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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2062-2068
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
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
Richard A. Nash,
Joseph H. Antin,
Chatchada Karanes,
Joseph W. Fay,
Belinda R. Avalos,
Andrew M. Yeager,
Donna Przepiorka,
Stella Davies,
Finn B. Petersen,
Pamela Bartels,
Donald Buell,
William Fitzsimmons,
Claudio Anasetti,
Rainer Storb, and
Voravit Ratanatharathorn
From the Clinical Research Division, Fred Hutchinson
Cancer Research Center, and the Department of Medicine, University of
Washington, Seattle, WA; Dana-Farber Cancer Institute and Brigham & Women's Hospital, Boston, MA; Wayne State University, Detroit, MI;
Baylor University, Sammons Cancer Center, Dallas, TX; Ohio State
University Hospitals, Columbus, OH; Emory Clinic, Atlanta, GA; MD
Anderson Cancer Center, Houston, TX; Fairview University Hospital,
Minneapolis, MN; University of Utah Medical School, Salt Lake City, UT;
Fujisawa Healthcare, Deerfield, IL; and University of Michigan,
Ann Arbor, MI,
After the transplantation of unmodified marrow from human leukocyte
antigen-matched unrelated donors receiving cyclosporine (CSP) and
methotrexate (MTX), the incidence of acute graft-versus-host disease
(GVHD) is greater than 75%. Tacrolimus is a macrolide compound that,
in previous preclinical and clinical studies, was effective in
combination with MTX for the prevention of acute GVHD. Between March
1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined
with a short course of MTX (n = 90), more than CSP and a short course
of MTX (n = 90), would reduce the incidence of acute GVHD after
marrow transplantation from unrelated donors. There was a significant
trend toward decreased severity of acute GVHD across all grades
(P = .005). Based on the Kaplan-Meier estimate, the
probability of grade II-IV acute GVHD in the tacrolimus group (56%)
was significantly lower than in the CSP group (74%;
P = .0002). Use of glucocorticoids for the management of
GVHD was significantly lower with tacrolimus than with CSP (65% vs
81%, respectively; P = .019). The number of patients
requiring dialysis in the first 100 days was similar (tacrolimus, 9;
CSP, 8). Overall and relapse-free survival rates for the tacrolimus and
CSP arms at 2 years was 54% versus 50% (P = .46) and
47% versus 42% (P = .58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the
combination of CSP and MTX, with no significant increase in toxicity,
infections, or leukemia relapse.
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