Brexucabtagene autoleucel is a chimeric antigen receptor (CAR) T-cell gene therapy. It is CD19-directed immunotherapy that works by using a patient's own genetically altered immune cells to kill B-cell cancer cells in the blood. Brexucabtagene autoleucel is indicated for use in adult patients with relapsed or refractory mantle cell lymphoma or B-cell precursor acute lymphoblastic leukemia. Cytokine release syndrome and severe neurotoxicity have been reported. Brexucabtagene autoleucel is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS. Information for this program enrollment is available at www.YescartaTecartusREMS.com or 1-844-454-5483.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Brexucabtagene autoleucel may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling brexucabtagene autoleucel; follow local biosafety guidelines applicable for disposal.
Route-Specific Administration
Injectable Administration
Visually inspect the contents of the infusion bag for any breaks or cracks before thawing. Do not infuse the contents if the bag is compromised; follow local guidelines or call Kite Pharma at 1-844-454-5483.
Intravenous Administration
-Brexucabtagene autoleucel is for autologous and intravenous use.
-Each dose of brexucabtagene autoleucel contains a maximum of 2 X 108 CAR-positive viable T-cells (mantle cell lymphoma patients) or 1 X 108 CAR-positive viable T-cells (acute lymphoblastic leukemia patients) suspended in a single patient-specific infusion bag; the total infusion bag volume is approximately 68 mL.
-Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
-Coordinate the timing of the brexucabtagene autoleucel 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 diphenhydramine (or another H1-antihistamine) approximately 60 minutes prior to the infusion; avoid corticosteroids use except in the case of a life-threatening emergency.
Preparation
-Match the patient's identity with the patient identifiers on the cassette; do not remove the product bag from the cassette if the patient-specific label does not match the intended recipient.
-Remove the product bag from the cassette; verify that the patient information on the cassette label matches the bag label.
-Put the infusion bag inside a second, sterile bag to protect against leaks and port contamination.
-Thaw the infusion bag at 37 degrees Celsius (C) using either a water bath or dry thaw method.
-Once there is no visible ice in the infusion bag, gently mix the contents of the bag to allow the clumps of cellular material to disperse.
-If visible cell clumps remain, continue to gently mix the contents of the bag; small clumps of cellular material should disperse with gentle manual mixing.
-Do not wash, spin down, and/or resuspend brexucabtagene autoleucel in new media prior to infusion.
-Storage: After thawing, give brexucabtagene autoleucel within 30 minutes if possible. The product may be stored at room temperature (20 to 25 degrees C) for up to 3 hours.
Intravenous (IV) Infusion
-Confirm the patient's identity with the patient identifiers on the infusion bag.
-Prime the tubing with normal saline prior to the infusion; do not use a leukocyte-depleting filter.
-Administer as an IV infusion within 30 minutes via gravity or a peristaltic pump until the infusion bag is empty.
-Gently agitate the product bag during the infusion to prevent cell clumping.
-Rinse the tubing with normal saline at the same infusion rate to ensure all product contents are delivered.
Coagulopathy (10%; grade 3 or higher, 2%) and bleeding (7%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Coagulopathy (17%; grade 3 or higher, 5%) and bleeding (13%; grade 3 or higher, 4%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). The term coagulopathy included disseminated intravascular coagulation (DIC) and increased international normalized ratio (INR). The term bleeding includes ocular hemorrhage including retinal hemorrhage, contusion, epistaxis, GI bleeding, hematoma, hypofibrinogenemia, intracranial bleeding, bleeding hemorrhoids, menorrhagia, petechiae, pulmonary alveolar hemorrhage, and vaginal bleeding.
Thrombosis was reported in 17% (grade 3 or higher, 4%) of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 4% of patients with relapsed or refractory acute lymphoblastic leukemia (n = 78) who received brexucabtagene autoleucel in clinical trials. The term thrombosis included deep vein thrombosis and pulmonary embolism.
Hypotension including orthostatic hypotension (57%; grade 3 or higher, 27%), sinus tachycardia (45%), bradycardia (10%), hypertension (18%; grade 3 or higher, 11%), and nonventricular arrhythmias (10%; grade 3 or higher, 4%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). The term nonventricular arrhythmias included atrial fibrillation, atrial flutter, cardiac flutter, palpitations, and supraventricular tachycardia (SVT). Hypotension (69%; grade 3 or higher, 33%), hypertension (13%; grade 3 or higher, 6%), sinus tachycardia (63%; grade 3 or higher, 6%), arrhythmias (15%; grade 3 or higher, 1%), heart failure (4%), and palpitations (3%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). The term arrhythmias included atrial fibrillation/flutter, atrial tachycardia, bradycardia, cardiac arrest, QT prolongation, T-wave inversion, pulseless electrical activity, and ventricular tachycardia.
