Updated Clinical Results: A Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein–Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab Plus Chemotherapy

Background: The ALLELE trial (NCT03394365) is investigating the effects of tabelecleucel, an off-the-shelf allogeneic Epstein–Barr virus (EBV)-specific cytotoxic T cell therapy, to treat relapsed/refractory EBV-associated post-transplant lymphoproliferative disease (R/R EBV+ PTLD) arising after solid organ transplant (SOT) or hematopoietic stem cell transplant (HCT). The trial started accrual in 2018 with results on 43 patients (pts) published previously (Mahadeo et al. Lancet Oncol 2024). Herein we report the safety and efficacy of tabelecleucel in a larger cohort.

Methods: In the ALLELE trial, pts receive tabelecleucel at 2x10⁶ cells/kg on days 1, 8 and 15 in 35-day cycles. Efficacy and safety outcomes are assessed. Response per clinical and radiographic assessment are evaluated by independent oncologic response adjudication (IORA; primary assessment) using Lugano Classification with LYRIC modification. Key endpoints include overall response rate (ORR), duration of response (DOR), time to response (TTR) and overall survival (OS). Pts are assessed up to 5 years.

Results: At data cut-off (9^th October 2023), 75 pts (49 SOT, 26 HCT) were enrolled, treated with tabelecleucel and included in the full analysis set. Median age was 44.4 years (range 2.7–81.5); 11 pts (14.7%) were <18 years (18.4% SOT; 7.7% HCT). 24% of pts ≥16 years had an ECOG score ≥2 and 50%/43.8% had intermediate/high-risk per PTLD-adapted prognostic index. Median time from transplant to diagnosis of EBV+ PTLD was 0.9 years (y; 0.2–26.2) for SOT and 3.9 months (mo; 0.6–66.0) for HCT. The median (min, max) time from EBV+ PTLD diagnosis to first dose of tabelecleucel was 4.6 months (mo; 0.6–190.5). The median number of prior therapies overall was 1.0 (1.0–5.0). Prior therapies included rituximab monotherapy (n=65; 86.7%), chemotherapy-containing regimens (35; 46.7%) and/or rituximab + chemotherapy (28; 37.3%).

The overall ORR was 50.7% (38/75, 95% CI 38.9, 62.4), SOT ORR was 51.0% (25/49, 95% CI 36.3, 65.6) and HCT ORR was 50.0% (13/26, 95% CI 29.9, 70.1). TTR was 1.1 month (mo; 0.6–9.0). The complete response (CR) per IORA was 28.0% (21/75, 95% CI 18.2, 39.6); partial response (PR) was 22.7% (17/75, 95% CI 13.8, 33.8). Median DOR was 23.0 (12.1; NE). Twenty of the 38 responders had CR or PR that lasted >6 months. Overall, the clinical benefit rate (pts with a CR, PR, or SD for 6 months or more) was 60.0%; 57.1% for SOT, 65.4% for HCT. The 1-year OS rate was 55.7% (95% CI 43.2, 66.4); 57.1% for SOT (95% CI 41.7, 69.9), 52.4% for HCT (95% CI: 30.4, 70.5). Median OS was 18.4 mo (95% CI 5.7, NE); 18.4 mo for SOT (95% CI: 5.0, NE), 18.6 mo for HCT (95% CI 2.9, NE). Responders to tabelecleucel had a 1-year OS rate of 78.7% (95% CI 61.8, 88.7) vs 28.2% for non-responders (95% CI 13.7, 44.7).

Serious treatment emergent AEs (TEAEs) and fatal TEAEs were reported in 65.4% and 19.2% of HCT and 61.2% and 18.4% of SOT pts, respectively. No fatal TEAEs were treatment-related. The safety profile was favorable and consistent with previous data, with no reports of tumor flare reactions, infusion reactions, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, marrow rejection, or transmission of infectious diseases. No events of graft vs host disease or organ rejection were reported as tabelecleucel-related.

Conclusions: Updated results from the ALLELE study confirm tabelecleucel efficacy with an ORR of 50.7% in 75 pts, along with DOR of ~23 months and median OS of 18.4 months, in patients who otherwise have a median OS of 0.7-4.1 months in the absence of available treatment options. The safety profile remains consistent with previous findings. These results represent a potential new treatment paradigm for pts with R/R EBV+ PTLD.