|
|
 Previous Article | Table of Contents | Next Article 
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
By
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.
 |
ABSTRACT |
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.
| |
INTRODUCTION |
ACUTE GRAFT-VERSUS-HOST disease (GVHD) is
a common immunologic complication which occurs in 40% to 50% of the
recipients of allogeneic bone marrow transplantation (BMT). The
immunologic event leading to injury of the target organs skin, liver,
and gutinvolves activation and clonal expansion of the donor's
effector T cells in response to the recipients' disparate major or
minor histocompatibility antigens.1 The morbidity and
mortality of this complication correlates with the severity of the
organ involvement.2-4 The main treatment strategy for acute
GVHD routinely entails the intensification of immunosuppression which
often leads to serious infectious complications.5-7 Death
in patients with acute GVHD is usually due to organ failure or
overwhelming infections. Thus, major research efforts in allogeneic BMT
over the past 2 decades have focused on the prevention of GVHD, mainly
with pharmacologic immunosuppressive agents. Since 1985, the
combination of cyclosporine and short-course methotrexate
(cyclosporine/methotrexate) has been studied extensively for the
prevention of acute GVHD against single agents such as cyclosporine or
methotrexate in randomized trials.8-13 Subsequently, this
combination has been adopted as standard care in most centers.
In the late 1980s, tacrolimus or FK506, a potent macrolide lactone
immunosuppressant, was introduced into clinical trials for the
prevention of rejection in recipients of solid-organ
transplants.14 In addition to its efficacy in the
prevention of organ rejection, tacrolimus has been shown to be
effective in the prevention of acute GVHD in murine and canine
models.15-17 Canine studies had shown a combination of
methotrexate and tacrolimus to be better than either drug
alone.18 Moreover, several pilot studies in recipients of
allogeneic marrow transplantation using tacrolimus for the
treatment19,20 and prevention of acute
GVHD21-24 suggested the efficacy of this agent, thus
providing the rationale for this randomized clinical trial comparing
the combination of methotrexate and tacrolimus to methotrexate and
cyclosporine for the prevention of acute GVHD in HLA-identical sibling
marrow transplantation in patients with hematologic malignancy.
We now report the results of a phase III open-label, randomized,
multicenter trial. The primary objective of this study was to compare
the incidence of moderate to severe (grade II-IV) acute GVHD. The
secondary objectives were to compare the relapse rate, overall
survival, disease-free survival (DFS), and the incidence of chronic
GVHD.
View larger version (9K):
[in this window]
[in a new window]
| Fig 1.
Cumulative incidence of grade II-IV acute GVHD of 165 patients who received cyclosporine/methotrexate, 44.4% ( ) and 164 patients who received tacrolimus/methotrexate, 31.9% ( ); absolute
difference = 12.5%, 95% CI =  23.9 to 1.2
(P = .01, Wilcoxon).
|
|
View larger version (9K):
[in this window]
[in a new window]
| Fig 2.
Cumulative incidence of grade III-IV acute GVHD of 165 patients who received cyclosporine/methotrexate, 17.1% () and 164 patients who received tacrolimus/methotrexate 13.3% (); absolute
difference = 3.8%, 95% CI interval = 12.1 to 4.5 (P = .2, Wilcoxon).
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 3.
Cumulative incidence of chronic GVHD of 165 patients who
received cyclosporine/methotrexate, 49.4% () and 164 patients who
received tacrolimus/methotrexate, 55.9% (); absolute difference = 6.5%, 95% CI = 8.0 to 21.1 (P = .8, Wilcoxon).
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 4.
Overall survivals at 2 years of 165 patients who received
cyclosporine/methotrexate, 57.2% () and 164 patients who received
tacrolimus/methotrexate 46.9% (); absolute difference = 10.3%,
95% CI interval = 21.1 to 0.5 (P = .02, Wilcoxon).
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 5.
Overall survivals at 2 years of patients with advanced
disease; 48 patients received cyclosporine/methotrexate, 41.7% ()
and 68 patients received tacrolimus/methotrexate, 24.8% ();
absolute difference = 16.9%, 95% CI = 34.3 to 0.4 (P = .006, Wilcoxon).
|
|
View larger version (10K):
[in this window]
[in a new window]
| Fig 6.
Overall survivals at 2 years of patients with nonadvanced
disease; 116 patients received cyclosporine/methotrexate 63.6% ()
and 97 patients received tacrolimus/methotrexate, 62.4% ();
absolute difference = 1.2%, 95% CI = 14.4 to 11.9 (P = .79, Wilcoxon).
|
|
View larger version (12K):
[in this window]
[in a new window]
| Fig 7.
DFSs at 2 years of 165 patients who received
cyclosporine/methotrexate, 50.4% () and 164 patients who received
tacrolimus/methotrexate 40.5% (); absolute difference = 9.9%,
95% CI = 20.7 to 0.8 (P = .01, Wilcoxon).
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 8.
DFSs of patients with advanced disease; 48 patients
received cyclosporine/methotrexate, 30.8% () and 68 patients
received tacrolimus/methotrexate, 20.4% (); absolute difference = 10.4%, 95% CI = 26.7 to 6.0 (P = .007, Wilcoxon).
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 9.
DFSs of patients with nonadvanced disease; 116 patients
received cyclosporine/methotrexate, 58.4% () and 97 patients
received tacrolimus/methotrexate, 54.5% (); absolute difference = 3.9%, 95% CI = 17.3 to 9.5 (P = .55, Wilcoxon).
|
|
| |
MATERIALS AND METHODS |
Subjects.
Patients must have fulfilled all the following eligibility criteria to
be included in the study: (1) a documented hematologic malignancy; (2)
recipient of a genotypically HLA-identical marrow transplantation; (3)
age of 12 years of age or older; and (4) patients or legal guardians
must sign the informed consent form approved by the Institutional
Review Board. Patients were ineligible if they had one of the following
exclusion criteria: (1) pregnant or unwilling to maintain an effective
contraception during the study; (2) a previous marrow transplant; (3)
serum creatinine 3.0 mg/dL; (4) carriers of any of the human
immunodeficiency viruses; and (5) use of a T-depleted marrow graft. In
addition, patients must have met the criteria of patient selection
according to the clinical protocols for marrow transplantation at the
study sites.
Study design.
