Breyanzi - Drug Monograph

Introduction

Breyanzi (lisocabtagene maraleucel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of certain hematologic malignancies. As an innovative cellular immunotherapy, Breyanzi represents a significant advancement in personalized cancer treatment, harnessing the patient's own genetically modified T-cells to target and eliminate cancer cells.

Mechanism of Action

Breyanzi is an autologous, genetically modified cellular immunotherapy that utilizes CAR T-cell technology. The drug works through the following mechanism:

• T-cells are collected from the patient via leukapheresis and genetically engineered to express a CAR specific for CD19
• The CAR consists of an anti-CD19 single-chain variable fragment (scFv) extracellular domain fused to intracellular T-cell signaling domains (4-1BB costimulatory domain and CD3-zeta activation domain)
• Upon reinfusion, these engineered T-cells recognize and bind to CD19-expressing target cells
• Binding triggers T-cell activation, proliferation, and cytotoxic activity against CD19-positive malignant B-cells
• The 4-1BB costimulatory domain enhances T-cell persistence and antitumor activity

Indications

Breyanzi is FDA-approved for the following indications:

• Treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including:

- Diffuse large B-cell lymphoma (DLBCL) not otherwise specified - High-grade B-cell lymphoma - Primary mediastinal large B-cell lymphoma - Follicular lymphoma grade 3B

• Treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma after at least two prior therapies (including a Bruton tyrosine kinase inhibitor)

Dosage and Administration

• The target dose is 50-110 × 10^6 CAR-positive viable T cells
• Administered as a single intravenous infusion

1. Leukapheresis to collect patient T-cells 2. Manufacturing process (3-4 weeks) 3. Lymphodepleting chemotherapy (fludarabine 30 mg/m²/day and cyclophosphamide 300 mg/m²/day for 3 days) 4. Breyanzi infusion 2-7 days after completion of lymphodepletion

• Renal impairment: No specific dosage adjustments recommended
• Hepatic impairment: No specific dosage adjustments recommended
• Elderly: Use with caution due to increased risk of severe adverse reactions
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Hypersensitivity to lisocabtagene maraleucel or any component of the formulation
• Active uncontrolled infection
• Pregnancy

Warnings and Precautions

• Cytokine Release Syndrome (CRS): May be life-threatening or fatal
• Neurologic Toxicities: May be life-threatening or fatal
• Secondary hematological malignancies have occurred
• Breyanzi is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS)

• Hypersensitivity reactions including anaphylaxis
• Prolonged cytopenias
• Increased risk of infections
• Hypogammaglobulinemia
• Secondary malignancies

Drug Interactions

• Immunosuppressive therapy: May interfere with Breyanzi activity
• Live vaccines: Contraindicated during and after Breyanzi treatment
• Tocilizumab and corticosteroids: Used for management of CRS and neurologic toxicities
• Antihypertensive medications: May require adjustment during CRS

Adverse Effects

• Cytokine release syndrome (94%)
• Fatigue (76%)
• Musculoskeletal pain (66%)
• Nausea (64%)
• Headache (57%)
• Pyrexia (54%)
• Constipation (52%)
• Diarrhea (43%)
• Cough (42%)
• Dizziness (41%)
• Decreased appetite (40%)
• Edema (39%)
• Hypoxia (37%)
• Tachycardia (35%)
• Rash (34%)
• Insomnia (32%)
• Chills (31%)
• Vomiting (30%)
• Hypotension (29%)
• Anxiety (28%)
• Abdominal pain (27%)
• Arrhythmia (26%)
• Neuropathy (25%)
• Tremor (24%)
• Confusion (23%)
• Infection (22%)
• Aphasia (21%)
• Delirium (20%)

• Grade ≥3 CRS (9%)
• Grade ≥3 neurologic toxicities (12%)
• Severe infections (15%)
• Prolonged cytopenias (45%)
• Tumor lysis syndrome

Monitoring Parameters

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

• Continuous monitoring for CRS signs (fever, hypotension, hypoxia) for at least 7 days
• Frequent neurologic assessments
• Daily CBC, electrolytes, renal and hepatic function
• Inflammatory markers (CRP, ferritin)
• Cardiac monitoring (ECG, troponin if indicated)
• Immunoglobulin levels
• Monitoring for signs of infection
• Long-term monitoring for secondary malignancies

Patient Education

• Understand the risks and benefits of CAR T-cell therapy
• Report all medications, including over-the-counter drugs and supplements
• Arrange for a caregiver to assist during the treatment period
• Plan for hospitalization and post-discharge monitoring

• Immediately report fever, chills, difficulty breathing, dizziness, or neurological symptoms
• Understand the signs and symptoms of CRS and neurologic toxicity
• Comply with all monitoring requirements

• Avoid driving or operating heavy machinery for 8 weeks
• Do not receive live vaccines
• Practice infection prevention measures
• Report any new or worsening symptoms
• Attend all follow-up appointments
• Use effective contraception for at least 1 year post-treatment
• Inform all healthcare providers about Breyanzi treatment

References

1. FDA Prescribing Information: Breyanzi (lisocabtagene maraleucel) 2. Abramson JS, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. 3. Nastoupil LJ, et al. Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119-3128. 4. Locke FL, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. 5. NCCN Guidelines® B-Cell Lymphomas. Version 3.2023. 6. Neelapu SS, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. 7. Schuster SJ, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56.