3 Trials Support Use of Naïve T-Cell Depletion Strategy in PBSC Grafts to Prevent Chronic GVHD

Investigators reported that depleting naïve T cells (TN) from peripheral blood stem cell (PBSC) allografts resulted in low incidence of graft-versus-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndrome.¹

Chronic GVHD (cGVHD) was mild and infrequent in patients enrolled in 3 phase 2 clinical trials (NCT00914940 [n = 41], NCT01858740 [n = 20], and NCT02220985 [n = 77]) and who had received TN-depleted peripheral blood stem-cell (PBSC) grafts.

The 3-year cumulative incidence of mild cGVHD was 7% (95% CI, 2%-11%) in the whole cohort. The incidence of moderate cGVHD was 1% (95% CI, 0%-2%), and severe incidence was 0%. Grade 3 acute GVHD (aGVHD) occurred in 4% of patients (95% CI, 1%-8%), and no grade 4 aGVHD was reported. The incidence of cGVHD was very low (7%) in recipients of HLA-matched TN-depleted PBSC, resulting in a 3-year cGVHD-free, relapse-free survival of 68%. These rates were similar across subgroups, including age, related or unrelated grafts, leukemia type, and conditioning regimen intensity.

Investigators addressed 138 patients with acute leukemia TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. Patients from the NCT00914940 and NCT01858740 trials received high-intensity conditioning with 25 mg/m2 fludarabine once per day for 5 days, 5 mg/kg thiotepa (Thioplex) once per day for 2 days, and total body irradiation. Patients under 50 years old in the NCT02220985 (n = 77) trial mostly received the same high-intensity conditioning, whereas patients aged 50 years and older or with comorbidities received intermediate-intensity myeloablative conditioning with 30 mg/m2 fludarabine once per day for 5 days, 50 mg/kg cyclophosphamide once per day for 1 day, 5 mg/kg thiotepa once per day for 2 days, and total-body irradiation. All patients then received HLA-matched, CD34-selected PBSC, followed immediately by CD45RA-depleted cells from the CD34-negative fraction. The NCT00914940 trial consisted of patients with HLA-matched related donors (MRD) and used tacrolimus (Prograf) for GVHD prophylaxis, whereas the NCT01858740 and NCT02220985 trials included patients with MRD or HLA-matched unrelated donors (MUD) and used tacrolimus plus methotrexate or tacrolimus plus mycophenolate mofetil (CellCept).

The median follow up was 4 years. The primary end point of the analysis from the cumulative data of these trials was cGVHD. Secondary end points included graft failure, grade 3 to 4 aGVHD within 1 year of hematopoietic cell transplantation (HCT), overall survival (OS), relapse, nonrelapse mortality (NRM), and survival free of moderate or severe cGVHD or relapse (cGVHD-free, relapse-free survival [CRFS]).

The cumulative incidence of grade 2 aGVHD was 71% (95% CI, 64%-79%). Recipients of MRD presented grade 3 aGVHD in 5% (95% CI, 0%-9%) of patients and grade 3 aGVHD presented in 4% (95% CI, 0%-9%) of patients with MUD grafts. Chronic GVHD was 7% (95% CI, 2%-13) in matched related donor grafts and 6% (95% CI, 0%-12%) in matched unrelated donor grafts.

At 3 years, OS was 77% (95% CI, 71%-85%), relapse was 23% (95% CI, 16%-30%), NRM was 8% (95% CI, 3%-13%), and CRFS was 68% (95% CI, 61%-76%).

Eligible patients were referred for allogeneic HCT for a high predicted risk of relapse following chemotherapy alone. Patients from the NCT00914940, NCT01858740, and NCT02220985 trials were enrolled at ages 14 to 55, 0 to 21, and 0 to 60, respectively. Fifty-nine percent of patients were female among all 3 trials.

Grades 3 to 5 nonhematologic adverse events reported are commonly found among patients who receive myeloablative HCT.

Researchers found that depletion of TN from PBSC allografts results in very low incidences of severe aGVHD and cGVHD without reduced risk of relapse or NRM. These results support this graft engineering strategy among other HTC approaches.

_Reference

_{Bleakley M, Sehgal A, Seropian S, et al. Naive T-Cell depletion to prevent chronic graft-versus-host disease. J Clin Oncol. Published online January 10, 2022. doi:10.1200/JCO.21.01755}