Orca-T Shows Efficacy, Reduced GVHD Risk in Acute Leukemia, MDS

Allogeneic stem cell transplant (allo-HSCT) is part of the standard treatment paradigm for acute leukemia and myelodysplastic syndrome (MDS). But like most therapies for hematologic malignancies, it carries significant risks, with a main concern being chronic graft-vs-host disease (cGVHD).

Orca-T, an investigational allogeneic T-cell immunotherapy, improved cGVHD-free survival compared with allo-HSCT in patients with acute leukemia or MDS in the phase 3 Precision-T trial (NCT05316701). The results, presented at the 51st Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), demonstrate Orca-T’s potential to improve outcomes in this patient population.¹

Caspian Oliai, MD, MS | Image credit: UCLA Health

“Simply stated, the unmet need in allotransplantation is to reduce the risk of [GVHD] without increasing the risk of infections or relapse,” Precision-T investigator Caspian Oliai, MD, MS, a medical oncologist and hematologist and medical director of the University of California Los Angeles Bone Marrow Transplantation Stem Cell Processing Center, told The American Journal of Managed Care (AJMC). Oliai was senior author on the abstract presented at EBMT.

Here, Oliai discusses the treatment’s mechanisms of action and the findings presented at the EBMT annual meeting, held March 30 to April 2, 2025, in Florence, Italy.

This transcript was lightly edited.

AJMC: Can you tell us the main results of the Precision-T trial evaluating Orca-T that were presented at the 51st Annual Meeting of the EBMT?

Oliai: Orca-T is a high-precision immunotherapy that’s composed of stem cells and immune cells that are derived from an allogeneic donor, and it leverages a highly purified and polyclonal T-regulatory cell population that’s capable of controlling alloreactive immune responses. We previously presented the phase 1b trial data, which showed that patients with acute leukemia and MDS who received myeloablative conditioning with Orca-T had low rates of toxicity and low rates of relapse. Based on that promising data, the current phase 3 trial that was presented at EBMT this year enrolled patients with acute leukemia and MDS who received myeloablative conditioning and then [randomly assigned] patients between Orca-T plus single-agent prophylaxis against [GVHD] with tacrolimus only vs standard allotransplant with double-agent prophylaxis with tacrolimus and methotrexate.

The primary end point of subjects who were free of moderate to severe [cGVHD] and alive at 1 year favored the Orca-T group—78% [in] Orca-T vs 38% in standard allotransplant. This corresponded to [an HR] of 0.26 and a P value that was statistically significant. When isolating out [cGVHD], 44% of subjects in the Orca-T arm did not experience moderate to severe [GVHD] compared with only 13% of subjects receiving standard allotransplant [who] were free of [cGVHD]. Also, if we look at the rate of severe infections, that was approximately doubled in patients who received standard allotransplant compared [with] Orca-T. Also, 1-year overall survival was 94% in Orca-T and 83% with standard allotransplant. Really importantly, nonrelapse mortality—meaning that what percentage of patients died from a complication that was not associated with relapse—was only 3% in the Orca-T arm at 1 year vs 13% with standard allotransplant.¹

Based on these results that were presented at EBMT, Orca-T with tacrolimus appears to be safer than standard allotransplant using double-agent prophylaxis with tacrolimus and methotrexate, while still providing excellent disease control for a curative potential for patients with hematologic malignancies.

AJMC: Discuss the mechanism of action in the mix of cells that make up the Orca-T. What is the clinical rationale for using these different cells together?

Oliai: If we think about the standard allograft and standard allogeneic hematopoietic cell transplantation, it’s composed of a variety of cell types that are typically administered together in a single infusion. However, the full benefits of this process could potentially be achieved by cellular selection, in which we purify for certain cell types that provide a therapeutic benefit while reducing or removing other cell types that pose a potential risk. The Orca-T strategy selects and separates into 3 distinct components. No. 1, the hematopoietic stem cells, they’re given on day 0. No. 2, the purified T-regulatory cells, they’re also given on day 0, but in a separate infusion. And then No. 3, the conventional T cells, which are given at a relatively reduced dose compared [with] standard allotransplant, and they’re given on day plus 2. So, this separation allows for the regulatory T cells to migrate to the solid organs first so that by the time the conventional T cells arrive, an immune barrier is in place that mitigates [GVHD] by preventing massive T-cell proliferation while still allowing for T-cell activation.

AJMC: Are there data on the rates of hospitalization posttreatment with Orca-T compared with traditional allo-HSCT?

Oliai: We have data with regard to rehospitalization between the 2 groups. In the phase 3 trial, the rehospitalization rate due to adverse events was lower with Orca-T—27% in the Orca-T group compared with 46% in the standard allogeneic transplant group. The reason why this is important is [that] if you think about the full costs associated with standard allogeneic transplant, they are not only based on the conditioning regimen and the cellular product that’s being infused; the full costs also include the immunosuppressants that you subsequently take. Also, as you mentioned, the cost of hospitalizations in the setting of both severe infections and the cost of rehospitalizations in the setting of severe [GVHD].

As the data presented at the EBMT meeting have shown, the rate of severe infection and the rate of GVHD are lower with Orca-T, so that could potentially lower the costs that are associated with the full allogeneic transplant process when you’re considering rehospitalization, that chunk of costs.

AJMC: Many patients require treatment for GVHD after allo-HSCT.² Are cost savings anticipated if the traditional post–allo-HSCT treatment is avoided?
Oliai: For sure, on the surface and overall. If the patient doesn’t develop GVHD, they’re not going to need those treatments for acute and chronic [GVHD] that you’re referring to. Some of them are very expensive medications like ruxolitinib [and] some of them are expensive intravenous infusions like axatilimab, [which] was recently FDA approved.^3,4 If we can avoid having patients require those, that’s the best way to cut down on costs for sure.

AJMC: Describe the challenges that clinicians face today in deciding whether a patient is a candidate for conventional allo-HSCT.

Oliai: In regard to candidacy for allo-HSCT, the main question that we use to approach these cases, especially in older patients, is, “Can the patient tolerate the combination of intensive conditioning and also the subsequent intensive immunosuppression that is necessary to achieve a cure from the specific hematologic malignancy?” Now, many older patients can’t tolerate this combination of intensive conditioning with immunosuppression at a high level. That, unfortunately, makes them ineligible for what is really the only curative strategy for most acute leukemias and MDS.

With Orca-T, as we’re seeing, the strategy is safer. There are lower rates of GVHD, there are lower rates of infection, and the reason why is because there’s less immunosuppression post Orca-T using only single-agent tacrolimus prophylaxis. Perhaps that can make more older patients eligible for this curative strategy for their hematologic malignancy.

References
1. 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 Meeting of the European Society for Blood and Marrow Transplantation; March 30-April 2, 2025; Florence, Italy. Oral session 15-01.
2. Hooker DS, Grabe-Heyne K, Henne C, Bader P, Toumi M, Furniss SJ. Improved therapeutic approaches are needed to manage graft-vs-host disease. Clin Drug Investig. 2021;41(11):929-939. doi:10.1007/s40261-021-01087-6
3. Joszt L. A novel approach to chronic GVHD with axatilimab: Dr Daniel Wolff. AJMC. October 18, 2024. Accessed April 15, 2025. https://www.ajmc.com/view/a-novel-approach-to-chronic-gvhd-with-axatilimab-dr-daniel-wolff
4. Santoro C. FDA approves axatilimab for chronic graft-vs-host disease. AJMC. August 15, 2024. Accessed April 15, 2025. https://www.ajmc.com/view/fda-approves-axatilimab-csfr-for-chronic-graft-vs-host-disease