Orca-T vs allogeneic hematopoietic stem cell transplantation (Precision-T): a multicenter, randomized phase 3 trial Open Access

Author(s): Meyer, Everett H.1; Salhotra, Amandeep2; Gandhi, Arpita P.3; Pantin, Jeremy4; Patel, Sagar S.5; Hoeg, Rasmus T.6; Gomez-Arteaga, Alexandra7; Faramand, Rawan8; Tamari, Roni9; Waller, Edmund K.10; Kosuri, Satyajit11; Jimenez Jimenez, Antonio M.12; Holter-Chakrabarty, Jennifer13; Dholaria, Bhagirathbhai14; Chen, Yi-Bin15; Hamilton, Betty K.16; Magenau, John17; Eghtedar, Alireza18; Murray, Joshua M.19; Pavlova, Anna19; Fernhoff, Nathaniel B.19; McClellan, James Scott19; Killian, M. Scott19; Li, Ai19; Negrin, Robert S.1; Oliai, Caspian20;
Source: Blood (2026) 147 (11): 1168–1177
Original Article
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Dr. Anjan Patel's Thoughts

This is an impressive advance in allo transplant, Orca-T cutting moderate–severe cGVHD dramatically (≈13% vs 44%) and nearly doubling cGVHD-free survival at 1 year (78% vs 38%) while also lowering NRM and serious infections is hard to ignore. Overall survival (OS) isn’t statistically different yet, but the combination of better disease control, less toxicity, and preserved immune reconstitution makes this feel like a meaningful step toward safer, more “engineered” transplants rather than just better immunosuppression.

ABSTRACT

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 regulatory T 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–mobilized peripheral blood from HLA-matched donors. The primary end point was survival free from moderate-to-severe chronic GVHD (cGVHD; cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm than in Tac/MTX (hazard ratio, 0.26; 95% confidence interval, 0.14-0.47; P< .001). One-year estimates were as follows: cGFS was 78.0% with Orca-T vs 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe cGVHD was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray test P< .001); overall survival was 93.9% with Orca-T vs 83.1% with Tac/MTX (P = .12); GVHD-free and relapse-free survival was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P< .001), respectively; nonrelapse mortality (NRM) was 3.4% with Orca-T vs 13.2% with Tac/MTX (P = .03). Orca-T met the primary end point of improved survival free from cGVHD compared with Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Moreover, significantly less toxicity was observed with Orca-T patients, including fewer serious infectious complications and less NRM. This trial was registered at www.clinicaltrials.gov as NCT05316701.

Author Affiliations

1Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA; 2Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 3Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland, OR; 4Sarah Cannon Transplant and Cellular Therapy Program TriStar Centennial Medical Center, HCA Healthcare, Nashville, TN; 5Transplant and Cellular Therapy Program, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT; 6Division of Malignant Hematology/Cellular Therapy and Transplantation, Comprehensive Cancer Center, University of California, Davis, Sacramento, CA; 7Weill Cornell Medicine, New York, NY; 8Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 9Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 10Bone Marrow and Stem Cell Transplant Center, Winship Cancer Institute of Emory University, Atlanta, GA; 11Division of Hematology and Oncology, University of Chicago Medicine, Chicago, IL; 12Division of Transplantation and Cell Therapy, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; 13Transplant & Cellular Therapy Clinic, OU Health Stephenson Cancer Center, Oklahoma City, OK; 14Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; 15Hematopoietic Cell Transplant and Cell Therapy Program, Massachusetts General Hospital, Boston, MA; 16Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, OH; 17Blood and Marrow Transplantation Program, Rogel Cancer Center, University of Michigan, Ann Arbor, MI; 18Colorado Blood Cancer Institute, HCA HealthONE Presbyterian St. Luke's, Denver, CO; 19Orca Bio, Menlo Park, CA; 20Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA

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