Brexucabtagene Autoleucel - Uses, Side Effects, and Warnings and Precautions

Overview

Brexucabtagene autoleucel is used for the treatment of mantle cell lymphoma (MCL). The drug is a CD19-directed genetically modified autologous T-cell immunotherapy available as a suspension for intravenous infusion. The drug is prepared by harvesting the T cells (T lymphocytes) of the patient itself and then genetically modified by retroviral transduction to express CAR (chimeric antigen receptor). The patient’s mononuclear cells are extracted by leukapheresis procedure. The drug was approved by the FDA (Food and Drug Administration) in 2021 for adult patients suffering from refractory or relapsed mantle cell lymphoma and acute lymphoblastic lymphoma.

Uses of Drug Brexucabtagene Autoleucel

• The drug is indicated for the treatment of refractory or relapsed MCL or mantle cell lymphoma (a rare form of non-Hodgkin’s lymphoma - cancerous B-cell) in adults.

• It is also used for treating refractory and relapsed acute lymphoblastic lymphoma (ALL) in adults.

• Treatment of leukemias.

Use In Specific Population

Pregnancy:

There is no data available on Brexucabtagene autoleucel effects on pregnant women. Also, the drug does not cause any developmental and reproductive toxicity. It is not clear if the drug can affect the fetus when administered to pregnant women. However, as per the mechanism of action of Brexucabtagene autoleucel, the transduced cells can cross the placenta, and they may cause fetal toxicity. Therefore, the drug is not recommended for pregnant women, and also those who conceive after taking Brexucabtagene autoleucel should discuss the same with the healthcare provider.

Lactation:

There is no data available regarding the presence of Brexucabtagene autoleucel in human milk, its effects on milk production, or its effects on breastfed infants. The drug should be prescribed to breastfeeding mothers after evaluating the potential health and developmental benefits and also the potential needs of the drug for the woman, and the adverse effects on the fetus and other underlying conditions.

Pediatric Use:

The safety and efficacy of Brexucabtagene autoleucel have not been established in a pediatric patient yet.

Geriatric Use:

There is no major difference between the safety and efficacy of Brexucabtagene autoleucel for MCL (mantle cell lymphoma) in young and older adults according to the clinical trial that included people of age group 65 years and 78 years.

Dose and Administration

For Intravenous Autologous Use Only: Every infusion bag of Brexucabtagene autoleucel contains 68 mL suspension of chimeric antigen receptor-positive T cells.

The drug is available in two dose forms:

• The Dose Recommended for Mantle Cell Lymphoma (MCL): The target dose of 2 × 106 CAR-positive viable T cells per kg body weight, along with a maximum of 2 × 108 CAR-positive viable T cells.

• The Dose Recommended for Acute Lymphoblastic Lymphoma (ALL): The target dose of 1 × 106 CAR-positive viable T cells per kg of body weight, along with a maximum of 1 × 108 CAR-positive viable T cells.

Administration of Dose for Mantle Cell Lymphoma (MCL): Brexucabtagene autoleucel is for intravenous autologous use only; therefore, the patient’s identity and the identifier on the infusion bag should match before administering it to the patient. If the patient-specific label information does not match, do not infuse the medication.

Pre-treatment for MCL: Lymphodepleting chemotherapy regimen of Cyclophosphamide 500 mg/m2 intravenously and Fludarabine 30 mg/m2 is given intravenously to a patient on each of the fifth, fourth, and third day before infusion of Brexucabtagene autoleucel.

Premedication for MCL: Premedicate the patient with Acetaminophen and Diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes before Brexucabtagene autoleucel infusion. The availability of Tocilizumab should be confirmed before infusing Brexucabtagene autoleucel.

Also, avoid prophylactic use of systemic corticosteroids as they may interfere with the activity of Brexucabtagene autoleucel.

For Patients

What Is Mantle Cell Lymphoma?

Mantle cell lymphoma, or MCL, is a rare type of non-Hodgkin’s lymphoma that is usually seen by the translocation in the gene CCND1. It is cancer or malignancy of the white blood cells in the body that fight infections.

What Is Brexucabtagene Autoleucel?

Brexucabtagene autoleucel is a genetically modified and CD-1-directed autologous T-cell immunotherapy used for the treatment of adult patients suffering from refractory or relapsed mantle cell lymphoma.

Why Is Brexucabtagene Autoleucel Prescribed to a Patient?

