Orca-T With Reduced-Intensity Conditioning Yields Robust Efficacy in Hematologic Malignancies

Orca-T following reduced-intensity conditioning generated durable efficacy outcomes and a trend toward a decreased incidence of acute graft-vs-host disease (aGVHD) in patients with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or myelodysplastic syndromes (MDS), according to findings from an ongoing phase 1 trial (NCT05088356), which were presented at the 2026 Transplantation & Cellular Therapy Meetings.¹

In the overall population (n = 53), no cases of graft failure or loss were observed. Two patients elected to receive a CD34-positive boost. Furthermore, the cumulative incidence of grade 2 to 4 aGVHD was 12.3% (95% CI, 5%-23%). No patients developed grade 3/4 aGVHD at 6 months. The 6-month estimated rate of moderate-to-severe chronic GVHD (cGVHD) was 10%. Additionally, all cases of aGVHD responded to treatment with systemic steroids. At a median follow-up of 12.2 months (range, 1.0-42.2), the respective estimated 12- and 24-month rates for key outcomes were as follows:

• Overall survival (OS): 88% (95% CI, 79%-98%); 84% (95% CI, 73%-96%)
• Recurrence-free survival (RFS): 82% (95% CI, 72%-94%); 79% (95% CI, 67%-92%)
• GVHD-free RFS (GRFS): 72% (95% CI, 60%-87%); 72% (95% CI, 60%-87%)
• Non-relapse mortality (NRM): 8.1% (95% CI, 2.5%-18%); 12% (95% CI, 4.0%-24%)
• Relapse: 9.7% (95% CI, 3.5%-20%); 9.7% (95% CI, 3.5%-20%)

Among the 8/8 matched population (n = 47), at a median follow-up of 16.8 months (range, 1.2-42.2), OS, RFS, GRFS, NRM, and relapse rates were 88%, 82%, 71%, 7.1%, and 11%, respectively. The estimated 6-month rate of grade 2 to 4 aGVHD in this population was 13%, and no cases of grade 3/4 GVHD were reported. The estimated 6-month rate of cGVHD was 12%.

In the 7/8 mismatched population (n = 6), at a median follow-up of 7.3 months (range, 1.0-21.2), the OS rate was 86%, the RFS rate was 86%, the GRFS rate was 86%, and the NRM rate was 14%. No patients relapsed in this population, and no cases of aGVHD or cGVHD were reported at 6 months.

In the arm that received the furthest-reduced–intensity conditioning regimen (arm A3), the 12-month OS rate was 95%, and the 12-month NRM rate was 0%.

“[This highlights] how the flexibility of Orca-T can help play with different conditioning regimens, and you can tailor it depending on the specific patient you’re taking to transplant,” Alejandro Villar-Prados, MD, PhD, said in a presentation of the data.

Villar-Prados is a translational investigator in the Department of Medicine at the Stanford School of Medicine at Stanford University in California.

What was the rationale for studying Orca-T plus reduced-intensity conditioning in hematologic malignancies?

The phase 3 PRECISION-T trial (NCT04013685) showed that among HLA-matched patients with acute leukemias or MDS undergoing myeloablative conditioning, Orca-T improved rates of survival free from GVHD compared with a conventional allograft.² However, Villar-Prados noted that the efficacy of Orca-T had yet to be established in older, more frail patients who are not eligible for myeloablative conditioning.¹

What was the design of the phase 1 trial evaluating Orca-T plus reduced-intensity conditioning in hematologic malignancies?

This trial enrolled patients between 18 and 75 years of age with high-risk acute leukemia in first complete response (CR1), beyond CR1, or with minimal residual disease positivity; chronic myeloid leukemia that was in accelerated, blast, or chronic phase; MDS; and myeloproliferative disorders.

The primary end points were to determine the safety and feasibility of engraftment time and donor chimerism by day 60 and beyond, as well as to measure the incidence of grade 3/4 aGVHD. Secondary end points included GRFS following hematopoietic cell transplantation (HCT), OS following HCT, and the incidence and severity of aGVHD and cGVHD.

