Generic Name

_Breyanzi_

Mechanism

• Engineering: Patient’s peripheral blood T cells are harvested (apheresis) and transduced ex vivo with a lentiviral vector encoding a CAR that combines:
• An anti‑CD19 single‑chain variable fragment (scFv) for antigen recognition
• An intracellular costimulatory domain (CD28 or 4‑1BB) and CD3ζ activation domain
• Target‑cell engagement: Upon infusion, the CAR‑T cells proliferate, home to lymphoid tissues, and bind CD19+ malignant B cells.
• Cytotoxic response: Engaged CAR‑T cells release perforin/granzyme and express cytokines (IFN‑γ, TNF‑α) → direct lysis and activation of innate immune effectors.
• Expansion and persistence: The product leads to an in‑vivo expansion peak, followed by gradual decline; long‑term persistence correlates with durable responses in some patients.

Pharmacokinetics

Indications

• Approved: Adults (≥18 yrs) with R/R large B‑cell lymphoma who have received ≥4 prior therapies, including an anti‑CD20 antibody, a cytotoxic regimen, and a second‑line therapy.
• Off‑label considerations: Investigational trials for other CD19+ B‑cell malignancies (e.g., ALL, DLBCL de‑novo).

Contraindications

• Contraindications:
• Active uncontrolled infection (except mild, self‑limited)
• CNS involvement > 30 mm or symptomatic leptomeningeal disease
• Pregnant or lactating women
• Serious heart failure (NYHA III–IV)
• Warnings:
• Cytokine release syndrome (CRS): potentially life‑threatening; requires close monitoring.
• Immune effector cell‑associated neurotoxicity syndrome (ICANS): neurocognitive changes, seizures possible.
• Infections: prolonged cytopenias → neutropenia, hypogammaglobulinemia.
• Tumor lysis syndrome (TLS): rare but possible for bulky disease.
• Myocardial infiltration: possible heart failure.

Dosing

• Lymphodepletion: 3 days of:
• Fludarabine 30 mg/m²/day IV
• Cyclophosphamide 500 mg/m²/day IV
• CAR‑T dose: 1 × 10⁶ CAR‑positive T‑cells/kg body weight
• Infusion:

1. Premedication: antipyretic (acetaminophen), antihistamine, and corticosteroid (dexamethasone 10 mg IV) recommended, especially for CRS mitigation.

2. Slow IV infusion over 60–120 min; monitor for infusion reactions.

3. Post‑infusion: ICU or high‑dependency unit observation for first 48 h; continuous monitoring of vitals and neurological status.

Adverse Effects

• Common (≥20 %)
• Fever, chills, nausea, vomiting
• Cytopenias (neutropenia, anemia, thrombocytopenia)
• Transient hypogammaglobulinemia
• Injection‑site reactions
• Serious (≥5 %)
• CRS: fever, hypotension, hypoxia, multi‑organ dysfunction
• ICANS: agitation, aphasia, seizures, cerebral edema
• Neurotoxicity: worsening encephalopathy
• Infections: opportunistic (CMV, fungal, viral)
• Cardiovascular: myocarditis, arrhythmias
• TLS: hyperuricemia, hyperkalemia, hyperphosphatemia

Monitoring

CRS and ICANS grading (Lee et al.) dictates escalation:
• CRS: Grade 1–2 → antipyretics; Grade 3–4 → tocilizumab + corticosteroids.
• ICANS: Grade 2–5 → dexamethasone + neuro‑consultation.

Clinical Pearls

• Early CRS detection: Educate staff on the early signs (fever ≥ 38 °C, tachycardia) – 50 % of patients develop CRS within 48 h. Prompt tocilizumab and steroids reduce ICU stays.
• Optimizing lymphodepletion: Tailor dose based on patient’s renal/hepatic function; avoid excessive cyclophosphamide in heart‑failure patients.
• Neurotoxicity prevention: Baseline MRI in patients with brain metastases; avoid concurrent radiotherapy when possible.
• Re‑infusion potential: Some patients may benefit from a second infusion (≤ 2 g cell dose) if initial response is suboptimal and remission status is achieved.
• Immunoglobulin replacement: Consider prophylactic IVIG once IgG  20 cm³, LDH > 4×ULN, CD19 density—may benefit from prophylactic tocilizumab.
• Documentation: Maintain a CRS score spreadsheet; this assists in timely intervention and quality metrics for CAR‑T programs.

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• *All information reflects current FDA labeling and peer‑reviewed literature up to 2024. Always consult the latest product insert for updates.*