Nausea (35%; grade 3 or higher, 1%), constipation (29%), diarrhea (28%; grade 3 or higher, 5%), decreased appetite/anorexia (26%), abdominal pain (17%), oral pain (16%), vomiting including retching (13%), dysphagia (10%; grade 3 or higher, 2%), and xerostomia (7%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). The term oral pain included gingival pain, lip pain, oral mucosal redness, and oropharyngeal pain. Nausea (41%; grade 3 or higher, 1%), diarrhea (32%; grade 3 or higher, 6%), decreased appetite/anorexia (22%; grade 3 or higher, 1%), abdominal pain (19%), constipation (24%), vomiting (21%; grade 3 or higher, 3%), dry mouth/xerostomia (6%), dysphagia (4%), and oral pain (1%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78).
Fever (94%; grade 3 or higher, 15%) and chills (41%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Fever (96%; grade 3 or higher, 38%) and chills (40%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78).
Fatigue was reported in 48% (grade 3 or higher, 1%) of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 37% (grade 3 or higher, 1%) of patients with relapsed or refractory acute lymphoblastic leukemia (n = 78) who received brexucabtagene autoleucel in clinical trials. The term fatigue included lethargy, asthenia, and malaise.
Edema was reported in 35% (grade 3 or higher, 2%) of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 29% (grade 3 or higher, 5%) of patients with relapsed or refractory acute lymphoblastic leukemia (n = 78) who received brexucabtagene autoleucel in clinical trials. The term edema included eyelid edema, fluid retention, face edema or swelling, peripheral edema, periorbital edema, peripheral swelling, and scrotal edema.
Musculoskeletal pain (37%; grade 3 or higher, 2%) and pain (17%; grade 3 or higher, 2%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). The term pain included allodynia, dysesthesia, ear pain/otalgia, facial pain, and noncardiac chest pain. Musculoskeletal pain (32%; grade 3 or higher, 5%), musculoskeletal weakness (13%; grade 3 or higher, 1%), pain (13%; grade 3 or higher, 1%), muscle cramps/spasms (4%), and musculoskeletal stiffness (3%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). The term musculoskeletal pain included arthralgia, back pain, bone pain, coccydynia, dysarthria, flank pain, groin pain, myalgia, neck pain, and extremity pain.
Motor dysfunction (17%; grade 3 or higher, 4%) was reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). The term motor dysfunction included asthenia, intensive care-acquired weakness, decreased mobility, muscle twitching, muscular weakness, and myopathy.
Hypogammaglobulinemia and serious infection including life-threatening and fatal opportunistic infections (e.g., HHV-6 infection, progressive multifocal leukoencephalopathy) have been reported with brexucabtagene autoleucel therapy. Monitor patients for signs and symptoms of infection prior to and after the brexucabtagene autoleucel infusion; evaluate for opportunistic infections, particularly in patients with neurologic events. Administer prophylactic antimicrobial therapy and other anti-infective therapy as medically indicated. Additionally, monitor immunoglobulin levels after brexucabtagene autoleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. Hypogammaglobulinemia including decreased immunoglobulin G levels (16%; grade 3 or higher, 1%) and infection (56%; grade 3 or higher, 30%) including pathogen unspecified (43%; grade 3 or higher, 24%), viral (18%; grade 3 or higher, 4%), bacterial (13%; grade 3 or higher, 6%), and fungal (9%) infections occurred in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Hypogammaglobulinemia (9%) and infection (44%; grade 3 or higher, 30%) including pathogen unspecified (28%; grade 3 or higher, 22%), viral (6%), bacterial (15%; grade 3 or higher, 8%), and fungal (13%; grade 3 or higher, 5%) infections were reported in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). Fatal sepsis and pneumonia were reported. Fungal infection included oral candidiasis. The infection term pathogen unspecified included conjunctivitis, device-related infection, mucosal infection, naso-pharyngitis, parotitis, pneumonia, sepsis/septic shock, sinusitis, upper respiratory tract infection, and urinary tract infection.
Insomnia (21%), delirium (18%; grade 3 or higher, 5%), and anxiety (16%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Insomnia (13%), delirium (18%; grade 3 or higher, 5%), and anxiety (12%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). The term delirium included agitation, delusion, disorientation, hallucinations, hypomania, irritability, nervousness, and personality change.