The primary endpoint of this study was the development of grade II-IV
acute GVHD. The secondary end points were DFS and the incidence of
chronic GVHD. We used the method of Makuch and Simon25 to
calculate the sample size based on the primary end pointthe development of moderate to severe (grade II-IV) acute GVHD, assuming that there was no difference in treatment efficacy between the two
groups. An estimated sample size of 150 patients in each treatment arm
was derived to ensure a probability of 80% that the upper 95%
confidence limit for the true difference in efficacy did not exceed
0.15.
Patients with hematologic malignancies who were candidates for BMT in
each center were randomized in a 1:1 allocation ratio to receive
tacrolimus or cyclosporine for GVHD prophylaxis. Patients were
stratified according to age (<40 v 40 years) and whether they were a male recipient of a marrow graft from an alloimmunized female. The stage of underlying malignancy was categorized as `nonadvanced disease' if patients had chronic myeloid leukemia in
chronic or accelerated phase, myelodysplasia, or if the disease was in
remission; otherwise they were categorized as having `advanced disease.' This study was monitored by an independent Data Safety Monitoring Board (DSMB). Results of interim analyses performed by the
DSMB were blinded to the investigators and sponsor. The analysis for
this report was based on the intent-to-treat principle.
Treatment protocol.
Preparative regimens were assigned according to the institutional
protocols at the clinical sites. Supportive care such as protective
isolation techniques, antimicrobial policy, and the use of intravenous
(IV) immune globulin was standardized within each clinical site and was
uniformly applied to the patients in both groups. All blood components
were irradiated before administration.
The day of transplantation was designated as day 0. Either tacrolimus
or cyclosporine was initiated on day 1 of transplantation. The
starting dose of tacrolimus (0.03 mg/kg/d) or cyclosporine (3 mg/kg/d)
was administered by continuous IV infusion. The dose of cyclosporine or
tacrolimus was calculated according to patient's lean body weight. The
route of administration was converted from IV to oral at the ratio of
1:4 when patients were able to tolerate oral intake. Dose modifications
of tacrolimus and cyclosporine were dependent primarily on serum
creatinine and the blood levels of tacrolimus or cyclosporine. A dose
reduction of at least 25% was mandatory for patients with a creatinine
elevated to greater than 2.0 times baseline and at least a 50%
reduction for patients with a creatinine greater than 3 times baseline.
Whole blood levels of tacrolimus26 and
cyclosporine27 were obtained three times a week during the
first 28 days posttransplantation, weekly between day 29 to day 56, and
every 4 weeks from day 57 to day 180. During the first 56 days of
transplantation, the whole blood level of tacrolimus by
IMx assay (Abbott, Abbott Park, IL) and cyclosporine by
monoclonal or high-performance liquid chromatography (HPLC) assay were
maintained between 10 and 40 ng/mL and 150 and 450 ng/mL, respectively.
Approximately halfway through the course of this clinical trial, the
upper therapeutic level of tacrolimus was reduced to 30 ng/mL. This
modification was recommended by the DSMB when excessive renal toxicity
associated with higher levels of tacrolimus was recognized during the
analysis of the solid-organ transplantation trials.28 The
dose of tacrolimus and cyclosporine were tapered by 20% per month
beginning on day 57 posttransplant and discontinued at the end of 6 months.
All patients also received a short course of methotrexate, 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and
11. The doses of methotrexate were adjusted according to the severity
of mucosal toxicity, weight gain, fluid retention, renal impairment,
and hepatic dysfunction. Elevation of serum creatinine to greater than
twice of the baseline, transaminases greater than 200 U/L, or total
bilirubin greater than 5.0 mg/dL required at least a 50% dose
reduction. More severe renal or hepatic dysfunction, fluid retention,
and severe fibrinous mucositis with threatening airway obstruction
resulted in withholding the methotrexate. Monitoring of methotrexate
blood levels and the decision to rescue patients with leucovorin were
left to the discretion of the investigators at the clinical sites.
However, leucovorin rescue was not permitted earlier than 24 hours
after the administration of methotrexate.
The development of acute and chronic GVHD were monitored throughout the
study. The severity of acute GVHD was graded by the investigators at
each clinical site using the consensus criteria.29 The
clinical and laboratory parameters collected to assess the grading of
acute GVHD included percent of body-surface area with skin rash, volume
of diarrhea, total bilirubin, and Karnofsky performance status. Tissue
biopsy samples were obtained to confirm the diagnosis of acute GVHD
whenever clinically feasible. The diagnosis and grading of chronic GVHD
were established according to clinical and pathologic criteria proposed
by Sullivan et al.30
Study end points and statistical analysis.
The difference in the distribution of categorical data was compared
using chi-square test or Fisher's exact test when appropriate. StatXact software (Cytel Software Corp, Cambridge, MA)
for microcomputer was used to perform the analysis of categorical
data.31 Student's t-test was used to compare the
means of continuous variables between two groups. The time to the
development of acute GVHD was calculated from the date of
transplantation to the date of onset of acute GVHD. Patients who did
not develop acute GVHD were censored on the date of their last contact,
relapse, or death, whichever occurred first. DFS was calculated from
the date of transplantation to the date of disease recurrence or death,
whichever occurred first. The Kaplan-Meier method was used to calculate
the estimates of the distributions of the time to eventsprobabilities
of relapse, acute and chronic GVHD, overall survival, and
DFS.32 The Wilcoxon test was used to compare the
Kaplan-Meier estimates between groups; and the 95% confidence interval
(CI) around the difference in Kaplan-Meier estimates between the
treatment groups was calculated using the variance derived from
Greenwood's formula. We used the Cox proportional hazards models to
estimate the relative risks of an event adjusted for the stage of
malignancy.33 All P values were two-sided and a
value of < .05 was considered statistically significant.
| |
RESULTS |
Patient demographics and characteristics.
From May 1993 to November 1994, 16 marrow transplantation centers in
North America enrolled 332 patients. Three of the 332 patients (1 in
the cyclosporine group and 2 in the tacrolimus group) randomized in the
study did not undergo marrow transplantation because of death or
life-threatening complications just before the procedure and were
considered ineligible. Of the remaining 329 patients, 165 patients were
randomized to receive tacrolimus and 164 patients were randomized to
receive cyclosporine. With the exception of the stage of malignancy
(advanced v nonadvanced disease), demographic characteristics
including the age of the patients, sex, Karnofsky performance status,
diagnosis, race, positive serology for cytomegalovirus (CMV), and male
recipients of an alloimmunized female donor were distributed equally
between the two treatment groups. By chance, there was a significantly larger number of patients with advanced disease assigned to the tacrolimus group (P = .02) (Table 1). Within
the subgroups of patients with nonadvanced and advanced disease, the
distributions of preparative regimens between two treatment groups were
not different (Table 2). The distribution for the number
of doses of methotrexate given to the patients between two treatment
arms were also not significantly different (Table 3).
