Introduction
Yescarta (axicabtagene ciloleucel) is a revolutionary chimeric antigen receptor (CAR) T-cell therapy developed by Kite Pharma, a Gilead Company. It represents a groundbreaking approach in cancer treatment, specifically engineered to target and eliminate CD19-expressing malignant cells. Yescarta received FDA approval in October 2017, marking a significant advancement in the treatment of refractory B-cell malignancies.
Mechanism of Action
Yescarta is an autologous anti-CD19 CAR T-cell therapy that works through a sophisticated immunologic mechanism. The therapy involves genetically modifying a patient's own T-cells to express a CAR that recognizes the CD19 antigen present on B-cells. This CAR consists of an anti-CD19 single-chain variable fragment (scFv) derived from murine FMC63 antibody, linked to CD28 costimulatory and CD3-zeta T-cell activation domains.
Upon reinfusion, these engineered CAR T-cells:
- Recognize and bind to CD19-positive target cells
- Become activated and proliferate extensively
- Release cytotoxic granules containing perforin and granzymes
- Induce apoptosis in CD19-expressing malignant cells
- Create long-term immunologic memory against CD19+ cells
Indications
Yescarta is FDA-approved for the treatment of:
- Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy
- 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) - Primary mediastinal large B-cell lymphoma - High-grade B-cell lymphoma - DLBCL arising from follicular lymphoma
- Adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy
Dosage and Administration
Dosing: Yescarta is administered as a single intravenous infusion at a target dose of 2 × 10^6 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 10^8 CAR-positive viable T cells. Administration Process:1. Leukapheresis: Collection of patient's T-cells 2. Manufacturing: Genetic modification and expansion of T-cells (3-4 weeks) 3. Lymphodepleting chemotherapy: Fludarabine 30 mg/m²/day and cyclophosphamide 500 mg/m²/day for 3 days prior to infusion 4. Infusion: Administer via intravenous route over approximately 30 minutes
Special Populations:- Renal impairment: No dosage adjustment recommended
- Hepatic impairment: Use with caution in patients with hepatic impairment
- Pediatric patients: Safety and effectiveness not established
- Geriatric patients: No specific dosage adjustment required
Pharmacokinetics
Expansion and Persistence: CAR T-cells undergo rapid expansion post-infusion, typically peaking within 7-14 days. CAR transgene persists in blood for months to years in responding patients. Distribution: CAR T-cells distribute to bone marrow, lymphoid tissues, and tumor sites. Cerebrospinal fluid penetration has been observed. Elimination: The elimination half-life varies significantly among patients. B-cell aplasia serves as a pharmacodynamic marker of CAR T-cell activity.Contraindications
Yescarta is contraindicated in patients with:
- Hypersensitivity to axicabtagene ciloleucel or any of its components
- Active uncontrolled infection
- Active hepatitis B, hepatitis C, or HIV infection
- Pregnancy (based on animal data and mechanism of action)
Warnings and Precautions
Cytokine Release Syndrome (CRS):- Occurs in approximately 90% of patients
- May be life-threatening or fatal
- Monitor for fever, hypotension, tachycardia, hypoxia, and organ toxicity
- Tocilizumab and corticosteroids are recommended for management
- Occur in approximately 65% of patients
- Include encephalopathy, headache, tremor, dizziness, aphasia, and seizures
- May be fatal or life-threatening
- Monitor for signs and symptoms continuously
Drug Interactions
- Corticosteroids: Avoid prophylactic corticosteroids as they may interfere with CAR T-cell expansion and efficacy
- Cytotoxic chemotherapy: May enhance myelosuppressive effects
- Live vaccines: Avoid administration for at least 2 weeks before and after treatment
- Immunosuppressive therapy: May interfere with CAR T-cell function and persistence
Adverse Effects
Very Common (≥10%):- Pyrexia (90%)
- Cytokine release syndrome (90%)
- Hypotension (60%)
- Tachycardia (50%)
- Fatigue (45%)
- Headache (40%)
- Nausea (40%)
- Diarrhea (35%)
- Encephalopathy (35%)
- Infection (35%)
- Decreased appetite (30%)
- Chills (30%)
- Constipation (25%)
- Vomiting (25%)
- Dizziness (20%)
- Cough (20%)
- Edema (20%)
- Hypoxia (20%)
- Tremor (20%)
- Arrhythmia (15%)
- Rash (15%)
- Insomnia (15%)
- Anxiety (10%)
- Back pain (10%)
- Severe cytokine release syndrome
- Neurologic toxicities
- Serious infections
- Prolonged cytopenias
- Tumor lysis syndrome
- Hypersensitivity reactions
Monitoring Parameters
Pre-infusion:- Complete blood count with differential
- Comprehensive metabolic panel
- Infectious disease screening
- Cardiac function assessment
- Pulmonary assessment
- Neurologic assessment
- Daily monitoring for CRS and neurologic toxicity
- Temperature every 4-6 hours
- Blood pressure, heart rate, respiratory rate, oxygen saturation
- Complete blood count with differential (at least 3 times weekly)
- Comprehensive metabolic panel (at least 3 times weekly)
- Coagulation parameters
- Immunoglobulin levels
- CAR T-cell expansion and persistence (qPCR)
- B-cell aplasia (monthly)
- Immunoglobulin levels (quarterly)
- Surveillance for secondary malignancies (lifelong)
- Monitoring for late effects including hypogammaglobulinemia
Patient Education
Before Treatment:- Understand the multi-step process including leukapheresis, manufacturing, and infusion
- Arrange for a caregiver to remain with you for at least the first 4 weeks after infusion
- Plan to stay within 2 hours of the treatment center for at least 4 weeks post-infusion
- Immediately report fever, chills, fatigue, dizziness, or breathing difficulties
- Monitor for neurologic symptoms including confusion, seizures, or speech changes
- Avoid driving or operating heavy machinery for at least 8 weeks after infusion
- Practice strict infection prevention measures
- Avoid live vaccines unless advised by your healthcare provider
- Use effective contraception during and after treatment
- Regular follow-up with your healthcare team is essential
- Report any new symptoms or health changes promptly
- Carry your patient wallet card at all times
- Inform all healthcare providers about your CAR T-cell therapy
References
1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-2544. 2. Yescarta [package insert]. Santa Monica, CA: Kite Pharma, Inc.; 2023. 3. Locke FL, Ghobadi A, Jacobson CA, 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. 4. FDA Approval: Yescarta (axicabtagene ciloleucel). U.S. Food and Drug Administration. October 18, 2017. 5. NCCN Guidelines®: B-Cell Lymphomas. Version 3.2023. 6. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56. 7. Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019;34:45-55.