Nephrotoxicity including renal insufficiency (18%; grade 3 or higher, 9%) and decreased urine output including urinary retention (11%; grade 3 or higher, 1%) occurred in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). The term renal insufficiency included acute kidney injury and increased serum creatinine. Renal impairment occurred in 6% of patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78).
Hypoxia (40%; grade 3 or higher, 20%), cough including upper-airway cough syndrome (38%), dyspnea including exertional dyspnea (24%; grade 3 or higher, 6%), pleural effusion (21%; grade 3 or higher, 5%), respiratory failure (6%), and pulmonary edema (4%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Hypoxia (31%; grade 3 or higher, 23%), cough (12%), dyspnea (12%; grade 3 or higher, 1%), respiratory failure (9%), pulmonary edema (6%), pleural effusion (4%), and pneumonitis (4%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in a nonrandomized trial (n = 78).
Rash was reported in 22% (grade 3 or higher, 4%) of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 31% of patients with relapsed or refractory acute lymphoblastic leukemia (ALL: n = 78) who received brexucabtagene autoleucel in clinical trials. The term rash included erythema, erythematous rash, bullous rash/dermatitis, pruritus, maculopapular rash, pustular rash, and urticaria. Additionally, skin lesion (4%), decubitus ulcer (3%), dry skin/xerosis (3%), skin ulcer (3%), alopecia (1%), hyperhidrosis (1%), drug hypersensitivity (1%), and skin hyperpigmentation (1%) were reported in brexucabtagene autoleucel-treated patients with ALL.
Dehydration was reported in 6% of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 5% of patients with relapsed or refractory acute lymphoblastic leukemia (n = 78) who received brexucabtagene autoleucel in clinical trials.
Severe hematologic toxicity following lymphodepleting chemotherapy and brexucabtagene autoleucel administration was commonly reported in clinical trials. Monitor complete blood counts regularly until hematologic recovery. Grade 3 or higher cytopenias not resolved by day 30 were reported in 55% of patients with mantle cell lymphoma (MCL; n = 82) and 20% of responding patients with acute lymphoblastic leukemia (ALL; n = 35); prolonged grade 3 or higher cytopenias included thrombocytopenia (38% and 12%, respectively), neutropenia (37% and 12%), and anemia (17% MCL only). Grade 3 or 4 lymphopenia (86%), leukopenia (95%), neutropenia (95%), anemia (55%), and thrombocytopenia (63%) were reported in patients with relapsed or refractory MCL who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Grade 3 or 4 lymphopenia (96%), leukopenia (99%), neutropenia (98%), anemia (77%), and thrombocytopenia (87%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). Additionally, febrile neutropenia was reported with brexucabtagene autoleucel therapy in 6% of patients with MCL and 35% of patients with ALL. Febrile neutropenia sometimes occurred concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated.
Grade 3 or 4 hypophosphatemia (30%), hypocalcemia (21%), hyponatremia (16%), and hypokalemia (10%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Grade 3 or 4 hypophosphatemia (47%), hypocalcemia (22%), hyponatremia (19%), and hypokalemia (13%) occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78).
Grade 3 or 4 hyperuricemia was reported in 17% of patients with relapsed or refractory mantle cell lymphoma (n = 82) and 19% of patients with relapsed or refractory acute lymphoblastic leukemia (n = 78) who received brexucabtagene autoleucel in clinical trials.
Grade 3 or 4 elevated hepatic enzymes including increased AST and ALT levels were reported in 15% of patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Grade 3 or 4 increased AST (23%) and ALT (31%) levels, increased direct bilirubin level (19%), and hyperbilirubinemia (10%) occurred in patients with acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78).
Antibody formation to FMC63 (the originating antibody of the anti-CD19 chimeric antigen receptor) may occur in patients who receive brexucabtagene autoleucel. In a nonrandomized trial (n = 82), 17 patients with relapsed or refractory mantle cell lymphoma tested positive for antibodies in an initial screening assay; however, all 17 patients were antibody negative at all time points when evaluated in another confirmatory assay. Antibody formation was found in 16 patients with acute lymphoblastic leukemia (n = 100) in another clinical trial; however, only 2 evaluable patients were confirmed to be antibody-positive after treatment.
