Lisocabtagene Maraleucel – Uses, Dosage, Side Effects

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
3 Views
Drugs (A - Z)

Lisocabtagene maraleucel is a CAR T-cell therapy for treatment-resistant or more severe B-cell lymphomas.

Lisocabtagene maraleucel is a chimeric antigen receptor (CAR) T-cell therapy, similar to brexucabtagene autoleucel and axicabtagene ciloleucel. Lisocabtagene maraleucel is a genetically modified autologous T-cell therapy that targets CD19, the B-lymphocyte surface antigen B4.[rx]

CAR T-cell therapy has changed the treatment of B-cell lymphomas, significantly increasing survival rates over standard therapy.[rx] However, data on the efficacy of CAR T-cell therapies on less severe forms of B-cell lymphoma are lacking.[rx] Despite the adverse reactions, the majority of patients given lisocabtagene maraleucel reported an overall increase in quality of life over a 1 year period.[rx]

Lisocabtagene maraleucel was granted FDA approval on 5 February 2021 [rx] and EC approval on 5 April 2022.[rx] It was later granted Health Canada approval on 6 May 2022.[rx]

Mechanism of action

Lisocabtagene maraleucel is chimeric antigen receptor (CAR) T-cell therapy that targets CD19, also known as the B-lymphocyte surface antigen B4.[rx] The CAR is composed of an FMC63 monoclonal antibody single chain variable fragment, IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3ζ activation domain.[rx] FMC63 is an IgG2a mouse monoclonal antibody that targets CD19.[rx] The IgG4 hinge region can interact with Fcγ receptors to modulate the response of hematopoietic cells. The CD28 transmembrane domain can stimulate the activity or tolerance of T-cells.[rx] 4-1BB enhances cytotoxic T-cell activity as well as the production of interferon-γ.[rx] The CD23ζ cytoplasmic domain mediates T-cell activation by CD2, a T-cell surface adhesion molecule.[rx]

Lisocabtagene maraleucel is a CAR T-cell therapy indicated to treat adults with relapsed or refractory large B-cell lymphoma after ≥2 systemic therapies, diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and grade 3B follicular lymphoma.[rx] It has a long duration of action as it is detected in patients up to a year after infusion.[rx] Patients should be counseled regarding the risk of cytokine release syndrome, false-positive HIV tests, effects on their ability to drive, hypersensitivity, infection, cytopenia, hypogammaglobulinemia, and secondary malignancies.[rx]

Indications

  • Lisocabtagene maraleucel is indicated to treat adults with relapsed or refractory large B-cell lymphoma after ≥2 systemic therapies, diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and grade 3B follicular lymphoma
  • High-Grade B-cell Lymphoma (HGBCL)
  • Lymphoma, Follicular, Grade 3b
  • Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
  • Refractory Diffuse Large B Cell Lymphoma (DLBCL)
  • Refractory Large B-cell Lymphoma
  • Relapsed Diffuse Large B-cell Lymphoma (DLBCL)
  • Lisocabtagene maraleucel is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B).
  • Lisocabtagene maraleucel is indicated for the treatment of adults with large B-cell lymphoma (LBCL) who have the refractory disease to first-line chemoimmunotherapy or relapse within twelve months of first-line chemoimmunotherapy, or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age.[rx]

Use in Cancer

Brexucabtagene autoleucel is approved to treat adults with:

  • Mantle cell lymphoma that has relapsed (come back) or is refractory (does not respond to treatment).
  • Precursor B lymphoblastic leukemia (a type of acute lymphoblastic leukemia) has relapsed or is refractory.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that brexucabtagene autoleucel provides a clinical benefit in these patients.

Contraindications

  • a bad infection
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • pregnancy
  • reactivation of hepatitis B infection

Dosage

Lymphoma

PRETREATMENT:

  • Administer the lymphodepleting chemotherapy regimen before infusion of this drug: fludarabine 30 mg/m2/day IV and cyclophosphamide 300 mg/m2/day IV for 3 days.
  • See the prescribing information for fludarabine and cyclophosphamide for information on dose adjustment in renal impairment.
  • Infuse this drug 2 to 7 days after completion of lymphodepleting chemotherapy.
  • Delay the infusion of this drug if the patient has unresolved serious adverse events from preceding chemotherapies, active uncontrolled infection, or active graft-versus-host disease (GVHD).

