Outcomes and treatment patterns of patients with primary mediastinal b-cell lymphoma after CAR-t cell therapy failure : A descar-t analysis

Abstract Background : Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of large B-cell lymphoma that usually responds well to frontline immunochemotherapy but has historically had a poor prognosis in the relapsed/refractory (R/R) setting. Although anti-CD19 CAR-T cell therapy has shown a high rate of sustained remissions in R/R PMBL, the clinical features and outcomes of patients (pts) who relapse after this treatment are still not well understood, despite representing a new unmet medical need. This study aimsto describe the characteristics, management, and post–CAR-T cell outcomes of these pts with a particular focus on responses to subsequent lines of therapy. Methods The CARTHYM study previously examined outcomes in 82 pts with PMBL who received anti-CD19 CAR-T cell therapy in France between October 2018 and February 2024, within the French DESCAR-T registry (NCT04328298). For this analysis, we included all pts who experienced disease progression after CAR-T cell therapy. The primary objective was to assess 1-year overall survival (OS) from the time of progression. Secondary objectives included evaluating responses to subsequent lines of treatment and their associated 1-year progression-free survival (PFS). Results: Among 82 patients with R/R PMBL treated with anti-CD19 CAR-T cells, 27 (33%) experienced disease progression and comprised the study population. Of these, 14 (52%) received axi-cel, 11 (40%) tisa-cel, and 2 (7%) liso-cel. The median age at infusion was 33 years. The Median time from CAR-T infusion to progression was 2 months (range: 0-5). No relapse occurred after 6 months. At progression, 59% had advanced-stage disease and 74% had elevated LDH levels. A repeat biopsy was performed in 12 pts, revealing PMBL in 7, grey-zone lymphoma in 2, DLBCL in 1, and necrosis in 2. At the time of disease progression after CAR-T cells and after a median follow-up of 34 months (6 - 71), the 1-year OS was 48.1% (mOS: 11.7 months). Twenty-two pts (81%) received at least one subsequent line of therapy; while five pts (19%) died without further treatment. Salvage treatments included checkpoint inhibitors (CPI, pembrolizumab or nivolumab) in 11 pts, with four of them received also brentuximab-vedotin; chemotherapy in 1 patient (Rituximab-bendamustine + polatuzumab-vedotin); anti-CD3/CD20 bispecific antibodies in 6 pts (glofitamab, epcoritamab or plamotamab); and various others therapy in 4 pts. Five pts received radiotherapy (alone: n=2; in consolidation: n=3), and three underwent stem cell transplants (autologous: n=2; allogeneic: n=1) in complete response (CR). Among treated pts, 41% (9/22) achieved a CR, and 5% (1/22) a partial response (PR), with a 1-year PFS of 41%. Notably, none of the pts who achieved CR relapsed. CPI-based regimens result in the highest response rates (CR in 7/11, 64%), compared to bispecific antibodies (1/6 CR) and other strategies (1/6 CR), resulting in significantly better 1-year PFS for pts treated with CPIs versus others (63.6% vs. 18.2%, p = 0.009). The 7 pts who received CPI-based salvage therapy and reached CR were alive without progression after 2 year. Conclusions: This study outlines the treatment features and outcomes of pts with PMBL who relapse after CAR-T cell therapy and highlights the potential of CPIs as a preferred treatment option following CAR-T cell failure. Given the young age of most pts and the frequent off-label use of CPIs across many countries, these findings emphasize the importance of a structured, multidisciplinary expert approach to support timely and individualized management decisions in this rare but potentially curable population.