Cytokine release syndrome (CRS) occurred in 91% (grade 3 or higher, 18%) of patients with relapsed or refractory mantle cell lymphoma (MCL; n = 82) and 92% (grade 3 or higher, 26%) of patients with relapsed or refractory acute lymphoblastic leukemia (ALL; n = 78) who received brexucabtagene autoleucel in clinical trials. One patient with MCL had a fatal CRS event; 3 patients with ALL had ongoing CRS at the time of death. Symptoms of CRS included fever (93%), hypotension (62%), tachycardia (59%), hypoxia (31%), chills (32%), headache (21%), fatigue (20%), and nausea (13%). Serious events that may be associated with CRS include hypotension, fever, hypoxia, tachycardia, and dyspnea. Observe patients closely for signs or symptoms of CRS daily for at least 7 days in MCL patients and 14 days in ALL patients in a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS. In patients with MCL and ALL, the median CRS time to onset was 3 days (range, 1 to 13 days) and 5 days (range, 1 to 12 days), respectively; the median duration of CRS was 10 days (range, 1 to 50 days) and 8 days (range, 2 to 63 days), respectively.
Neurotoxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 81% (grade 3 or higher, 37%) of patients with relapsed or refractory mantle cell lymphoma (MCL; n = 82) and 87% (grade 3 or higher, 35%) of patients with relapsed or refractory acute lymphoblastic leukemia (ALL; n = 78) who received brexucabtagene autoleucel in clinical trials. Neurologic toxicity was ongoing at the time of death in 3 patients with MCL and 6 patients with ALL. Neurologic toxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Symptoms of neurotoxicity included encephalopathy (57%), headache (37%), tremor (34%), confusion (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%); serious events that occurred after therapy included encephalopathy, aphasia, confusion, and seizures. Monitor patients closely for signs or symptoms of neurotoxicity/ICANS daily for at least 7 days in MCL patients and 14 days in ALL patients in a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion; administer supportive care and/or corticosteroids as indicated. Monitor patients with grade 2 or higher neurotoxicity including ICANS with continuous cardiac telemetry and pulse oximetry. Consider nonsedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis in these patients. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities. Encephalopathy (51%; grade 3 or higher, 24%), tremor (38%; grade 3 or higher, 2%), headache including migraine (35%; grade 3 or higher, 1%), aphasia (20%; grade 3 or higher, 7%), dizziness including syncope (18%; grade 3 or higher, 6%), neuropathy (13%; grade 3 or higher, 2%), ataxia (7%), seizures (5%), and increased intracranial pressure (2%) were reported in patients with relapsed or refractory mantle cell lymphoma who received brexucabtagene autoleucel in a nonrandomized trial (n = 82). Encephalopathy (63%; grade 3 or higher, 27%), headache (38 1%), tremor (29 1%), dizziness including syncope (13 1%), seizure (8%), ataxia (5%), peripheral neuropathy (4%), myoclonus (3%), paraparesis (3%), brain/cerebral edema (1%), brain herniation (1%), cauda equina syndrome (1%), and monoplegia (1%) occurred in patients with acute lymphoblastic leukemia who received brexucabtagene autoleucel in another nonrandomized trial (n = 78). Fatal cerebral edema was reported. The term encephalopathy included altered consciousness, amnesia, aphagia, balance disorder, cognitive disorder/impaired cognition, confusion, attention disturbance, dysgraphia, dyskinesia, immune effector cell-associated neurotoxicity syndrome, memory impairment, mental status changes, speech disorder, neurotoxicity, and somnolence/drowsiness. The term neuropathy included hyperesthesia, peripheral neuropathy, and paresthesias. In patients with MCL and ALL, the median times to onset of neurotoxicity were 6 days (range, 1 to 32 days) and 7 days (range, 1 to 51 days), respectively; the median durations of neurotoxicity were 21 days (range, 2 to 454 days) and 15 days (range, 1 to 397 days), respectively.
Grade 3 or 4 hyperglycemia occurred in 22% of patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in a clinical trial (n = 78).
Visual impairment occurred in 9% of patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in a clinical trial (n = 78).
Grade 3 or 4 hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) occurred in 3 patients (4%) with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in a clinical trial (n = 78). All patients who developed HLH/MAS had concurrent cytokine release syndrome symptoms and neurologic events after brexucabtagene autoleucel administration. Treat HLH/MAS using institutional guidelines. The median time to HLH/MAS onset was 8 days (range, 6 to 9 days) and the median duration was 5 days (range, 2 to 8 days).
Tumor lysis syndrome (TLS) occurred in 1% of patients with relapsed or refractory acute lymphoblastic leukemia who received brexucabtagene autoleucel in a clinical trial (n = 78).
T-cell malignancies, including chimeric antigen receptor (CAR)-positive lymphoma, have been reported in patients who received treatment with CD19-directed autologous CAR T-cell immunotherapy in clinical trials and postmarketing surveillance. If a patient develops a new primary malignancy following treatment with brexucabtagene autoleucel, contact Kite at 1-844-454-5483 for instructions on how to collect patient samples for testing for the presence of the CAR transgene. Report suspected adverse events, including T-cell malignancies, to the FDA.
