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Orca-T given with reduced intensity conditioning led to robust myeloid/T-cell engraftment and low rates of acute GVHD in hematologic malignancies.
The use of the allogeneic immunotherapy Orca-T following reduced intensity conditioning (RIC) led to robust myeloid and T-cell engraftment, along with low rates of acute graft-vs-host disease (GVHD) and moderate-to-severe chronic GVHD, in patients with hematologic malignancies, according to data from a phase 1 trial (NCT05088356).1
Findings presented at the
“Orca-T is safe and feasible to be used in the RIC allogeneic hematopoietic stem cell transplant [allo-HCT] setting, where we observed robust myeloid and T-cell engraftment despite early T-cell mixed chimerism,” lead study author Alejandro Villar-Prados, MD, PhD, said in a presentation of the data.
Villar-Prados is a resident in the Translational Investigator Program at Stanford Medicine in California.
The FDA is
The phase 1 trial sought to evaluate the use of Orca-T in the context of RIC.1 The study included patients 18 to 75 years of age with high-risk acute leukemia who were in first complete remission (CR1), were beyond CR1, or had minimal residual disease (MRD) positivity; those with chronic myelogenous leukemia in accelerated, blast, or second chronic phase; and those with MDS or myeloproliferative neoplasms (MPNs).
Enrolled patients underwent RIC from days –7 to –2. They then received infusion of hematopoietic stem and progenitor cells, plus regulatory T cells (Tregs), at 3 x 106 Tregs/kg on day 0; conventional T cells at 3 x 106 on day 2; and tacrolimus at 5 to 10 ng/mL on day 3. Patients with mismatched donors were also given ruxolitinib (Jakafi) at 5 mg twice per day or mycophenolate mofetil at 1000 mg twice per day on day 4.
For patients with 8/8 HLA matched donors, conditioning regimens comprised fludarabine at 160 mg/m2, melphalan at 50 mg/m2, and total body irradiation (TBI) at 4 Gy, plus tacrolimus as GVHD prophylaxis (n = 11); fludarabine at 160 mg/m2, thiotepa at 10 mg/kg, and TBI at 4 Gy, plus tacrolimus as GVHD prophylaxis (n = 12); and fludarabine at 160 mg/m2, thiotepa at 5 mg/kg, and TBI at 3 Gy, plus tacrolimus as GVHD prophylaxis (n = 23). In the final group, outpatient administration per physician discretion was given to 6 patients.
For patients with 7/8 HLA matched donors, conditioning regimens were fludarabine at 160 mg/m2, thiotepa at 10 mg/kg, and TBI at 4 Gy, plus tacrolimus and mycophenolate mofetil as GVHD prophylaxis (n = 2); or fludarabine at 160 mg/m2, thiotepa at 5 mg/kg, and TBI at 3 Gy, plus tacrolimus in combination with mycophenolate mofetil or ruxolitinib as GVHD prophylaxis (n = 5).
The study’s primary end points were engraftment time and donor chimerism by day 60; and the incidence of grade 3/4 acute GVHD. Secondary end points comprised GVHD- and relapse-free survival (GRFS) after allo-HCT, overall survival (OS) after allo-HCT, and the incidence and severity of acute/chronic GVHD.
The median follow-up time for the overall population was 16.7 months. Patients had a median age of 68 years (range, 60-75), and most patients were male (62%) and While (79%). The median Karnofsky performance status was 80 (range, 70-100), and the median HCT comorbidity index was 1 (range, 0-6). Malignancy subtypes included AML (58%), MDS (30%), ALL (4%), mixed phenotype leukemia (2%), and MPNs (6%). Notably, 75% of patients were in CR prior to transplant.
For patients with AML, 2022 European Leukemia Network risk stratifications included favorable risk (19%), intermediate risk (39%), and adverse risk (42%). Sixty-five percent of patients with AML had MRD-positive disease. For those with MDS, risk stratification per Revised International Prognostic Staging System criteria included very high risk (13%), high risk (31%), and intermediate risk (56%).
Thirty-one percent of patients had matched related donors, 62% had matched unrelated donors, and 13% had mismatched donors.
Findings also showed that the cumulative incidence of grade 2 to 3 infections was 32% (95% CI, 20%-44%); however, the rate of grade 3 infections was 6% (95% CI, 1.5%-14%).
Relapses occurred in 8.1% (95% CI, 3%-18%) of patients, including 3 patients with AML and 2 patients with MDS. The non-relapse mortality rate was 10% (95% CI, 4%-20%).
The OS and GRFS rates at 1 years following transplant were 88% (95% CI, 79%-98%) and 72% (95% CI, 60%-87%), respectively. In patients who were eligible to receive the outpatient RIC regimen, the 1-year OS and GRFS rates were 95% (95% CI, 87%-100%) and 80% (95% CI, 65%-100%), respectively.
An ongoing phase 2 trial (NCT07216443) is further investigating the use of Orca-T with RIC or nonmyeloablative conditioning in patients with AML or MDS.3
Disclosures: Villar-Prados did not report any financial conflicts of interest.
