The FDA has approved Orca-T (Tregzi, Orca Bio) for use in matched-donor hematopoietic stem cell transplants (HSCTs) with a myeloablative preparative regimen for hematopoietic and immunologic reconstitution and to improve chronic graft-vs-host-disease (GVHD)-free survival in adults with hematologic malignancies.

Orca-T is a specialized stem cell transplant designed specifically to reduce the risk for chronic GVHD. It’s manufactured for each patient from matched donor cells and is the “first and only precision-engineered cell therapy for allogeneic transplant in adults with hematological malignancies,” Orca Bio said in a press release announcing the approval.

Conventional transplants deliver an unsorted mix of donor cells. Orca‑T is more controlled: Patients receive stem and progenitor cells upfront with highly purified regulatory T cells in higher proportions than conventional transplants to suppress GVHD. A couple days later, they receive conventional T cells to accelerate hematopoietic and immune reconstitution and produce graft-vs-leukemia activity. 

Donor cells are collected and sent to an Orca Bio facility for processing into an Orca-T graft. Stem and regulatory T cells are shipped to the treatment center as fresh infusions, while conventional T cells are shipped cryopreserved. 

Approval was based on the open-label Precision-T trial involving 187 US adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. They were randomized evenly to receive either a conventional HSCT or an Orca-T transplant using HLA-matched donors following myeloablative conditioning. Patients received standard GVHD prophylaxis, which included tacrolimus in both arms plus methotrexate in the conventional transplant group.

At 1 year, survival free of moderate to severe chronic GVHD, the primary outcome of the trial, was 78% with Orca-T vs 38.4% in the conventional arm. The cumulative incidence of moderate-to-severe chronic GVHD was 12.6% with Orca-T vs 44% with conventional transplant, and a combined endpoint of GVHD and relapse-free survival was 63.1% with Orca-T vs 30.9%. 

Nonrelapse mortality with Orca-T was 3.4% vs 13.2% with conventional transplant, but there was no difference in 1-year relapse-free survival, about 75% in both arms. Overall survival was numerically higher with Orca-T, at 93.9% vs 83.1%, but the difference was not statistically significant (P = .12).

“Despite less pharmacological GVHD prophylaxis, Orca-T improved survival free from chronic GVHD due to less GVHD and fewer deaths,” the investigators concluded.

However, an editorial published with the results sounded some notes of caution, including the need for follow-up beyond 1 year.

“[I]n the past few years, there has been a shift away from calcineurin inhibitor/methotrexate GVHD prophylaxis to posttransplant cyclophosphamide (PTCy) regimens,” noted Robert J. Soiffer, MD, of Dana-Farber Cancer Institute in Boston.

“How the Orca-T approach will fare against PTCy regimens will need to be explored in a future study,” he wrote.

The most common adverse reactions in 20% or more of patients in Precision-T who received Orca-T were mucositis, diarrhea, rash, viral infections, infections with unspecified pathogens, abdominal pain, vomiting, nausea, bacterial infections, hemorrhage, acute GVHD, edema, and fungal infections. 

However, there were fewer serious treatment-emergent adverse events and a lower likelihood of rehospitalization with Orca-T. The 1-year cumulative incidence of grade 3 infections also favored Orca-T, at 8.4% vs 16.1% with conventional transplant.

Prescribing information includes warnings and precautions for graft failure, GVHD, infusion reactions, infectious agent transmission, secondary malignancies, and malignancies of donor origin.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net