Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant...

Orca-T is a cellular immunotherapy comprising purified donor hematopoietic progenitor stem cells (HSPCs), regulatory T cells (Tregs) and conventional T cells (Tcons). Both Orca-T and post-transplant cyclophosphamide (PTCy) have demonstrated superior graft-versus-host disease (GVHD) control compared to tacrolimus and methotrexate (Tac/MTX) in randomized clinical trials. Orca-T achieves immune tolerance through high purity regulatory T cells in contrast to broad pharmacological immunosuppression with PTCy regimens.

The principal goal of this study was to evaluate the long-term overall survival (OS) of Orca-T compared to PTCy.

In this retrospective analysis, long-term survival follow-up was collected from a multicenter Phase 1b study of Orca-T that was initiated in 2019. OS outcomes were evaluated against a cohort of patients receiving PTCy-based GVHD prophylaxis, using a registry dataset obtained from the Center for International Blood and Marrow Transplant Research/NMDP (CIBMTR-NMDP). To ensure comparability, inclusion criteria were aligned with Orca-T Ph3 eligibility, specifically: age ≤65 years, diagnosis of intermediate- or high-risk AML or ALL in complete remission or MDS, myeloablative conditioning (MAC), and an 8/8 HLA-matched donor. The analysis included 76 Orca-T patients and 360 PTCy patients.

Orca-T was associated with significantly higher OS over a 3-year follow-up period compared to PTCy (HR=0.41; log-rank p=0.003). OS at 1, 2, and 3 years for Orca-T was 96% (95% CI: 88%-99%), 86% (76%-92%), and 83% (73%-90%), respectively. For the PTCy cohort, OS at 1, 2, and 3 years was 81% (77%-85%), 72% (67%-77%), and 66% (60%-71%), respectively. A propensity score-matched analysis (n=76/group) confirmed the primary findings (HR=0.40; log-rank test p = 0.010), as did a multivariable Cox model adjusted for recipient age, sex, disease, DRI, HCT-CI, and donor type (adjusted HR = 0.38; 95% CI 0.21-0.71; p = 0.002). The advantage persisted in sensitivity analyses excluding bone marrow grafts from the comparator and restricting both arms to the overlapping 2019-2021 transplant era (HR range across all specifications, 0.36-0.48). Three-year non-relapse mortality was lower with Orca-T (3.1% vs 10%; Gray's p = 0.0497), while relapse did not differ significantly; within the PTCy cohort, outcomes did not differ by MMF use. The OS advantage for Orca-T was consistently observed across age, disease type, and other clinical subgroups.

Within the limitations of this retrospective analysis, these results suggest that survival following alloHSCT may be improved with Orca-T relative to PTCy.