Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

Abstract

Purpose: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (T_N) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of T_N-depletion of peripheral blood stem-cell (PBSC) grafts.

Methods: One hundred thirty-eight patients with acute leukemia received T_N-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of T_N. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD.

Results: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years.

Conclusion: Depletion of T_N from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

Trial registration: ClinicalTrials.gov NCT00914940 NCT01858740 NCT02220985.

FIG 1.

Study flow diagram. HCT, hematopoietic cell transplantation; MMF, mycophenolate mofetil; MRD, matched related donors; MTX, methotrexate; MUD, matched unrelated donors; T_N, naive T cells; UCB, umbilical cord blood.

FIG 2.

Cumulative incidence of (A) grade III-IV aGVHD, (B) grade II aGVHD, and (C) cGVHD. aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease.

FIG 3.

Relative risks of (A) relapse and (B) death in naive T cells-depleted peripheral blood stem cell recipients who developed acute graft-versus-host disease (grade II-III) compared with those who did not. HCT, hematopoietic cell transplantation; MRD, matched related donors; MUD, matched unrelated donors.

FIG 4.

Relapse and survival. (A) Cumulative incidence of relapse, (B) probability of OS, (C) probability of RFS, (D) probability of CRFS, (E) probability of GRFS, and (F) cumulative incidence of NRM. CRFS, cGVHD-free, relapse-free survival; GRFS, GVHD-free, relapse-free survival; NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival.

FIG 5.

CRFS in subject subgroups. Probability of CRFS by (A) donor source, (B) conditioning intensity, (C) lymphoid or myeloid malignancy, (D) disease risk, (E) age, (F) clinical trial, (G) sex, and (H) institution. CRFS, cGVHD-free, relapse-free survival; UPMC, University of Pittsburgh Medical Center.