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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2303-2314
Phase III Study Comparing Methotrexate and Tacrolimus (Prograf,
FK506) With Methotrexate and Cyclosporine for Graft-Versus-Host
Disease Prophylaxis After HLA-Identical Sibling Bone Marrow
Transplantation
Voravit Ratanatharathorn,
Richard A. Nash,
Donna Przepiorka,
Steven M. Devine,
Jared L. Klein,
Daniel Weisdorf,
Joseph W. Fay,
Auayporn Nademanee,
Joseph H. Antin,
Neal P. Christiansen,
Richard van der Jagt,
Roger H. Herzig,
Mark R. Litzow,
Steven N. Wolff,
Walter L. Longo,
Finn B. Petersen,
Chatchada Karanes,
Belinda Avalos,
Rainer Storb,
Donald N. Buell,
Rochelle M. Maher,
William
E. Fitzsimmons, and
John R. Wingard
From the University of Michigan, Ann Arbor; Fred Hutchinson Cancer
Research Center, Seattle, WA; M.D. Anderson Cancer Center, Houston, TX;
Lutheran General Hospital, Chicago, IL; Wayne State University,
Detroit, MI; University of Minnesota, Minneapolis; Baylor University
Medical Center, Dallas, TX; City of Hope National Medical Center,
Duarte, CA; Brigham and Women's Hospital, Boston, MA; Ohio State
University, Columbus, OH; Roswell Park Memorial Institute, Buffalo, NY;
Ottawa General Hospital, Ottawa, Ontario, Canada; University of
Louisville, Louisville, KY; Mayo Clinic, Rochester, MN; Vanderbilt
University Medical Center, Nashville, TN; University of Wisconsin,
Madison; University of Utah, Salt Lake City; Fujisawa USA, Deerfield,
IL; and University of Florida, Gainesville.
We report the results of a phase III open-label, randomized,
multicenter trial comparing tacrolimus/methotrexate to
cyclosporine/methotrexate for graft-versus-host disease (GVHD)
prophylaxis after HLA-identical sibling marrow transplantation in
patients with hematologic malignancy. The primary objective of this
study was to compare the incidence of moderate to severe (grade II-IV)
acute GVHD. Secondary objectives were to compare the relapse rate,
disease-free survival, overall survival, and the incidence of chronic
GVHD. Patients were stratified according to age (<40 v  40)
and for male recipients of a marrow graft from an alloimmunized female.
There was a significantly greater proportion of patients with advanced
disease randomized to tacrolimus arm (P = .02). The
incidence of grade II-IV acute GVHD was significantly lower in patients
who received tacrolimus than patients in the cyclosporine group (31.9%
and 44.4%, respectively; P = .01). The incidence of grade
III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3%
in the tacrolimus group. There was no difference in the incidence of
chronic GVHD between the tacrolimus and the cyclosporine group (55.9%
and 49.4%, respectively; P = .8). However, there was a
significantly higher proportion of patients in the cyclosporine group
who had clinical extensive chronic GVHD (P = .03). The
relapse rates of the two groups were similar. The patients in the
cyclosporine arm had a significantly better 2-year disease-free
survival and overall survival than patients in the tacrolimus arm,
50.4% versus 40.5% (P = .01) and 57.2% versus 46.9%
(P = .02), respectively. The significant difference in the
overall and disease-free survival was largely the result of the
patients with advanced disease, 24.8% with tacrolimus versus 41.7%
with cyclosporine (P = .006) and 20.4% with tacrolimus
versus 28% with cyclosporine (P = .007), respectively.
There was a higher frequency of deaths from regimen-related toxicity in
patients with advanced disease who received tacrolimus. There was no
difference in the disease-free and overall survival in patients with
nonadvanced disease. These results show the superiority of
tacrolimus/methotrexate over cyclosporine/methotrexate in the
prevention of grade II-IV acute GVHD with no difference in disease-free
or overall survival in patients with nonadvanced disease. The survival
disadvantage in advanced disease patients receiving tacrolimus warrants
further investigation.
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