BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option for patients with high-risk hematologic malignancies such as acute leukemia and myelodysplastic syndromes (MDS). However, transplant complications such as graft-versus-host disease (GVHD) limit outcomes and quality of life. Orca-T is an investigational, precision-engineered, investigational cell therapy designed to safely control immune reconstitution. Combined with single-agent tacrolimus, Orca-T has shown superior survival free of moderate-to-severe cGVHD compared to conventional allograft plus tacrolimus and methotrexate (Tac/MTX). While Tac/MTX remains standard in myeloablative alloHSCT, many centers have adopted post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. Recently, the CIBMTR released outcomes data with unrelated donors and PTCy, enabling a registry-based comparator. This analysis retrospectively compares clinical outcomes between patients treated with Orca-T and those receiving myeloablative alloHSCT with PTCy-based prophylaxis.

METHODS An Orca-T data set was derived from patients receiving an 8/8 HLA matched unrelated donor treated on the phase 3 Precision-T study (NCT05316701). PTCy patient data were derived from the publicly available dataset accompanying a published study of unrelated donors (Shaffer et al, JCO, 2024), and a subset was derived from patients who received myeloablative conditioning prior to alloHSCT with an 8/8 HLA matched unrelated donor and PTCy-based prophylaxis regimens between 2017 and 2021. Both datasets were further selected so that the analysis included all patients ≤65 years old, had a diagnosis of AML, ALL or MDS, and excluded patients with active disease or low DRI scores. Statistical analyses between the resulting 45 Orca-T patients and 475 PTCy patients were performed in R. Log-rank tests and Gray's tests were used to assess survival outcomes and cumulative incidence rates, respectively.

RESULTS Orca-T was produced in a centralized GMP facility, and administered in 19 centers across the U.S. All patients enrolled in study received their product and were successfully infused.

Orca-T patients (n=45) had a median age of 42 (IQR 32-52 years). PTCy patients (n=475) had a median age of 49 (IQR 39-59 years). Respectively, male patients comprised 69% and 61% of the Orca-T and PTCy populations. The most frequent disease type in both populations was AML. The majority of patients in the Orca-T (62%) and PTCy (64%) had intermediate disease risk index (DRI) scores, with the remainder of the patients having high disease risk index scores or MDS.

Salient clinical outcomes for the Orca-T and the PTCy patients were:

  • 1-year OS: 94% (78%, 98%) for Orca-T vs 81% (78%, 85%) for PTCy

  • 1-year RFS: 86% (70%, 94%) for Orca-T vs 70% (65%, 74%) for PTCy

  • 1-year GRFS: 71% (51%, 83%) for Orca-T vs 61% (57%, 66%) for PTCy

  • 1-year NRM: 0% (NA, NA) for Orca-T vs 7% (7.3%, 13%) for PTCy*

  • 1-year relapse: 13.8% (5%, 27%) for Orca-T vs 21% (16%, 24%) for PTCy

  • Day 180 acute GVHD III-IV: 5.3% (1%,16%) for Orca-T vs 5.0% (3%,7%) for PTCy

  • 1-year moderate-severe cGVHD: 14.7% (4%, 31%) for Orca-T vs 8.2% (6 %, 11%) for PTCy

  • 1-year OS in >50y age group: 100% (NA, NA) for Orca-T vs 75% (69%, 80%) for PTCy

*indicates statistical significance at p<.05

CONCLUSIONS In this retrospective comparison of patients with high-risk hematologic malignancies undergoing alloHSCT with matched unrelated donors, Orca-T was associated with favorable overall survival and lower non-relapse mortality compared to PTCy-based GVHD prophylaxis. These findings align with results from the randomized Phase 3 study, in which Orca-T was associated with low rates of transplant complications and high rates of overall survival. The successful manufacturing, distribution, and infusion of Orca-T across 19 centers across the US further demonstrate the feasibility of this cell therapy across a wide geography. Notably, these outcomes were achieved using only single-agent tacrolimus for pharmacological GVHD prophylaxis, in contrast to the triple-agent regimen used with PTCy, implicating the potential role of immune reconstitution in both disease control and mitigating posttransplant complications. Additional studies are needed to identify the specific clinical factors such as infection and organ toxicity that may account for the potential differences in OS.

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2025
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