia (13%)

            1-10%

            All grades

            • Viral infectious disorders (10%)
            • Motor dysfunction (10%)
            • Aphasia (10%)
            • Anxiety (10%)
            • Delirium (10%)
            • Hemorrhage (10%)

            Grade >3

            • Encephalopathy (9%)
            • Bacterial infections (5%)
            • Hypertension (4.5%)
            • Cytokine release syndrome (4.1%)
            • Fatigue (3.4%)
            • Hypotension (3.4%)
            • Abdominal pain (3%)
            • Renal failure (3%)
            • Decreased appetite (2.6%)
            • Dizziness (2.6%)
            • Dyspnea (2.6%)
            • Musculoskeletal pain (2.2%)
            • Aphasia (2.2%)
            • Delirium (2.2%)
            • Nausea (1.5%)
            • Hemorrhage (1.5%)
            • Viral infections (1.5%)
            • Edema (1.1%)
            • Motor dysfunction (1.1%)
            • Headache (1.1%)

            <1%

            Grade >3

            • Upper respiratory tract infection (0.7%)
            • Diarrhea (0.4%)
            • Vomiting (0.4%)
            • Insomnia (0.4%)
            • Rash (0.4%)
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            Warnings

            Black Box Warnings

            Cytokine release syndrome

            • Cytokine release syndrome (CRS), including fatal or life-threatening reactions, reported in a majority of patients
            • Do not administer to patients with active infection or inflammatory disorders
            • Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids
            • Patients should seek immediate medical attention if signs or symptoms of CRS occur at any time; at the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab, and corticosteroids as indicated

            Neurological toxicities

            • Neurologic toxicities, including life-threatening reactions, reported; these may occur concurrently with CRS or after CRS resolution; monitor and provide supportive care and/or corticosteroids as needed
            • The most common neurological toxicities were encephalopathy, headache, tremor, aphasia, and delirium
            • Monitor for neurological events for at least 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities

            Restricted access program

            • Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Breyanzi REMS program
            • Further information is available at www.yescartatecartusrems.com or 1-888-423-5436
            • REMS requirements
              • Healthcare facilities that dispense and administer lisocabtagene maraleucel must be enrolled and comply with the REMS requirements
              • Certified healthcare facilities must have onsite immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hr after CAR T-cell IV infusion, if needed for treatment of CRS
              • Certified healthcare facilities must ensure training about CRS management and neurological toxicities for healthcare providers who prescribe, dispense, or administer CAR T-cells

            Contraindications

            None

            Cautions

            CRS, including fatal or life-threatening reactions, occurred (see Black Box Warnings and Adverse Effects)

            Available only through a restricted access program

            Allergic reactions may occur during infusion; serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide in the product

            Serious infections, including life-threatening or fatal infections, reported; before administering, infection prophylaxis for neutropenia should follow local guidelines; monitor for signs and symptoms of infection after treatment and manage infections with broad-spectrum antibiotics, fluids, and other supportive care

            Viral reactivation can occur; hepatitis B virus (HBV) reactivation can result in fulminant hepatitis, hepatic failure, and death; perform screening for HBV, hepatitis C virus, and HIV in accordance with clinical guidelines before collection of cells for manufacturing

            Prolonged cytopenias may occur and last for several weeks following lymphodepleting chemotherapy and CAR T-cell infusion; monitor blood cell counts prior to and after therapy administration

            B-cell aplasia and hypogammaglobulinemia can occur; monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines

            Secondary malignancies may develop; monitor patient life-long for secondary malignancies

            Neurological toxicities

            • Neurological toxicities, which may be severe or life-threatening, can occur following treatment
            • The most common neurologic toxicities include encephalopathy, tremor, aphasia, delirium, headache, ataxia, and dizziness
            • Serious events including cerebral edema and seizures occurred; fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, were reported
            • Owing to the potential for neurological events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following treatment; advise patients to refrain from driving and engaging in hazardous occupations or activities
            • Monitor daily during first week following infusion for signs and symptoms of neurologic toxicities, then at least weekly for 4 weeks
            • HIV and the lentivirus used to make lisocabtagene maraleucel have limited, short spans of identical genetic material (RNA); therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received lisocabtagene maraleucel

