Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning
Baron, Frédéric; Sandmaier, Brenda M.; Storer, Barry E.et al.
2007 • In Biology of Blood and Marrow Transplantation, 13 (9), p. 1041-1048
[en] We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmycloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day + 40 with taper through day + 96) and cyclosporine (CSP; given from day -3 to day + 100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of NMF, given at full dosing until day + 150 and then tapered through day + 180, and a shortened course of CSP, through day + 80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade ll-1V aGVHD and 45% extensive cGVHD (P =.03, and P =.43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P =.89, P =.02, and P =.08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning. (c) 2007 American Society for Blood and Marrow Transplantation
Disciplines :
Surgery Immunology & infectious disease Hematology
Author, co-author :
Baron, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning
Publication date :
September 2007
Journal title :
Biology of Blood and Marrow Transplantation
ISSN :
1083-8791
eISSN :
1523-6536
Publisher :
Elsevier Science Inc, New York, United States - New York
Hallemeier C., Girgis M., Blum W., et al. Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants. Biol Blood Marrow Transplant 10 (2004) 310-319
Wong R., Giralt S.A., Martin T., et al. Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 102 (2003) 3052-3059
Nagler A., Aker M., Or R., et al. Low-intensity conditioning is sufficient to ensure engraftment in matched unrelated bone marrow transplantation. Exp Hematol 29 (2001) 362-370
Chakraverty R., Peggs K., Chopra R., et al. Limiting transplantation-related mortality following unrelated donor stem cell transplantion by using a nonmyeloablative conditioning regimen. Blood 99 (2002) 1071-1078
Maris M.B., Niederwieser D., Sandmaier B.M., et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102 (2003) 2021-2030
Giralt S., Estey E., Albitar M., et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89 (1997) 4531-4536
Slavin S., Nagler A., Naparstek E., et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91 (1998) 756-763
McSweeney P.A., Niederwieser D., Shizuru J.A., et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97 (2001) 3390-3400
Baron F., Maris M.B., Sandmaier B.M., et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 23 (2005) 1993-2003
Storb R., Yu C., Wagner J.L., et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 89 (1997) 3048-3054
Niederwieser D., Maris M., Shizuru J.A., 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 101 (2003) 1620-1629
Baron F., Maris M.B., Storer B.E., et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with chronic myeloid leukemia. Biol Blood Marrow Transplant 11 (2005) 272-279
Baron F., Maris M.B., Storer B.E., et al. High doses of transplanted CD34+ cells are associated with rapid T-cell engraftment and lessened risk of graft rejection, but not more graft-versus-host disease after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation. Leukemia 19 (2005) 822-828
Maris M.B., Sandmaier B.M., Storer B.E., et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant 12 (2006) 454-465
Shi Y., Sahai B.M., and Green D.R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 339 (1989) 625-626
Kirk A.D., Burkly L.C., Batty D.S., et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 5 (1999) 686-693
Li Y., Li X.C., Zheng X.X., Wells A.D., Turka L.A., and Strom T.B. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 5 (1999) 1298-1302
Blaha P., Bigenzahn S., Koporc Z., et al. The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. [Erratum: Blood. 2003;102:1950]. Blood 101 (2003) 2886-2893
Chapuis A.G., Paolo R.G., D'Agostino C., et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 6 (2000) 762-768
Izeradjene K., and Revillard J.P. Apoptosis of superantigen-activated T cells induced by mycophenolate mofetil treatment. Transplantation 71 (2001) 118-125
Koc S., Leisenring W., Flowers M.E.D., et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100 (2002) 48-51
Junghanss C., Marr K.A., Carter R.A., et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8 (2002) 512-520
Sandmaier B.M., Maloney D.G., Maris M.B., et al. Conversion of low donor chimerism following nonmyeloablative conditioning for hematopoietic cell transplantation (HCT) using pentostatin and donor lymphocyte infusion (DLI). Blood 104 (2004) 57a
Baron F., Baker J.E., Storb R., et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104 (2004) 2254-2262
Baron F., and Sandmaier B.M. Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia 20 (2006) 1690-1700 (review)
Sorror M.L., Maris M.B., Storb R., et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106 (2005) 2912-2919
Baron F., and Sandmaier B.M. Current status of hematopoietic stem cell transplantation after nonmyeloablative conditioning. Curr Opin Hematol 12 (2005) 435-443
Burroughs L., Mielcarek M., Leisenring W., et al. Extending postgrafting cyclosporine decreases the risk of severe graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation. Transplantation 81 (2006) 818-825
de Lima M., Anagnostopoulos A., Munsell M., et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 104 (2004) 865-872
Crawley C., Lalancette M., Szydlo R., et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 105 (2005) 4532-4539
Baron F., Storb R., Storer B.E., et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopietic cell transplantation. J Clin Oncol 24 (2006) 4150-4157
Mielcarek M., Martin P.J., Leisenring W., et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 102 (2003) 756-762
Mielcarek M., Burroughs L., Leisenring W., et al. Prognostic relevance of "early-onset" graft-versus-host disease following nonmyeloablative hematopoietic cell transplantation. Br J Haematol 129 (2005) 381-391
Cao T.M., Shizuru J.A., Wong R.M., et al. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose. Blood 105 (2005) 2300-2306
Blaise D.P., Boiron J.M., Faucher C., et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 104 (2005) 1931-1938
Bornhauser M., Thiede C., Platzbecker U., et al. Dose-reduced conditioning and allogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients. Clin Cancer Res 7 (2001) 2254-2262
Kansu E., Gooley T., Flowers M.E.D., et al. Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial. Blood 98 (2001) 3868-3870 (brief report)