Acute GVHD.
The incidence of grade II-IV acute GVHD was significantly lower in
patients who received tacrolimus than patients in the cyclosporine group31.9% and 44.4%, respectively. The absolute difference between the two groups was 12.5% (95% CI for the difference, 23.9 to 1.2; P = .01) (Fig 1). However, the
incidence of grade III-IV acute GVHD was similar, 17.1% with
cyclosporine and 13.3% with tacrolimus. The absolute difference
between the two groups was 3.8% (95% CI for the difference, 12.1
to 4.5; P = .2) (Fig 2). Using the Cox
regression model, the relative risk of grade II-IV acute GVHD in the
cyclosporine group compared with the tacrolimus group was 1.61 when
adjusted for disease stage (P = .01). The distributions of
the organ involvement by acute GVHD were not significantly different
between patients who received tacrolimus or cyclosporine regardless of
disease stage (Table 4).
Chronic GVHD.
At 2 years of follow up, there was no difference in the incidence of
chronic GVHD between the tacrolimus and the cyclosporine groups55.9%
and 49.4%, respectively (absolute difference 6.5%; 95% CI, 8.0 to
21.1) (P = .8) (Fig 3). Chronic GVHD developed in 50 patients in the tacrolimus group (27 patients had extensive disease and 23 patients had limited disease) and 54 patients in the
cyclosporine group (41 patients had extensive disease and 13 patients
had limited disease). There was a significantly higher proportion of
patients in the cyclosporine group with clinical extensive disease
(P = .03).
Survival and relapse.
The patients who received cyclosporine had a significantly better
survival than patients who received tacrolimusthe 2-year survival
rates were 57.2% and 46.9%, respectively (absolute difference 10.3%;
95% CI, 21.1 to 0.5) (P = .02) (Fig 4).
When the overall survival was adjusted for the disease stage using Cox
regression model, the relative risk of death was 0.75 in favor of
cyclosporine group (P = .07). However, the advantage in the
overall survival was limited to the patients with advanced disease,
24.8% in the tacrolimus group and 41.7% in the cyclosporine group,
respectively (absolute difference 16.9%; 95% CI, 34.3 to 0.4)
(P = .006) (Fig 5). The survival rates in
patients with nonadvanced disease were not different, 62.4% in the
tacrolimus group and 63.6% in the cyclosporine group, respectively
(absolute difference 1.2%; 95% CI, 14.4 to 11.9)
(P = .79) (Fig 6). Collectively, the
distributions for the causes of death between the two treatment groups
in patients with nonadvanced disease were not different (Table
5). However, in the patients with advanced disease,
there was a higher frequency of deaths from GVHD in patients who
received cyclosporine (P = .06, Fisher's) and from
regimen-related toxicity in patients who received tacrolimus
(P = .04, Fisher's). Cox regression models were used to
evaluate the interactions of tacrolimus with other nephrotoxic agents
(aminoglycosides, furosemide, vancomycin, and amphotericin-B) and its
association with early posttransplant mortality (deaths within day 56 after transplantation). None of these agents were found to have
significant association with early posttransplant mortality when
administered concomitantly with tacrolimus (data not shown).
Forty-one patients in the tacrolimus group and 36 patients in the
cyclosporine group relapsed. There was no difference in relapse rates
between patients who received tacrolimus (24.8%; 95% CI, 18.2 to
31.4) and patients who received cyclosporine (22.0%; 95% CI, 15.7 to
28.3) (P = .54). The relapse rates were similar regardless of
the stage of malignancy (data not shown).
The DFS at 2 years for patients receiving tacrolimus and cyclosporine
was 40.5% and 50.4%, respectively (absolute difference 9.9%; 95%
CI, 20.7 to 0.8) (P = .01) (Fig 7). The
significant difference in DFS was largely the result of a difference
among patients with advanced disease, 20.4% in the tacrolimus group and 30.8% in the cyclosporine group, respectively (absolute difference 10.4%; 95% CI, 26.7 to 6.0, P = .007) (Fig
8). The DFSs among patients with nonadvanced disease
were similar between the two groups, 54.5% in the tacrolimus group and
58.4% in the cyclosporine group (absolute difference 3.9%; 95% CI,
17.3 to 9.5) (P = .55) (Fig 9).
Engraftment.
The median times to the recovery of absolute neutrophil counts 0.5 × 109/L did not differ between the tacrolimus and
cyclosporine groups (19 and 20 days, respectively) (P = .78).
Neutrophil recovery was also not different in the subgroups of patients
who had advanced or nonadvanced disease (advanced disease: 18 days in
the tacrolimus group and 19 days in the cyclosporine group; nonadvanced
disease: 21 days in the tacrolimus group and 21 days in the
cyclosporine group). The frequencies and durations of platelet and red
blood cell transfusions did not differ significantly between the
tacrolimus and cyclosporine groups, or between subgroups of advanced or
nonadvanced disease (data not shown).
Toxicities.
The incidences of renal toxicity, veno-occlusive disease of the liver,
and hyperglycemic events during 26 weeks of scheduled immunosuppressive
therapy are shown in Table 6. The incidence of serum
creatinine increasing above 2 mg/dL within 8 weeks of transplantation
was significantly higher in the tacrolimus group (P = .03)
but was not different from the cyclosporine arm at 26 weeks
(P = .16). The incidence of renal failure requiring
hemodialysis was significantly higher in the tacrolimus group, of which
the patients with advanced disease accounted for most of the events and
the difference between treatment groups. The incidence of hyperglycemia
requiring insulin within 8 weeks of transplantation (in patients with
no prior history of diabetes) was significantly higher in the
tacrolimus group but was not different at 26 weeks. The incidence of
hypertension requiring antihypertensive medications was significantly
higher in the cyclosporine group (P = .001). The incidence of
veno-occlusive disease was similar. Neurologic side effects were also
similar in both groups: approximately 25% of the patients had tremor
or headache and 10% or less had confusion, nervousness, or
paresthesia.
