Background: Patients with R/R FL experience progressively shorter remissions with each successive line of therapy, and the disease is largely considered incurable (Batlevi et al. Blood Cancer J. 2020). Patients who relapsed < 24 months after initiating first-line chemoimmunotherapy (POD24) have inferior overall survival compared with those who did not experience POD24 (Casulo, Barr. Blood. 2019). However, outcomes of R/R FL have improved with the introduction of novel options including chimeric antigen receptor (CAR) T-cell therapy, a highly effective approach with potential to change the treatment paradigm (Jacobson et al. Lancet Oncol. 2021; Freedman, Jacobson. Am J Hematol. 2020). Axi-cel, an autologous anti-CD19 CAR T-cell therapy, is approved for the treatment of R/R FL. In ZUMA-5, a single-arm, Phase 2 study of axi-cel in indolent non-Hodgkin lymphoma, patients with FL (n = 127) had a median progression-free survival of 40.2 months and median overall survival not yet reached after median follow-up of 41.7 months, with manageable long-term safety (Neelapu et al. ASH 2022. Abstract 4660). In ZUMA-5, POD24 did not adversely affect progression-free survival or overall survival. ZUMA-22 is a Phase 3, open-label, multicenter, randomized controlled trial that will evaluate the efficacy and safety of axi-cel compared with standard-of-care therapy in patients with R/R FL. Methods: The study will enroll approximately 230 adult patients with FL (Grades 1-3a) who have either had 1 prior line of therapy and experienced POD24 or had ≥2 prior lines of systemic therapy. Patients will be randomized 1:1 to receive axi-cel or standard-of-care therapy. Patients in the standard-of-care therapy arm will receive investigator’s choice of either rituximab + lenalidomide, rituximab + CHOP, or rituximab + bendamustine. Patients in the axi-cel arm will undergo leukapheresis, followed by optional bridging therapy, lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×10⁶ CAR T cells/kg). The primary endpoint is progression-free survival by blinded central assessment per Lugano classification (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete and overall response rates, duration of response, overall survival, event-free survival, time to next treatment, safety, and quality-of-life assessments. Additional key inclusion criteria are ECOG 0-1, presence of ≥1 measurable lesion, and adequate bone marrow and organ function. Those with HIV or hepatitis B or C and an undetectable viral load are eligible. Key exclusion criteria are a history of large B-cell lymphoma or transformed FL, and FL Grade 3b. The study is currently open and actively accruing patients at several sites globally (NCT05371093). Clinical trial information: NCT05371093.