The chance of graft-rejection after allogeneic hematopoietic cell transplantation using conventional

The chance 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. than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion Fumonisin B1 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 (< 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. Introduction Bone-marrow failure syndromes (BMFS) such as severe aplastic anemia (SAA) pure red cell aplasia (PRCA) paroxysmal nocturnal hemoglobinuria (PNH) and refractory-anemia myelodysplastic syndrome (RA-MDS) can be cured by allogeneic hematopoietic cell transplantation (HCT) [1- 3]. For younger patients with SAA HCT from an HLA-identical sibling is associated with excellent long-term survival [4]. When used as upfront therapy survival rates have been reported to be as Fumonisin B1 high as Fumonisin B1 90% from a single institution and ~70-80% from transplant registry data which more likely reflects the general experience [5]. Since older age is associated with a significant increase in the risk of transplant-related mortality (TRM) HCT for older patients with SAA (i.e. age ≥40 years) is typically reserved for those who have failed immunosuppressive therapy (IST) [6 7 HCT can be used to salvage patients with SAA who have failed IST [8] although outcome in this situation is worse than undergoing transplantation upfront [9]. Allogeneic HCT can also cure PNH although regimens that use conventional myeloablative conditioning are associated with mortality rates as high as 40% [10]. Eculizumab a monoclonal antibody to C5a has recently proven to be highly effective in preventing both hemolysis and thrombosis associated with PNH [11 12 However this agent requires life-long therapy is expensive and may be unaffordable to many patients with PNH. Allogeneic HCT using reduced intensity conditioning is reported to be a potentially safer transplant approach for these patients [13 14 Reduced intensity transplants rely on engrafting donor Mouse monoclonal to CD23. The CD23 antigen is the low affinity IgE Fc receptor, which is a 49 kDa protein with 38 and 28 kDa fragments. It is expressed on most mature, conventional B cells and can also be found on the surface of T cells, macrophages, platelets and EBV transformed B lymphoblasts. Expression of CD23 has been detected in neoplastic cells from cases of B cell chronic Lymphocytic leukemia. CD23 is expressed by B cells in the follicular mantle but not by proliferating germinal centre cells. CD23 is also expressed by eosinophils. T-cells to mediate a graft-versus-host hematopoietic effect Fumonisin B1 which eradicates GPI-negative stem cells [3]. Despite the improved safety of this transplant approach life-threatening complications and regimen related mortality still occur. Therefore allogeneic HCT is usually reserved for PNH patients who have failed or are not candidates for eculizumab treatment. To reduce graft-versus-host disease (GVHD) the optimal source of hematopoietic progenitor cells (HPCs) for allogeneic HCT for BMFS remains bone-marrow (BM) [15 16 Patients with BMFS traditionally were transplanted with BM as a HPC source. Studies have shown that the transplanted BM CD34+ cell-dose correlates with this risk of graft-rejection TRM and overall survival (OS) [17 18 Although chronic-GVHD occurs less commonly with BM as compared to granulocyte colony-stimulating factor (G-CSF) mobilized PBPC transplants [19] BM allografts have lower CD34+ cell numbers which increases the risk of graft-rejection [20]. In particular patients with SAA who are older have failed prior IST are heavily transfused and/or are alloimmunized have a high risk of graft-rejection/failure after HCT using BM allografts with historical graft-rejection rates in the range of 15-20% [21 22 Several strategies have been employed to decrease this risk of graft-failure for Fumonisin B1 patients with BMFS at high-risk for graft-failure. The use of G-CSF mobilized PBPC allografts that contain higher numbers of CD341 HPCs and T-cells appears to be associated with improved donor engraftment [23]. However G-CSF mobilized PBPC allografts contain high numbers of T-cells which undergo alterations in their cytokine polarization status [24] leading to an increased incidence of chronic-GVHD as.