            Immunization with live viral vaccines

            • Safety of immunization with live viral vaccines during or following treatment has not been studied
            • Vaccination with live-virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CAR T-cell treatment, and until immune recovery afterwards
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            Pregnancy & Lactation

            Pregnancy

            Data are not available in pregnant females

            No animal reproductive and developmental toxicity studies have been conducted

            Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia

            Not recommended during pregnancy, and pregnancy after infusion should be discussed with treating physician

            Verify pregnancy status of females with reproductive potential; sexually active females of reproductive potential should have a pregnancy test prior to starting treatment

            Infertility: Data are unavailable

            Contraception

            • See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy
            • Limited exposure data available concerning the duration of contraception following treatment

            Lactation

            Unknown if distributed in human breast milk

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells

            Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28, 4-1BB (CD137), and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines

            This cascade of events leads to killing of CD19-expressing cells

            Absorption

            Peak plasma time: 12 days

            Peak plasma concentration, median: 35,335 copies/mcg (responsive patients); 15,527 copies/mcg (nonresponsive [NR] patients)

            AUC (0-28d): 273,552 copies/mcg⋅day (responsive patients); 155,240 copies/mcg⋅day (NR patients)

            Elimination

            Present in peripheral blood for up to 2 yr

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            Administration

            IV Preparation

            Thawing

            • Carefully remove vials from cartons and place on protective barrier pad
            • Thaw at room temperature until there is no visible ice in vials
            • Thaw all vials at the same time
            • Keep CD8 and CD4 components separate

            Preparing syringes

            • Based on concentration of CAR-positive viable T cells for each component, >1 vial of each of the CD8 and CD4 components may be required to complete a dose
            • Prepare separate syringes for each CD8 or CD4 component vial received
            • Volume drawn up and infused may differ for each component as indicated on the RFI Certificate; do NOT draw up excess volume into syringe
            • Each vial contains 5 mL with a total extractable volume of 4.6 mL of CD8 or CD4 component T cells; RFI Certificate for each component indicates the volume (mL) of cells to be drawn up into each syringe
            • Use the smallest Luer-lock tip syringe necessary (1, 3, or 5 mL) to draw up specified volume from each vial
            • Use 5-mL syringe for volumes <3 mL
            • Draw up CD8 component first; affix CD8 syringe labels to syringe(s) beforehand
            • See specific instructions and diagrams in prescribing information for needle gauge, length, and angle when puncturing port septum
            • Repeat process for CD4 component

            IV Administration

            • For autologous use only
            • Do NOT use leukodepleting filter
            • Ensure tocilizumab and emergency equipment are available before infusion and during the recovery period
            • Confirm patient identity matches identifiers on syringe label
            • Proceed with administration as soon as possible after preparation
            • Total time from removal from frozen storage to patient administration should not exceed 2 hr as indicated by the time entered on the syringe label

            Administration steps

            • Use IV 0.9% NaCl to flush all infusion tubing before and after each CD8 or CD4 component administration
            • Administer entire volume of CD8 component IV at infusion rate of ~0.5 mL/minute, using the closest port or Y-arm
            • NOTE: Infusion time will vary, but usually <15 minutes for each component
            • If >1 syringe required for full cell dose of CD8 component, administer volume in each syringe consecutively without any time between administering the contents of the syringes (unless there is a clinical reason [eg, infusion reaction] to hold the dose)
            • After CD8 component administered, flush tubing with 0.9% NaCl, using enough volume to clear tubing and length of IV catheter
            • Administer CD4 component second, immediately after administration of CD8 component completed, using steps described for the CD8 component, then flush tubing as described
            • Follow universal precautions and local biosafety guidelines applicable for handling and disposal, to avoid potential transmission of infectious disease

            Storage

            Shipped directly to cell lab or clinical pharmacy associated with infusion center in vapor phase of a liquid nitrogen shipper

            Store vials in the vapor phase of liquid nitrogen (≤ -130ºC) in a temperature-monitored system

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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