Orca-T Leads to Retrospective OS Improvement in High-Risk Hematologic Malignancies After Allo-HCT

Allo-HCT in Hematologic Malignancies
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Treatment with Orca-T led to a low rate of graft-vs-host disease (GVHD), a low rate of infections, and high overall survival (OS) in patients with high-risk hematologic malignancies who underwent allogeneic hematopoietic stem cell transplant (allo-HCT), according to data from a phase 1b trial (NCT04013685).¹ Additionally, OS was improved in this patient population when retrospectively compared with patients from the CIBMTR registry who received post-transplant cyclophosphamide.

Findings presented at the 2024 ASH Annual Meeting showed that patients treated with Orca-T during the phase 1b portion of the study (n = 154) experienced 1-, 2-, and 3-year OS rates of 88% (95% CI, 83%-94%), 80% (95% CI, 74%-87%), and 76% (95% CI, 69%-84%), respectively.

In the cohort selected for retrospective comparison with the CIBMTR registry, patients treated with Orca-T in the phase 1b study (n = 77) achieved a 1-year OS rate of 96% (95% CI, 88%-99%) compared with 82% (95% CI, 78%-87%) for those given post-transplant cyclophosphamide (n = 293). The 2-year OS rates were 88% (95% CI, 78%-94%) and 73% (95% CI, 68%-79%), respectively. The respective 3-year OS rates were 86% (95% CI, 73%-92%) and 67% (95% CI, 61%-74%).

“There are 2 emerging strategies in the field [of allo-HCT]: Orca-T and post-transplant cyclophosphamide. [Both] still require data to read out to determine if they’re going to be standards in the field of myeloablative conditioning, but they both look promising,” lead study author Caspian Oliai, MD, MS, said in an interview with OncLive^®. “Orca-T achieves low non-relapse mortality and low toxicities by using single-agent GVHD prophylaxis with tacrolimus, in comparison with the post-transplant cyclophosphamide approach that typically relies on 3 immunosuppressants to achieve lower non-relapse mortality and toxicities.”

Oliai is a medical oncologist at Westwood Cancer Center and a clinical instructor at the David Geffen School of Medicine at the University of California, Los Angeles.

Orca-T Background and Phase 1b Trial Design

During the presentation, Oliai noted that the potential for transplant-related mortality currently limits the widespread use of allo-HCT, particularly in older patients. Whereas conventional transplants feature a heterogenous mix of different cell types, Orca-T is a precision-engineered cell therapy comprised of proprietary, composition-defined stem and T cells.

“The standard graft in [allo-HCT] contains a variety of cell types, which are typically administered together in a single infusion,” Oliai said. “In comparison, Orca-T selects and separates [these cells] into 3 distinct components.”

The phase 1b study enrolled patients 18 to 75 years of age with high-risk hematologic malignancies including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), high- or very high–risk myelodysplastic syndrome (MDS), and myelofibrosis. Patients needed to be eligible for myeloablative conditioning, have an HCT-specific comorbidity index of no greater than 4, have a Karnofsky performance status of at least 70, and have adequate organ function.

During the study, enrolled patients underwent myeloablative conditioning on days –10 to –2 before receiving an infusion of hematopoietic stem and progenitor cells, as well as regulatory T cells (Tregs) at a dose of 3 x 10⁶ Treg/kg. On day 2, patients received an infusion of conventional T cells at a dose of 3 x 10⁶ T cells/kg, and on day 3, single-agent tacrolimus was administered at a target dose of 1 to 10 ng/mL. Notably, no methotrexate, post-transplant cyclophosphamide, or other immunosuppressive therapies were given with Orca-T.

The trial’s primary end points were the incidence of dose-limiting toxicities and the rate of primary graft failure through day 28.

In the full phase 1b cohort (n = 154), the median age was 50 years (IQR, 39-58), and the majority of patients were male (57%), White (66%), and not Hispanic or Latino (75%). Seventy-four percent of patients had myeloid malignancies such as AML, MDS, and myelofibrosis, and 26% had lymphoid malignancies such as ALL and mixed-phenotype acute leukemia. Patients had a disease risk index of high (31%), intermediate (59%), or MDS (10%). Remission status included first complete remission (CR; 53%), second CR (14%), MDS (14%), and missing (19%). Fifty-one percent of patients had matched related donors, 47% had matched unrelated donors, and 1% had single mismatch donors. The median follow-up for the cohort was 30 months (range, 0-54).

To select the cohorts for the retrospective comparison, investigators started with the full phase 1b cohort and patients from the CIBMTR registry (n = 2585). After using factors such as treatment date, myeloablative conditioning, HLA match, age, disease, Orca-T regimen, and GVHD prophylaxis, 77 patients were included in the Orca-T group, and 293 patients were featured in the post-transplant cyclophosphamide group.

The median age was 49 years (range, 39-58) in the Orca-T arm vs 48 years (range, 37-58) in the post-transplant cyclophosphamide arm. The majority of patients were male (Orca-T, 57%; post-transplant cyclophosphamide, 57%), had myeloid malignancies (70%; 72%), had intermediate-risk disease (65%; 64%), were in first CR (60%; 63%), had mismatch unrelated donors (52%; 85%), were Black or African American (68%; 84%), and were not Hispanic or Latino (75%; 82%).

Additional Retrospective Efficacy Data

Findings from the retrospective analysis also showed that patients 50 years of age or younger in the selected Orca-T group (n = 39) achieved a 1-year OS rate of 95% (95% CI, 88%-100%) compared with 86% (95% CI, 81%-92%) for those in the post-transplant cyclophosphamide group (n = 170). In patients over 50 years of age, the 1-year OS rates were 97% (95% CI, 92%-100%) for Orca-T (n = 38) vs 77% (95% CI, 70%-85%) for post-transplant cyclophosphamide (n = 123).

The 1-year non-relapse mortality rates were 2% for the selected Orca-T arm (n = 77) vs 8% for the post-transplant cyclophosphamide arm (n = 290). The respective 1-year relapse-free survival rates were 83% and 71%.

Phase 1b Safety Data and Next Steps of Research

Primary graft failure was reported in 2% of safety-evaluable patients treated with Orca-T in the phase 1b study (n = 150); no instances of secondary graft failure were reported. Moderate to severe chronic GVHD occurred in 13% of patients, and 5% of patients had grade 3 or higher acute GVHD.

Twenty-eight percent of patients experienced grade 1 to 3 infections, 5% had a grade 4 infection, and 1% had a grade 5 infection. The non-relapse mortality rate was 9%.

Orca-T is under further evaluation in the phase 3 Precision-T trial (NCT05316701), which is evaluating Orca-T vs standard allo-HCT in patients with advanced hematologic malignancies.² The study has completed enrollment.¹

“We’re going to get phase 3 data [for Orca-T] in the near future, and we’re excited for that,” Oliai concluded. “Hopefully we also get phase 3 data for post-transplant cyclophosphamide, but that might be a little later. It’s exciting for the field to [potentially] improve with these 2 approaches.”

References

1. Oliai CH, Hoeg RT, Gandhi A, et al. Observational comparison of overall survival between phase 1b Orca-T and registry-based post-transplant cyclophosphamide patients. Blood. 2024;144(suppl 1):694. doi:10.1182/blood-2024-205917
2. Precision-T: a randomized study of Orca-T in recipients undergoing allogeneic transplantation for hematologic malignancies (Orca-T). ClinicalTrials.gov. Updated May 28, 2024. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT05316701