Orca-T versus allogeneic hematopoietic stem cell transplantation (PRECISION-T): a multicenter, randomized phase 3 trial

To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Early phase studies suggested improved outcomes with Orca-T, an allogeneic T-cell immunotherapy that uses purified donor Treg cells to prevent GVHD with significantly less immunosuppression. This phase 3 trial randomized adult patients (N=187) with acute leukemias or myelodysplastic syndrome undergoing myeloablative conditioning to receive either Orca-T with tacrolimus or a conventional allograft with tacrolimus and methotrexate (Tac/MTX), using granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood from HLA-matched donors. The primary endpoint was survival free from moderate-to-severe chronic GVHD (cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm compared to Tac/MTX (P0.001; HR 0.26; 95% CI, 0.14 to 0.47). One-year estimates were as follows: cGFS was 78.0% with Orca-T versus 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray's test P0.001), while overall survival (OS) was 93.9% with Orca-T versus 83.1% with Tac/MTX (P=0.12); GVHD and relapse-free survival (GRFS) was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P0.001), respectively; non-relapse mortality (NRM) was 3.4% with Orca-T versus 13.2% with Tac/MTX (P=0.03). Orca-T met the primary endpoint of improved survival free from cGVHD compared to Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Additionally, significantly less toxicity was observed with Orca-T patients including fewer serious infectious complications and less non-relapse mortality. (ClinicalTrials.gov number NCT05316701).