Brexucabtagene Autoleucel – Uses, Dosage, Side Effects

Mantle cell lymphoma is a heterogeneous sub-category of non-Hodgkin’s lymphoma that can be classified as either an aggressive nodal or an indolent leukemic non-nodal variant. Despite the introduction of Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib, the prognosis? for MCL patients remains poor and those that relapse? following BTK inhibitor therapy has few treatment options.

More recently, chimeric antigen receptor (CAR) T cell therapies have been developed that modify a patient’s own T cells using viral? transduction to bind to and destroy cancerous cells. These therapies differ in manufacturing methodology, viral vector, chimeric antigen choice, and the internal co-stimulatory domains of the chimeric antigen.^[rx] Similar to axicabtagene ciloleucel, brexucabtagene autoleucel employs a murine anti-CD19 single-chain variable fragment (scFv) linked to internal CD28- and CD3ζ-derived co-stimulatory domains. However, the preparation of brexucabtagene autoleucel, previously referred to as KTE-X19, uses a method of T cell enrichment that decreases the prevalence of CD19-expressing tumor cells in the CAR T cell preparation.^[rx]

Brexucabtagene autoleucel was granted accelerated approval for the treatment of relapsed and refractory MCL by the FDA on July 24, 2020, and is currently available through Kite Pharma Inc. under the tradename TECARTUS.^[rx]

Mechanism of action

Mantle cell lymphoma (MCL) is a heterogeneous sub-category of B cell non-Hodgkin’s lymphoma typified by overexpression of cyclin D1 and SOX-11 as well as mutations in numerous genes including TP53; overall, these changes lead to increased cell growth, apoptosis inhibition, and cell-adhesion-mediated drug resistance.^[rx] Based on the 2016 World Health Organization guidelines, MCL can be generally subdivided into aggressive nodal and indolent leukemic non-nodal subtypes.^[rx,rx] Bruton’s tyrosine kinase (BTK) inhibitors can be used following a relapse? of front-line therapy, but patients who relapse after BTK inhibitor therapy have a poor prognosis?.^[rx]

Chimeric antigen receptors (CARs) are synthetic immunoreceptors that can be introduced into T cells ex vivo using viral? transduction and that allow for major histocompatibility complex (MHC)-independent direction of T cells to any cell possessing the complementary antigen.^[rx] Brexucabtagene autoleucel employs a murine anti-CD19 single-chain variable fragment (scFv) linked to internal CD28- and CD3ζ-derived co-stimulatory domains.^[rx] Brexucabtagene autoleucel is prepared from the patient’s own peripheral blood mononuclear cells using a leukapheresis methodology that excludes CD19-expressing tumor cells to avoid potential activation and exhaustion of CAR T cells during manufacturing.¹ Collected cells are activated with anti-CD3 and anti-CD28 antibodies along with IL-2, transduced with a replication-incompetent retroviral vector, and subsequently expanded prior to infusion.^[rx]

Once infused into the patient, the CAR T cells bind to CD19 antigens on the surface of both normal and cancerous B cells, leading to CAR T cell activation and expansion. Activated CAR T cells secrete cytokines and chemokines including, but not limited to, IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and soluble IL-2 (sIL2Rα), leading to tumor cell lysis and anti-tumor activity

Indications

• Brexucabtagene autoleucel is a modified autologous chimeric antigen receptor (CAR) T-cell immunotherapy indicated for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adult patients.^[rx] It is additionally indicated for the treatment of adults with relapsed or refractory B-cell precursor acute? lymphoblastic leukemia (ALL).^[rx]
• Brexucabtagene autoleucel has been granted accelerated approval based on results from a single-arm, open-label, multicentre clinical trial; continued approval may be contingent on confirmatory trials.^[rx]

• Refractory Mantle Cell Lymphoma
• Relapsed Mantle Cell Lymphoma
• Refractory B-cell precursor acute? lymphoblastic leukemia
• Relapsed B cell precursor Acute? lymphoblastic leukemia

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) that 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.

Brexucabtagene autoleucel is only available as part of a special program called Tecartus REMS (Risk Evaluation and Mitigation StrategiesExit Disclaimer).

Brexucabtagene autoleucel is also being studied in the treatment of other types of cancer.

Contraindication?

• 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

• Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 IV and fludarabine 30 mg/m2 IV on each of the fifth, fourth, and third days before infusing this drug.
• Each single infusion bag contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL; the dose is 2 x 10(6) CAR-positive viable T cells/kg, with a maximum of 2 x 10(8) CAR-positive viable T cells
• Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusing this drug.
• Avoid prophylactic use of systemic? corticosteroids as it may interfere with the activity of this drug.

Dose Adjustments

Management of Severe Adverse Reactions Cytokine Release Syndrome:

• Identify CRS based on clinical presentation.
• Evaluate for and treat other causes of fever?, hypoxia, and hypotension?.
• If CRS is suspected, manage according to recommendations.
• Patients who experience Grade 2 or higher CRS (e.g., hypotension?, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive care supportive therapy.

