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.

Allogeneic transplantation using CD34+ selected peripheral blood progenitor cells combined with non‐mobilized donor T cells for refractory severe aplastic anaemia

“…The increase in GVHD observed with PBSC transplants is probably due to these grafts containing an average 20-fold higher dose of T-cells that have undergone granulocyte colony-stimulating factor (G-CSF)-induced T-helper cell type 2 (Th2) cytokine polarization (Ferrara & Krenger, 1998;Sloand et al, 2000;Skert et al, 2009). Furthermore, with PBSC transplantation for SAA, rapid donor T-cell engraftment frequently occurs, which is significantly associated with an increased risk of chronic GVHD (Pantin et al, 2013).…”

“…Acute GVHD was graded using established criteria (Przepiorka et al , ). Chronic GVHD was evaluated prospectively based on National Institutes of Health consensus criteria (Filipovich et al , ) and was retrospectively reclassified as limited or extensive for comparison between patients in this study and a cohort of previously reported BMFS patients who received an unmanipulated PBSC transplant using the identical conditioning regimen and GVHD prophylaxis (Pantin et al , ). Overall survival was defined as the time from transplantation to death from any cause.…”

“…We, and others, have shown that fludarabine‐based PBSC transplantation overcomes the risk of graft rejection in heavily transfused and allo‐immunized SAA patients refractory to IST (Gomez‐Almaguer et al , ; Srinivasan et al , ; Maury et al , ; Novitzky et al , ; Maury & Aljurf, ; Pantin et al , , ). However, improvement in engraftment with PBSC transplantation was offset by a higher incidence of acute and chronic GVHD compared with BMT.…”

“…Here we report the results of 15 heavily‐transfused patients with BMFS, most with ATG‐refractory SAA at high risk for graft rejection, who underwent this new transplant approach. We compare their outcomes with a cohort of 56 patients with SAA and other BMFS who received an unmanipulated PBSC transplant using the identical conditioning regimen and GVHD prophylaxis (Pantin et al , ).…”

Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor

“…Previously, we have shown that a transplant regimen utilizing cyclophosphamide, fludarabine, and equine ATG conditioning with a G-CSF-mobilized PBSC transplant results in excellent engraftment and survival in heavily transfused SAA patients who have failed prior immunosuppressive therapy. However, this regimen often results in very rapid donor T cell engraftment, which was recently shown to be an independent variable in a multivariate analysis increasing the risk of chronic GVHD [ 14 ].…”