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Brief report
Administration of cyclosporine for 24 months compared with 6 months
for prevention of chronic graft-versus-host disease: a prospective
randomized clinical trial
Emin Kansu, Ted Gooley, Mary E. D. Flowers, Claudio Anasetti, H. Joachim Deeg, Richard A. Nash, Jean E. Sanders,
Robert P. Witherspoon, Frederick R. Appelbaum, Rainer Storb, and Paul J. Martin
This study compared the incidence of
clinical extensive chronic graft-versushost disease (GVHD), transplantationrelated mortality, survival, and relapsefree survival among recipients randomly
assigned to receive a 24-month or a
6-month course of cyclosporine prophylaxis after transplantation of allogeneic
marrow from an HLA-identical sibling or
alternative donor. Patients who did not
have clinical manifestations of chronic
GVHD on day 80 after transplantation
were eligible for the study if they previously had acute GVHD or if a skin biopsy
showed histologic evidence of chronic
GVHD. Clinical extensive chronic GVHD
developed in 35 of the 89 patients (39%) in
the 24-month group and 37 of the 73
patients (51%) in the 6-month group. The
hazard of developing chronic GVHD was
not significantly different in the 2 groups
(hazard ratio ⴝ 0.76; 95% confidence interval, 0.48-1.21; P ⴝ .25). In addition,
there were no significant differences between the 2 groups in transplantationrelated mortality, survival, or disease-free
survival. (Blood. 2001;98:3868-3870)
© 2001 by The American Society of Hematology
Introduction
Chronic graft-versus-host disease (GVHD) remains the principal
cause of late transplantation-related morbidity and mortality after
allogeneic marrow transplantation.1 Histologic evidence of GVHD
in the skin or lip mucosa and a history of acute GVHD have been
used to predict development of chronic GVHD in patients without
clinical manifestations of the disease by day 80 after transplantation.2 Administration of prednisone did not prevent development of
clinical manifestations in patients who had only histologic evidence of GVHD in the skin or lip by day 80.3 Likewise,
administration of thymic factors or immunoglobulin did not
prevent chronic GVHD.4,5
Standard GVHD prophylaxis with methotrexate (MTX) and
cyclosporine (CSP) involves a tapering of CSP doses after day 50
and discontinuation of CSP administration by day 180.6 With this
regimen, chronic GVHD tends to occur during the CSP tapering
and the ensuing 6 months after discontinuation.7 The hypothesis
that chronic GVHD might be prevented by extending administration of CSP beyond 6 months7 was supported by results from
single-arm studies.8-10 Here, we compared chronic GVHD, transplantation-related mortality, survival, and disease-free survival in
patients randomly assigned to receive a 6-month or 24-month
course of CSP prophylaxis.
Study design
Patients with aplastic anemia or any other nonmalignant disease, myelodysplasia, chronic myeloid leukemia in chronic phase, or hematologic malignant diseases in remission were eligible for this study between day 80 and
day 100 after they had undergone an allogeneic marrow transplantation if
From the Division of Clinical Research, Fred Hutchinson Cancer Research
Center, and the Department of Medicine, University of Washington, Seattle,
Washington
Submitted March 13, 2001; accepted August 9, 2001.
Supported by Public Health Service grants CA15704, HL36444, CA18221, and
CA18029 from the National Institutes of Health.
3868
they previously had acute GVHD or if a skin biopsy showed histological
evidence of subclinical GVHD. Patients were excluded if they had
manifestations of clinical extensive chronic GVHD, recurrent malignant
disease, serum creatinine levels above 177 ␮mol/L (2.0 mg/dL) or more
than twice the normal values, hypertension uncontrolled by medications, or
previous life-threatening toxicity due to CSP. Patients receiving at least 2
mg/kg of body weight of prednisone per day for treatment of acute GVHD
were not eligible. Patients receiving lower doses of prednisone were
eligible, and treatment was tapered to discontinuation within 6 to 8 weeks
after enrollment.
