CAR-T cells in newly diagnosed high-risk large B cell lymphoma

<title>Abstract</title> <p> <bold>Background</bold> Standard immunochemotherapy yields suboptimal outcomes in patients with newly diagnosed high-risk large B-cell lymphoma (LBCL). The ZUMA-12 trial demonstrated the feasibility of CD19 chimeric antigen receptor (CAR) T-cell therapy as a first-line treatment, yet more data are needed to support its broader application in this setting. Furthermore, how to design better integrated strategies to further enhance the efficacy and safety of frontline CAR T-cell therapy remains an open question. <bold>Methods</bold> In this single-center phase II trial, we enrolled patients with newly diagnosed high-risk LBCL. Patients received two cycles of rituximab, lenalidomide, and Zanubrutinib (ZR ² ), followed by CD19 CAR T-cell infusion. The primary endpoint was complete response (CR) rate after CAR T-cell therapy. <bold>Results</bold> A total of 43 patients were enrolled (median age, 69 years; 44% ≥70). After ZR ² debulking, the overall response rate was 92.9%, with a CR rate of 33.3%. Among the 40 patients who received CAR T‑cell therapy, the primary endpoint was met, with a CR rate of 95.1% (95% CI: 83.5%-99.4%). At a median follow-up of 25.6 months, estimated 2-year progression-free survival, overall survival and duration of response were 84%, 97.6% and 86.2%, respectively. Cytokine release syndrome occurred in 25% of patients (grade 3 in 2.5%); no neurotoxicity or treatment-related deaths occurred. <bold>Conclusions</bold> In this phase II trial, ZR ² debulking followed by sequential CD19 CAR T-cell therapy resulted in a high CR rate, durable responses, and a favorable safety profile in patients with newly diagnosed high-risk LBCL. Larger randomized trials are warranted. (ClinicalTrials.gov number, NCT04661020.) </p>