Orca-T Improves Moderate to Severe cGVHD-Free Survival in Hematologic Malignancies

Treatment with Orca-T plus tacrolimus significantly improved moderate to severe chronic graft-vs-host-disease (cGVHD)–free survival (cGFS), incidence of cGVHD, and GVHD-free relapse-free survival (GRFS) compared with conventional allograft plus tacrolimus and methotrexate, according to findings from the phase 3 component of the Precision-T trial (NCT05316701) presented at the SOHO 2025 Annual Meeting.1

Findings showed that the 1-year cGFS rate was 78% (95% CI, 65.0%-86.6%) with Orca-T vs 38.4% (95% CI, 26.2%-50.5%) with tacrolimus and methotrexate (HR, 0.26; 95% CI, 0.14-0.47; log-rank P < .00001). The 1-year incidence rate of moderate to severe cGVHD was 12.6% (95% CI, 5.3%-23.1%) and 44% (95% CI, 31.3%-56.1%), respectively (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test P = .00002).

“The trial met its primary end point, demonstrating higher cGFS with Orca-T, likely driven by reduced cGVHD [incidence], and a positive trend in overall survival [OS],” Rawan Faramand, MD, of Moffitt Cancer Center in Tampa, Florida, and study coauthors wrote in the poster presentation.

How Was Precision-T Designed and What Was the Focus?

GVHD remains a primary treatment-related complication after allogeneic hematopoietic stem cell transplant (allo-HSCT) despite multimodal prophylaxis. Orca-T is an investigational allogeneic T-cell immunotherapy that uses high-purity regulatory T cells to prevent GVHD.

The primary purpose of the study was to compare moderate to severe cGFS in patients who received either Orca-T or standard GVHD prophylaxis with tacrolimus/methotrexate. Secondary end points included cumulative incidence of cGVHD, GRFS, and OS.

Previous findings from the study were presented at the 51st Annual EBMT Meeting.2

The study enrolled patients between aged 18 and 65 years with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL), or mixed-phenotype acute leukemia (MPAL) who would have been eligible to receive standard allo-HSCT and were in complete response (CR)/CR with incomplete hematologic recovery (CRi).1

A total of 187 patients were enrolled and randomly assigned: 93 to Orca-T and 94 to tacrolimus/methotrexate, which comprised the intention-to-treat population. Ultimately, 89 patients received Orca-T, and 93 received tacrolimus/methotrexate. Eighty-eight and 85 patients completed trial follow-up in the Orca-T and tacrolimus/methotrexate arms, respectively, and 88 and 94 patients were included in the respective safety populations for each arm.

Regarding baseline characteristics, the mean patient age was 43.6 years, and 26.7% were 55 years or older. Most patients were male (55.1%), White (74.3%), and had a primary diagnosis of AML (53.5%). Most patients also had matched sibling donors (50.8%) and an intermediate Disease Risk Index score (81.3%). Baseline Hematopoietic Cell Transplantation–specific Comorbidity Index scores were 0 (24.1%), 1 (25.7%), 2 (22.5%), 3 (17.1%), 4 (10.2%), or 5 (0.5%).

What Additional Efficacy and Safety Measures Were Presented for Orca-T?

Additional findings from the trial demonstrated that the 1-year OS rate was 93.9% (95% CI, 85.8%-97.4%) with Orca-T vs 83.1% (95% CI, 72.9%-89.8%) with tacrolimus/methotrexate (HR, 0.49; 95% CI, 0.20-1.22; log-rank P = .11823). The 1-year rates of GRFS were 63.1% (95% CI, 50.1%-73.6%) and 30.9% (95% CI, 20.0%-42.5%) with Orca-T and tacrolimus/methotrexate, respectively (HR, 0.37; 95% CI, 0.23-0.60; log-rank P = .00003).

Moreover, the cumulative incidence of grade 3 infections at 1 year was 8.4% (95% CI, 3.6%-16%) with Orca-T vs 16% (95% CI, 9.2%-25%) with tacrolimus/methotrexate. The primary causes of death in the Orca-T arm were relapse (n = 4), infection (n = 2), and GVHD (n = 1). In the tacrolimus/methotrexate arm, the primary causes of death were relapse (n = 3), infection (n = 3), GVHD (n = 5), and organ failure (n = 4).

With respect to survival outcomes, the 1-year non-relapse mortality rate was 3.4% in the Orca-T arm vs 13% in the tacrolimus/methotrexate arm. The 1-year RFS rates were 76% and 74%, respectively. A total of 39% and 56% of patients had a serious treatment-emergent adverse effect (AE) in the Orca-T and tacrolimus/methotrexate arms, respectively. The 1-year incidence of grade 2 or greater acute GVHD was 22% in the Orca-T arm vs 30% in the tacrolimus/methotrexate arm. The 1-year rates of grade 3 or greater acute GVHD were 6.2% and 16%, respectively. A total of 17% and 49% of patients in the respective arms had cGVHD.

In terms of engraftment and hospitalization, the median time to neutrophil engraftment was 13 days and 14 days in the Orca-T and tacrolimus/methotrexate arms, respectively. The median timing of platelet engraftment was 17 days and 18 days, respectively. A total of 27% and 46% of patients in the Orca-T and tacrolimus/methotrexate arms were rehospitalized because of an AE. There were no graft failures in either arm, and only 1 case of secondary graft failure occurred in the Orca-T arm.

References

1. Faramand R, Salhotra A, Gandhi A, et al. A randomized phase 3 trial in patients with hematologic malignancies demonstrates improved survival free of chronic GVHD with Orca-T compared to conventional allogeneic hematopoietic stem cell transplant. Presented at: SOHO 2025 Annual Meeting; September 3-6, 2025; Houston, TX. Abstract CT-262.
2. Meyer EH, Salhotra A, Gandhi AP, et al. Orca-T demonstrates improved survival free of chronic GvHD compared to conventional allogeneic hematopoietic stem cell transplant: a randomized phase 3 trial in advanced hematologic malignancies. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS15-01.