Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia

Rainer Storb, H. Joachim Deeg, John Whitehead, Frederick Appelbaum, Patrick Beatty, William Bensinger, C. Dean Buckner, Reginald Clift, Kristine Doney, Vernon Farewell, John Hansen, Roger Hill, Lawrence Lum, Paul Martin, Robert Mcguffin, Jean Sanders, Patricia Stewart, Keith Sullivan, Robert Witherspoon, Gary C Yee & 1 others E. Donnall Thomas

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Abstract

We treated 93 patients who had acute non-lymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate post-grafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival. (N Engl J Med 1986; 314:729–35.), HIGH-DOSE chemoirradiation therapy and transplantation of marrow from HLA-identical siblings have been used successfully to treat patients with acute nonlymphoblastic leukemia in the first remission1 2 3 4 5 6 or with chronic myelocytic leukemia in the chronic phase.7 8 9 10 11 12 However, acute graft versus host disease continues to decrease survival among these patients. Studies in laboratory animals have shown two approaches to be effective in obviating graft versus host disease. A technique that involves the removal of T cells from the marrow inoculum is being explored in a number of centers.13 14 15 16 17 18 The other approach is the prophylactic use of immunosuppressive agents for 3 to 12 months.

Original languageEnglish (US)
Pages (from-to)729-735
Number of pages7
JournalNew England Journal of Medicine
Volume314
Issue number12
DOIs
StatePublished - Mar 20 1986

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Graft vs Host Disease
Methotrexate
Cyclosporine
Leukemia
Transplantation
Bone Marrow
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Siblings
Survival
Whole-Body Irradiation
Laboratory Animals
Immunosuppressive Agents
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Cyclophosphamide
Survival Rate
T-Lymphocytes
Incidence

ASJC Scopus subject areas

  • Medicine(all)

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Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia. / Storb, Rainer; Deeg, H. Joachim; Whitehead, John; Appelbaum, Frederick; Beatty, Patrick; Bensinger, William; Buckner, C. Dean; Clift, Reginald; Doney, Kristine; Farewell, Vernon; Hansen, John; Hill, Roger; Lum, Lawrence; Martin, Paul; Mcguffin, Robert; Sanders, Jean; Stewart, Patricia; Sullivan, Keith; Witherspoon, Robert; Yee, Gary C; Thomas, E. Donnall.

In: New England Journal of Medicine, Vol. 314, No. 12, 20.03.1986, p. 729-735.

Research output: Contribution to journalArticle

Storb, R, Deeg, HJ, Whitehead, J, Appelbaum, F, Beatty, P, Bensinger, W, Buckner, CD, Clift, R, Doney, K, Farewell, V, Hansen, J, Hill, R, Lum, L, Martin, P, Mcguffin, R, Sanders, J, Stewart, P, Sullivan, K, Witherspoon, R, Yee, GC & Thomas, ED 1986, 'Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia', New England Journal of Medicine, vol. 314, no. 12, pp. 729-735. https://doi.org/10.1056/NEJM198603203141201
Storb, Rainer ; Deeg, H. Joachim ; Whitehead, John ; Appelbaum, Frederick ; Beatty, Patrick ; Bensinger, William ; Buckner, C. Dean ; Clift, Reginald ; Doney, Kristine ; Farewell, Vernon ; Hansen, John ; Hill, Roger ; Lum, Lawrence ; Martin, Paul ; Mcguffin, Robert ; Sanders, Jean ; Stewart, Patricia ; Sullivan, Keith ; Witherspoon, Robert ; Yee, Gary C ; Thomas, E. Donnall. / Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia. In: New England Journal of Medicine. 1986 ; Vol. 314, No. 12. pp. 729-735.
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AU - Storb, Rainer

AU - Deeg, H. Joachim

AU - Whitehead, John

AU - Appelbaum, Frederick

AU - Beatty, Patrick

AU - Bensinger, William

AU - Buckner, C. Dean

AU - Clift, Reginald

AU - Doney, Kristine

AU - Farewell, Vernon

AU - Hansen, John

AU - Hill, Roger

AU - Lum, Lawrence

AU - Martin, Paul

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AU - Sanders, Jean

AU - Stewart, Patricia

AU - Sullivan, Keith

AU - Witherspoon, Robert

AU - Yee, Gary C

AU - Thomas, E. Donnall

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N2 - We treated 93 patients who had acute non-lymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate post-grafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival. (N Engl J Med 1986; 314:729–35.), HIGH-DOSE chemoirradiation therapy and transplantation of marrow from HLA-identical siblings have been used successfully to treat patients with acute nonlymphoblastic leukemia in the first remission1 2 3 4 5 6 or with chronic myelocytic leukemia in the chronic phase.7 8 9 10 11 12 However, acute graft versus host disease continues to decrease survival among these patients. Studies in laboratory animals have shown two approaches to be effective in obviating graft versus host disease. A technique that involves the removal of T cells from the marrow inoculum is being explored in a number of centers.13 14 15 16 17 18 The other approach is the prophylactic use of immunosuppressive agents for 3 to 12 months.

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