All patients gave written informed consent as approved by our institutional
review board before being randomly assigned to continue oral CSP prophylaxis
for either 6 or 24 months after transplantation. Randomization was stratified
according to patient age below 20 years or 20 years or higher, HLA-identical
sibling donor or alternative donor, previous presence or absence of acute GVHD,
current presence or absence of chronic GVHD on skin biopsy evaluation, and
current treatment with or without prednisone.
All patients were given CSP and MTX for GVHD prophylaxis.6 In
patients who did not have acute GVHD, the dose of oral CSP was tapered by
5%/week from a baseline dose of 12.5 mg/kg per day, beginning on day 50
after transplantation. In the 6-month treatment arm, CSP prophylaxis ended
on day 180. In the 24-month arm, the dose of CSP was maintained at 6.0
mg/kg per day from day 120 through day 540, reduced to 5.5 mg/kg per day
from day 541 through 569, and then tapered by 5%/week through day 720.
A total of 169 patients were randomly assigned—90 to the 24-month
group and 79 to the 6-month group. An audit disclosed that one patient
assigned to the 24-month group was not eligible because of recurrent
malignant disease. Informed consent could not be documented for 3
patients assigned to the 6-month group. Three other patients assigned to the
6-month group were not eligible because of clinical extensive chronic
GVHD at the time of random assignment (one patient) or because they had
received a peripheral blood stem cell transplantation instead of a marrow
Reprints: Paul Martin, Fred Hutchinson Cancer Research Center D2-100, PO
Box 19024, Seattle, WA 98109-1024; e-mail: [email protected].
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2001 by The American Society of Hematology
BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
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BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
EXTENDED CYCLOSPORINE TO PREVENT CHRONIC GVHD
transplantation (2 patients). Demographic characteristics of the 162 remaining patients were similar in the 2 treatment arms (Table 1).
The diagnosis and grading of chronic GVHD were established according to
clinical and pathological criteria.11 The assigned schedule of CSP administration
was abandoned when clinical extensive chronic GVHD developed in a patient,
and treatment was prescribed according to available protocols.
The primary end point of this study was the incidence of clinical
extensive chronic GVHD, with follow-up to either the time of recurrent
malignant disease or date of last contact. Secondary end points were
transplantation-related mortality, overall survival, and survival without
recurrent malignant disease. A sample size of 80 patients in each treatment
arm was planned to provide 90% power for detecting a decrease in the
incidence of clinical extensive chronic GVHD from 70% in the 6-month
arm2 to 45% in the 24-month arm. Cumulative incidence rates were used to
estimate the probabilities of chronic GVHD and transplantation-related
mortality.12 The Kaplan-Meier method was used to estimate overall and
disease-free survival.13 A log rank test was used to compare hazards, and
2-sided P values below .05 were considered to represent statistical
significance. The minimum follow-up period among surviving patients
without chronic GVHD at the time of analysis was 2.1 years.
Results and discussion
Results are summarized in Figure 1. Clinical extensive chronic
GVHD developed in 35 of the 89 patients randomly assigned to the
24-month group, for a cumulative incidence of 39% (95% confidence interval [CI], 29%-49%) at 3 years after transplantation. In
the 6-month group, clinical extensive chronic GVHD developed in
37 of the 73 patients, for a cumulative incidence of 51% (95% CI,
39%-62%) at 3 years after transplantation. The hazard ratio (HR)
for clinical extensive chronic GVHD in the 24-month group
compared with the 6-month group was 0.76 (95% CI, 0.48-1.21;
P ⫽ .25). In 7 patients in the 24-month group and 6 in the 6-month
group, clinical extensive chronic GVHD developed before any
differences in administration of CSP began on day 120 after
transplantation. The HR for clinical extensive chronic GVHD after
Table 1. Patient characteristics
Duration of CSP prophylaxis
6 months
(n ⫽ 73)
24 months
(n ⫽ 89)
Less than 20 years
15 (21)
12 (13)
20 years or older
58 (79)
77 (87)
Female/female
14 (19)
18 (20)
Female/male
14 (19)
19 (21)
Male/female
22 (30)
19 (21)
Male/male
23 (32)
33 (37)
HLA-identical sibling
29 (40)
39 (44)
Other
44 (60)
50 (56)
Characteristic
Patient age
Donor/recipient sex
Donor type
History of grades II-III GVHD
No
17 (23)
22 (25)
Yes
56 (77)
67 (75)
Negative
27 (37)
34 (38)
Positive
46 (63)
55 (62)
Skin biopsy results*
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Figure 1. Results showing that outcomes were similar in patients who received
24 months of cyclosporine prophylaxis (bolded line) and in those given 6
months of such prophylaxis (thin line). Tic marks indicate the end of follow-up in
surviving patients. No new cases of chronic GVHD were diagnosed more than 4
years after transplantation.
