Paper Details

ABSTRACT

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only potentially curative therapy for many hematologic malignancies. The use of alloHSCT is limited by graft-versus-host disease (GVHD), a sustained immune reaction initiated by the donor T cells against the recipient’s normal healthy tissues, commonly the liver, skin, gastrointestinal (GI) tract, and lungs. Historically, steroid-resistant acute GVHD (aGVHD) is associated with high nonrelapse mortality (NRM) and poor overall survival. Allogeneic regulatory T cell immunotherapy with HSPC and T cells-vldq (Orca-T) is a precision-engineered allogeneic stem cell and T-cell immunotherapy for alloHSCT, that leverages highly purified, regulatory T cells to control alloreactive immune responses. The study met its primary endpoint, demonstrating superior survival free from moderate-to-severe chronic GVHD (cGFS) with Orca-T compared to conventional allograft with tacrolimus/methotrexate (Tac/MTX) (Meyer et al. Blood 2026). Here we report aGVHD outcomes from the Ph3 Precision-T trial (NCT05316701)
Methods: Eligible adults (aged 18-65), with an 8/8 HLA-matched donor,  undergoing myeloablative alloHSCT for acute leukemia in complete remission or high-risk myelodysplastic syndrome (MDS) (≤10% BM blasts) were randomized 1:1 to receive either Orca-T with single-agent Tac or unmanipulated peripheral blood stem cells plus Tac/MTX (control arm). Tac goal was 5-10 ng/mL and taper was allowed starting at day 90 in both arms. Endpoints evaluated in this post-hoc analysis included incidence of aGVHD and NRM. All staging and grading of aGVHD was performed according to MAGIC standardization and was independently assessed by the Endpoint Adjudication Committee (EAC). Patients (pts) with aGVHD requiring systemic therapy were classified based on response to first-line corticosteroids as either having complete response, steroid-dependent, or steroid-refractory/resistant (SR).
Results: A total of 88 Orca-T and 94 control arm pts were included in safety set (median follow up was 11.4 months [range, 0.2-24.3]); key demographics and baseline characteristics were previously reported (Meyers, et al. Blood 2026). Overall, 30 pts (34%) with Orca-T developed aGVHD (all grade) vs 44 pts (47%) in the control arm. Grade 2 to 4 aGVHD events occurred in 19% of Orca-T pts vs 23% of control arm. Fewer pts in the Orca-T arm experienced  grade ≥3  aGVHD events as compared to the control arm, 7% (n=6) vs 13% (n=12), respectively.  In pts who required systemic steroid treatment, 6 pts in the Orca-T arm were SR vs 14 of pts in the control  arm.  In SR Orca-T pts 1-year cumulative incidence of NRM was 16.7% (95% CI 0.8-51.7) vs 30.8% (95% CI 9.5-55.4) in SR control arm. The sites of involvement for grade 3 or 4 aGVHD events in the Orca-T arm were lower GI (2 pts), upper GI (3 pts) and liver (1 pt); no skin events reported. In the Orca-T arm, 1 patient received second-line ruxolitinib; aGVHD did not resolve. In the control arm sites reported were lower GI (9 pts), skin (2 pts) and liver (1 pt). In the control arm, ruxolitinib was used as second-line therapy in 7 pts, of whom 3 achieved resolution of aGVHD. The median duration of all grade aGVHD events was 45.0 days (range: 6 to 616) days in the Orca-T arm and 69.5 days (range: 1 to 433) in the control arm. All grade aGVHD events resolved in 21 of 30 pts in the Orca-T arm and 34 of 44 pts in the control arm. Among those pts with resolution aGVHD events (all grade), the median time to resolution was 36.0 days (range: 6 to 109) in the Orca-T arm and 53.0 days (range: 7 to 388) in the control arm.
Conclusions: Orca-T demonstrated improved aGVHD outcomes compared to conventional allograft with Tac/MTX across multiple clinically meaningful outcomes. Orca-T was associated with a lower incidence of all-grade aGVHD , shorter median duration of aGVHD events, and faster time to resolution, suggesting Orca-T not only reduces the frequency of alloreactive immune responses but attenuates their clinical course. Fewer Orca-T pts developed grade 3 or 4 aGVHD, with no grade 3 or 4 skin events, a finding consistent with effective early immune regulation at peripheral GVHD target sites. Among the subset of pts who did develop SR aGVHD, 1-year NRM was lower in the Orca-T arm; due to the small number of pts in this subgroup the results should be interpreted with caution. The improvement in aGVHD outcomes support the clinical benefit of Orca-T for alloHSCT.