Background
Phase III multicenter RCT (PRECISION-T), N=187 adults with acute leukemias or MDS undergoing myeloablative conditioning with G-CSF-mobilized peripheral blood from HLA-matched donors. Orca-T is a precision Treg-enriched allogeneic graft enabling GVHD prophylaxis with reduced pharmacologic immunosuppression. Tested Orca-T + single-agent tacrolimus vs conventional allograft + tacrolimus/methotrexate.
Interventions and follow up
Arm A: Orca-T (precision-engineered Treg-enriched donor graft) + tacrolimus alone.
Arm B: Conventional allograft + tacrolimus + methotrexate (Tac/MTX).
Primary endpoint: Survival free from moderate-to-severe chronic GVHD (cGVHD-free survival, cGFS).
mFollow up: NR.
Arm B: Conventional allograft + tacrolimus + methotrexate (Tac/MTX).
Primary endpoint: Survival free from moderate-to-severe chronic GVHD (cGVHD-free survival, cGFS).
mFollow up: NR.
Results
cGFS (primary): HR 0.26 (95% CI 0.14–0.47); P<.001.
1-yr cGFS: 78.0% (Orca-T) vs 38.4% (Tac/MTX).
Moderate-severe cGVHD (1-yr CI): 12.6% vs 44.0%; Gray test P<.001.
GRFS: 63.1% vs 30.9%; P<.001.
OS: 93.9% vs 83.1%; P=.12.
NRM: 3.4% vs 13.2%; P=.03.
1-yr cGFS: 78.0% (Orca-T) vs 38.4% (Tac/MTX).
Moderate-severe cGVHD (1-yr CI): 12.6% vs 44.0%; Gray test P<.001.
GRFS: 63.1% vs 30.9%; P<.001.
OS: 93.9% vs 83.1%; P=.12.
NRM: 3.4% vs 13.2%; P=.03.
Adverse events
Infections: Fewer serious infectious complications with Orca-T vs Tac/MTX.
NRM: Lower non-relapse mortality (3.4% vs 13.2%); reduced immunosuppression did not increase GVHD or relapse.
NRM: Lower non-relapse mortality (3.4% vs 13.2%); reduced immunosuppression did not increase GVHD or relapse.
Conclusions
Orca-T met its primary endpoint of improved survival free from chronic GVHD versus standard Tac/MTX, with markedly lower moderate-to-severe cGVHD, superior GRFS, and lower NRM. A precision Treg-enriched graft is a new low-toxicity GVHD-prophylaxis option in myeloablative HLA-matched transplantation, though it requires centralized GMP manufacturing.
Key Limitations
Requires centralized GMP cell-engineering and rapid logistics, limiting broad applicability. OS difference not significant (P=.12). Limited to myeloablative HLA-matched transplantation; longer follow-up needed to confirm durable GVHD and relapse benefit.
Clinical Context
First randomized phase 3 evidence for an engineered Treg-enriched graft as GVHD prophylaxis. Orca-T is investigational (not yet FDA/EMA-approved); positive PRECISION-T results position it as a potential low-toxicity alternative to standard calcineurin/methotrexate and PTCy-based prophylaxis within ASTCT frameworks, pending regulatory review.