Kymriah - Drug Monograph

Introduction

Kymriah (tisagenlecleucel) is a groundbreaking chimeric antigen receptor (CAR) T-cell therapy developed by Novartis. It represents a novel class of immunotherapies that genetically modifies a patient's own T-cells to target and destroy cancer cells. Approved by the FDA in 2017, Kymriah was the first CAR T-cell therapy to receive regulatory approval, marking a significant advancement in the treatment of certain hematologic malignancies.

Mechanism of Action

Kymriah is an autologous CD19-directed genetically modified autologous T-cell immunotherapy. The mechanism involves:

• Collection of patient's T-cells via leukapheresis
• Genetic modification using a lentiviral vector to express a CAR targeting CD19
• CAR consists of an extracellular anti-CD19 single-chain variable fragment (scFv) linked to intracellular CD3ζ and 4-1BB costimulatory domains
• Upon reinfusion, these engineered T-cells recognize and eliminate CD19-expressing cells
• The 4-1BB costimulatory domain enhances T-cell expansion and persistence

Indications

Kymriah is FDA-approved for: 1. Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse 2. 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) - High-grade B-cell lymphoma - DLBCL arising from follicular lymphoma

Dosage and Administration

• ALL: 0.2-5.0 × 10⁶ CAR-positive viable T-cells per kg body weight
• DLBCL: 0.6-6.0 × 10⁸ CAR-positive viable T-cells (non-weight based)

1. Leukapheresis for T-cell collection (3-4 weeks before infusion) 2. Manufacturing process (typically 3-4 weeks) 3. Lymphodepleting chemotherapy (fludarabine 30 mg/m²/day + cyclophosphamide 500 mg/m²/day for 3 days) 4. Kymriah infusion 2-14 days after lymphodepletion 5. Administer as a single intravenous infusion over 30-60 minutes

• 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

Pharmacokinetics

• CAR T-cells expand rapidly post-infusion, peaking within 7-14 days
• Persistence detectable for months to years in some patients
• B-cell aplasia serves as a pharmacodynamic marker of activity

• Localizes to bone marrow and lymphoid tissues
• Crosses blood-brain barrier in limited quantities

• Cellular elimination through natural turnover processes
• Half-life not characterized using conventional pharmacokinetic methods

Contraindications

• Hypersensitivity to tisagenlecleucel or any component of the formulation
• Active uncontrolled infection
• Pregnancy (based on mechanism of action)

Warnings and Precautions

• Life-threatening systemic inflammatory response
• Onset typically within days to weeks after infusion
• May require tociliuzumab and/or corticosteroids

• Can range from headache to cerebral edema
• May occur concurrently with or after CRS resolution

• May occur during or shortly after infusion

• Prolonged cytopenias may increase infection risk
• Monitor for signs and symptoms of infection

• Elevated liver enzymes reported
• Monitor liver function tests

• May persist for several weeks after infusion

Drug Interactions

• Avoid live vaccines during treatment and until immune recovery
• Corticosteroids and other immunosuppressants may interfere with CAR T-cell expansion and persistence
• Lymphodepleting chemotherapy required for optimal efficacy

Adverse Effects

• Cytokine release syndrome (77%)
• Pyrexia (57%)
• Hypogammaglobulinemia (45%)
• Headache (37%)
• Thrombocytopenia (32%)
• Nausea (29%)
• Fatigue (27%)

• Severe CRS (47%)
• Neurologic toxicities (37%)
• Serious infections (32%)
• Tumor lysis syndrome
• Prolonged cytopenias
• Hypersensitivity reactions

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel
• Inflammatory markers (CRP, ferritin)
• Cardiac function assessment
• Neurologic assessment

• Continuous monitoring for ≥7 days in certified healthcare facility
• Temperature every 4 hours
• Vital signs every 4 hours
• Daily weight and fluid balance
• CBC, electrolytes, LFTs daily
• CRS assessment using ASTCT grading system
• Neurologic assessments every 8 hours
• Immunoglobulin levels
• CAR T-cell expansion monitoring (qPCR)

• B-cell recovery
• Immunoglobulin levels
• Late-onset adverse events
• Disease response assessment

Patient Education

• Understand the risk-benefit profile of treatment
• Recognize early signs of CRS (fever, fatigue, hypotension)
• Identify neurologic symptoms (headache, confusion, seizures)
• Report any signs of infection promptly
• Avoid pregnancy during and after treatment
• Inform all healthcare providers about CAR T-cell therapy history
• Understand need for prolonged follow-up care
• Be aware of potential need for immunoglobulin replacement therapy
• Carry patient wallet card provided by manufacturer

References

1. FDA Prescribing Information: Kymriah (tisagenlecleucel). 2022 2. Maude SL, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439-448 3. Schuster SJ, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56 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. Version 4.2023 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