Abstract
Fludarabine phosphate, a purine analogue currently used in the therapy of hematological malignancies, is known to cause immunosuppression and long-lasting T cell lymphopenia. In this study, the effect of fludarabine on murine graft-versus-host disease occurring after marrow transplantation across major and minor histocompatibility barriers was evaluated. Survival of (BALB/c × C57BL/6)F1 mice irradiated and transplanted across the major histocompatibility barrier with C57BL/6 spleen cells, and subsequently treated with fludarabine was significantly longer than that of the control animals (P < 0.0001). On the other hand, fludarabine had no effect on the graft-versus-host disease and survival of cba mice transplanted by b10.br and of BALB/c mice transplanted by b10.d2 spleen cells across the minor histocompatability barrier. The results indicate that in certain murine models, particularly a major mismatch, fludarabine has the potential to induce bilateral tolerance and stable chimerism after marrow transplantation. Bone Marrow Transplantation (2000) 25, 263–266.
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References
Thomas ED, Storb R, Clift RA et al. Bone marrow transplantation New Engl J Med 1975 292: 832–843
Nash RA, Storb R . Graft-versus-host effect after allogeneic hematopoietic stem cell transplantation: GVHD and GVL Curr Opin Immunol 1996 8: 674–680
Ferrara JLM . Cytokine dysregulation as a mechanism of graft-versus-host disease Curr Opin Immunol 1993 5: 794–799
Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation Blood 1990 75: 555–562
Slavin S, Ackerstein A, Naparstek E et al . The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD? Bone Marrow Transplant 1990 6: 155–161
Truitt RL, Atasoylu AA . Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of NHC-compatible bonemarrow Bone Marrow Transplant 1991 8: 51–58
Weiden PL, Flournoy N, Thomas ED et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts New Engl J Med 1979 300: 1068–1073
Sullivan KM, Storb R, Buckner CD et al. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms New Engl J Med 1989 320: 828–834
Pigaditou A, Rohatiner AZS, Whelan JS et al. Fludarabine in low-grade lymphoma Semin Oncol 1993 20: (Suppl. 7) 24–27
Johnson S, Smith AG, Loffler H et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocyte leukaemia. The French Cooperative Group on CLL Lancet 1996 347: 1432–1438
O'Brien S, Kantarjian H, Beran M et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment Blood 1993 82: 1695–1700
Gandhi V, Estey E, Kentin MJ, Plunkett W . Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy J Clin Oncol 1993 11: 116–124
Wijermans PW, Gerrits WB, Haak HL . Severe immunodeficiency in patients treated with fludarabine monophosphate Eur J Haematol 1993 50: 292–296
Dighiero G . Potential immunological action of purine nucleoside analogues Drugs 1994 47: (Suppl. 6) 57–62
Gratwohl A, Hermans J, Apperley J et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia Blood 1995 86: 813–818
Chao NJ, Schmidt GM, Niland JC et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease New Engl J Med 1993 329: 1225–1230
Nash RA, Etzioni R, Storb R et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study Blood 1995 85: 3746–3753
Goodman ER, Fiedor PS, Fein S et al. Fludarabine phosphate: a DNA synthesis inhibitor with potent immunosuppressive activity and minimal clinical toxicity Am Surg 1996 62: 435–442
Weiss L, Reich S, Slavin S . Effect of cyclosporine A and methylprednisolone on the graft-versus-leukemia effects across major histocompatability barriers in mice following allogeneic bone marrow transplantation Bone Marrow Transplant 1990 6: 229–233
Chun HG, Leyland-Jones B, Cheson BD . Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies J Clin Oncol 1991 9: 175–188
Mehta J, Powles R, Singhal S et al. T cell-depleted allogeneic bone marrow transplantation from a partially HLA-mismatched unrelated donor for progressive chronic lymphocytic leukemia and fludarabine-induced bone marrow failure Bone Marrow Transplant 1996 17: 881–883
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 1998 91: 756–763
Giralt S, Estey E, Albitar N et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy Blood 1997 89: 4531–4536
Kapelushnik J, Or R, Slavin S, Nagler A . A fludarabine-based protocol for bone marrow transplantation in Fanconi's anemia Bone Marrow Transplant 1997 20: 1109–1110
Priebe T, Platsoucas CD, Seki H et al. Purine nucleoside modulation of functions of human lymphocytes Cell Immunol 1990 129: 321–328
Myint H, Coppelstone JA, Orchard J et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia Br J Haematol 1995 91: 341–344
Briz M, Cabrera R, Sanjuán I et al. Diagnosis of transfusion-associated graft-versus-host disease by polymerase chain reaction in fludarabine-treated B-chronic lymphocytic leukaemia Br J Haematol 1995 91: 409–411
Zulian GB, Roux E, Tiercy JM et al. Transfusion-associated graft-versus-host disease in a patient treated with Cladribine (2-chlorodeoxyadenosine): demonstration of exogenous DNA in various tissue extracts by PCR analysis Br J Haematol 1995 89: 83–89
Briones J, Pereira A, Alcorta I . Transfusion-associated graft-versus-host disease (TA-GVHD) in fludarabine-treated patients: is it time to irradiate blood component? Br J Haematol 1996 93: 737–741
Lee TH, Donegan E, Slichter S, Busch MP . Transient increase in circulating donor leukocytes after allogeneic transfusions in immunocompetent recipients compatible with donor cell proliferation Blood 1995 85: 1207–1214
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This work was supported in part by an educational grant from Schering, Berlin, Germany.
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Or, R., Weiss, L., Amir, G. et al. The prophylactic potential of fludarabine monophosphate in graft-versus-host disease after bone marrow transplantation in murine models. Bone Marrow Transplant 25, 263–266 (2000). https://doi.org/10.1038/sj.bmt.1702107
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DOI: https://doi.org/10.1038/sj.bmt.1702107
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