| |
DISCUSSION |
Since the late 1960s, the pharmacologic prophylaxis of acute GVHD after
allogeneic marrow transplantation has evolved from the introduction of
monotherapy using methotrexate or cyclosporine to the development of
combination therapycyclosporine/methotrexate.11,34-40 Similar to cyclosporine in its development as an immunosuppressant, the
success of tacrolimus in kidney,41-43 liver,44
and heart45 transplantation served as a leading indicator
for its possible application in the prevention of acute GVHD in
allogeneic marrow transplantation. Indeed, experimental animal studies
showed synergism between tacrolimus and methotrexate for prevention of
acute GVHD and showed significant improvement of survival over
monotherapy.18 Preceding the initiation of this present
study, there were three pilot studies of tacrolimus conducted to study
the pharmacokinetics of tacrolimus and to estimate its efficacy and
safety of tacrolimus for the prevention of acute GVHD in HLA-matched
sibling and unrelated donor transplantation.21-23 Two of
these studies were conducted in the recipients of histocompatible
sibling donor marrow transplantation.21,22 In a study on 27 patients who received tacrolimus monotherapy, the rate of grade II-IV
acute GVHD was 41%.21 In the other study on 18 patients
who received either tacrolimus alone or in combination with
methotrexate or steroid, the rate of grade II-IV acute GVHD was
44%.22 The remaining study, conducted on the recipients of
an unrelated marrow transplantation, reported an incidence of grade
II-IV acute GVHD of 42%.23 Taken together, these data strongly suggested substantial efficacy of tacrolimus for the prevention of acute GVHD in allogeneic marrow transplantation.
The results of this study confirm the efficacy of tacrolimus and also
suggest the superiority of tacrolimus/methotrexate over that of
cyclosporine/methotrexate for the prevention of acute GVHD in
recipients of an allogeneic marrow transplantation. The difference in
the efficacy of these two regimens could not be attributed to the
cumulative dose of methotrexate given or pharmacologic interaction
between tacrolimus and methotrexate.46 However, the
survival of patients who had advanced disease was significantly poorer
in the tacrolimus/methotrexate group. It is intriguing that the
survival of patients with advanced disease who received cyclosporine in
this study was much better than in other studies reported in the
literature.36,47,48 Moreover, in the cyclosporine arm, we
observed an unexpectedly higher incidence of fatal regimen-related toxicity in patients with nonadvanced disease compared to patients with
advanced disease (26% v 7%, respectively). The reasons for these contradictory findings are unclear. On the other hand, the patients with advanced disease in the tacrolimus group had a survival rate comparable to similar patients in other studies using
cyclosporine. Several subsequent studies of tacrolimus which included
patients with advanced disease found no increase in treatment-related
toxicity or mortality.24,49-51
By our definition of `advanced disease,' this group of patients
comprised a heterogeneous population with diverse diagnoses and perhaps
receiving a higher intensity of preparative regimen, which might have
heightened the organ toxicity in patients who received
tacrolimus/methotrexate. Consequently, patients with advanced disease
were a less than ideal population for a study of this nature in which
many of these adverse factors may confound the analysis. This
contention has been emphasized by other investigators in several
studies, in which only good-risk (nonadvanced disease) patients were
included in their study designs.9-13,52 The survival outcomes of nonadvanced disease patients in our study were consistent with previous randomized trials in patients with good-risk
disease.9,10,13 In this subset of patients, the overall
survival and DFS of patients who received tacrolimus/methotrexate and
cyclosporine/methotrexate were similar. Recently two other randomized
studies using the same study design have compared
tacrolimus/methotrexate and cyclosporine/methotrexate. One study
was conducted in patients with nonadvanced disease receiving a matched
unrelated donor transplantation,53 and the other study included both sibling matched donor and unrelated donor
transplantation.54 Both of these studies reported
superiority of tacrolimus/methotrexate over that of
cyclosporine/methotrexate in the prevention of acute GVHD, with no
difference in survival or relapse.
Based on the superior results of tacrolimus for the prevention of acute
GVHD shown in this and other recently completed randomized trials, this
agent is likely to have a major role in the prevention of acute GVHD in
allogeneic transplantation. The lower incidence of extensive chronic
GVHD in patients treated with tacrolimus in this study is unique and
needs confirmation. The long-term impact of tacrolimus on the clinical
course of extensive chronic GVHD remains a subject of further
investigation. Regarding the nephrotoxicity of tacrolimus in our
current patient population, a retrospective analysis to correlate whole
blood tacrolimus levels with toxicity and efficacy was undertaken.
There was no correlation between whole blood concentration of
tacrolimus and acute GVHD. On the other hand, the incidence of
nephrotoxicity was significantly increased when the whole blood
concentration of tacrolimus exceeded 20 ng/mL.55 It is
possible that the upper limit of the targeted blood level of 30 to 40 ng/mL used in this study might have adversely influenced the survival.
Further studies to define the drug levels to minimize toxicity while
preserving a high level of immunosuppressive effect of this agent are
crucial to optimize its therapeutic index.
| |
FOOTNOTES |
Submitted February 24, 1998;
accepted May 28, 1998.
Supported by Fujisawa, USA, Deerfield, IL.
Address reprint requests to Voravit Ratanatharathorn, MD, Associate
Professor of Internal Medicine, B1-207 Cancer Center, University of
Michigan Medical Center, 1500 E Medical Center Dr, Ann Arbor, MI
48109-0914; e-mail: vratanat{at}umich.edu.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank the members of the Data Safety Monitoring Board (Thomas
Fleming, PhD [Chair], Donald Steinmuller, MD, and Elena Bloom, MD),
the statistical staff at Fujisawa USA who provided the technical supports (Jin Zhu, PhD, Ronald Kershner, PhD, Sarah Young, PhD, Revathy
Rangarajan, MS, and Jay Erdman, MS), the data managers, clinical
research associates, and the nursing and medical staffs at each study
site, all of whom had substantial contribution to the success of this
study.
| |
REFERENCES |
1.
Antin JH,
Ferrara JLM:
Cytokine dysregulation and acute graft-versus-host disease.
Blood
80:2964,
1992[Abstract/Free Full Text]
2.
Vogelsang GB,
Hess AD,
Santos GW:
Acute graft-versus-host disease: Clinical characteristics in the cyclosporine era.
