Orca-Q Leads to Low Rates of GVHD, Non-Relapse Mortality in High-Risk Hematologic Malignancies After Allo-HCT

Treatment with Orca-Q led to rapid immune reconstitution with a low risk of infection and low rates of graft-vs-host disease (GVHD) and non-relapse mortality in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplant (allo-HCT), according to data from the dose-expansion arm of a phase 1 trial (NCT03802695).

Findings presented at the 2024 ASH Annual Meeting showed that no instances of primary graft failure were reported in any patients in arm C (n = 14); 1 patient (7%) experienced secondary graft failure. Mild chronic GVHD (cGVHD) was reported in 1 patient (7%), and no patients had moderate-to-severe cGVHD. The rates of grade 2 and grade 3 acute GVHD (aGVHD) were 14% (n = 2) and 7% (n = 1), respectively. Grade 2 infections were reported in 14% of patients (n = 2), and 7% (n = 1) had a grade 3 infection. No patients experienced non-relapse mortality.

Regarding efficacy, the 1-year overall survival (OS) rate was 85% (95% CI, 52%-96%). The 1-year relapse-free survival (RFS) and GVHD RFS (GRFS) rates were 85% and 77%, respectively.

“The early results [from the dose-expansion trial] are very promising, and the idea of having regimen free of GVHD [prophylaxis] is almost like a dream for our transplanters,” lead study author Mehrdad Abedi, MD, said in an interview with OncLive®. “We know about all the morbidity and mortality of the prophylactic regimen. Having very little or no GVHD and no transplant-related mortality is very significant.”

Abedi is a professor of medicine in the Division of Malignant Hematology/Cellular Therapy and Transplantation at the University of California, Davis Comprehensive Cancer Center in Sacramento.

Orca-Q Background and Dose-Expansion Design

Conventional allo-HCTs involve the infusion of a heterogenous mix of different cell types, whereas Orca-Q features a fully defined composition of stem and immune cells intended to improve outcomes. These cell types include high-purity hematopoietic stem and progenitor cells intended to induce rapid blood reconstitution and long-term immune reconstitution; high-purity regulatory T cells and invariant natural killer (NK) T cells for augmented GVHD control; and high-purity T-cell subsets for the rapid control of infection and leukemia.

“Usually, we also give immune cells at the time [of allo-HCT]. Those immune cells are a mixture of T cells, NK cells, B cells, antigen-presenting cells, and so on. We want those immune cells to work and cause a graft-vs-leukemia effect and a graft-vs-infection effect there. However, an adverse effect of immune cells is [the potential for] GVHD. The medications we use to prevent GVHD are immune suppressive, which can affect the graft as well,” Abedi said. “[With Orca-Q], we’re trying to give some of the immune cells, but not the immune cells that cause GVHD.”

The multicenter, dose-expansion portion of the study enrolled patients 18 to 65 years of age with high-risk hematologic malignancies including acute myeloid leukemia (AML); acute lymphoblastic leukemia (ALL); very high– or high-risk myelodysplastic syndrome; and myelofibrosis. Patients needed to be eligible for myeloablative conditioning; have an 8-of-8 HLA-matched related or unrelated donor; have a HCT-specific comorbidity index (HCT-CI) of no more than 4; have a Karnofsky performance status of 70 or higher; and have adequate organ function.

Enrolled patients underwent myeloablative conditioning on days –10 to –2, followed by an infusion of Orca-Q on day 0. In the post-infusion phase, no post-transplant cyclophosphamide or other immunosuppressive therapies were given.

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

Enrolled patients in arm C had a median age of 41 years (range, 25-66), and the median follow-up for the cohort was 585 days (range, 35-1050). Additionally, 6 patients (42.9%) were female, 13 patients were White, and 11 were not Hispanic or Latino. Primary disease types included ALL (14.3%), AML (50.0%), chronic myeloid leukemia (14.3%), and myelofibrosis (21.4%).
The majority of patients (78.6%) underwent myeloablative conditioning with a busulfan, fludarabine, and thiotepa (BFT) regimen, and the remainder (21.4%) received total body irradiation–based regimens. Disease-risk indexes included high (14.3%), intermediate (78.6%), and low (7.1%). HCT-CI scores included 0 (50.0%), 1 (14.3%), 2 (21.4%), and 3 (14.3%). Notably, 57.1% of patients were in first complete remission (CR) at baseline; 1 patient (7.1%) was in second CR, and another patient (7.1%) was in third CR.

Additional Data

Findings also showed that the median time to engraftment of neutrophils and platelets was 11 days for the overall population.

In the subgroup of patients who underwent BFT myeloablative conditioning (n = 11), no instances of primary or secondary graft failure were reported. No patients in this subgroup experienced cGVHD; 2 patients (18%) had grade 2 aGVHD, but no patients had grade 3 aGVHD. No grade 2 or 3 infections were reported in this group, and the non-relapse mortality rate was 0.

The 1-year OS, RFS, and GRFS rates for the BFT subgroup were 90% (95% CI, 47%-99%), 90%, and 90%, respectively.

Enrollment in the phase 1 trial is ongoing in the United States.

“We need to keep enrolling patients [to trials]. The only way we learn about new things is by enrolling additional patients there. If you have center [participating] in thi trial, please enroll patients. If you don't have a center, please refer patients to us or other centers that are enrolling these patients,” Abedi concluded.

Disclosures: Dr Abedi reported being part of a speakers bureau for AbbVie, Bristol Myers Squibb, and Gilead Sciences; holding private stock option for CytoDyn; receiving research funding from Autolus, Bristol Myers Squibb, Gilead Sciences, and Orca Bio; and serving as a consultant for Bristol Myers Squibb and Autolus.

Reference

Abedi M, Srour SA, Salhotra A, et al. Preliminary safety and efficacy of myeloablative Orca-Q with no GvHD prophylaxis for treatment of advanced hematologic malignancies. Blood. 2024;144(suppl 1):382. doi:10.1182/blood-2024-204256