PREMEDICATION:

  • Premedicate the patient with acetaminophen (650 mg orally) and diphenhydramine (25 to 50 mg IV or orally), or another H1-antihistamine, 30 to 60 minutes prior to therapy with this drug.
  • Avoid prophylactic use of systemic corticosteroids, as they may interfere with the activity of this drug.
  • A single dose of this drug contains 50 to 110 x 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components), with each component supplied separately in 1 to 4 single-dose vials. Each mL contains 1.5 x 10(6) to 70 x 10(6) CAR-positive viable T cells (3). See the respective Certificate of Release for Infusion (RFI Certificate) for each component, for the actual cell counts and volumes to be infused.

ADMINISTRATION:

  • When this drug has been drawn into syringes, proceed with the administration as soon as possible.
  • The total time from removal from frozen storage to patient administration should not exceed 2 hours as indicated by the time entered on the syringe label.

STEPS:

  • 1) Use IV normal saline to flush all the infusion tubing prior to and after each CD8 or CD4 component administration.
  • 2) Administer the entire volume of the CD8 component IV at an infusion rate of approximately 0.5 mL/min, using the closest port or Y-arm. NOTE: The time for infusion will vary but will usually be less than 15 minutes for each component.
  • 3) If more than one syringe is required for a full cell dose of the CD8 component, administer the volume in each syringe consecutively without any time between administering the contents of the syringes (unless there is a clinical reason [e.g., infusion reaction] to hold the dose).
  • 4) After the CD8 component has been administered, flush the tubing with normal saline, using enough volume to clear the tubing and the length of the IV catheter. 5) Administer the CD4 component second, immediately after administration of the CD8 component is complete, using steps 1 through 4, as described for the CD8 component. Following administration of the CD4 component, flush the tubing with normal saline, using enough volume to clear the tubing and the length of the IV catheter.
  • Consult the manufacturer’s product information for preparation and administration.

Dose Adjustments

CRS GRADING AND MANAGEMENT GUIDANCE:
GRADE 1 (fever):

  • Tocilizumab: If less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg); if 72 hours or more after infusion, treat symptomatically.
  • Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 24 hours; if 72 hours or more after infusion, treat symptomatically.

GRADE 2 (symptoms require and respond to moderate intervention; oxygen requirement less than 40% FiO2, or hypotension responsive to fluids or low dose of one vasopressor, or Grade 2 organ toxicity):

  • Tocilizumab: Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate the dose and frequency of dexamethasone (10 to 20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone, and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.
  • Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10 to 20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours or 4 doses in total. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate the dose and frequency of dexamethasone (10 to 20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.

GRADE 3 (symptoms require and respond to aggressive intervention; oxygen requirement greater than or equal to 40% FiO2, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity, or Grade 4 transaminitis):

  • Per Grade 2: If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate the dose and frequency of dexamethasone (10 to 20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.
  • Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: Administer dexamethasone 20 mg IV every 12 hours. If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate the dose and frequency of dexamethasone (10 to 20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.

GRADE 4 (life-threatening symptoms; requirements for ventilator support or continuous venovenous hemodialysis [CVVHD] or Grade 4 organ toxicity [excluding transaminitis]):

  • Per Grade 2: If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use. If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.
  • Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: Administer dexamethasone 20 mg IV every 6 hours. If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use. If no improvement or continued rapid progression, maximize dexamethasone and switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants.

Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses total.

NEUROLOGIC TOXICITY

  • Monitor patients for neurologic toxicities.
  • Rule out other causes of neurologic symptoms.
  • Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities.
  • If neurologic toxicity is suspected, manage it according to the recommendations below.
  • If concurrent CRS is suspected during neurologic toxicity, administer corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades, tocilizumab, and antiseizure medication according to the neurologic toxicity outlined below:
  • GRADE 1: Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours or more after infusion, observe. If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.
  • GRADE 2: Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 mg IV every 12 hours for 2 to 3 days, or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided 4 times a day; taper within 7 days).
  • GRADE 3: Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 g to 2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m2.
  • GRADE 4: Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 g to 2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m2.