Brexucabtagene autoleucel is prescribed to a patient for treating leukemias and lymphomas. Mainly it is used to treat refractory or relapsed mantle cell lymphoma in adult patients. The drug can be given in combination with drugs to treat certain conditions. Therefore, a person should inform the doctor about all the medication they are consuming to avoid any risk of side effects.

What Precautions Should Be Taken by a Person While Starting Brexucabtagene Autoleucel?

• A person should inform the doctor about any allergic reaction to Brexucabtagene autoleucel, any other drug, or any ingredient present in Brexucabtagene autoleucel.

• The doctor should also be informed about all the prescription and non-prescription drugs, herbal supplements, vitamins, and nutritional products that a person is taking. This helps the doctor to monitor the side effects and also manage the dose adjustment if needed.

• The patient should also inform the doctor about all the past and present medical conditions if present, including kidney, liver, heart, gastro, and lung diseases.

• A woman planning to get pregnant or already conceived should not take this medication. Therefore, the doctor must be informed about the pregnancy.

• If a person is already taking Brexucabtagene autoleucel, they must inform the doctor, pharmacist, or other healthcare professionals about the same drug and how it can interact with other drugs. Therefore, to prevent adverse effects, doctors should be informed beforehand.

• Since the medication makes users a little drowsy, heavy machinery operation and driving should be avoided for at least eight weeks after taking it.

• The drug can cause symptoms of infections, such as sore throat, chills, fever, flu-like symptoms, cough, change in sputum color, pain while urinating, ear pain, and mouth sores. A person should contact the doctor immediately.

What Are the Side Effects of Brexucabtagene Autoleucel?

Side effects caused by Brexucabtagene autoleucel include:

• Fever, headache, nausea, chills.

• Rapid heart rate.

• Hypotension or low blood pressure.

• Infection.

• Cough.

• Fatigue.

• Tremors.

• Irregular heartbeats.

• Diarrhea, constipation, decreased appetite.

• Fluid retention.

• Shortness of breath.

• Insomnia.

• Motor dysfunction.

• Rash.

• Musculoskeletal pain.

• Encephalopathy (decrease in blood flow to the brain)

• Hypoxia or low blood oxygen.

• Cytokine release syndrome.

• Pleural effusion or fluid around the lungs.

• Aphasia or difficulty in speaking and understanding language.

Missed Dose:

The drug is given to a patient in the hospital setting at the scheduled intervals by the healthcare staff. Therefore, there are fewer chances of missing a dose. However, if such an incident happens, consult the doctor before taking the missed dose.

Drug Supply, Storage, and Disposal:

Brexucabtagene autoleucel is stored in a vapor phase of liquid nitrogen and then supplied in a dry shipper of liquid nitrogen. The drug is given to a patient in the hospital or clinical setting only. Therefore, a person does not have to store the drug at home. The drug is stored frozen in the vapor phase of liquid nitrogen at less than or equal to minus 150 degrees Celsius. The drug is disposed of according to the FDA (Food and Drug Administration) guidelines and protocols for safe drug disposal.

For Doctors

Clinical Pharmacology

Mechanism of Action:

Brexucabtagene autoleucel is a CD-19-directed genetically engineered T cell autologous immunotherapy that binds to CD-19, expressing normal cells and cancer cells. Studies have shown that due to the binding of anti-CD-19 CAR T cells to CD-19-expressing target cells, the CD-3 and CD-28 zeta co-stimulator domains activate signaling pathways that cause activation secretion, acquisition of effectors function, and proliferation of chemokines and cytokines. These events cause the death of CD-19-expressing cells.

Pharmacodynamics:

After the infusion of Brexucabtagene autoleucel, chemokines, cytokines, and other blood molecules show transient elevation. Peak elevation of these molecules in the blood is generally observed within a week after infusion. The levels of these molecules come back to normal baselines approximately within 28 days. The drug can cause B cell aplasia due to its on-target effects.

Pharmacokinetics:

In patients suffering from MCL, the initial rapid expansion and decline to normal baseline levels of the target dose of 2 × 106 anti-CD19 CAR T cells/kg of Brexucabtagene autoleucel in ZUMA-2, anti-CD19 CAR T cells are approximately three months. The peak levels of anti-CD19 CAR T cells usually occur within the initial 15 days after Brexucabtagene autoleucel infusion.

Ingredients:

Active Ingredients: Brexucabtagene autoleucel.

Inactive Ingredients: Albumin (human), five percent DMSO (dimethyl sulfoxide).

Dose Form and Strength:

Brexucabtagene autoleucel is available in infusion bags as cell suspensions.

