What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?
One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA-haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft-versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus-leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with "late" prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.
Division of Clinical Research Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
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Storb
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Pepe
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Anasetti
F R
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Appelbaum
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Beatty
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Doney
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Martin
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Stewart
K M
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Sullivan
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Witherspoon
D000208:Acute Disease; D000741:Anemia, Aplastic / Q000601:surgery*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide / Q000627:therapeutic use; D003524:Cyclosporins / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy; D007938:Leukemia / Q000188:drug therapy / Q000601:surgery*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D009190:Myelodysplastic Syndromes / Q000601:surgery*; D011241:Prednisone / Q000627:therapeutic use*; D011897:Random Allocation; D012307:Risk Factors; D014916:Whole-Body Irradiation
D003524:Cyclosporins; D005047:Etoposide; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate