First-line salvage therapies in relapsed/refractory large B-cell lymphoma after second- or third-line CD19-directed CAR T-cell therapy
Year: 2025
Type: conference-abstract
Abstract: Introduction CD19-directed CAR T-cell (CAR-T) therapy is increasingly deployed in earlier lines of treatment for relapsed/refractory large B-cell lymphoma (r/r LBCL), including 2nd and 3rd line settings. This shift raises important questions about post-CAR-T management, yet existing data largely reflect heavily pretreated patients, limiting relevance to current practice. In this evolving context, the clinical features, salvage strategies, and outcomes following relapse after early-line CAR-T remain poorly defined. Objective To determine the effectiveness of first-line salvage therapies and associated survival outcomes in patients with r/r LBCL relapsing after as2nd or 3rd line CAR-T therapy. Methods This international, multicenter retrospective cohort study included LBCL patients from five institutions, who received CAR-T therapy as 2nd or 3rd line therapy. Response was assessed per Lugano criteria. One-year progression-free survival (PFS) and overall survival (OS) were calculated from the initiation of salvage therapy. Prognostic factors were evaluated using univariable and multivariable Cox regression models. Results:Among 557 LBCL patients treated with 2nd line (31%) and 3rd line (69%) CAR-T, the 1-year OS and PFS was 76% (95% CI 73-80) and 54% (49-58), respectively; 18% were refractory to CAR-T therapy. Cumulative incidence (CI) of relapse/progression at 1-year post-CAR-T was 42% (37-46), with a median time to relapse of 2.9 months (IQR 1.2-6.0). Notably, the complete responses (CR) rates and relapse or progression CI were comparable between 2nd and 3rd line CAR-T (71% vs. 66% and 37% vs. 44%, respectively). Of 232 patients who relapsed or progressed following CAR-T, 182 (78%) received subsequent treatment. The median age of the treated cohort was 63 years (IQR 52-73); 52% had received axi-cel, 24% tisa-cel, 18% liso-cel, and 6% point of care CD19-CAR-T product. Most patients had received CAR-T as 3rd line therapy (72%), with the remainder treated in the 2nd line setting. Overall response rate (ORR) to post-CAR-T treatment was 49% (34% CR, 15% PR). With a median follow up of 22 months (IQR 8-40), 1-year OS from post-CAR-T treatment was 47% (95% CI 39-56) and PFS was 29% (22-38). In multivariable Cox regression adjusting for age, disease transformation, CAR-T product, and best response to CAR-T, the line of prior CAR-T therapy was not associated with OS (HR 1.29, 95% CI, 0.75–2.23) or PFS (HR 0.95, 95% CI, 0.61–1.47). One-year OS rates following salvage therapy was comparable between 2nd and 3rd line groups (44% vs. 48%, p=0.76), as was PFS (23% and 31%, p=0.66). Post-CAR-T treatments were heterogeneous, with the most common being involved-site radiation therapy (ISRT)- (n=39) followed by bispecifics- (n=37), bendamustine- (n=23), and polatuzumab- (n=21) containing regimens. Checkpoint inhibitors-containing regimens were administered to 14 patients. These categories were not mutually exclusive and therefore not directly comparable. Among patients treated with polatuzumab-containing regimens, 14% had prior exposure to the same agent; while bispecific-containing regimens had 27% previous exposure to polatuzumab, and 3% to bispecifics. Response rates to systemic treatments varied by regimen-containing group: polatuzumab- and checkpoints inhibitors-containing regimens demonstrated the highest ORR (57%), followed by bispecifics- containing regimens (56%). At 1-year from post-CAR-T treatments OS was approximately 50%, reaching the highest with checkpoint inhibitors- (70%), followed by bispecifics- (60%), and the lowest with anthracycline/platinum based chemotherapies-containing regimens (33%). However, lower PFS (around 30%) was observed, ranging from 51% with bispecifics-, followed by checkpoint inhibitors- (44%), to bendamustine-containing regimens (8%). Conclusions:This large, multicenter study is among the first to evaluate first-line salvage therapies in patients with LBCL relapsing after 2nd or 3rd line CD19 CAR-T. Salvage treatments yielded meaningful responses and survival, regardless of CAR-T therapy line. Immunotherapy-based regimens demonstrated encouraging activity, though longer follow-up is needed to confirm durability of response and survival benefit. These findings may guide future post–CAR-T treatment considerations and support further exploration of immunotherapy-based approaches in this high-risk population.
Source: Blood
Authors: Silvia Escribano Serrat, Andrew Ip, Jaime Sanz, Marina Gomez-Llobell, Sigrun Einarsdottir, Ronit Marcus, Ori Ben Valid, Noa Golan Accav, Yara Abu Ahmad, Shimrit Harlev, Uri Greenbaum, Andre Goy, Teng Fei, Mika Geva, Gilles Salles, Michael Scordo, Lia Palomba, Jennifer Lue, Jae Park, Heiko Schoder, Craig Sauter, Burcin Agridag Ucpinar, Gunjan Shah, Kai Rejeski, Ofrat Beyar-Katz, Abraham Avigdor, Miguel-Angel Perales, Roni Shouval
Institutions: Universitat Autònoma de Barcelona, Memorial Sloan Kettering Cancer Center, Hackensack University Medical Center, Hospital Universitari i Politècnic La Fe, Tel Aviv University, Sheba Medical Center, Rambam Health Care Campus, Soroka Medical Center, LMU Klinikum, Ludwig-Maximilians-Universität München
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417012459
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