Dr Leslie on the 5-Year Follow-Up of the ZUMA-5 Trial in R/R Indolent NHL

“The question is: Is CAR T-cell therapy potentially curative for a proportion of patients who have indolent lymphoma? If it is, how do we identify those patients, and for those for whom it is not curable, how do we consolidate or fine tune what happens afterwards to improve long-term overall response?”

Lori A Leslie, MD, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, Hackensack Meridian Health’s John Theurer Cancer Center; assistant professor, Hackensack Meridian School of Medicine, discusses 5-year follow-up results from the phase 2 ZUMA-5 trial (NCT03105336) evaluating axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL).

The ZUMA-5 trial is evaluating the CAR T-cell therapy axi-cel in patients with indolent lymphoma, including follicular lymphoma and marginal zone lymphoma, Leslie begins. To qualify for enrollment, patients needed to have received at least 2 prior lines of therapy, including an anti-CD20 antibody and an alkylating agent, with a median of 3 prior therapies reported. The study’s primary end point was overall response rate, which was previously reported as 94% (95% CI, 88%-97%) in the follicular lymphoma cohort, with a complete response (CR) rate of 79%, she reports. Cytokine release syndrome (CRS) and neurologic toxicities occurred in most patients but were predominantly low grade, making the therapy generally tolerable, Leslie emphasizes.

The study’s primary analysis and subsequent 3-year follow-up demonstrated durable responses, raising key questions about relapse patterns in indolent lymphomas, she expands. Unlike diffuse large B-cell lymphoma, where relapses typically occur within the first year of treatment, indolent lymphoma relapses appear to be less frequent and occur later, according to Leslie. At the 3-year follow-up, there were few late relapses, and these findings were confirmed in the 5-year follow-up presented at the 2024 ASH Annual Meeting, Leslie explains. At the 5-year follow-up, investigators observed minimal disease progression, no further lymphoma-related deaths, and no new safety concerns, as CRS and neurologic toxicities remained early events, she notes.

The 5-year data highlighted the possibility that CAR T-cell therapy could be curative for some patients with indolent lymphoma, Leslie continues. Only 4 patients experienced relapse beyond 24 months post-leukapheresis, she says. Questions remain about identifying patients most likely to achieve durable responses and refining post-treatment strategies for those at higher risk of relapse to improve long-term outcomes, she concludes.