Medicine
67:163,
1988[Medline]
[Order article via Infotrieve]
3.
Ferrara JL,
Deeg HJ:
Graft-versus-host disease.
N Engl J Med
324:667,
1991[Medline]
[Order article via Infotrieve]
4.
Gratwohl A,
Hermans J,
Apperley J,
Arcese W,
Bacigalupo A,
Bandini G,
di Bartolomeo P,
Boogaerts M,
Bosi A,
Carreras E,
Devergie A,
Ferrant A,
Fibbe WE,
Frassoni F,
Gahrton G,
Goldman J,
Iriondo A,
Jacobsen N,
Kolb HJ,
Link H,
Michallet M,
Prentice HG,
Reiffers J,
Rhee FV,
Ruutu T,
Schwaighofer H,
Vernant JP,
deWitte T,
Niederwieser D,
for the Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation:
Acute graft-versus-host disease: Grade and outcome in patients with chronic myelogenous leukemia.
Blood
86:813,
1995[Abstract/Free Full Text]
5.
Weisdorf D,
Haake R,
Blazar B,
Miller W,
McGlave P,
Ramsay N,
Kersey J,
Filipovich A:
Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: An analysis of clinical risk features and outcome.
Blood
75:1024,
1990[Abstract/Free Full Text]
6.
Martin PJ,
Schoch G,
Fisher L,
Byers V,
Anasetti C,
Appelbaum FR,
Beatty PG,
Doney K,
McDonald GB,
Sanders JE,
Sullivan KM,
Storb R,
Thomas ED,
Witherspoon RP,
Lomen P,
Hanninga J,
Hansen JA:
A retrospective analysis of therapy for acute graft-versus-host disease: Initial treatment.
Blood
76:1464,
1990[Abstract/Free Full Text]
7.
Martin PJ,
Schoch G,
Fisher L,
Byers V,
Appelbaum FR,
McDonald GB,
Storb R,
Hansen JA:
A retrospective analysis of therapy for acute graft-versus-host disease: Secondary treatment.
Blood
77:1821,
1991[Abstract/Free Full Text]
8.
Storb R,
Pepe M,
Deeg HJ,
Anasetti C,
Appelbaum FR,
Bensinger WI,
Buckner CD,
Clift RA,
Doney K,
Hansen JA,
Martin PJ,
Pettinger M,
Sanders JE,
Singer J,
Stewart P,
Sullivan KM,
Thomas ED,
Witherspoon RP:
Long-term follow-up of a controlled trial comparing a combination of methotrexate plus cyclosporine with cyclosporine alone for prophylaxis of graft-versus-host disease in patients administered HLA-identical marrow grafts for leukemia [letter].
Blood
80:560,
1992[Free Full Text]
9.
Storb R,
Deeg HJ,
Pepe M,
Appelbaum F,
Anasetti C,
Beatty PG,
Bensinger WI,
Berenson R,
Buckner CD,
Clift RA,
Doney K,
Longton G,
Hansen JA,
Hill R,
Loughran T Jr,
Martin P,
Singer J,
Sanders J,
Stewart P,
Sullivan KM,
Witherspoon R,
Thomas ED:
Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: Long-term follow-up of a controlled trial.
Blood
73:1729,
1989[Abstract/Free Full Text]
10.
Storb R,
Deeg HJ,
Whitehead J,
Applebaum 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 G,
Thomas ED:
Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.
N Engl J Med
314:729,
1986[Abstract]
11.
Ringden O,
Horowitz MM,
Sondel P,
Gale RP,
Biggs JC,
Champlin RE,
Deeg HJ,
Dicke K,
Masaoka T,
Powles RL,
Rimm AA,
Rozman C,
Sobocinski KA,
Speck B,
Zwaan FE,
Bortin MM:
Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?
Blood
81:1094,
1993[Abstract/Free Full Text]
12.
Storb R,
Leisenring W,
Deeg HJ,
Anasetti C,
Appelbaum F,
Bensinger W,
Buckner CD,
Clift R,
Doney K,
Hansen J,
Martin P,
Sanders J,
Stewart P,
Sullivan K,
Thomas ED,
Witherspoon R:
Long-term follow-up of a randomized trial of graft-versus-host disease prevention by methotrexate/cyclosporine versus methotrexate alone in patients given marrow grafts for severe aplastic anemia [letter].
Blood
83:2749,
1994[Free Full Text]
13.
Storb R,
Deeg HJ,
Farewell V,
Doney K,
Appelbaum F,
Beatty P,
Bensinger W,
Buckner CD,
Clift R,
Hansen J:
Marrow transplantation for severe aplastic anemia: Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease.
Blood
68:119,
1986[Abstract/Free Full Text]
14. Fung JJ, Abu-Elmagd K, Todo S, Shapiro R, Tzakis A, Jordan M,
Armitage J, Jain A, Alessiani M, Martin M, Bronster O, Stieber A,
Kormos R, Selby R, Gordon R, Przepiorka D, Bloom E, Starzl TE: Overview
of FK506 in transplantation, in Terasaki P (ed): Clinical Transplants.
Los Angeles, CA, UCLA Tissue Typing Laboratory, 1991, p 115
15.
Blazar BR,
Taylor PA,
Fitzsimmons WE,
Vallera DE:
FK506 inhibits graft-versus-host disease and bone marrow graft rejection in murine recipients of MHC disparate donor grafts by interfering with mature peripheral T cell expansion post-transplantation.
J Immunol
153:1836,
1994[Abstract]
16.
Markus PM,
Cai X,
Ming W,
Demetris AJ,
Fung JJ,
Starzl TE:
Prevention of graft-versus-host disease following allogeneic bone marrow transplantation in rats using FK506.
Transplantation
52:590,
1991[Medline]
[Order article via Infotrieve]
17.
Yu C,
Storb R,
Deeg HJ,
Graham TC,
Schuening FG,
Huss R,
Seidel K,
Fitzsimmons WE:
Tacrolimus (FK506) and methotrexate regimens to prevent graft-versus-host disease after unrelated dog leukocyte antigen (DLA) nonidentical marrow transplantation.
Bone Marrow Transplant
17:649,
1996[Medline]
[Order article via Infotrieve]
18.
