In a multi-center collaboration, we carried out T-replete, peripheral blood stem cell (PBSC) transplants from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplant cyclophosphamide (Cy) as GvHD prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50mg/kg IV on days 3 and 4 post-infusion of PBSC (mean 6.4×106/kg CD34+ cells, mean 2.0 ×108/kg CD3+ cells). The median times to neutrophil (500/mcL) and platelet (>20,000/mcL) recovery were 17 and 21 days respectively. All but two of the patients achieved full engraftment. The one-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8% respectively. There were no cases of grade IV GvHD. The two-year cumulative incidence of chronic GHVD was 18%. With a median follow up of 509 days, overall survival (OS) and event free survival (EFS) at two years were 48% and 51%, respectively. The two-year cumulative incidences of non-relapse mortality (NRM) and relapse were 23% and 28% respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow (BM) as the graft source for haploidentical transplantation following reduced intensity conditioning.
Mesenchymal stromal cells (MSCs) are important in the support of hematopoiesis. In this pilot study, we evaluated the safety and efficiency of donor-expanded MSC infusion after allogeneic hematopoietic stem cell transplantation (HSCT) in six patients with poor hematopoietic recovery. MSCs were infused without HSC and without conditioning at a dose of 1 x 10(6)/kg weight. Two patients displayed rapid hematopoietic recovery (days 12 and 21), and four patients showed no response. The two patients who showed hematopoietic recovery were in first complete remission (CR1) compared to the other heavily pretreated patients. There were no toxic side effects linked to MSC infusion. One patient developed cytomegalovirus (CMV) reactivation 12 days following the MSC infusion and died from CMV disease. We found that infusion of MSCs without HSC co-infusion can restore medullary function in some patients with poor hematopoietic recovery. Our data suggest that patients with a less damaged stroma could benefit from this approach.
High-dose cyclophosphamide given early after allogeneic hemopoietic cell transplantation has been shown to be effective prophylaxis against graft-versus-host disease (GVHD) in the setting of HLA-matched myeloablative bone marrow grafts, allowing avoidance of long-term immunosuppression with calcineurin inhibitors in some patients. Whether this approach is feasible using granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell grafts is unknown. We conducted an exploratory phase 2 trial of cyclophosphamide given at 50 mg/kg i.v. on days 3 and 4 after transplantation as sole GVHD prophylaxis in recipients of G-CSF-mobilized peripheral blood stem cell grafts from HLA-matched related or unrelated donors after reduced-intensity conditioning therapy with fludarabine, carmustine, and melphalan. Five patients, ages 52 to 67 years, with high-risk hematologic malignancies were enrolled. Four of the 5 developed severe acute GVHD of grades 3 to 4, requiring treatment with methylprednisolone and cyclosporine; 3 were steroid refractory and were given salvage therapy. One of these 4 patients died of hepatic GVHD, one died of sepsis, and 2 survived. We conclude that post-transplantation cyclophosphamide is inadequate as sole GVHD prophylaxis in the context of peripheral blood reduced-intensity conditioning transplantations from HLA-matched donors. This trial is registered at ACTRN12613001154796.
Our PCR-guided and rituximab-based preemptive approach to avoid PTLD after allogeneic hematopoietic stem-cell transplantation is feasible but probably overtreated patients. Prospective trials are strongly needed, they should use uniform PCR techniques and consider higher threshold values for treatment initiation.
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