Infusion-related reactions were reported in postmarketing surveillance of brexucabtagene autoleucel.
Life-threatening cases of cytokine release syndrome (CRS) have been reported with brexucabtagene autoleucel. Do not administer brexucabtagene autoleucel in patients with active infection or inflammatory disorders. Confirm that 2 tocilizumab doses are available at the facility site prior to the brexucabtagene autoleucel infusion. Closely observe for signs or symptoms of CRS daily for at least 7 days in mantle cell lymphoma patients and 14 days in acute lymphoblastic leukemia patients at a certified healthcare facility following the infusion, and continue monitoring for at least 4 weeks after the infusion. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS.
Severe neurotoxicity (e.g., immune effector cell-associated neurotoxicity syndrome [ICANS], encephalopathy, seizures, aphagia) has been reported with brexucabtagene autoleucel therapy. Neurologic toxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Most cases of neurotoxicity occurred within 8 weeks of the brexucabtagene autoleucel infusion. Advise patients to avoid driving or operating machinery or performing other dangerous duties for 8 weeks after the brexucabtagene autoleucel infusion due to the risk of neurologic events (e.g., mental status changes, seizures) and altered or decreased consciousness or coordination. Observe closely for signs or symptoms of neurotoxicity daily for at least 7 days in mantle cell lymphoma patients or 14 days in acute lymphoblast leukemia patients at a certified healthcare facility following the infusion, and continue monitoring for at least 4 weeks after the infusion. Exclude other causes of neurologic symptoms. Administer supportive care and/or corticosteroids as indicated. Monitor patients with grade 2 or higher neurotoxicity with continuous cardiac telemetry and pulse oximetry. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis in these patients. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities.
Because of the risk of cytokine release syndrome and neurological toxicities, use requires an experienced clinician with training in the management of these toxicities. Brexucabtagene autoleucel administration also requires a specialized care setting that is enrolled in the YESCARTA and TECARTUS 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 brexucabtagene autoleucel infusion).
Allergic reactions including anaphylaxis may occur with brexucabtagene autoleucel therapy. Premedicate patients with acetaminophen and diphenhydramine prior to the brexucabtagene autoleucel infusion. Reactions may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in the product. Use brexucabtagene autoleucel with caution in patients with a history of DMSO or aminoglycoside hypersensitivity.
Vaccination with live viral vaccines during or following treatment with brexucabtagene autoleucel has not been studied. Live virus vaccination is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and until immune recovery after brexucabtagene autoleucel therapy.
Prolonged cytopenias (e.g., anemia, neutropenia, and thrombocytopenia) have been reported following brexucabtagene autoleucel therapy. Monitor complete blood counts regularly until hematologic recovery.
Due to the risk of a new primary malignancy, including T-cell malignancies, life-long monitoring is recommended following brexucabtagene autoleucel therapy.
Hypogammaglobulinemia and B-cell aplasia may occur with brexucabtagene autoleucel therapy. Monitor immunoglobulin levels after brexucabtagene autoleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines.
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 brexucabtagene autoleucel. Screen all patients for HBV, hepatitis C virus, and HIV prior to cell collection (leukapheresis).
Serious infections including bacterial infection, fungal infection, and viral infection have been reported with brexucabtagene autoleucel therapy; some cases were life-threatening or fatal. Monitor patients for signs and symptoms of infection prior to and after the brexucabtagene autoleucel infusion; administer prophylactic antimicrobial therapy and other anti-infective therapy as medically indicated. Febrile neutropenia has also been reported following brexucabtagene autoleucel therapy; it may occur concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated.
Patients who receive brexucabtagene autoleucel should avoid cell, organ, tissue, and blood donation.
False-positive HIV test results have been reported in patients who received treatment with chimeric antigen receptor (CAR) T-cell immunotherapy, such as brexucabtagene autoleucel. The use of gammaretroviral or lentiviral vectors to reprogram T-cells as part of CAR T-cell therapy 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.
Pregnancy should be avoided by females of reproductive potential during brexucabtagene autoleucel treatment; pregnancy after brexucabtagene autoleucel administration should be discussed with the treating physician. There are no available data with brexucabtagene autoleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if brexucabtagene autoleucel 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.
Counsel patients about the reproductive risk and contraception requirements during brexucabtagene autoleucel treatment. Sexually active females of reproductive potential should undergo pregnancy testing prior to brexucabtagene autoleucel therapy; confirm negative results. 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 brexucabtagene autoleucel. There are no data on the effect of brexucabtagene autoleucel on fertility.