Storb R,
Raff RF,
Appelbaum FR,
Deeg HJ,
Fitzsimmons W,
Graham TC,
Pepe M,
Pettinger M,
Sale G,
van der Jagt R,
Schuening FG:
FK-506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated dog leukocyte antigen-nonidentical donors.
Transplantation
56:800,
1993[Medline]
[Order article via Infotrieve]
19.
Koehler MT,
Howrie D,
Mirro J,
Neudorf S,
Blatt J,
Corey S,
Wollman M,
Kelly-Ekeroth V,
Reyes J:
FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation.
Bone Marrow Transplant
15:895,
1995[Medline]
[Order article via Infotrieve]
20.
Kanamaru A,
Takemoto Y,
Kakishita E,
Dohy J,
Kodera Y,
Moriyama Y,
Shibata A,
Kasai M,
Katoh S,
Saitoh H,
Matsuda T,
Hattori M,
Okamoto S,
Asano S,
Horiuchi A,
Harada M,
Hiraoka A,
Masaoka T,
for the Japanese FK506 BMT Study Group:
FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporin and/or other immunosuppressants.
Bone Marrow Transplant
15:885,
1995[Medline]
[Order article via Infotrieve]
21.
Fay JW,
Wingard JR,
Antin JH,
Collins RH,
Pineiro LA,
Blazar BR,
Saral R,
Bierer BE,
Przepiorka D,
Fitzsimmons WE,
Maher RM,
Weisdorf DJ:
FK506 (tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation.
Blood
87:3514,
1996[Abstract/Free Full Text]
22.
Nash RA,
Etzioni R,
Storb R,
Furlong T,
Gooley T,
Anasetti C,
Appelbaum FR,
Doney K,
Martin P,
Slattery J,
Sullivan K,
van der Jagt R,
Witherspoon R,
Jusko WJ,
Zager RA,
Deeg HJ:
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
85:3746,
1995[Abstract/Free Full Text]
23.
Nash RA,
Pineiro LA,
Storb R,
Deeg HJ,
Fitzsimmons WE,
Furlong T,
Hansen JA,
Gooley T,
Maher RM,
Martin P,
McSweeney PA,
Sullivan KM,
Anasetti C,
Fay JW:
FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors.
Blood
88:3634,
1996[Abstract/Free Full Text]
24.
Przepiorka D,
Ippoliti C,
Khouri I,
Woo M,
Mehra R,
Le Bherz D,
Giralt S,
Gajewski J,
Fischer H,
Fritsche H,
Deisseroth AB,
Cleary K,
Champlin R,
van Besien K,
Andersson B,
Maher R,
Fitzsimmons W:
Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation.
Blood
88:4383,
1996[Abstract/Free Full Text]
25.
Makuch R,
Simon R:
Sample size requirements for evaluating a conservative therapy.
Cancer Treat Rep
62:1037,
1978[Medline]
[Order article via Infotrieve]
26.
Grenier FC,
Luczkiw J,
Bergmann M,
Lunetta S,
Morrison M,
Blonski D,
Shoemaker K,
Kobayashi M:
A whole blood FK 506 assay for the IMx analyzer.
Transplant Proc
23:2748,
1991[Medline]
[Order article via Infotrieve]
27.
Zucchelli GC,
Pilo A,
Chiesa MR,
Scarlattini M,
Bizollon CA:
Progress report of an external quality assessment scheme for cyclosporine assay.
Ther Drug Monit
18:273,
1996[Medline]
[Order article via Infotrieve]
28. The U.S. Multicenter Liver Study Group: A comparison of
tacrolimus (FK 506) and cyclosporine for immunosuppression in liver
transplantation. N Engl J Med 331:1110, 1994
29.
Przepiorka D,
Weisdorf D,
Martin P,
Klingermann HG,
Beatty P,
Hows J,
Thomas ED:
1994 Consensus Conference on Acute GVHD Grading.
Bone Marrow Transplant
15:825,
1995[Medline]
[Order article via Infotrieve]
30.
Sullivan KM,
Shulman HM,
Storb R,
Weiden PL,
Witherspoon RP,
McDonald GB,
Schubert MM,
Atkinson K,
Thomas ED:
Chronic graft-versus-host disease in 52 patients: Adverse natural course and successful treatment with combination immunosuppression.
Blood
57:267,
1981[Abstract/Free Full Text]
31. Mehta C, Patel N: StatXact-Turbo-Statistical
software for exact nonparametric inference. Cambridge, MA, Cytel
Software Corp, 1992
32.
Kaplan EL,
Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457,
1958
33. Cox DR: Regression models and life-tables (with Discussion). J R
Stat Soc (Section B) 34:187, 1972
34.
Deeg HJ,
Storb R,
Thomas ED,
Flournoy N,
Kennedy MS,
Banaji M,
Appelbaum FR,
Bensinger WI,
Buckner CD,
Clift RA,
Doney K,
Fefer A,
McGuffin R,
Sanders JE,
Singer J,
Stewart P,
Sullivan KM,
Witherspoon RP:
Cyclosporine as prophylaxis for graft-versus-host disease: A randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia.
Blood
65:1325,
1985[Abstract/Free Full Text]
35.
Storb R,
Deeg HJ,
Pepe M,
Anasetti C,
Appelbaum FR,
Bensinger W,
Buckner CD,
Clift RA,
Doney K,
Hansen J,
Longton G,
Martin P,
Sanders JE,
Singer J,
Stewart P,
Sullivan KM,
Thomas ED,
Witherspoon RP:
Long-term follow-up of three controlled trials comparing cyclosporine versus methotrexate for graft-versus-host disease prevention in patients given marrow grafts for leukemia [letter].
Blood
79:3091,
1992[Free Full Text]
36.
Irle C,
Deeg HJ,
Buckner CD,
Kennedy M,
Clift R,
Storb R,
Appelbaum FR,
Beatty P,
Bensinger W,
Doney K,
Cheever M,
Fefer A,
Greenberg P,
Hill R,
Martin P,
McGuffin R,
Sanders J,
Stewart P,
Sullivan K,
Witherspoon R,
Thomas ED:
Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine.
Leuk Res
9:1255,
1985[Medline]
[Order article via Infotrieve]
37.
Storb R,
Deeg HJ,
Thomas ED,
Appelbaum FR,
Buckner CD,
Cheever MA,
Clift RA,
Doney KC,
Flourney N,
Kennedy MS,
Loughran TP,
McGuffin RW,
Sale GE,
Sanders JE,
Singer JW,
Stewart PS,
Sullivan KM,
Witherspoon RP:
Marrow transplantation for chronic myelocytic leukemia: A controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease.
