Clinical Pearls & Morning Reports
Patients with large B-cell lymphoma who have disease that is resistant to primary or salvage chemoimmunotherapy or who have had a relapse after transplantation have an extremely poor prognosis. Recently, in a large, international, retrospective research study involving patients with non-Hodgkin’s lymphoma (SCHOLAR-1), investigators found an objective response rate of 26%, a complete response rate of 7%, and a median overall survival of 6.3 months with existing therapies among patients who had aggressive B-cell lymphoma that was resistant to chemotherapy or who had a relapse within 12 months after autologous stem-cell transplantation. Read the NEJM Original Article.
Q: What is axicabtagene ciloleucel?
A: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. It consists of a single-chain variable fragment extracellular domain targeting CD19 proteins with CD3ζ (also called CD247) and CD28 intracellular domains that signal T-cell activation. In this therapy, T cells that have been removed from a patient are genetically engineered to express anti-CD19 CARs and are then injected back into the patient.
Q: What have early studies of axi-cel for refractory B-cell lymphomas shown?
A: Single-institution studies of anti-CD19 CAR T-cell therapy have shown high response rates in refractory B-cell lymphomas after the failure of conventional therapy. A phase 1 multicenter study (ZUMA-1) involving seven patients with refractory large B-cell lymphoma showed that axi-cel could be centrally manufactured and safely administered. An overall response to axi-cel therapy was reported in five patients and a complete response in four patients, with an ongoing complete response in three patients reported at 1 year. Neelapu et al. recently reported the results of the primary analysis of phase 2 of ZUMA-1 and an updated analysis with 1 year of follow-up.
A: In the phase 2 trial of axi-cel therapy conducted by Neelapu et al., 82% of the 101 patients with refractory large B-cell lymphoma who were treated had an objective response, and 54% had a complete response. These findings compare favorably with the results of the recent SCHOLAR-1 study of existing therapies for this disease. With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. Although most responses occurred in the first month, 23 patients had a complete response as late as 15 months. The median overall survival was not yet reached (95% CI, 12.0 months to could not be estimated), with overall survival rates of 78% (95% CE, 69 to 85) at 6 months, 59% (95% CI, 49 to 68) at 12 months, and 52% (95% CI, 41 to 62) at 18 months.
A: During treatment, all 101 patients who had received axi-cel had adverse events, which were grade 3 or higher in 95%. The most common adverse events of any grade were pyrexia (in 85% of the patients), neutropenia (in 84%), and anemia (in 66%). The most common adverse events of grade 3 or higher were neutropenia (in 78%), anemia (in 43%), and thrombocytopenia (in 38%). The cytokine release syndrome occurred in 94 patients (93%). Most cases were of low grade (37% of grade 1 and 44% of grade 2), with 13% grade 3 or higher (9% of grade 3, 3% of grade 4, and 1% of grade 5). Neurologic events occurred in 65 patients (64%); 28% were grade 3 or higher. The most common neurologic events of grade 3 or higher were encephalopathy (in 21% of the patients), confusional state (in 9%), aphasia (in 7%), and somnolence (in 7%).