Tecartus - Drug Monograph

Introduction

Tecartus (brexucabtagene autoleucel) is a CD19-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. It represents a groundbreaking advancement in the treatment of certain hematologic malignancies, specifically engineered to recognize and eliminate CD19-expressing cancer cells. Approved by the FDA in 2020, Tecartus is among the first CAR-T cell therapies demonstrating significant efficacy in challenging B-cell malignancies.

Mechanism of Action

Tecartus works through a sophisticated immunologic mechanism:

• Autologous T-cell collection: Patient's T-cells are collected via leukapheresis
• Genetic modification: T-cells are genetically engineered to express a CAR targeting CD19 antigen
• CAR structure: Contains an anti-CD19 single-chain variable fragment (scFv) coupled to CD28 costimulatory and CD3-zeta T-cell activation domains
• Target recognition: Engineered CAR T-cells recognize and bind to CD19 antigen on malignant B-cells
• T-cell activation: Binding triggers T-cell activation, proliferation, and cytotoxic response
• Target cell elimination: Activated CAR T-cells induce apoptosis of CD19+ cells through:

- Perforin/granzyme-mediated cytotoxicity - Fas/FasL pathway activation - Cytokine release (IFN-γ, TNF-α)

Indications

FDA-approved indications:

• Mantle cell lymphoma (MCL): For adult patients with relapsed or refractory MCL who have received at least two prior lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor
• B-cell acute lymphoblastic leukemia (ALL): For adult patients (≥18 years) with relapsed or refractory B-cell precursor ALL

Dosage and Administration

• Fixed dose of 2 × 10^6 CAR-positive viable T-cells per kg body weight
• Maximum dose: 2 × 10^8 CAR-positive viable T-cells

1. Leukapheresis: T-cell collection 2-4 weeks before infusion 2. Manufacturing: 3-4 weeks for genetic modification and expansion 3. Lymphodepleting chemotherapy: - Fludarabine 25 mg/m²/day for 3 days - Cyclophosphamide 900 mg/m²/day for 3 days - Administered 2-7 days before infusion 4. Infusion: - Single intravenous infusion - Premedication with acetaminophen and diphenhydramine - Administer over approximately 30 minutes - Must be completed within 30 minutes of thawing

• Renal impairment: No formal studies; use with caution
• Hepatic impairment: No formal studies; use with caution
• Elderly: No dosage adjustment required
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• CAR T-cells expand rapidly post-infusion (peak at 10-14 days)
• Persistence detectable for months to years in responders
• B-cell aplasia serves as pharmacodynamic marker

• Primarily distributes to bone marrow, lymphoid tissues, and tumor sites
• Crosses blood-brain barrier (relevant for CNS involvement)

• Cellular elimination mechanisms
• Half-life variable among patients

Contraindications

• Hypersensitivity to brexucabtagene autoleucel or any component of formulation
• Active uncontrolled infection
• Pregnancy (based on mechanism and potential risks)

Warnings and Precautions

1. Cytokine Release Syndrome (CRS): - Occurrence: >90% of patients - Grade ≥3: 15-25% - May be fatal - Requires prompt management with tocilizumab and/or corticosteroids

2. Neurologic Toxicity: - Occurrence: >80% of patients - Grade ≥3: 25-35% - Includes immune effector cell-associated neurotoxicity syndrome (ICANS) - May be fatal

• Prolonged cytopenias: ≥ Grade 3 cytopenias lasting >28 days
• Hypogammaglobulinemia: Requires IVIG replacement
• Secondary malignancies: Theoretical risk of insertional oncogenesis
• Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)
• Tumor lysis syndrome
• Serious infections
• Hypersensitivity reactions

Drug Interactions

• Corticosteroids: May interfere with CAR T-cell expansion and efficacy (avoid prophylactic use)
• Cytokine inhibitors (tocilizumab): Used for toxicity management without affecting efficacy
• Lymphodepleting chemotherapy: Essential for optimal CAR T-cell expansion
• Live vaccines: Contraindicated during and after treatment
• Immunosuppressive therapies: May affect CAR T-cell function

Adverse Effects

• Pyrexia (93%)
• Cytokine release syndrome (91%)
• Hypotension (69%)
• Tachycardia (66%)
• Fatigue (64%)
• Headache (57%)
• Nausea (53%)
• Edema (51%)
• Infection (48%)
• Neurologic events (87%)

• Grade 3-4 cytopenias (neutropenia, thrombocytopenia, anemia)
• Severe infections
• Life-threatening CRS and neurologic toxicity
• Prolonged cytopenias
• Tumor lysis syndrome

Monitoring Parameters

• Comprehensive metabolic panel
• Complete blood count with differential
• Infectious disease screening
• Cardiac function assessment
• Neurologic evaluation

• Daily for first 7-10 days:

- Temperature and vital signs - Oxygen saturation - Neurologic assessment (using ICANS tool) - CBC, electrolytes, renal function, LFTs - Inflammatory markers (CRP, ferritin)

• Frequent monitoring:

- CAR T-cell expansion (qPCR) - B-cell aplasia (flow cytometry) - Immunoglobulin levels - Infection surveillance

• Monthly CBC and metabolic panel for first year
• Quarterly immunoglobulin levels
• Regular assessment for secondary malignancies
• Vaccination status and need for revaccination

Patient Education

• Understand the risk of CRS and neurotoxicity and report immediately:

- Fever ≥38°C - Chills or rigors - Confusion or difficulty speaking - Dizziness or lightheadedness - Shortness of breath

• Avoid driving or operating machinery for 8 weeks
• Do not receive live vaccines
• Practice strict infection prevention
• Report any signs of infection promptly
• Plan for frequent follow-up visits

• Maintain adequate hydration
• Follow a balanced diet
• Avoid alcohol consumption
• Use reliable contraception (for both males and females)

• Ensure proximity to treatment center for first 4 weeks
• Have emergency contact information readily available
• Understand when to seek immediate medical attention

References

1. FDA Prescribing Information: Tecartus (brexucabtagene autoleucel) 2. Wang M, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020;382(14):1331-1342. 3. Shah BD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. 4. Neelapu SS, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. 5. NCCN Guidelines: B-Cell Lymphomas and Acute Lymphoblastic Leukemia 6. Lee DW, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.