Orca-T demonstrates favorable quality of life and healthcare resource use compared to standard allohsct plus tac/MTX for GVHD prevention in a randomized Phase 3 clinical trial (Precision-T)

Abstract

Abstract Background: Conventional allogeneic hematopoietic stem cell therapy (alloHSCT) is associated with increased toxicity and infections due to the use of multiagent immunosuppression. Orca-T, a high-precision engineered allogeneic T cell immunotherapy, which utilizes single-agent graft-versus-host disease (GVHD) prophylaxis, recently demonstrated superior survival free of chronic GVHD (HR = 0.26, p-value <0.00001), significantly lower overall incidence of moderate to severe chronic GVHD (12.6% versus 44.0%; p-value <0.001), and fewer serious infections and deaths at 1 year compared to alloHSCT in a phase 3 clinical trial. This study analyzes health-related quality of life (HRQoL) and hospitalization patterns between arms. Methods: Adults undergoing myeloablative alloHSCT for acute leukemia in complete remission, aged 18 to 65, with intermediate or high disease risk index, or high-risk myelodysplastic syndrome with ≤10% bone marrow (BM) blasts, and human leukocyte antigen (HLA)-matched related or unrelated donors, were randomized 1:1 to receive either Orca-T (plus tacrolimus) or unmanipulated peripheral blood stem cells plus Tac/MTX for GVHD prevention. Exploratory outcomes included comparison of HRQoL and hospitalization data as a proxy for healthcare resource utilization. HRQoL was assessed using the validated Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) instrument, a validated 50-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT-specific well-being with scores ranging from 0-164, with higher scores indicating better quality of life. Patients completed serial HRQoL questionnaires at screening and predetermined time points thereafter. A statistical model utilizing repeated measurements from the same individual over time was used to compare changes in HRQoL at each timepoint, from baseline to 1-year post-treatment. In addition, duration of initial hospitalization, rates of re-hospitalization, average total hospitalized days, and hospitalization-free survival rates were compared between treatment arms. Results: A total of 88 (Orca-T) and 94 (Tac/MTX) patients were evaluated in the safety analysis, with 5.7% vs. 9.6% grade 3-4 acute and 12.5% vs. 34.0% moderate to severe GVHD, respectively. Survey completion rates of (90.9 vs. 86.2%) at baseline, and 66.7 vs 65.8% were reported at 1 year in Orca-T vs. Tac/MTX groups. FACT-BMT total scores were consistently higher among Orca-T recipients across all time points compared to patients on the Tac/MTX arm and demonstrated a smaller decline from baseline in the Orca-T arm on day 14 (Adjusted Mean= -7.74, SE=2.18 for Orca T vs Adjusted Mean = -13.69, SE=2.22 for Tac/MTX) with a faster return to baseline scores. In the Orca-T arm, scores exceeded baseline at day 100 (Adjusted Mean=1.34, SE=2.41) and day 365 (Adjusted Mean=12.00, SE=3.32), whereas in the Tac/MTX arm, scores did not exceed baseline until day 365 (Adjusted Mean=3.66, SE=3.51). With respect to subscales, scores for Orca-T recipients exceeded baseline across physical well-being, functional well-being, and transplant-specific subscales by day 100, while the Tac/MTX recipients remained below baseline. By day 365, all Orca-T measurements for these subscales were higher by a magnitude of 2X or more compared to the comparator arm. The median (Q1, Q3) duration of hospitalization during study treatment was 24.5 days (22.0, 26.5) for recipients of Orca-T and 24.0 days (22.0, 28.0) for Tac/MTX recipients. Subsequent rehospitalizations due to adverse events occurring in 24 (27.3%) Orca-T recipients versus 43 (45.7%) Tac/MTX recipients, and average total hospitalization days per patient of 30.6 and 40.8 days, respectively. One Orca-T and four Tac/MTX patients were admitted to the ICU. Lastly, rehospitalization-free survival at 18 months was significantly better for Orca-T compared to the control group [66.4% (95% CI: 54.0, 76.2) versus 33.8% (95% CI: 18.5, 49.9), P=0.0096, hazard ratio 0.53 (0.32, 0.86)]. Conclusions:Patients transplanted using Orca-T appear to have marked HRQoL advantages over unmanipulated alloHSCT plus Tac/MTX recipients, with less decrement, faster recovery to baseline, higher rates of improvement above baseline, fewer ICU stays, lower likelihood of rehospitalization, lower total hospital days, and higher rehospitalization free survival potentially reflecting better early post-transplant recovery and/or lower GVHD symptom burden.