Paper Details

ABSTRACT

Introduction: Chronic graft-versus-host disease (cGVHD) is a critical barrier to the long-term success of allogeneic hematopoietic stem cell transplantation (alloHSCT), driving late organ toxicity, prolonged immunosuppression, and non-relapse mortality (NRM). Pharmacological prophylaxis strategies utilize broad, non-selective immunosuppression which can delay immune reconstitution, cause infection, and worsen regimen related toxicities. Because these toxicities escalate with age, conditioning intensity is frequently de-escalated for older patients (pts), trading disease control for tolerability. Allogeneic regulatory T cell immunotherapy with HSPC and T cells-vldq (Orca-T) that leverages highly purified, regulatory T cells to control alloreactive immune responses with single agent tacrolimus (Tac). The Ph3 Precision-T study met its primary endpoint, demonstrating superior survival free from moderate-to-severe chronic GVHD (cGFS) with Orca-T compared to a control arm with tacrolimus/methotrexate (Tac/MTX) (Meyer et al.Blood 2026). Here we report the 2-year follow-up, including updated overall survival (OS) from the randomized 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 (≤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). Data reported is from a post-hoc analysis that follows 2 years from last pt enrollment. The following transplant outcomes were evaluated in the overall population, OS, cGFS, cGVHD (moderate-to-severe), relapse free survival (RFS) and NRM. To assess impact of age within myeloablative eligible pts, a subgroup analysis was conducted in pts ≥44 years. 

Results: A total of 89 Orca-T and 94 control arm pts were treated; key demographics and baseline characteristics were previously reported (Meyer, et al.Blood 2026). Orca-T was manufactured in a centralized GMP facility, distributed, and infused successfully at 19 centers across the U.S. with a vein-to-vein time of <72 hours.

At the data cut-off, OS at 1-year was 92% (95% CI: 84.0-96.1) in Orca-T vs 77% (95% CI: 67.2-84.5) in the control arm (p =.147). The 2-year estimated OS was 84% (95% CI: 73.7- 89.9) in Orca-T vs 73% (95% CI: 62.9-81.3) in the control arm (p=.109). Orca-T pts had a 2-year estimated cGFS of 68% (95% CI: 55.1-77.2) vs 17% (95% CI: 9.5-26.7) in the control arm (p<.00001). The 2-year estimated cumulative incidence of moderate-to-severe cGVHD was 17% (95% CI: 9.6-25.3) in Orca-T and 58% (95% CI: 46.8-67.3) in the control arm (p<.00001). Two year estimated RFS was 72% (95% CI: 61.1-80.2) and 66% (95% CI: 55.3-75.0) in Orca-T and the control arm, respectively (p=.285). The 2-year estimated cumulative incidence of NRM was 6% (95% CI: 2.2-12.2) and 17% (95% CI: 10.1-25.6) in Orca-T and the control arm, respectively (p = .025; post-hoc).  Relapse rates at 2-years were 22% with Orca-T vs 17% in the control arm (p=.468). Safety results with longer follow-up showed no new signals as compared to previous reports. In a subgroup analysis of post-transplant outcomes in pts ≥ the median study age of 44 years (Orca-T [n=55] vs control arm [n=60]), estimated 2-year OS was 82% with Orca-T vs 58% in the control arm (p=.009). At 2 years post-transplant, NRM was 6% with Orca-T vs 28% in the control arm (p=.005), and the relapse rate was 18% and 18% (p=.974), respectively.

Conclusions: At the 2-year timepoint, Orca-T maintained a durable cGVHD-free survival advantage (2-year cGFS 68% vs 17%), together with low moderate-to-severe cGVHD, low NRM, and a favorable safety profile vs the control arm. Two-year relapse rates were similar between study arms. In the overall population, OS point estimates were numerically higher for Orca-T at 1 and 2 years but did not reach statistical significance. As age is an important determinant for conditioning intensity, a subgroup analysis of pts in the older age range for myeloablative eligibility ( ≥44 y/o), demonstrated favorable improvements in OS and NRM with MAC-Orca-T (nominal p-values < 0.05). Collectively, these results establish Orca-T as a graft-engineering approach that delivers durable protection from GVHD without compromising relapse control with a potential benefit in older pts.