[en] Purpose We have used a nonmyelorablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HILA-matched related (n = 192) or unrelated donors (n = 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD, P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning. (c) 2005 by American Society of Clinical Oncology.
Disciplines :
Hématologie Oncologie
Auteur, co-auteur :
Baron, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Maris, M. B.
Sandmaier, B. M.
Storer, B. E.
Sorror, M.
Diaconescu, R.
Woolfrey, A. E.
Chauncey, T. R.
Flowers, M. E. D.
Mielcarck, M.
Maloney, D. G.
Storb, R.
Langue du document :
Anglais
Titre :
Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning
Barnes DWH, Corp MJ, Loutit JF, et al: Treatment of murine leukaemia with x-rays and homologous bone marrow: Preliminary communication. Br Med J 2:626-627, 1956
Weiden PL, Flournoy N, Thomas ED, et al: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068-1073, 1979
Weiden PL, Sullivan KM, Flournoy N, et al: Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529-1533, 1981
Maraninchi D, Gluckman E, Blaise D, et al: Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet 2:175-178, 1987
Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555-562, 1990
Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041-2050, 1995
Collins RHJ, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15:433-444, 1997
Kolb HJ, Schmidt C, Barrett AJ, et al: Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767-776, 2004
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: 756-763, 1998
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 89:4531-4536, 1997
Khouri IF, Keating M, Körbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998
Schetelig J, Thiede C, Bornhauser M, et al: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: The Cooperative German Transplant Study Group. J Clin Oncol 21:2747-2753, 2003
Branson K, Chopra R, Kottaridis PD, et al: Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 20:4022-4031, 2002
Escalon MP, Champlin RE, Saliba RM, et al: Nonmyeloablative allogeneic hematopoietic transplantation: A promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 22:2419-2423, 2004
Girgis M, Hallemeier C, Blum W, et al: Chimerism and clinical outcomes of 110 unrelated donor bone marrow transplant recipients conditioned with low dose (550 cGy), single exposure total body irradiation and cyclophosphamide. Blood DOI 10.1182/blood-2003-07-2346
Spitzer TR, McAfee S, Sackstein R, et al: Intentional induction of mixed chimerism and achievement of antitumor responses after non-myeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 6:309-320, 2000
McSweeney PA, Niederwieser D, Shizuru JA, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390-3400, 2001
Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 343:750-758, 2000
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 responses. Blood 94:3234-3241, 1999
Maris MB, Niederwieser D, Sandmaier BM, et al: HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102:2021-2030, 2003
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 101:1620-1629, 2003
Baron F, Baker JE, Storb R, et al: Kinetics of engraftment in patients with hematological malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104:2254-2262, 2004
Sorror ML, Maris MB, Storer B, et al: Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: Influence of pretransplant comorbidities. Blood 104:961-968, 2004
Diaconescu R, Flowers CR, Storer B, et al: Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104:1550-1558, 2004
Maloney DG, Molina AJ, Sahebi F, et al: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447-3454, 2003
Petersdorf EW, Gooley TA, Anasetti C, et al: Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 92:3515-3520, 1998
Charlson M, Szatrowski TP, Peterson J, et al: Validation of a combined comorbidity index. J Clin Epidemiol 47:1245-1251, 1994
Mielcarek M, Martin PJ, Leisenring W, et al: Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 102:756-762, 2003
Koc S, Leisenring W, Flowers MED, et al: Therapy for chronic graft-versus-host disease: A randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100: 48-51, 2002
Junghanss C, Marr KA, Carter RA, 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 8:512-520, 2002
Baron F, Little MT, Storb R: Kinetics of engraftment following allogeneic hematopoietic cell transplantation with reduced-intensity or nonmyeloablative conditioning. Blood Rev doi: 10.1016/j.blre.2004.06.003
Bethge WA, Hegenbart U, Stuart MJ, et al: Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 103:790-795, 2004
Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18:695-706, 1999
Wagner JL, Seidel K, Boeckh M, et al: De novo chronic graft-versus-host disease in marrow graft recipients given methotrexate and cyclosporine: Risk factors and survival. Biol Blood Marrow Transplant 6:633-639, 2000
Marijt WA, Heemskerk MH, Kloosterboer FM, et al: Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A 100:2742-2747, 2003
Gratwohl A, Hermans J, Apperley J, et al: Acute graft-versus-host disease: Grade and outcome in patients with chronic myelogenous leukemia. Blood 86:813-818, 1995
Nordlander A, Mattsson J, Ringden O, et al: Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 10:195-203, 2004
Sullivan KM, Weiden PL, Storb R, et al: Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 73:1720-1728, 1989
Kanda Y, Izutsu K, Hirai H, et al: Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate. Leukemia 18:1013-1019, 2004
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 100: 1903-1909, 2002
Fukuda T, Boeckh M, Carter RA, et al: Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood 102:827-833, 2003
Storb R, Prentice RL, Buckner CD, et al: Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings: Beneficial effect of a protective environment. N Engl J Med 308:302-307, 1983
Nash RA, Pepe MS, Storb R, et al: Acute graft-versus-host disease: Analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood 80:1838-1845, 1992
Neudorf S, Sanders J, Kobrinsky N, et al: Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood 103:3655-3661, 2004
Storb R, Prentice RL, Sullivan KM, et al: Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med 98:461-466, 1983
Blaise D, Kuentz M, Fortanier C, et al: Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: A report from the Société Française de Greffe de Moelle. J Clin Oncol 18:537-571, 2000
Cutler C, Giri S, Jeyapalan S, et al: Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: A meta-analysis. J Clin Oncol 19:3685-3691, 2001
Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175-181, 2001
Storb R, Etzioni R, Anasetti C, et al: Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 84:941-949, 1994
Zaucha JM, Gooley T, Bensinger WI, et al: CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation. Blood 98:3221-3227, 2001
Nash RA, Antin JH, Karanes C, et al: Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 96:2062-2068, 2000
Ratanatharathorn V, Nash RA, Przepiorka D, et al: Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host-disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 92:2303-2314, 1998
Storb R, Deeg HJ, Farewell V, et al: Marrow transplantation for severe aplastic anemia: Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68:119-125, 1986
Storb R, Deeg HJ, Whitehead J, et al: Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729-735, 1986
