Kymriah (tisagenlecleucel)
Clinical Profile & Access Information
An independent clinical reference for Kymriah — the first FDA-approved CAR-T therapy for B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma.
Product Overview
| Brand Name | Kymriah |
| Generic Name | tisagenlecleucel |
| Manufacturer | Novartis |
| Target Antigen | CD19 → |
| CAR Construct | CD19 scFv + 4-1BB costimulatory domain + CD3ζ signaling domain |
| FDA Approval | August 2017 (first CAR-T therapy) |
| EMA Approval | August 2018 |
| Administration | Single intravenous infusion (autologous CAR-T cells) |
| Manufacturing | Patient's own T-cells collected via leukapheresis, genetically modified ex vivo, expanded, and reinfused |
Kymriah was the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval, marking a pivotal moment in cancer immunotherapy. It remains one of the most widely administered CAR-T products globally.
For general information on how CAR-T therapy works, please visit our CAR-T Cell Therapy Hub → For information on the CD19 target specifically, see CD19 CAR-T →
Mechanism of Action
Kymriah is an autologous CD19-directed CAR-T cell therapy. The mechanism involves:
- T-Cell Collection: Patient's own T-cells are collected via leukapheresis.
- Genetic Modification: T-cells are transduced with a lentiviral vector encoding a CAR that recognizes CD19.
-
CAR Structure:
- Targeting domain: Single-chain variable fragment (scFv) derived from anti-CD19 antibody
- Costimulatory domain: 4-1BB (CD137), which promotes T-cell persistence and reduces exhaustion
- Signaling domain: CD3ζ, which activates T-cell cytotoxic function
- Expansion: Modified cells are expanded ex vivo to achieve therapeutic doses.
- Reinfusion: Patient receives lymphodepleting chemotherapy (fludarabine/cyclophosphamide), followed by single infusion of CAR-T cells.
- Mechanism: CAR-T cells bind CD19 on B-cells (normal and malignant), activate cytotoxic response, and persist long-term due to 4-1BB signaling.
Approved Indications
Kymriah is approved for the following indications (specific indications vary by region):
B-Cell Acute Lymphoblastic Leukemia (B-ALL)
- Patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse
- FDA label: "B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse"
Diffuse Large B-Cell Lymphoma (DLBCL)
- Adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy
- Includes DLBCL not otherwise specified (NOS), DLBCL arising from follicular lymphoma, and high-grade B-cell lymphoma
Follicular Lymphoma (FL)
- Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy
- EMA indication: FL grade 1-3A after two or more lines of systemic therapy
Note: Indications have evolved since initial approval. Always consult the most current regional prescribing information for specific line-of-therapy requirements and age restrictions.
Clinical Evidence Summary
Kymriah's approval was based on pivotal multicenter clinical trials:
ELIANA Trial (B-ALL)
- Phase II, single-arm, multicenter study
- Pediatric and young adult patients with r/r B-ALL
- Demonstrated high rates of minimal residual disease (MRD)-negative remission
- Long-term follow-up shows durable responses in a subset of patients
JULIET Trial (DLBCL)
- Phase II, single-arm, global study
- Adult patients with r/r DLBCL after ≥2 prior lines
- Demonstrated durable complete responses in patients with refractory disease
- Long-term follow-up (median >40 months) shows sustained responses in responders
ELARA Trial (FL)
- Phase II, single-arm, global study
- Adult patients with r/r FL after ≥2 prior lines
- Demonstrated high overall response rates with durable remissions
Key Considerations:
- All pivotal trials were single-arm (no control group)
- Patient populations were highly selected (good performance status, adequate organ function)
- Results may not generalize to all patients in routine clinical practice
- Long-term safety data continue to be collected through post-marketing studies
Safety Profile
Kymriah carries significant safety risks that require careful patient selection and monitoring. The following are based on FDA prescribing information and clinical trial data.
Boxed Warnings (FDA)
Cytokine Release Syndrome (CRS):
- Occurs in majority of patients (typically within first 1-14 days post-infusion)
- Symptoms: fever, hypotension, hypoxia, organ dysfunction
- Severe (Grade 3-4) CRS occurs in approximately 10-20% of patients
- Management: tocilizumab (IL-6 receptor antagonist), corticosteroids, supportive care
- Kymriah is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program
Neurologic Toxicities (ICANS):
- Immune effector cell-associated neurotoxicity syndrome (ICANS)
- Symptoms: encephalopathy, aphasia, seizures, cerebral edema
- Typically occurs within first 10 days post-infusion
- Severe (Grade 3-4) ICANS occurs in approximately 5-15% of patients
- Management: corticosteroids, supportive care
Other Serious Adverse Reactions
- Prolonged cytopenias: Neutropenia, thrombocytopenia, anemia (may persist for weeks to months)
- Infections: Increased risk due to B-cell aplasia and hypogammaglobulinemia; prophylactic antimicrobials and immunoglobulin replacement may be required
- Hemophagocytic lymphohistiocytosis (HLH)/Macrophage activation syndrome (MAS): Rare but potentially fatal
- Hypogammaglobulinemia: Expected on-target effect due to B-cell aplasia; requires monitoring and immunoglobulin replacement
Long-Term Monitoring
- Patients must be monitored long-term for persistent cytopenias, infections, and secondary malignancies
- Annual follow-up recommended for at least 15 years per FDA requirement
Regulatory Status
| Region | Regulatory Authority | Approval Status | Approval Date |
|---|---|---|---|
| United States | FDA | Approved | August 2017 |
| European Union | EMA | Approved | August 2018 |
| United Kingdom | MHRA | Approved | 2018 |
| Japan | PMDA | Approved | 2019 |
| China | NMPA | Not approved | — |
Note: Regulatory status may change. Always verify current approval status with regional regulatory authorities.
Cost & Access Information
Pricing (Approximate, Out-of-Pocket for International Patients)
| Country | Approximate Cost (USD) | Notes |
|---|---|---|
| United States | $475,000 | List price; does not include hospitalization, supportive care, or management of complications |
| European Union | €320,000 - €373,000 | Varies by country; may be subject to national pricing agreements |
| Other Regions | Variable | Contact local Novartis representatives for pricing |
Total Treatment Cost Considerations
- The drug acquisition cost is only one component
- Additional costs include:
- Leukapheresis and cell collection
- Lymphodepleting chemotherapy
- Hospitalization (typically 2-4 weeks minimum)
- Management of CRS/ICANS (tocilizumab, corticosteroids, ICU care if needed)
- Long-term follow-up and monitoring
- Immunoglobulin replacement therapy
- Total treatment episode cost can exceed $500,000-$800,000 in the US when all components are included
Insurance Coverage
- Coverage varies significantly by insurer, country, and specific indication
- Many insurers require prior authorization and documentation of eligibility criteria
- Patients should contact their insurance provider directly to verify coverage before treatment
International Access
- Kymriah is available only at certified treatment centers
- Treatment centers must be REMS-certified (US) or equivalent
- International patients must coordinate with certified centers in their region
- Our platform can facilitate introductions to certified treatment centers, but we cannot guarantee access or coverage
For patients exploring treatment options: Our platform can help you understand what records a treating center may need and facilitate introductions to certified centers. Request an Information-Based Case Review →