What is axicabtagene ciloleucel?
Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T cell, a form of immunotherapy. Autologous T cells are collected from patients and genetically modified ex vivo to express a receptor which recognizes the CD19 antigen. The receptor is antibody-derived and fused with co-stimulatory domains CD28 and CD3-zeta. This therapy was approved in October 2017.
How does axicabtagene ciloleucel work?
After cell infusion, the CAR T cells bind to CD19+ cells and co-stimulatory domains activate downstream intracellular processes. This results in cellular activation, proliferation, and recruitment of other effector cells via cytokine secretion, ultimately resulting in CD19+ cell death.
What is this approved for?
Axicabtagene ciloleucel is FDA-approved for adult patients with relapsed or refractory (R/R) large B-cell lymphoma who have failed two or more lines of prior therapy.
What is the basis for this approval?
Axicabtagene ciloleucel was approved based on the results of the ZUMA-1 trial. This was a phase I/II, single-arm, multi-center study that included 108 evaluable patients. All patients were adults with R/R large B-cell lymphoma who had previously received an anti-CD20 antibody plus an anthracycline. Most patients had received at least three prior lines of therapy, and 23 percent had a previous autologous stem cell transplant. After a median follow-up of 27.1 months, objective response rate was 83 percent, comprising of 58 percent complete responses and 25 percent partial responses. The median duration of response for all patients was 11.1 months and was not yet reached for those with complete responses. The median overall survival had not yet been reached, and median progression-free survival was 5.9 months. Patients with durable remissions had higher peak cell concentrations and area under the curve in the first 28 days after infusion (Lancet Oncol 2019;20:31-42).
How do you administer this drug?
After the CAR T cells are manufactured and received by the treatment center, patients should receive lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide for 3 days, starting 5 days prior to cell infusion. On the day of cell infusion, patient identity should be verified against the identifiers on the cassette and product bag. Cells are shipped cryopreserved and must be thawed, then infused within 3 hours of thawing.
Are there any premedications needed for axicabtagene ciloleucel?
Patients should receive acetaminophen and diphenhydramine approximately 60 minutes prior to cell infusion. Corticosteroids should be avoided.
What are the common side effects associated with axicabtagene ciloleucel (> or =10%)?
In the ZUMA-1 study, cytokine release syndrome (CRS) occurred in 95 percent of patients, with grade 3 or greater CRS occurring in 11 percent of patients. Median time to onset of CRS was 2 days and duration was 7 days. The most common manifestations of CRS were fever, hypotension, tachycardia, hypoxia, and chills. Neurologic complications occurred in 87 percent of patients, and 32 percent of those were grade 3 or greater. Median time to onset was 4 days, with a duration of 17 days. The most common manifestations of neurotoxicity were encephalopathy, headache, tremor, dizziness, and delirium. Other common side effects include infection, prolonged myelosuppression, and hypogammaglobulinemia.
What are the uncommon side effects associated with axicabtagene ciloleucel (less than 10%)?
Less common toxicities include electrolyte abnormalities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, capillary leak syndrome, transaminitis, thrombosis, coagulopathy, arthralgias, and arrhythmias.
Are there any important drug interactions I should be aware of?
No drug/drug interactions have been described. Immunosuppressants, or any medication that affects T-cell function/activity (including corticosteroids), should be avoided unless needed for the management of severe toxicity.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No adjustments are required, although these patients were not included in clinical trials. All patients should receive a target dose of 2 x 106 cells/kg.
Sites must be authorized by Kite (https://www.yescartarems.com/) in order to administer axicabtagene ciloleucel. Sites must follow requirements set out by the REMS program, which include having at least two doses of tocilizumab available, as well as ensuring proper training for all health care personnel who prescribe, administer, or dispense the product.
What should my patients know about axicabtagene ciloleucel?
Patients should be aware that they will require daily monitoring for at least the first 7 days after the infusion at the health care facility. They also must remain in close proximity for 4 weeks after infusion. Driving should be avoided for at least 8 weeks after infusion. Patients will be provided a wallet card that indicates they have received axicabtagene ciloleucel, and they should alert all health care providers of their receipt of axicabtagene ciloleucel.
What useful links are available regarding axicabtagene ciloleucel?
Any ongoing clinical trials related to axicabtagene ciloleucel?
A randomized phase III study, ZUMA-7, is currently enrolling that compares axicabtagene ciloleucel to standard therapy for R/R diffuse large B-cell lymphoma (DLBCL). It is also being studied in combination with PD-L1 inhibition for R/R DLBCL, as well as monotherapy for indolent lymphomas. More information is available at https://clinicaltrials.gov.
ADAM MELARAGNO, PHARMD, BCOP, is Clinical Pharmacy Specialist in Blood and Marrow Transplant at University of Rochester Medical Center in New York. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.