Side Effects

The Most Common

  • constipation
  • stomach pain
  • loss of appetite
  • rash
  • causing high fever and flu-like symptoms and neurologic toxicities
  • numbness, pain, tingling, or burning feeling in feet or hands
  • feeling tired
  • tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins at the injection site
  • bruising or bleeding
  • fever, sore throat, chills, or other signs of infection
  • confusion
  • fast or irregular heartbeat
  • confusion, trouble concentrating, memory problems;
  • decreased consciousness;
  • tremors, or a seizure; or
  • signs of infection–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath.

More Common

  • Agitation
  • back pain
  • bleeding gums
  • bloody urine
  • blurred vision
  • body aches or pain
  • burning, numbness, tingling, or painful sensations
  • chest pain
  • chills
  • coma
  • confusion
  • cough
  • coughing up blood
  • decrease frequency or amount of urine
  • diarrhea
  • difficulty swallowing
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • drowsiness
  • ear congestion
  • fast, pounding, or irregular heartbeat or pulse
  • fever
  • hallucinations
  • headache
  • hives, itching
  • holding false beliefs that cannot be changed by fact

Rare

  • increased menstrual flow or vaginal bleeding
  • increased thirst
  • irritability
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • mood or mental changes
  • muscle or bone pain
  • muscle spasm, tenderness, twitching, jerking, wasting, or weakness
  • nausea
  • nosebleeds
  • painful or difficult urination
  • paralysis
  • pounding in the ears
  • problems with speech or speaking
  • prolonged bleeding from cuts
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • red or black, tarry stools
  • red or dark brown urine
  • runny or stuffy nose
  • seizures
  • shakiness and unsteady walk
  • shakiness in the legs, arms, hands, or feet
  • skin rash
  • slow or fast heartbeat
  • sneezing
  • sore throat
  • stiff neck
  • stomach pain
  • sweating
  • trembling and shaking of the hands or feet
  • trouble breathing
  • ulcers, sores, or white spots in the mouth
  • unsteadiness, awkwardness, trembling, or other problems with muscle control or coordination
  • unusual bleeding or bruising
  • unusual excitement, nervousness, or restlessness
  • unusual tiredness or weakness
  • vomiting
  • weight gain

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

There are no available data on the use of this drug in animal or human pregnancy. Based on its mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia; therefore, the administration is not recommended in pregnancy. If a pregnancy occurs during therapy, the physician should be notified immediately.

Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

How should this medicine be used?

Lisocabtagene maraleucelcomes as a suspension (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a doctor’s office or infusion center. It is usually given as two infusions over a total period of up to 30 minutes as a one-time dose. Before you receive your lisocabtagene maraleucel dose, your doctor or nurse will administer other chemotherapy medications to prepare your body for lisocabtagene maraleucel.

Before your dose of lisocabtagene maraleucel injection is to be given, a sample of your white blood cells will be taken at a cell collection center using a procedure called leukapheresis (a process that removes white blood cells from the body). Because this medication is made from your own cells, it must be given only to you. It is important to be on time and to not to miss your scheduled cell collection appointment(s) or to receive your treatment dose. You should plan to stay near where you received your lisocabtagene maraleucel treatment for at least 4 weeks after your dose. Your healthcare provider will check to see if your treatment is working and monitor you for any possible side effects. Talk to your doctor about how to prepare for leukapheresis and what to expect during and after the procedure.

What special precautions should I follow?

Before receiving lisocabtagene maraleucel,

  • tell your doctor and pharmacist if you are allergic to lisocabtagene maraleucel, any other medications, or any of the ingredients in lisocabtagene maraleucel. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had hepatitis B virus or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You will need to have a pregnancy test before you start lisocabtagene maraleucel. If you become pregnant while receiving lisocabtagene maraleucel, call your doctor immediately.
  • you should know that lisocabtagene maraleucel injection may make you drowsy and cause confusion, weakness, dizziness, seizures, and coordination problems. Do not drive a car or operate machinery for at least 8 weeks after your lisocabtagene maraleucel dose.
  • do not donate blood, organs, tissues, or cells for transplantation after you receive your lisocabtagene maraleucel injection.
  • check with your doctor to see if you need to receive any vaccinations. Do not have any vaccinations without talking to your doctor for at least 6 weeks before starting chemotherapy, during your lisocabtagene maraleucel treatment, and until your doctor tells you that your immune system has recovered.

References

Related Articles

      No widgets added. You can disable footer widget area in theme options - footer options

      RxHarun
      Logo