[en] We investigate the feasibility of CD34-selected peripheral blood stem cell (PBSC) transplantation followed by pre-emptive CD8-depleted donor lymphocyte infusions (DLI) after a minimal conditioning regimen. Six patients with advanced hematological malignancies ineligible for a conventional myeloablative transplant (n=5) or metastatic renal cell carcinoma (n=1), and with an HLA-identical (n=4) or alternative (n=2) donor were included. The nonmyeloablative conditioning regimen consisted in 2 Gy TBI alone (n=4), 2 Gy TBI and fludarabine (RCC patient, n=1) or cyclophosphamide and fludarabine (patient who had previously received 12 Gy TBI, n=1). Post transplant immunosuppression was carried out with cyclosporin (CyA) and mycophenolate mofetil (MMF). Initial engraftment was achieved in all patients. One out of six patients (17%) experienced grade > or =2 acute GVHD only after abrupt cyclosporin discontinuation and alpha interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19-30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response. We conclude that CD34-selected NMSCT followed by CD8-depleted DLI is feasible and preserves engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.
Disciplines :
Hematology
Author, co-author :
Baron, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Baudoux, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > Thérapie cellulaire
Frere, Pascale ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Tourqui, Soraya
Schaaf-Lafontaine, Nicole ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Herens, Christian ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
De Prijck, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Fillet, Georges ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Beguin, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Language :
English
Title :
Low T-cell chimerism is not followed by graft rejection after nonmyeloablative stem cell transplantation (NMSCT) with CD34-selected PBSC.
Baron F, Beguin Y. Nonmyeloablative allogeneic hematopoietic stem cell transplantation. J Hematother Stem Cell Res 2002; 11: 243-263.
Storb R. Allogeneic hematopoietic stem cell transplantation - yesterday, today, and tomorrow. Exp Hematol 2003; 31: 1-10.
Carella AM, Giralt S, Slavin S. Low intensity regimens with allogencic hematopoietic stem cell transplantation as treatment of hematologic neoplasia. Haematologica 2000; 85: 304-313.
Storb R, Yu C, Wagner JL et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immuno-suppression after marrow transplantation. Blood 1997; 89: 3048-3054.
McSweeney PA, Storb R. Mixed chimerism: Preclinical studies and clinical applications. Biol Blood Marrow Transplant 1999; 5: 192-203.
Zaucha JM, Zellmer E, Georges G et al. G-CSF-mobilized peripheral blood mononuclear cells added to marrow facilitates engraftment in nonmyeloablated canine recipients: CD3 cells are required. Biol Blood Marrow Transplant 2001; 7: 613-619.
Zaucha JM, Yu C, Zellmer E et al. Effects of extending the duration of postgrafting immunosuppression and substituting granulocyte-colony-stimulating factor-mobilized peripheral blood mononuclear cells for marrow in allogeneic engraftment in a nonmyeloablative canine transplantation model. Biol Blood Marrow Transplant 2001; 7: 513-516.
Zaucha JA, Yu C, Lothrop Jr CD et al. Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation. Biol Blood Marrow Transplant 2001; 7: 14-24.
McSweeney PA, Niederwieser D, Shizuru J et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390-3400.
Niederwieser D, Maris M, Shizuru JA et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620-1629.
Pelot MR, Pearson DA, Swenson K et al. Lymphohematopoietic graft-versus-host reactions can be induced without graft-versus-host disease in murine mixed chimeras established with a cyclophosphamide-based non-myeloablative conditioning regimen. Biol Blood Marrow Transplant 1999; 5: 133-143.
Mapara MY, Kim YM, Wang SP et al. Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: A critical role for host antigen-presenting cells. Blood 2002; 100: 1903-1909.
Baron F, Siquet J, Schaaf-Lafontaine N et al. Pre-emptive immunotherapy with CD8-depleted donor lymphocytes after CD34-selected allogeneic peripheral blood stem cell transplantation. Haematologica 2002; 87: 78-88.
Baron F, Baudoux E, Frere P et al. Nonmyeloablative stem cell transplantation with CD8-depleted or CD34- selected peripheral blood stem cells. J Hematother Stem Cell Res 2002; 11: 301-314.
Baron F, Baudoux E, Fillet G, Beguin Y. Retrospective comparison of CD34-selected allogeneic peripheral blood stem cell transplantation followed by CD8-depleted donor lymphocyte infusions with unmanipulated bone marrow transplantation. Hematology 2002; 7: 137-143.
Przepiorka D, Weisdorf D, Martin P et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825-828.
Margolis J, Vogelsang G. Chronic graft-versus-host disease. J Hematother Stem Cell Res 2000; 9: 339-346.
Thiede C, Bornhausser M, Oelschlägel U et al. Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic bone marrow transplantation (BSCT) using multiplex PCR amplification of short tandem repeat markers. Leukemia 2001; 15: 293-302.
Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562-1568.
Kreiter S, Winkelmann N, Schneider PM et al. Failure of sustained engraftment after non-myeloablative conditioning with low-dose TBI and T cell-reduced allogeneic peripheral stem cell transplantation. Bone Marrow Transplant 2001; 28: 157-161.
Gorner M, Kordelas L, Thalheimer M et al. Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine. Bone Marrow Transplant 2002; 29: 621-624.
Spitzer TR, McAfee S, Sackstein R et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 2000; 6: 309-320.
Dey BR, McAfee S, Sackstein R et al. Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: 604-612.
Orsini E, Alyea EP, Chillemi A et al. Conversion to full donor chimerism following donor lymphocyte infusion is a associated with disease response in patients with multiple myeloma. Biol Blood Marrow Transplant 2000; 6: 375-386.
Shimoni A, Gajewski JA, Donato M et al. Long-term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia after allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant 2001; 7: 568-575.
Soiffer RJ, Alyea EP, Hochberg E et al. Randomized trial of CD8+ T-cell depletion in the prevention of graft-versus-host disease associated with donor lymphocyte infusion. Biol Blood Marrow Transplant 2002; 8: 625-632.
Kobbe G, Schneider P, Aivado M et al. Reliable engraftment, low toxicity, and durable remissions following allogeneic blood stem cell transplantation with minimal conditioning. Exp Hematol 2002; 30: 1346-1353.
Antin JH, Childs R, Filipovich AH et al. Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: Recommendations from a workshop at the 2001 tandem meetings. Biol Blood Marrow Transplant 2001; 7: 473-485.
Childs R, Clave E, Contentin N et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune response. Blood 1999; 94: 3234-3241.