CRS GRADING AND MANAGEMENT GUIDANCE:

• GRADE 1 (symptoms require symptomatic treatment only (e.g., fever?, nausea?, fatigue?, pain? in the head or upper neck. সহজ বাংলা: মাথাব্যথা।" data-rx-term="headache" data-rx-definition="Headache means pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।">headache?, myalgia, malaise): If not improving after 24 hours, administer tocilizumab at 8 mg/kg IV over 1 hour (not to exceed 800 mg); do not administer corticosteroids.
• 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: Administer tocilizumab at 8 mg/kg IV over 1 hour (not to exceed 800 mg; repeat every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses if no improvement in CRS; if improving discontinue tocilizumab; corticosteroids: Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab; if improving, taper corticosteroids.
• 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): Administer tocilizumab at 8 mg/kg IV over 1 hour (not to exceed 800 mg; repeat every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses if no improvement in CRS; if improving discontinue tocilizumab; corticosteroids: Administer methylprednisolone 1 mg/kg IV 2 times a day or equivalent dexamethasone (e.g., 10 mg IV every 6 hours) until Grade 1, then taper corticosteroids; if improving, manage as Grade 2; if not improving, manage as Grade 4
• GRADE 4 (life-threatening symptoms; requirements for ventilator support or continuous venovenous hemodialysis [CVVHD], or Grade 4 organ toxicity (excluding transaminitis): Administer tocilizumab at 8 mg/kg IV over 1 hour (not to exceed 800 mg; repeat every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen; limit to a maximum of 3 doses in 24 hours; maximum total of 4 doses if no improvement in CRS; if improving discontinue tocilizumab; corticosteroids: Administer methylprednisolone 1000 mg IV daily for 3 days; if improving, taper corticosteroids and manage as Gr manage as Grade 3; if not improving, consider alternate immunosuppressants.

NEUROLOGIC TOXICITY:

• Monitor patients for neurologic toxicities.
• Rule out other causes of neurologic symptoms.
• Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry.
• Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities.
• Consider non-sedating antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis for any Grade 2 or higher neurologic toxicities.

NEUROLOGIC TOXICITY GRADING AND MANAGEMENT GUIDANCE:
GRADE 1 (e.g., mild somnolence, confusion, encephalopathy [mild limiting of ADLs], dysphasia [not impairing ability to communicate]):

• With concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 1 CRS.
• No concurrent CRS: Initiate supportive care.

GRADE 2 (e.g., moderate somnolence, moderate confusion, encephalopathy [limiting instrumental ADLs], dysphasia [moderate impairing ability to communicate spontaneously], seizures):

• With concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; if not improving within 24 hours after starting tocilizumab, administer dexamethasone 10 mg IV every 6 hours until the event is Grade 1 or less, then taper corticosteroids; if improving, discontinue tocilizumab; if still not improving, manage as Grade 3; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.
• No concurrent CRS: Administer dexamethasone 10 mg IV every 6 hours until Grade 1 or less; if improving taper corticosteroids; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.

GRADE 3 (e.g., somnolence [obtundation or stupor], confusion [severe disorientation], encephalopathy [limiting self-care ADLs], dysphasia [severe receptive or expressive characteristics impairing ability to read, write, or communicate intelligibly]):

• With concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; administer dexamethasone 10 mg IV with the first dose of tocilizumab and repeat dose every 6 hours; continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids; if improving, discontinue tocilizumab and manage as Grade 2; if still not improving, manage as Grade 4; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.
• No concurrent CRS: Administer dexamethasone 10 mg IV every 6 hours; continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids; if not improving, manage as Grade 4; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.

GRADE 4 (e.g., life-threatening consequences, urgent intervention indicated, requirement for mechanical ventilation, consider cerebral edema?):

• With concurrent CRS: Administer tocilizumab per Table 1 for management of Grade 2 CRS; administer methylprednisolone 1000 mg IV daily with first dose of tocilizumab and continue methylprednisolone 1000 mg IV daily for 2 more days; if improving, then manage as Grade 3; if not improving, consider alternate immunosuppressants; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.
• No concurrent CRS: Administer methylprednisolone 1000 mg IV daily for 3 days; if improving, then manage as Grade 3; if not improving, consider alternate immunosuppressants; consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure? prophylaxis.

Side Effects

The Most Common

• constipation
• stomach pain
• loss of appetite
• mouth pain
• difficulty swallowing
• rash
• pale skin or shortness of breath
• fever, sore throat, chills, or other signs of infection
• unusual bruising or bleeding
• decreased urination frequency or amount
• numbness, pain, tingling, or burning feeling in feet or hands

More Common

• Fever (100.4°F/38°C or higher)
• Low white blood cells (can occur with a fever)
• Low red blood cells
• Low blood pressure (dizziness or lightheadedness, headache, feeling tired, short of breath)
• Fast heartbeat
• Confusion
• Difficulty speaking or slurred speech
• Nausea
• Diarrhea
• severe drowsiness;
• trouble speaking or writing;
• trouble with daily activities;
• a seizure;
• severe ongoing nausea, vomiting, or diarrhea;
• blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath;
• kidney problems–little or no urination, swelling in your feet or ankles, feeling tired or short of breath; or
• fluid build-up in or around the lungs–pain when you breathe, feeling short of breath while lying down, wheezing, gasping for breath, cough with foamy mucus, cold and clammy skin, anxiety, rapid heartbeats.

Rare

• Neurologic problems (such as seizures, stroke, or memory loss)
• Lung or breathing problems
• Heart problems
• Liver problems
• Kidney problems
• A recent or active infection
• slurred speech;
• fever, chills, cough, or other signs of infection;
• feeling tired or light-headed;
• fast or irregular heartbeats;
• tremor, problems with speech or muscle movement;
• headache, muscle or joint pain;
• nausea, loss of appetite;
• diarrhea, constipation;
• swelling, kidney problems;
• rash; or sleep problems (insomnia).

Drug Interaction

Pregnancy and Lactation

Pregnancy

There are no available data on TECARTUS use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with TECARTUS to assess whether TECARTUS can cause fetal harm when administered to a pregnant woman. It is not known if TECARTUS has the potential to be transferred to the fetus. Based on the mechanism of action of TECARTUS, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, TECARTUS is not recommended for women who are pregnant. Pregnancy after TECARTUS infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively.

Lactation

There is no information regarding the presence of TECARTUS in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TECARTUS and any potential adverse effects on the breastfed infant from TECARTUS or from the underlying maternal condition.

References