This trial enrolled patients across 5 evaluable arms:

1. Arm A1 (n = 11): cell dose–finding arm; patients received 8/8 HLA-matched transplant following fludarabine/melphalan plus total-body irradiation (TBI) at 400 cGy
2. Arm A2 (n = 12): patients received 8/8 HLA-matched transplant following fludarabine plus thiotepa at 10 mg/kg and TBI at 400 cGy
3. Arm A3 (n = 24): patents received 8/8 HLA-matched transplant following fludarabine plus thiotepa at 5 mg/kg and TBI at 300 cGy
4. Arm C1 (n = 2): patients received 7/8 HLA-matched transplant following fludarabine plus thiotepa at 10 mg/kg and TBI at 400 cGy
5. Arm C1 (n = 4): patients received 7/8 HLA-matched transplant following fludarabine plus thiotepa at 5 mg/kg and TBI at 300 cGy

“There was potential concern of issues with engraftment,” Villar-Prados explained. “Thus, when we designed this trial, we ended up testing multiple conditioning regimens as well as different intensities, and testing how this can [affect] engraftment in patients.”

Baseline characteristics revealed that patients who received Orca-T had a median age of 68 years (range, 66-71), most were male (62%) and had an HCT-specific Comorbidity Index score of 2 or lower (66%). Disease diagnoses included ALL (4%), AML (60%), MDS (30%), and myelofibrosis (6%). Donor types included mismatched (7/8; 11%), matched related (8/8; 21%), and matched unrelated (8/8; 68%).

How did Orca-T plus reduced-intensity conditioning compare with PTCy plus reduced-intensity conditioning in patients with hematologic malignancies?

The investigators then compared the Orca-T cohort with a cohort of 587 patients from an unfiltered CIBMTR dataset who had received reduced-intensity conditioning followed by post-transplant cyclophosphamide (PTCy) plus tacrolimus (Prograf) and mycophenolate mofetil GVHD prophylaxis.

Compared with patients in the PTCy cohort, patients in the Orca-T cohort achieved higher estimated 12- and 24-month OS rates (P = .079; P = .034), RFS rates (P = .03; P = .016), and GRFS rates (P = .047; P = .015), as well as numerically lower 12- and 24-month NRM rates (P = .2; P = .3) and relapse rates (P = .1; P = .035). Additionally, the 6-month rate of grade 2 to 4 aGVHD was lower with Orca-T vs PTCy (P = .066), as was the 6-month rate of grade 3/4 aGVHD (P = .088). There was little difference observed between the 12- and 24-month rates of moderate-to-severe cGVHD between the arms (P = .902).

“We did not see a strong favoring of Orca-T vs PTCy in terms of aGVHD, but we were noticing a trend in the higher incidence of grade 3 and 4 [aGVHD] in the PTCy cohort, and we did not see any difference in terms of the severity or the incidence of chronic moderate-to-severe GVHD between the 2 groups,” Villar-Prados reported.

What are the next steps for investigating Orca-T in hematologic malignancies?

“These data suggest that Orca-T in combination with reduced-intensity conditioning is safe and effective, leading to robust myeloid and T-cell engraftment, [as well as a] low incidence of chronic and acute GVHD,” Villar-Prados concluded. “The high RFS [rate suggests a] potentially strong graft-vs-leukemia effect. Lastly, [this] seems to be a regimen that can be tolerated in the outpatient setting.”

Based on these phase 1 results, a multicenter, open-label phase 2 trial (NCT07216443) is investigating the safety, tolerability, and efficacy of Orca-T in adult patients with AML or MDS who are eligible to receive reduced-intensity or nonmyeloablative allogeneic HCT but not myeloablative conditioning.³ These patients must have an 8/8 HLA-matched related or unrelated donor. Patients will receive investigator’s choice of reduced-intensity or nonmyeloablative conditioning regimen followed by Orca-T and GVHD prophylaxis with tacrolimus. This trial is currently enrolling.

Disclosures: Villar-Prados had no disclosures.

References

1. Villar-Prados A, Pavlova A, Fernhoff N, et al. Interim clinical outcomes in Orca-T with reduced intensity conditioning: an observational comparison to registry-based post-transplant cyclophosphamide patients. Presented at: 2026 Transplantation & Cellular Therapy Meetings. February 4-7, 2026. Salt Lake City, Utah. Abstract 14.
2. Meyer E, Salhotra A, Gandhi A, et al. Orca-T versus allogeneic hematopoietic stem cell transplantation (PRECISION-T): a multicenter, randomized phase 3 trial. Blood. Published online December 12, 2025. doi:10.1182/blood.2025031313
3. Trial of Orca-T following reduced intensity or nonmyeloablative conditioning in patients with acute myeloid leukemia or myelodysplastic syndrome. ClinicalTrials.gov. Updated January 8, 2026. Accessed February 5, 2026. https://clinicaltrials.gov/study/NCT07216443