Blood
66:698,
1985[Abstract/Free Full Text]
38.
Biggs JC,
Atkinson K,
Gillett E,
Downs K,
Concannon A,
Dodds A:
A randomized prospective trial comparing cyclosporine and methotrexate given for prophylaxis of graft-versus-host disease after bone marrow transplantation.
Transplant Proc
18:253,
1986[Medline]
[Order article via Infotrieve]
39.
Ringden O,
Backman L,
Lonnqvist B,
Heimdahl A,
Lindholm A,
Bolme P,
Gahrton G:
A randomized trial comparing use of cyclosporin and methotrexate for graft-versus-host disease prophylaxis in bone marrow transplant recipients with haematological malignancies.
Bone Marrow Transplant
1:41,
1986[Medline]
[Order article via Infotrieve]
40.
Storb R,
Deeg HJ,
Fisher L,
Appelbaum F,
Buckner CD,
Bensinger W,
Clift R,
Doney K,
Irle C,
McGuffin R,
Martin P,
Sanders J,
Schoch G,
Singer J,
Stewart P,
Sullivan K,
Witherspoon R,
Thomas ED:
Cyclosporine v methotrexate for graft-versus-host disease prevention in patients given marrow grafts for leukemia: Long-term follow-up of three controlled trials.
Blood
71:293,
1988[Abstract/Free Full Text]
41.
Shapiro R,
Jordan ML,
Scantlebury VP,
Vivas C,
Gritsch HA,
McCauley J,
Ellis D,
Gilboa N,
Lombardozzi-Lane S,
Randhawa P,
Demetris AJ,
Irish W,
Hakala TR,
Simmons RL,
Fung JJ,
Starzl TE:
Tacrolimus in renal transplantation.
Transplant Proc
28:2117,
1996[Medline]
[Order article via Infotrieve]
42.
Jordan ML,
Naraghi R,
Shapiro R,
Smith D,
Vivas CA,
Scantlebury VP,
Gritsch HA,
McCauley J,
Randhawa P,
Demetris AJ,
McMichael J,
Fung JJ,
Starzl TE:
Tacrolimus rescue therapy for renal allograft rejectionFive-year experience.
Transplantation
63:223,
1997[Medline]
[Order article via Infotrieve]
43.
Shapiro R,
Scantlebury VP,
Jordan ML,
Vivas C,
Gritsch HA,
Ellis D,
Gilboa N,
Lombardozzi-Lane S,
Irish W,
Fung JJ,
Hakala TR,
Simmons RL,
Starzl TE:
Tacrolimus in pediatric renal transplantation.
Transplantation
62:1752,
1996[Medline]
[Order article via Infotrieve]
44.
Fung JJ,
Eliasziw M,
Todo S,
Jain A,
Demetris AJ,
McMichael JP,
Starzl TE,
Meier P,
Donner A:
The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation.
J Am Coll Surg
183:117,
1996[Medline]
[Order article via Infotrieve]
45.
Pham SM,
Kormos RL,
Hattler BG,
Kawai A,
Tsamandas AC,
Demetris AJ,
Murali S,
Fricker FJ,
Chang HC,
Jain AB,
Starzl TE,
Hardesty RL,
Griffith BP:
A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: Intermediate-term results.
J Thorac Cardiovasc Surg
111:764,
1996[Abstract/Free Full Text]
46.
Wingard JR,
Nash RA,
Ratanatharathorn V,
Fay JW,
Klein JL,
Przepiorka D,
Maher RM,
Devine SM,
Boswell G,
Bekersky I,
Fitzsimmons W:
Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.
Bone Marrow Transplant
20:49,
1997[Medline]
[Order article via Infotrieve]
47.
Brown RA,
Wolff SN,
Fay JW,
Pineiro L,
Collins RH Jr,
Lynch JP,
Stevens D,
Greer J,
Herzig RH,
Herzig GP:
High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: A study by the North American Marrow Transplant Group.
Blood
85:1391,
1995[Abstract/Free Full Text]
48.
Doney K,
Fisher LD,
Appelbaum FR,
Buckner CD,
Storb R,
Singer J,
Fefer A,
Anasetti C,
Beatty P,
Bensinger W,
Clift R,
Hansen J,
Hill R,
Loughran TP Jr,
Martin P,
Petersen FB,
Sanders J,
Sullivan KM,
Stewart P,
Weiden P,
Witherspoon R,
Thomas ED:
Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival.
Bone Marrow Transplant
7:453,
1991[Medline]
[Order article via Infotrieve]
49.
Przepiorka D,
Ippoliti C,
Khouri I,
Anderlini P,
Mehra R,
Giralt S,
Gajewski J,
Fritsche H,
Deisseroth AB,
Cleary K,
Champlin R,
van Biesen K,
Andersson B,
Korbling M:
Allogeneic transplantation for advanced leukemia: Improved short-term outcome with blood stem cell grafts and tacrolimus.
Transplantation
62:1806,
1996[Medline]
[Order article via Infotrieve]
50.
Uberti JP,
Silver SM,
Adams PW,
Jacobson P,
Scalzo A,
Ratanatharathorn V:
Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies.
Bone Marrow Transplant
19:1233,
1997[Medline]
[Order article via Infotrieve]
51.
Devine SM,
Geller RB,
Lin LB,
Dix SP,
Holland HK,
Maurer D,
O'Toole K,
Keller J,
Connaghan DG,
Heffner LT,
Hillyer CD,
Rodey GE,
Winton EF,
Maher RM,
Fitzsimmons WE,
Wingard JR:
The outcome of unrelated donor marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis.
Biol Blood Marrow Transplant
3:25,
1997[Medline]
[Order article via Infotrieve]
52.
Chao NJ,
Schmidt GM,
Niland JC,
Amylon MD,
Dagis AC,
Long GD,
Nademanee A,
Negrin RS,
O'Donnell MR,
Parker PM,
Smith EP,
Snyder DS,
Stein AS,
Wong RM,
Blume KG,
Forman S:
Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease.