day 120 among the 149 remaining patients was 0.72 (95% CI,
0.43-1.20; P ⫽ .21). Fifteen patients in the 24-month group
discontinued treatment with CSP 2 to 18 months (median, 12
months) earlier than prescribed by the protocol. Chronic GVHD
developed in only 2 of these patients.
Sixteen patients in the 24-month group and 13 in the 6-month
group died. Infections and recurrent malignant disease were the
most common causes of death. The cumulative incidence of
transplantation-related mortality at 3 years was 7% in the 24-month
group and 8% in the 6-month group; the hazard was not significantly different in the 2 groups (HR ⫽ 1.1; 95% CI, 0.4-3.2;
P ⫽ .83). Overall survival at 3 years was 88% in the 24-month
group and 84% in the 6-month group, and the risk of death was
similar (HR ⫽ 1.0; 95% CI, 0.5-2.1; P ⫽ .99). The rate of survival
without recurrent malignant disease at 3 years was 77% in the
24-month group and 79% in the 6-month group. The risk of failure
to survive without recurrent disease was similar in the 2 groups
(HR ⫽ 1.1; 95% CI, 0.6-2.0; P ⫽ .74).
The incidence of chronic GVHD in this study was lower than
the 69% incidence among patients with positive results on a skin
biopsy assessment or a previous history of acute GVHD described
by Loughran et al.2 Among the patients studied by Wagner et al,14
however, we found a 40% incidence of chronic GVHD among
those who met the entry criteria for the current study (unpublished
data, February 2001). Despite careful analysis, reasons for the
decreased incidence of chronic GVHD in this study compared with
our earlier experience2 were not readily apparent.
In conclusion, this randomized clinical trial did not show any
significant advantage for extended CSP prophylaxis in reducing the
incidence of clinical chronic GVHD or improving survival after
allogeneic marrow transplantation. These results do not support the
suggestion derived from earlier single-arm studies that prolonged
administration of CSP might decrease the risk of chronic GVHD.8-10
More effective approaches are needed to prevent chronic GVHD
after allogeneic hematopoietic stem cell transplantation.
Treatment with prednisone*
No
8 (11)
7 (8)
Yes
65 (89)
82 (92)
Values are numbers (percentages).
CSP indicates cyclosporine; GVHD, graft-versus-host disease.
*At time of enrollment.
Acknowledgments
We thank the physicians and nurses who cared for the patients and
Aurora Brandvold, RN, and Judy Campbell, RN, for assistance
with data collection and data management.
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3870
KANSU et al
BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
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From www.bloodjournal.org by guest on June 11, 2017. For personal use only.
2001 98: 3868-3870
doi:10.1182/blood.V98.13.3868
Administration of cyclosporine for 24 months compared with 6 months for
prevention of chronic graft-versus-host disease: a prospective randomized
clinical trial
Emin Kansu, Ted Gooley, Mary E. D. Flowers, Claudio Anasetti, H. Joachim Deeg, Richard A. Nash, Jean E.
Sanders, Robert P. Witherspoon, Frederick R. Appelbaum, Rainer Storb and Paul J. Martin
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