Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes

Abstract

The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).

Copyright © 2013 Wiley Periodicals, Inc.

Figures

Figure 1

Lineage specific chimerism and time to full-donor chimerism. (A) Percentage donor T-cell and myeloid chimerism per patient (N = 56) over time. (B) Cumulative incidence of full-donor T-cell and myeloid chimerism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Post-transplant outcomes. (A) Cumulative incidence of acute-GVHD. (B) Cumulative incidence of chronic-GVHD. (C) Overall survival. (D) Cumulative incidence of transplant-related mortality (TRM). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

Cumulative incidence of chronic-GVHD in relationship to the time full-donor T-cell chimerism was achieved and time to discontinuation of systemic immuno-suppression. (A) Impact of time to full-donor T-cell chimerism on chronic-GVHD. (B) Impact of time to full-donor T-cell chimerism on extensive chronic-GVHD. Full-donor T-cell chimerism was defined as the first time to ≥95% donor-derived T-cells in the peripheral blood. (C) Overall probability of discontinuation of systemic immunosup pression. (D) Cumulative incidence of discontinuation of systemic immunosuppression in relationship to the time full-donor T-cell chimerism was achieved. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

Survival of patients in relationship to the speed at which full-donor T-cell chimerism occurred. The speed of donor T-cell engraftment could be determined in 55/56 patients, while one patient died early before donor T-cell chimerism could be assessed. Six deaths occurred in the group who achieved rapid fulldonor T-cell chimerism≤ day 30 (n = 45), while no deaths occurred among those (n = 10) who had delayed donor T-cell engraftment (full-donor T-cell chimerism ≥day 45). The mortality rate was not statistically different between these two groups (P > 0.2).