It is not known if brexucabtagene autoleucel is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for brexucabtagene autoleucel and any potential adverse effects on the breast-fed infant from brexucabtagene autoleucel or from the underlying maternal condition.
For the treatment of mantle cell lymphoma (MCL):
NOTE: Brexucabtagene autoleucel has been designated an orphan drug by the FDA for the treatment of MCL.
-for the treatment of relapsed or refractory MCL:
Intravenous dosage:
Adults: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose. Premedicate patients with acetaminophen and diphenhydramine (or another H1-antihistamine) approximately 60 minutes prior to the brexucabtagene autoleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The primary endpoint of objective response rate (assessed by an independent review committee) was 91% in 68 patients with relapsed or refractory mantle cell lymphoma (MCL) who received a single infusion of brexucabtagene autoleucel in a multicenter, phase 2 trial (the ZUMA-2 trial). The complete response rate was 68%. At a median follow-up time of 35.6 months (range, 25.9 to 56.3 months), the median duration of response was 28.2 months, the median progression-free survival (PFS) time was 25.8 months, and the median overall survival (OS) time was 46.6 months. Additionally, the estimated 24-month PFS rate was 52.9% and the 30-month OS rate was 60.3%. Following leukapheresis and T-cell collection, all patients had lymphocyte depletion with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (500 mg/m2 IV daily for 3 doses); each was given on the fifth, fourth, and third days prior to the brexucabtagene autoleucel infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was permitted at the investigator's discretion in patients with a high disease burden. In this study, eligible patients (median age, 65 years; range, 38 to 79 years) had received prior therapy that must have included anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and a Bruton tyrosine kinase (BTK) inhibitor (e.g., ibrutinib or acalabrutinib); 97% of patients had stage III or IV disease, 43% of patients had received an autologous stem-cell transplant, and 81% of patients had received at least 3 prior therapies (range, 1 to 5 therapies).
For the treatment of acute lymphocytic leukemia (ALL):
NOTE: Brexucabtagene autoleucel has been designated an orphan drug by the FDA for the treatment of acute lymphoblastic leukemia.
-for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia:
Intravenous dosage:
Adults: 1 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 1 X 108 CAR-positive viable T-cells) as a single IV dose. Premedicate patients with acetaminophen and diphenhydramine (or another H1-antihistamine) approximately 60 minutes prior to the brexucabtagene autoleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The primary endpoint of complete remission (CR) including CR with incomplete hematological recovery (Cri) was 71% in 55 evaluable patients with relapsed or refractory acute lymphoblastic lymphoma who received a single infusion of brexucabtagene autoleucel in a multicenter, phase 2 trial (the ZUMA-3 trial). The CR rate was 56%. An allogeneic stem-cell transplant (SCT) was given as consolidation therapy in 10 patients (18%). At a median follow-up time of 16.4 months, the median duration of response was 12.8 months, relapse-free survival (RFS) was 11.6 months, and overall survival (OS) was 18.2 months. The 12-month OS rate was 71%. Following leukapheresis and T-cell collection, all patients had lymphocyte depletion with fludarabine (25 mg/m2 IV over 30 minutes daily for 3 doses; given on days -4, -3, and -2) and cyclophosphamide (900 mg/m2 IV over 60 minutes for 1 dose on day -2) prior to the brexucabtagene autoleucel infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was permitted; 93% of patients received bridging therapy. Patients (median age, 40 years; range, 18 to 84 years) had received a median of 2 prior therapies; 27% of patients had Philadelphia chromosome-positive disease, 42% of patients had received an allogeneic SCT, and 47% of patients had received at least 3 prior therapies.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Cytokine Release Syndrome (CRS)
NOTE: Do not exceed 3 tocilizumab doses in a 24-hour period. Do not exceed 4 doses if there is no clinical improvement in CRS.
Grade 1 toxicity (i.e., fever, nausea, fatigue, headache, myalgia, malaise): If there is no improvement within 24 hours, administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg).
Grade 2 toxicity (i.e., oxygen requirement less than 40% FiO2, hypotension responsive to fluids or a low-dose of 1 vasopressor agent, or grade 2 organ toxicity): Administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg); repeat tocilizumab 8 mg/kg IV every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. If there is no improvement within 24 hours after starting tocilizumab, start methylprednisolone 1 mg/kg IV twice daily or dexamethasone 10 mg IV every 6 hours. Continue corticosteroids until the toxicity resolves to grade 1 or less, then taper the corticosteroid. Discontinue tocilizumab and taper corticosteroids if toxicity is improving.
