Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts

J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8.

Abstract

Background: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively.

Methods: In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution.

Results: All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell-replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years.

Conclusion: Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory.

Trial registration: ClinicalTrials.gov (NCT 00914940).

Trial registration: ClinicalTrials.gov NCT00914940.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Animals
  • Chronic Disease
  • Disease-Free Survival
  • Female
  • Graft vs Host Disease / drug therapy
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / prevention & control
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Hematopoietic Stem Cell Transplantation / methods*
  • Histocompatibility Testing
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia / immunology
  • Leukemia / therapy*
  • Lymphocyte Depletion / methods
  • Male
  • Mice
  • Middle Aged
  • Myelodysplastic Syndromes / immunology
  • Myelodysplastic Syndromes / therapy
  • T-Lymphocyte Subsets / immunology
  • Tissue Donors
  • Transplantation Conditioning
  • Transplantation, Homologous
  • Young Adult

Substances

  • Adrenal Cortex Hormones

Associated data

  • ClinicalTrials.gov/NCT00914940