Zamtocabtagene autoleucel, a tandem CD20-CD19-directed CAR T-cell therapy, for second line treatment of large B-cell lymphoma in patients ineligible for transplantation (DALY 2-EU): primary analysis of an open-label, multicentre, randomised phase 2 study

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• Picked for Hematology (paper of the day, 27 October 2026): Randomized second-line CAR-T trial in large B-cell lymphoma

Abstract

BACKGROUND: Anti-CD19 CAR T-cell therapy is the standard second-line treatment for patients with relapsed or refractory large B-cell lymphoma. However, there is no evidence from randomised controlled trials in patients ineligible for transplantation. To address this gap, we compared zamtocabtagene autoleucel (zamto-cel), a CAR T-cell therapy directed at CD20 and CD19, with rituximab-gemcitabine-oxaliplatin (R-GemOx) chemoimmunotherapy in patients ineligible for transplantation with relapsed or refractory large B-cell lymphoma. METHODS: DALY 2-EU is an open-label, multicentre, randomised, phase 2 trial conducted at 45 centres across 12 countries in Europe. Eligible patients were adults (aged ≥18 years) with second-line relapsed or refractory large B-cell lymphoma confirmed histologically who were ineligible for transplantation and had received first-line chemoimmunotherapy containing a combination of an anthracycline-based regimen and an anti-CD20 monoclonal antibody, with Eastern Cooperative Oncology Group performance status score of 2 or less. Patients were randomly assigned (1:1) to zamto-cel (single intravenous infusion of 2·5 × 106 fresh (ie, non-cryopreserved) CAR T-cells per kg, capped at 100 kg, produced in a closed automated system) or R-GemOx (rituximab [375 mg/m2 intravenously on day 1], gemcitabine [1000 mg/m2 intravenously on day 1 or 2], and oxaliplatin [100 mg/m2 intravenously on day 1 or 2] administered for up to eight 14-day cycles). Randomisation was done with an interactive web response system and stratified by age, gender, lactate dehydrogenase, International Prognostic Index, histology, time to relapse after the start of first-line therapy, and country. The primary endpoint was event-free survival assessed by a masked independent review committee and compared all patients randomly assigned to the zamto-cel and R-GemOx groups using a one-sided log-rank test. Safety was assessed in all patients who received study treatment. This ongoing trial is registered with ClinicalTrials.gov (NCT04844866). FINDINGS: Between Oct 14, 2021, and Jul 16, 2024, 219 patients were screened and 160 were randomly assigned to zamto-cel (n=82) and R-GemOx (n=78). The median age was 74·0 years (IQR 70·5-77·0). Patients were predominantly male (100 [63%] of 160 were men and 60 [38%] women) and White (91 [57%]), with race not reported for 64 (40%). Median vein-to-vein time for zamto-cel was 15 days (IQR 15-16). With a median follow-up of 17·0 months (IQR 9·0-22·8), event-free survival was longer in the zamto-cel group than in the R-GemOx group (6·21 months [95% CI 3·84-13·77] vs 2·53 months [1·97-3·35]; HR 0·39 [95% CI 0·27-0·58]; p<0·0001). Grade 3 or higher treatment-emergent adverse events occurred in 63 (83%) of 76 with zamto-cel and in 65 (86%) of 76 with R-GemOx. The most common grade 3-4 adverse events were neutropenia (28 [37%] with zamto-cel and 17 [22%] with R-GemOx), anaemia (11 [14%] and 12 [16%]), and decreased neutrophil count (20 [26%] and seven [9%]). Serious adverse events occurred in 31 (41%) patients with zamto-cel and 50 (66%) with R-GemOx, most commonly malignant neoplasm progression (11 [14%] and 38 [50%]), cytokine release syndrome (CRS; six [8%] and none), and immune effector cell-associated neurotoxicity syndrome (four [5%] and none). Treatment-related deaths occurred in two (3%) of 82 patients with zamto-cel (due to CRS and haemophagocytic lymphohistiocytosis) and in one (1%) of 78 with R-GemOx (malignant lymphoma progression). INTERPRETATION: The risk-benefit ratio observed in the DALY 2-EU study supports consideration of zamto-cel as a second-line standard treatment option for patients with relapsed or refractory large B-cell lymphoma who are ineligible for transplantation. FUNDING: Miltenyi Biomedicine.

Abstract as published, via PubMed.