Grade 3 toxicity (i.e., oxygen requirement of 40% FiO2 or greater, hypotension requiring high-dose or multiple vasopressor agents, grade 3 organ toxicity, or grade 4 transaminitis): Administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg); repeat tocilizumab 8 mg/kg IV every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. Start methylprednisolone 1 mg/kg IV twice daily or dexamethasone 10 mg IV every 6 hours. Continue corticosteroids until the toxicity resolves to grade 1 or less, then taper the corticosteroid. If the toxicity is not improving, give methylprednisolone 1,000 mg IV daily for 3 days. Discontinue tocilizumab and taper corticosteroids if toxicity is improving.
Grade 4 toxicity (i.e., requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or grade 4 organ toxicity (excluding transaminitis): Consider intensive care supportive therapy. Administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg); repeat tocilizumab 8 mg/kg IV every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. Start methylprednisolone 1,000 mg IV daily for 3 days. If the toxicity improves, begin methylprednisolone 1 mg/kg IV twice daily or dexamethasone 10 mg IV every 6 hours. Continue corticosteroids until the toxicity resolves to grade 1 or less, then taper the corticosteroid. If the toxicity is not improving, consider alternate immunosuppressants. Discontinue tocilizumab and taper corticosteroids if toxicity is improving.
Neurologic Toxicity
NOTE: Consider seizure prophylaxis with a non-sedating anti-seizure medication (e.g., levetiracetam) for grade 2 or higher neurotoxicity.
Grade 1 toxicity (e.g., mild drowsiness or sleepiness, mild disorientation, mild limiting of activities of daily living (ADLs), dysphagia that does not impair the ability to communicate): If no concurrent CRS, administer supportive care only. In patients with concurrent CRS, administer tocilizumab as per the management of grade 1 CRS toxicity.
Grade 2 toxicity (e.g., moderate drowsiness or sleepiness that limits instrumental ADLs, moderate disorientation, encephalopathy that limits instrumental ADLs, moderate dysphagia that impairs ability to communicate spontaneously, seizures): If no concurrent CRS, start dexamethasone 10 mg IV every 6 hours until the toxicity resolves to grade 1 or less; taper corticosteroids when toxicity improves. In patients with concurrent CRS, administer tocilizumab as per the management of grade 2 CRS toxicity. If there is no improvement in 24 hours after starting tocilizumab, add dexamethasone 10 mg IV every 6 hours until the toxicity resolves to grade 1 or less, then taper corticosteroids. Discontinue tocilizumab when toxicity improves. If toxicity is not improving, manage according to grade 3 neurotoxicity.
Grade 3 toxicity (e.g., somnolence resulting in obtundation or stupor, severe disorientation, encephalopathy that limits self-care ADLs, dysphagia resulting in severe receptive or expressive characteristics that impairs ability to read, write, or communicate intelligibly): If no concurrent CRS, start dexamethasone 10 mg IV every 6 hours until the toxicity resolves to grade 1 or less, then taper corticosteroids. If toxicity is not improving, manage according to grade 4 neurotoxicity. In patients with concurrent CRS, administer tocilizumab as per the management of grade 2 CRS toxicity. Starting with the first tocilizumab dose, give dexamethasone 10 mg IV every 6 hours until the toxicity resolves to grade 1 or less, then taper corticosteroids. Discontinue tocilizumab when toxicity improves; continue management as with grade 2 toxicity. If toxicity is not improving, manage according to grade 4 neurotoxicity.
Grade 4 toxicity (e.g., life-threatening consequences, urgent intervention indicated, mechanical ventilation requirement, consider cerebral edema): If no concurrent CRS, start methylprednisolone 1,000 mg IV daily for 3 days. If the toxicity improves, begin dexamethasone 10 mg IV every 6 hours until the toxicity resolves to grade 1 or less, then taper corticosteroids. If the toxicity is not improving, consider alternate immunosuppressants. In patients with concurrent CRS, administer tocilizumab as per the management of grade 2 CRS toxicity. Starting with the first tocilizumab dose, give methylprednisolone 1,000 mg IV daily for 3 days. If toxicity is improving, continue management as with grade 3 toxicity. If toxicity is not improving, consider alternate immunosuppressants.
Maximum Dosage Limits:
-Adults
Mantle cell lymphoma: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose.
Acute lymphoblastic leukemia: 1 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 1 X 108 CAR-positive viable T-cells) as a single IV dose.
-Geriatric
Mantle cell lymphoma: 2 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 2 X 108 CAR-positive viable T-cells) as a single IV dose.
