Late failure of aggressive B-cell lymphoma following CAR T-cell therapy: a LYSA study from the DESCAR-T registry Open Access

• This study investigates outcomes and treatments of aggressive LBCLs presenting failure after 3 months from CAR T-cells infusion.

• Bispecific antibodies improve PFS after CAR T relapse compared to other therapies.

Large B-cell lymphoma (LBCL) patients (pts) failing anti-CD19 Chimeric Antigen Receptor (CAR) T-cells therapy exhibit poor prognosis. Most progressions/relapses occur within 3 months from infusion while only a few events occur thereafter (late failure, LF). We analyze features, treatments and outcomes of pts with LF from DESCAR-T, a nationwide registry collecting real-life data for pts treated with approved CAR T-cell therapy in France. Between July 2018 and March 2024, 298 (39.9%) LBCL LF pts (median age 62 years, range 18-79, M 61.7%) were collected from DESCAR-T. Most pts had diffuse large B-cell lymphoma (DLBCL, n=205, 68.8%), advanced stage disease (84.6%) and age-adjusted International Prognostic Index (aaIPI) of 2-3 (59.3%) at CAR T eligibility. After failure, 76.5% pts received a systemic therapy and overall response rate (ORR) was 22.6% (complete response 18%). At a median follow-up since first late failure event of 13.8 (95% Confidence Interval [CI], 12.1-15.4) months, the median PFS-2 and OS-2 were 4.4 (95%CI, 3.8-5.8) and 13.2 (95% CI, 9.6-18) months, respectively. Compared to chemotherapy (HR=0.350, 95%CI, 0.193-0.633) and to pooled other treatments groups (HR=0.483, 95%CI, 0.290-0.805), salvage treatment with bispecific antibodies (BsAb) after CAR T failure showed better PFS-2. Radiotherapy obtained prolonged responses in some pts with 12-months PFS-2 of 41.5% (95%CI, 22.5-59.5). The present work is the first study describing LBCL pts with late failure after CAR T. BsAbs seem to be more effective compared to other strategies in LF setting and this should be considered in the design of new clinical trials.