Generic Name

Yescarta

Mechanism

• Autologous CAR‑T cell platform: patient’s peripheral blood mononuclear cells are collected, genetically modified ex‑vivo to express a chimeric antigen receptor (CAR) targeting CD19, and expanded.
• CD19‑specific cytotoxicity: the CAR contains an extracellular scFv that binds CD19 on B‑cell malignancies, a CD3ζ signaling domain, and a costimulatory domain (CD28) that enhances T‑cell activation, proliferation, and persistence.
• Rapid tumor cell lysis: CD19+ cells are recognized, leading to CAR‑T activation, cytokine secretion (IL‑2, IFN‑γ), and lysis of malignant B‑cells.

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Pharmacokinetics

• Formulation: cell product, not a conventional small molecule; pharmacokinetics described as *cell expansion* and *clearance* phases post‑infusion.
• Distribution: systemic, cells traffic to lymphoid tissues; peak CAR‑T cell numbers observed ~5–7 days post‑infusion.
• Elimination: gradual decline; CAR‑T cells persist ≥6 months in most patients; long‑term persistence may occur in ~20 %.
• Cytokine kinetics: peak cytokine release correlates with CRS severity, typically within 24–48 h.

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Indications

• Adult patients with relapsed or refractory large B‑cell lymphoma (including diffuse large B‑cell lymphoma, follicular lymphoma, high‑grade B‑cell lymphoma, or Burkitt lymphoma) after ≥2 prior systemic therapies.
• Indicated for disease that is *CD19‑positive* and *eligible for hematopoietic stem‑cell rescue*.

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Contraindications

• Active, uncontrolled infection (bacterial, fungal, or viral including HIV, HBV, HCV).
• Uncontrolled heart failure or known severe cardiopulmonary disease.
• Uncontrolled cerebral edema or intracranial mass lesions.
• Severe autoimmune disease (e.g., SLE, RA) requiring active immunosuppression.
• Known hypersensitivity to any component of the cell product.
• Concomitant immunosuppressive agents can impair CAR‑T efficacy.

Warnings
• Cytokine Release Syndrome (CRS)—life‑threatening cytokine storm requiring prompt recognition and management.
• Immune‑mediated neurotoxicity (ICANS)—encephalopathy, seizures, or cerebral edema.
• Persistent B‑cell aplasia → hypogammaglobulinemia; risk of recurrent infections.
• Long‑term immunosuppression → secondary malignancies and autoimmunity.

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Dosing

• Dose: 2 × 10⁶ CAR‑T cells/kg (target product); actual cell dose varies with patient weight (typical range: 1.0 – 1.8 × 10⁷ cells.); the final product includes ≥30 × 10⁶ cells.
• Procedure:

1. *Leukapheresis* → collection of autologous T‑cells.

2. *Manufacturing* (approx. 14–21 days).

3. *Pre‑conditioning Lymphodepleting Chemotherapy* (fludarabine 30 mg/m² IV × 2 days + cyclophosphamide 500 mg/m² IV × 1 day).

4. *Intravenous infusion* over 30–60 min.
• Post‑infusion: patients stay in hospital ≥7 days for CRS/ICANS monitoring; oral monitoring may be acceptable after day 7 if stable.

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Adverse Effects

Common (≥10 %)
• Cytokine Release Syndrome (fever, hypotension, hypoxia).
• Neurotoxicity (headache, confusion).
• B‑cell aplasia (anemia, thrombocytopenia, neutropenia).
• Prolonged infusion reactions (rigor, chills).

Serious (≥1 %)
• Grade 3–4 CRS requiring *tocilizumab* and/or *steroids*.
• Grade 4 neurotoxicity requiring ICU support.
• Life‑threatening infections (sepsis).
• Hypogammaglobulinemia → opportunistic infections.
• Secondary malignancies (t‑cell lymphoma, myelodysplastic syndrome).

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Monitoring

• Vitals: continuous monitoring for at least 48 h post‑infusion.
• Neurologic assessment: daily NIH grade scoring for ICANS.
• Laboratory: CBC with differential, CMP, ferritin, CRP & IL‑6 baseline and daily during first week.
• Immunoglobulin levels: IgG every 3 months; consider IVIG if <400 mg/dL.
• Imaging: PET‑CT at 3–4 weeks post‑infusion to assess response.
• Infection surveillance: cultures, viral PCRs, and prophylaxis per institutional protocol.

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Clinical Pearls

• Early CRS recognition is key: a ≥2 °C rise in fever or drop in blood pressure within 24 h is often the earliest sign.
• Tocilizumab first line, steroids second: start tocilizumab for CRS grades 2–4; reserve high‑dose steroids for refractory cases or ICANS.
• Lymphodepletion drives efficacy: adequate fludarabine/cyclophosphamide levels correlate with CAR‑T expansion and response.
• Humoral immunity is compromised: consider routine IVIG replacement starting 3–6 months after infusion, especially if IgG <400 mg/dL or recurrent infections.
• Off‑label IL‑6 receptor blockade: emerging data suggest anakinra may ameliorate steroid‑refractory CRS with fewer metabolic side effects.
• Timing of reinfusion: avoid therapeutic agents that strongly affect T‑cell function (e.g., high‑dose steroids, abatacept) within 60 days post‑infusion.
• Patient selection matters: high tumor burden correlates with severe CRS; pre‑treat bulky disease when possible to mitigate toxicity.
• Vaccinations: schedule live vaccines at least 6 months after infusion; inactivated vaccines can be given anytime post‑infusion but may be less immunogenic.

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