Acute lymphoblastic leukemia: 1 X 106 CAR-positive viable T-cells per kg of body weight (maximum dose of 1 X 108 CAR-positive viable T-cells) as a single IV dose.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Chikungunya Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Intranasal Influenza Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Rotavirus Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Typhoid Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during brexucabtagene autoleucel therapy, and prior to immune recovery following treatment with brexucabtagene autoleucel. 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.
Brexucabtagene autoleucel 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 domains, CD28 and CD3-zeta, activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. The binding of CAR to CD19 activates brexucabtagene autoleucel 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, the cells are genetically modified using retroviral transduction to express a CAR comprised of a murine anti-CD19 single chain variable fragment linked to CD28 and CD3-zeta co-stimulatory domains.
To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis; enriched; activated with anti-CD3 antibody in the presence of IL-2; transduced with the replication incompetent retroviral vector containing the anti-CD19 CAR transgene; expanded to large numbers in a cell culture; and then washed, formulated into a suspension, and cryopreserved.
Brexucabtagene autoleucel is administered intravenously. The number of anti-CD19 chimeric antigen receptor (CAR) T-cells in blood correlated with objective response in patients with mantle cell lymphoma and with complete remission in patients with acute lymphoblastic leukemia following brexucabtagene autoleucel administration in clinical trials. The time to peak anti-CD19 CAR T-cell levels occurred within 15 days following the brexucabtagene autoleucel infusion.
Pharmacodynamics: Peak levels of cytokines and chemokines (e.g., IL-6, IL-8, IL-10, IL-15, TNF-alpha, IFN-gamma, and sIL2R-alpha) were observed within 8 days of the brexucabtagene autoleucel infusion; these levels typically returned to baseline within 28 days.
-Route-Specific Pharmacokinetics
Intravenous Route
In patients with mantle cell lymphoma, the median anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax level was higher (102.4 vs. 12 cells/microliter (microL)) in 51 patients who achieved an objective response with brexucabtagene autoleucel therapy compared with 8 patients who were nonresponders in a nonrandomized trial. Additionally, the median anti-CD19 CAR T-cell AUC(0-28 days) value was higher (1,487 vs. 169.5 cells/microL x days) in responders. In patients with acute lymphoblastic leukemia, the median anti-CD19 CAR T-cell Cmax level was 38.4 cells/ microL in 32 patients who achieved an overall complete remission (CR) and 0.5 cells/microL in 17 patients who did not have an overall CR in a nonrandomized trial; the median anti-CD19 CAR T-cell AUC(0-28 days) values were 424 and 7.9 cells/microL X days, respectively.
-Special Populations
Geriatric
The median anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax and AUC(0-28 days) values were lower in patients with mantle cell lymphoma aged 65 years and older (n = 39; Cmax, 74.1 cells/microL; AUC, 876.5 cells/microL x days) who received brexucabtagene autoleucel compared with patients younger than 65 years (n = 28; Cmax, 112.5 cells/microL; AUC, 1,640.2 cells/microL x days) in a nonrandomized trial.
Gender Differences
Gender had no significant impact on brexucabtagene autoleucel AUC(0-28 days) or Cmax values in patients with mantle cell lymphoma.
Other
Immunosuppressive therapy
In patients with mantle cell lymphoma, the median anti-CD19 chimeric antigen receptor (CAR) T-cell Cmax and AUC(0-28 days) values were higher in patients who received brexucabtagene autoleucel and immunosuppressive therapy with tocilizumab alone (n = 10; Cmax, 86.5 cells/microL; AUC, 1,888.9 cells/microL x days) or tocilizumab plus corticosteroids (n = 37; Cmax, 167.2 cells/microL; AUC, 1,996 cells/microL x days) compared with patients who did not receive immunosuppressive therapy with tocilizumab or corticosteroids (n = 18; Cmax, 24.7 cells/microL; AUC, 360.4 cells/microL x days) in a nonrandomized trial. In patients with acute lymphoblastic leukemia, the anti-CD19 CAR T-cell Cmax and AUC(0-28 days) values were higher in patients who received tocilizumab alone (n = 9; Cmax, 11.2 cells/microL; AUC, 137.4 cells/microL x days) or tocilizumab plus corticosteroids (n = 34; Cmax, 49.2 cells/microL; AUC, 454.1 cells/microL x days) compared with patients who did not receive immunosuppressive therapy with tocilizumab or corticosteroids (n = 11; Cmax, 5.7 cells/microL; AUC, 60.7 cells/microL x days) in a nonrandomized trial.