Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Kymriah® (tisagenlecleucel) is an autologous chimeric antigen receptor (CAR) T-cell therapy that uses a patient’s own immune cells for the targeted elimination of cancer cells. This genetically modified autologous immunotherapy is directed at antigen CD19. A single dose contains a suspension of CAR-positive viable T-cells, and patients should receive 0.6 to 6.0×108 CAR-positive T-cells.1
Kymriah is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who have undergone at least 2 lines of systemic therapy, including those with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from follicular lymphoma, and high-grade B-cell lymphoma.1,2
Kymriah was developed by Novartis Pharmaceuticals Corporation and has been approved by the US Food and Drug Administration (FDA) for the treatment of DLBCL in May 2018 and by the European Medicines Agency (EMA) in August 2018.2,3
Mechanism of Action
Diffuse large B-cell lymphoma is a common and aggressive subtype of lymphoma affecting adults, and it represents approximately 30% to 40% of all non-Hodgkin lymphoma cases that are diagnosed every year.4 Standard treatment for DLBCL is chemoimmunotherapy, but as between 45% and 50% of patients with DLBCL relapse, these patients may require second-line chemotherapy treatments, salvage regimens, or CAR T-cell therapy.5
CAR T-cell therapy, which uses the patient’s autologous T-cells, has shown response as a potential treatment strategy in relapsed or refractory DLBCL.4,6 Kymriah contains the patient’s T-cells that have been genetically modified with a lentiviral vector to express a CAR. This CAR can then identify and attach to the CD19 protein, which is expressed on the surface of cancer cells.6,7 The CAR is formed by a murine single-chain antibody fragment capable of identifying CD19 protein, a CD8 hinge, and a transmembrane region fused to domains for 4-1BB and CD3-zeta.1 Following CD19-binding, the CAR induces T-cell expansion and activation for further elimination of the marked cells. This is possible since CD3-zeta is crucial for T-cell activation and antitumor activity, while 4-1BB promotes the expansion and persistence of Kymriah.1,8
Read more about DLBCL experimental therapies
Manufacturing and Administration
As an autologous immunotherapy, Kymriah requires the collection of the patient’s peripheral blood mononuclear cells in a process called leukapheresis. These cells are then sent to a laboratory for cellular enrichment, transduction with the lentiviral vector, and activation. The modified cells are then expanded before formulation in a suspension.1
Pretreatment with lymphodepleting chemotherapy may be necessary to prepare the patient’s body for infusion with Kymriah, which can then be administered 2 to 11 days after this regimen is complete. A single dose of Kymriah is recommended for relapsed or refractory DLBCL treatment and is administered intravenously. However, the infusion should be delayed when serious adverse events occur following previous chemotherapies or if the patient presents with an active uncontrolled infection.1
The infusion must be administered in a Risk Evaluation and Mitigation Strategy (REMS)-certified healthcare facility, and patients must be closely monitored during the first week and within proximity of the REMS facility for a month following infusion.1
Read more about DLBCL treatment
The administration of Kymriah may lead to cytokine release syndrome (CRS) and neurological toxicities, which can be life threatening. Common adverse reactions experienced with Kymriah use are CRS, fever, diarrhea, nausea, fatigue, hypotension, edema, hemorrhage, dyspnea, headache, and infection.1
The REMS facility should closely monitor for signs of CRS and neurological toxicities. If CRS is detected, the patient may require hospitalization and should begin treatment with tocilizumab and/or corticosteroids as indicated.
Get full prescribing information for Kymriah at MPR
Safety and Efficacy in Trials and Trial Results
The safety and efficacy of Kymriah has been reported in JULIET (NCT02445248), a multicenter, open-label, single-arm, phase 2 clinical trial conducted in adult patients with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma.9 These patients had undergone at least 2 lines of systemic therapy (including rituximab and anthracycline) or had relapsed after an autologous hematopoietic stem cell transplant. Participants first completed lymphodepleting chemotherapy and then received tisagenlecleucel, and they were followed up for 9.4 months.9
The overall response rate determined for 68 patients was 50%, with 32% showing a complete response and 18% demonstrating a partial response.1,2 Adverse events reported in this trial included CRS, infection, pyrexia, diarrhea, nausea, hypotension, fatigue, edema, and headache.1 The best overall response rate at 14 months of follow-up was 52%, with 40% of patients showing a complete response, while 12% had partial responses.10
Long-term outcomes have also been evaluated recently, indicating a prolonged activity of the treatment and an acceptable safety profile, with an overall response rate of 53% in 61 patients after a follow-up of 40.3 months. Adverse events such as anemia, CRS, neutropenia, hypophosphatemia, and thrombocytopenia have been reported.11
The JULIET trial is still ongoing, with 115 patients receiving treatment with tisagenlecleucel.9
Read more about DLBCL prognosis
1. Kymriah. Prescribing information. Novartis Pharmaceuticals Corporation; 2022. Accessed August 5, 2022.
2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. US Food and Drug Administration (FDA); May 3, 2018.
3. Novartis receives European Commission approval of its CAR-T cell therapy, Kymriah® (tisagenlecleucel). News release. Novartis; August 27, 2018.
4. Wang L, Li LR, Young KH. New agents and regimens for diffuse large B cell lymphoma. J Hematol Oncol. 2020;13(1):175. doi:10.1186/s13045-020-01011-z
5. Susanibar-Adaniya S, Barta SK. 2021 Update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol. 2021;96(5):617-629. doi:10.1002/ajh.26151
6. Treatment process. Novartis Pharmaceuticals Corporation. Accessed August 5, 2022.
7. Kymriah. European Medicines Agency (EMA). Updated May 19, 2022. Accessed August 5, 2022.
8. Mechanism of action. Novartis Pharmaceuticals Corporation. Accessed August 5, 2022.
9. Study of efficacy and safety of CTL019 in adult DLBCL patients (JULIET). ClinicalTrials.gov. May 15, 2015. Updated June 3, 2022. Accessed August 5, 2022.
10. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
11. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(10):1403-1415. doi:10.1016/S1470-2045(21)00375-2
Reviewed by Hasan Avcu, MD, on 8/14/2022.