• A single dose of Brexucabtagene autoleucel for mental cell lymphoma contains 2 × 106 CAR-positive viable T cells per kg of body weight, a maximum of 2 × 108 CAR-positive viable T cells (for patients 100 kg and above) in approximately 68 mL suspension in an infusion bag.

• A single dose of Brexucabtagene autoleucel for acute lymphoblastic lymphoma contains 1 × 106 CAR-positive viable T cells per kg of body weight maximum of 1 × 108 CAR-positive viable T cells (for patients 100 kg and above) in approximately 68 mL suspension in an infusion bag.

What Are the Warnings and Precautions for the Drug?

Neurological Toxicity:

The treatment with Brexucabtagene autoleucel can cause fatal and life-threatening reactions. Studies show that the median time for the neurological effects to occur is six days, ranging from one to 32 days, and a median duration of 21 days, ranging from two to 454 days, in people suffering from mantle cell lymphoma. The most common neurological symptoms include long-term tremors, encephalopathy, anxiety, dizziness, a confusional state, agitation, aphasia, and delirium. Therefore, patients of MCL should be infused with at least two doses of Tocilizumab or corticosteroids before the administration of Brexucabtagene autoleucel. The MCL patient is monitored for at least seven days in the hospital setting for CRS and four weeks after the infusion.

Cytokine Release Syndrome (CRS):

Treatment with Brexucabtagene autoleucel causes life-threatening reactions. According to some studies, CRS can occur in almost 91 percent of people with mantle cell lymphoma (MCL). The onset of CRS was noticed to be seven days, in the range of one to 13 days, and ten days was the median duration in the range of one to 50 days in MCL patients. The key manifestations of MCL included tachycardia, hypotension, fatigue, chills, headaches, hypoxia, fever, and nausea.

Therefore, doctors should infuse two doses of Tocilizumab into a patient with mantle cell lymphoma, monitor them for seven days in the hospital, and schedule a four-week follow-up post-discharge. They should also counsel the patient that cytokine release syndrome can occur at any time; therefore, they should consult the doctor immediately.

Hypersensitivity Reaction:

Brexucabtagene autoleucel can cause serious hypersensitivity reactions due to the residual Gentamicin or dimethyl sulfoxide (DMSO) present in the drug.

Prolonged Cytopenias:

Patients also experience prolonged cytopenia mainly due to Brexucabtagene autoleucel infusion and lymphodepletion chemotherapy. Studies show that people with MCL, higher or grade three cytopenias usually do not resolve within 30 days post-infusion of Brexucabtagene autoleucel and develop anemia, neutropenia, and thrombocytopenia. Therefore, doctors should monitor the blood count of the patient regularly post-infusion of Brexucabtagene autoleucel.

Secondary Malignancies:

Patients treated with Brexucabtagene autoleucel often develop secondary malignancies. Therefore, patients should be advised and monitored for life-long screening for secondary malignancies.

Hypogammaglobulinemia:

Patients receiving treatment with Brexucabtagene autoleucel often develop hypogammaglobulinemia and B cell aplasia. Studies show that almost 16 percent of people suffering from mantle cell lymphoma develop hypogammaglobulinemia. Thus, patients should be carefully monitored for immunoglobulin levels after infusing Brexucabtagene autoleucel. The case should be managed with antibiotic prophylaxis for infection control and immunoglobulin replacement.

Macrophage Activation Syndrome or Hemophagocytic Lymphohistiocytosis (MAS/HL):

This can also cause fatal and life-threatening events followed by treatment with Brexucabtagene autoleucel. The median onset time of MAS/HL is usually eight days, and the median duration is five days, with a range of six to nine and four to eight days, respectively. Patients developed neurological symptoms and CRS symptoms after the infusion of Brexucabtagene autoleucel. Therefore, a patient suffering from MAS/HL should be given proper treatment as per institutional standards.

Adverse Reactions of Brexucabtagene Autoleucel In MCL Patients:

• CRS (cytokine release syndrome).

• Encephalopathy.

• Fever.

• Tachycardia (heartbeat faster than normal).

• Severe infection.

• Musculoskeletal pain.

• Cough.

• Hypoxia (having insufficient oxygen).

• Chills.

• Tremors.

• Nausea.

• Headache.

• Constipation.

• Edema (swelling causing fluid to accumulate in the body).

• Aphasia (language disorder)

• Dyspnea (sensation of not getting enough air).

• Pleural effusion (collection of fluid in tissues).

• Motor dysfunction.

• Diarrhea.

• Fatigue.

• Insomnia.

• Rash.

Contraindications

There is no suggested contraindication for Brexucabtagene Autoleucel.