Axicabtagene ciloleucel led to “continued durable responses” in patients with relapsed/refractory indolent non-Hodgkin lymphoma, according to three-year follow-up data from the ZUMA-5 trial.
Ibrahim Yakoub-Agha, MD, PhD, of the Centre Hospitalier Universitaire de Lille and the University of Lille, and colleagues conducted the research and presented their findings during the European Society for Blood and Marrow Transplantation-European Hematology Association Fifth European CAR T-cell Meeting.
The multicenter, single-arm phase II trial evaluated axicabtagene ciloleucel, an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with follicular lymphoma or marginal zone lymphoma (MZL). Dr. Yakoub-Agha and colleagues presented updated clinical and pharmacological outcomes from the trial with a median of three or more years of follow-up.
The study included 159 patients with relapsed/refractory follicular lymphoma (n=127) or MZL (n=31) who received at least two prior lines of therapy, including a CD20-directed monoclonal antibody plus an alkylating agent. Of those patients, 152 received axicabtagene ciloleucel, including 124 patients with follicular lymphoma and 28 with MZL. Patients underwent leukapheresis followed by conditioning chemotherapy and an axicabtagene ciloleucel infusion of 2 × 106 CAR T-cells/kg. The study’s primary endpoint was the overall response rate (ORR).
The median follow-up was 40.5 months as of March 31, 2022. The ORR and complete response rates were “similar to the two-year analysis,” Dr. Yakoub-Agha and colleagues wrote. The overall median duration of response was 38.6 months. In patients with follicular lymphoma, the median duration of response was 38.6 months, while it was not reached in patients with MZL. The median duration of response was not reached in patients with a complete response but was 4.9 months in patients who had a partial response.
The overall median progression-free survival (PFS) was 40.2 months. In patients with follicular lymphoma, the median PFS was 40.2 months, while it was not reached in patients with MZL.
In the 70 patients with follicular lymphoma who progressed within 24 months, the median PFS was 40.2 months. The median PFS was not reached in the 41 patients with follicular lymphoma who did not progress within 24 months.
The estimated 36-month PFS was “consistent in all patients with [indolent non-Hodgkin lymphoma], regardless of other high-risk characteristics,” according to Dr. Yakoub-Agha and colleagues.
The median time to next treatment was not reached. The median overall survival (OS) was also not reached, with a 36-month OS rate of 75%. The 36-month lymphoma-specific PFS was 65%, while the 36-month lymphoma-specific survival rate was 89%. The medians of lymphoma-specific PFS and survival were not reached.
The peak CAR T-cell levels were higher in patients who had ongoing responses at 36 months (53.9 cells/µL) than in those who relapsed (29.6 cells/µL) or in patients who did not respond to the therapy (22.2 cells/µL).
“In patients with [follicular lymphoma], engraftment index (peak CAR T-cell levels/tumor burden) in combination with elevated baseline regulatory T-cell-related biomarkers was associated with relapse,” Dr. Yakoub-Agha and colleagues wrote. “Multivariable analyses in patients with [follicular lymphoma] identified key covariates that differentially associated with efficacy and toxicity.”
Grade 3 or higher adverse events of interest that occurred among treated patients since the two-year analysis were “largely in recently enrolled patients with MZL” and included one neurologic event, four cytopenias, and two infections, one of which was in a patient with follicular lymphoma, according to the study’s authors.
Since the two-year analysis of ZUMA-5, 10 patients died, with one dying due to progression, three dying due to adverse events unrelated to axicabtagene ciloleucel, and six dying from other causes.
“After three years of follow-up in ZUMA-5, [axicabtagene ciloleucel] demonstrated continued durable responses in patients with [relapsed/refractory indolent non-Hodgkin lymphoma], with improved survival observed in patients with MZL with longer follow-up,” Dr. Yakoub-Agha and colleagues concluded. “Late progression or death due to lymphoma or study treatment were uncommon and no new safety signals arose since the two-year analysis. Preinfusion immunosuppressive [regulatory T-cell]-related biomarkers associated with relapse in patients with [follicular lymphoma].”
Yakoub-Agha I, Neelapu SS, Chavez JC, et al. 3-year follow-up analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Presented at the European Society for Blood and Marrow Transplantation-European Hematology Association Fifth European CAR-T cell Meeting; February 9-11, 2023; Rotterdam, Netherlands.