N Engl J Med
329:1225,
1993[Abstract/Free Full Text]
53. (abstr, suppl 1)
Nash RA,
Antin J,
Karanes C,
Fay J,
Avalos B,
Yeager AM,
Przepiorka D,
Davies S,
Petersen F,
Buell D,
Fitzsimmons W,
Bartels P,
Hansen J,
Anasetti C,
Storb R,
Ratanatharathorn V:
Phase III study comparing tacrolimus (FK506) with cyclosporine (CSP) for prophylaxis of acute graft-versus-host disease (GVHD) after marrow transplantation from unrelated donors.
Blood
90:561a,
1997
54. (abstr, suppl 1)
Hiraoka AF:
Results of a phase III study on prophylactic use of FK506 for acute GVHD compared with cyclosporin in allogeneic bone marrow transplantation.
Blood
90:561a,
1997
55. (abstr, suppl 1)
Wingard JR,
Nash RA,
Przepiorka D,
Ratanatharathorn V,
Devine S,
Klein J,
Weisdorf D,
Fay J,
Nademanee A,
Antin J,
Karanes C,
Avalos B,
Christens N,
van der Jagt R,
Herzig R,
Litzow M,
Wolff S,
Longo W,
Petersen F,
Buell D,
Maher R,
Fitzsimmons W:
Relationship of tacrolimus (Prograf, FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation.
Blood
88:460a,
1996
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Fujii, G. Cuvelier, K. She, S. Aslanian, H. Shimizu, A. Kariminia, M. Krailo, Z. Chen, R. McMaster, A. Bergman, et al.
Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group
Blood,
March 15, 2008;
111(6):
3276 - 3285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Marty, J. Bryar, S. K. Browne, T. Schwarzberg, V. T. Ho, I. V. Bassett, J. Koreth, E. P. Alyea, R. J. Soiffer, C. S. Cutler, et al.
Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis
Blood,
July 15, 2007;
110(2):
490 - 500.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Sakoda, D. Hashimoto, S. Asakura, K. Takeuchi, M. Harada, M. Tanimoto, and T. Teshima
Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
Blood,
February 15, 2007;
109(4):
1756 - 1764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Z. Pavletic, S. L. Carter, N. A. Kernan, J. Henslee-Downey, A. M. Mendizabal, E. Papadopoulos, R. Gingrich, J. Casper, S. Yanovich, D. Weisdorf, et al.
Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation
Blood,
November 1, 2005;
106(9):
3308 - 3313.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Baron, M. B. Maris, B. M. Sandmaier, B. E. Storer, M. Sorror, R. Diaconescu, A. E. Woolfrey, T. R. Chauncey, M. E.D. Flowers, M. Mielcarek, et al.
Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning
J. Clin. Oncol.,
March 20, 2005;
23(9):
1993 - 2003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Iwasaki
Recent Advances in the Treatment of Graft-Versus-Host Disease
Clin. Med. Res.,
November 1, 2004;
2(4):
243 - 252.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Antin, H. T. Kim, C. Cutler, V. T. Ho, S. J. Lee, D. B. Miklos, E. P. Hochberg, C. J. Wu, E. P. Alyea, and R. J. Soiffer
Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation
Blood,
September 1, 2003;
102(5):
1601 - 1605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.C. Taussig, A.J. Davies, J.D. Cavenagh, H. Oakervee, D. Syndercombe-Court, S. Kelsey, J.A.L. Amess, A.Z.S. Rohatiner, T.A. Lister, and M.J. Barnett
Durable Remissions of Myelodysplastic Syndrome and Acute Myeloid Leukemia After Reduced-Intensity Allografting
J. Clin. Oncol.,
August 15, 2003;
21(16):
3060 - 3065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. D. Seaton, R. M. Szydlo, E. Kanfer, J. F. Apperley, and R. Russell-Jones
Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host disease and analysis of predictors of response
Blood,
August 15, 2003;
102(4):
1217 - 1223.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Grewal, J. N. Barker, S. M. Davies, and J. E. Wagner
Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood?
Blood,
June 1, 2003;
101(11):
4233 - 4244.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Deeg, B. Storer, J. T. Slattery, C. Anasetti, K. C. Doney, J. A. Hansen, H.-P. Kiem, P. J. Martin, E. Petersdorf, J. P. Radich, et al.
Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome
Blood,
July 30, 2002;
100(4):
1201 - 1207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. A. Tabbara, K. Zimmerman, C. Morgan, and Z. Nahleh
Allogeneic Hematopoietic Stem Cell Transplantation: Complications and Results
Arch Intern Med,
July 22, 2002;
162(14):
1558 - 1566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mehta, S. Singhal, C. Cutler, and J. H. Antin
Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell Transplantation: A Little Methotrexate Goes a Long Way
J. Clin. Oncol.,
January 15, 2002;
20(2):
603 - 606.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. T. Ho and R. J. Soiffer
The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation
Blood,
December 1, 2001;
98(12):
3192 - 3204.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Przepiorka, P. Anderlini, R. Saliba, K. Cleary, R. Mehra, I. Khouri, Y. O. Huh, S. Giralt, I. Braunschweig, K. van Besien, et al.
Chronic graft-versus-host disease after allogeneic blood stem cell transplantation
Blood,
September 15, 2001;
98(6):
1695 - 1700.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. McSweeney, D. Niederwieser, J. A. Shizuru, B. M. Sandmaier, A. J. Molina, D. G. Maloney, T. R. Chauncey, T. A. Gooley, U. Hegenbart, R. A. Nash, et al.
Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects
Blood,
June 1, 2001;
97(11):
3390 - 3400.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. K. Waller, H. Rosenthal, T. W. Jones, J. Peel, S. Lonial, A. Langston, I. Redei, I. Jurickova, and M. W. Boyer
Larger numbers of CD4bright dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation
Blood,
May 15, 2001;
97(10):
2948 - 2956.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Nash, J. H. Antin, C. Karanes, J. W. Fay, B. R. Avalos, A. M. Yeager, D. Przepiorka, S. Davies, F. B. Petersen, P. Bartels, et al.
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
Blood,
September 15, 2000;
96(6):
2062 - 2068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Przepiorka, T. L. Smith, J. Folloder, I. Khouri, N. T. Ueno, R. Mehra, M. Korbling, Y. O. Huh, S. Giralt, J. Gajewski, et al.
Risk Factors for Acute Graft-Versus-Host Disease After Allogeneic Blood Stem Cell Transplantation
Blood,
August 15, 1999;
94(4):
1465 - 1470.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract