Summary:
Cyclosporine (CSP) and short course methotrexate (MTX) have been the gold standard for GVHD prophylaxis for decades. Problems associated with MTX include increased time to hematopoietic engraftment, mucositis, and other organ toxicities. The combination of CSP with mycophenolate mofetil (MMF) has been used successfully for the prevention of graft rejection and GVHD in nonmyeloablative transplantation. We performed a prospective randomized trial comparing CSP and MTX with CSP and MMF in myeloablative (busulfan based) allogeneic 6/6 matched sibling bone marrow transplantation (BMT). The group receiving MMF (n=21) had significantly less severe mucositis than did the group receiving MTX (n=19) (21 vs 65%, P=0.008). Median time to neutrophil engraftment was more rapid in the MMF group (11 vs 18 days, P<0.001). The incidence of acute GVHD, as well as 100 day survival, was similar for both groups. The reduced toxicity of the CSP and MMF arm resulted in premature study closure. We conclude that a GVHD prophylaxis regimen of CSP and MMF after a myeloablative allogeneic preparative regimen is associated with faster hematopoietic engraftment, decreased incidence of mucositis, similar incidence of aGVHD, and comparable survival as compared to CSP and MTX.
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References
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 1986; 314: 729–735.
Storb R, Deeg HJ, Pepe M et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 1989; 73: 1729–1734.
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 disease. Blood 2003; 101: 1620–1629.
Weissinger F, Sandmaier BM, Maloney DG et al. Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings. Blood 2001; 98: 3584–3588.
Feinstein LC, Sandmaier RB, Maloney DG et al. Allografting after nonmyeloablative conditioning as a treatment after a failed conventional hematopoietic cell transplant. Biol Blood Marrow Transplant 2003; 9: 266–272.
Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after nonmyelablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.
Grosskreutz C, Ross V, Scigliano E et al. Low-dose total body irradiation, fludarabine, and antithymocyte globulin conditioning for nonmyelablative allogeneic transplantation. Biol Blood Marrow Transplant 2003; 9: 453–459.
Sonis ST, Oster G, Fuchs H et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205.
Marmont AM, Horowitz MM, Gale RP et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.
Goker H, Haznedaroglu IC, Chao NJ . Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001; 29: 259–277.
Peniket AJ, Ruix de Elvira MC, Taghipour G et al. An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. BMT 2003; 31: 667–678.
Sullivan KM, Deeg HJ, Klosterman A et al. Hyperactue graft-vs-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood 1986; 67: 1172–1175.
Storb R, Deeg HJ, Pepe M et al. Graft-versus-host disease prevention by methotrexate combined with cyclosporine compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial. Br J Haematol 1989; 72: 567–572.
Locatelli F, Bruno B, Zecca M et al. Cyclosporine A and short-term methotrexate versus cyclosporine A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood 2000; 96: 1690–1697.
Ringdén O, Orowitz MM, Sondel P et al. Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia? Blood 1993; 81: 1094–1101.
Ruutu T, Niederwieser D, Gratwhoh A, Apperley JF . A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT). BMT 1997; 19: 759–764.
Locatelli F, Bruno B, Zecca M et al. Cyclosproine A and short-term methotrexate versus cyclosporine A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood 2000; 96: 1690–1697.
Gondo H, Marada M, Taniguchi S et al. Cyclosporine combined with methylprednisolone or methotrexate in prophylaxis of moderate to sever acute graft-versus-host disease. BMT 1993; 12: 437–441.
Epstein JB, Schubert MM . Oral mucositis in myelosuppressive cancer therapy. Oral Surg Oral Med Oral Pathol 1999; 88: 273–276.
Atkinson K, Downs K . Omission of day 11 methotrexate does not appear to influence the incidence of moderate to severe acute graft-versus-host disease, chronic graft-versus-host disease, relapse rate or survival after HLA-identical sibling bone marrow transplantation. BMT 1995; 16: 755–758.
Kumar S, Wolf RC, Chen MG et al. Omission of day +11 methotrexate after allogeneic bone marrow transplantation is associated with increased risk of severe acute graft-versus-host disease. BMT 2002; 30: 161–165.
Kobashigawa J, Miller L, Renlund D et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66: 507–515.
Sollinger HW . Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–232.
Mookerjee B, Altomonte V, Vogelsand G . Salvage therapy for refractory chronic graft-versus-host disease with mycophenolate mofetil and tacrolimus. BMT 1999; 24: 517–520.
Basara N, Blau WI, Kiehl MG et al. Efficacy and safety of mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant recipient. Transplant Proc 1998; 30: 4087–4089.
Busca A, Saroglia EM, Lanino E et al. Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (CGVHD) in children receiving bone marrow transplantation. BMT 2000; 25: 1067–1071.
Bornhäuser M, Schuler U, Proksen G et al. Mycophenolate mofetil and cyclosporine as graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Transplantation 1999; 67: 499–504.
Yu C, Seidel K, Nash RA et al. Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-nonidentical unrelated marrow grafts. Blood 1998; 91: 2581–2587.
Ruescher TJ, Sodeifi A, Scrivani SJ et al. The impact of mucositis on á-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematological malignancies. Cancer 1998; 82: 2275–2281.
Bolwell BJ, Kalaycio M, Sobecks R et al. A multivariable analysis of factors influencing mucositis after autologous progenitor cell transplantation. BMT 2002; 30: 587–591.
Przepiorka D, Ippoliti C, Khouri I et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. Blood 1996; 88: 4383–4389.
Yau JC, Dimopoulos MA, Huan SD et al. An effective acute graft-vs-host disease prophylaxis with minidose methotrexate, cyclosporine, and single-dose methylprednisolone. Am J Hematol 1991; 38: 288–292.
Denine SM, Geller RB, Lin LB et al. The outcomes of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versushost disease prophylaxis. Biol Blood Marrow Transplant 1997; 3: 25–33.
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Bolwell, B., Sobecks, R., Pohlman, B. et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant 34, 621–625 (2004). https://doi.org/10.1038/sj.bmt.1704647
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DOI: https://doi.org/10.1038/sj.bmt.1704647
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