Nonmyeloablative stem cell transplantation with CD8-depleted or CD34-selected peripheral blood stem cells.
Baron, Frédéric ; Baudoux, Etienne ; Frere, Pascale et al
in Journal of Hematotherapy & Stem Cell Research (2002), 11(2), 301-14
To decrease the incidence of graft-versus-host disease (GVHD) observed after nonmyeloablative stem cell transplantation (NMSCT), we studied the feasibility of CD8-depleted or CD34-selected NMSCT followed ... [more ▼]
To decrease the incidence of graft-versus-host disease (GVHD) observed after nonmyeloablative stem cell transplantation (NMSCT), we studied the feasibility of CD8-depleted or CD34-selected NMSCT followed by CD8-depleted preemptive donor lymphocyte infusion (DLI) given in incremental doses on days 40 and 80. Fourteen patients with high-risk malignancies and an HLA-identical sibling (n = 8) or alternative donor (n = 6) but ineligible for a conventional transplant were included. Nonmyeloablative conditioning regimen consisted in 2 Gy total body irradiation (TBI) alone, 2 Gy TBI and fludarabine (previously untreated patients) or cyclophosphamide and fludarabine (patients who had previously received > or =12 Gy TBI). Patients 1-4 (controls) received unmanipulated peripheral blood stem cells (PBSC) and DLI and patients 5-14 CD8-depleted or CD34-selected PBSC followed by CD8-depleted DLI. Post-transplant immunosuppression was carried out with cyclosporine A (CsA) and mycophenolate mofetil (MMF). Initial engraftment was seen in all patients, but 1 patient (7%) later rejected her graft. The actuarial 180-day incidence of grades II-IV acute GVHD was 75% for patients 1-4 versus 0% for patients 5-14 (p = 0.0019). Five of 14 patients were in complete remission (CR) 180 days after the transplant and 6/14 had partial responses. The 1-year survival rate was 69%, and nonrelapse and relapse mortality rates were 16 and 18%, respectively. We conclude that CD8-depleted or CD34-selected NMSCT followed by CD8-depleted DLI is feasible and considerably decreases the incidence of acute GVHD while preserving engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report. [less ▲]Detailed reference viewed: 32 (6 ULg)
Nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Baron, Frédéric ; Beguin, Yves
in Journal of Hematotherapy & Stem Cell Research (2002), 11(2), 243-63
Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment for selected hematological malignancies. Its curative potential is largely mediated by an immune-mediated ... [more ▼]
Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment for selected hematological malignancies. Its curative potential is largely mediated by an immune-mediated destruction of malignant cells by donor lymphocytes termed graft-versus-leukemia (GVL) effect. However, because of its toxicity, conventional allogeneic HSCT is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols (nonmyeloablative stem cell transplantation or NMSCT) based on a two-step approach: first, the use of immunosuppressive (but nonmyeloablative) preparative regimens providing sufficient immunosuppression to achieve engraftment of allogeneic hematopoietic stem cells and, in a second step, destruction of malignant cells by the GVL effect. Preliminary results showed that NMSCT were feasible with a relatively low transplant-related mortality (TRM), even in patients older than 65 years. In addition, strong antitumor responses were observed in several hematological malignancies as well as in some patients with renal cell carcinoma. After discussing the mechanisms and efficacy of the GVL effect as well as the rationale for NMSCT strategies, this article reviews the first results of ongoing clinical trials. Innovative modalities that may permit amplification of the GVL effect while minimizing the risk of GVHD are discussed. Because the benefits of NMSCT over alternative forms of treatment remain to be demonstrated, this strategy should be restricted to patients included in clinical trials. [less ▲]Detailed reference viewed: 9 (1 ULg)