Blood, 15 December 2001, Vol. 98, No. 13, pp. 3868-3870
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
From the Division of Clinical Research, Fred Hutchinson
Cancer Research Center, and the Department of Medicine, University of
Washington, Seattle, Washington
 |
Abstract |
This study compared the incidence of clinical extensive chronic
graft-versus-host disease (GVHD), transplantation-related mortality,
survival, and relapse-free 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 = 0.76; 95% confidence interval,
0.48-1.21; P = .25). In addition, there were no
significant differences between the 2 groups in transplantation-related
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 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 µmol/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 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 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.
View larger version (21K):
[in this window]
[in a new window]
| 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.
|
|
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.
| |
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.
| |
Footnotes |
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.
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.
Reprints: Paul Martin, Fred Hutchinson Cancer Research
Center D2-100, PO Box 19024, Seattle, WA 98109-1024; e-mail:
pmartin{at}fhcrc.org.
| |
References |
1.
Sullivan KM.
Graft-versus-host disease. In:
Forman SJ,Blume KG,Thomas ED, eds.
Hematopoietic Cell Transplantation. Cambridge, MA: Blackwell Scientific Publications; 1999:515-536.
2.
Loughran TP, Sullivan K, Morton T, et al.
Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation.
Blood.
1990;76:228-234[Abstract/Free Full Text].
3.
Sullivan KM, Witherspoon RP, Storb R, et al.
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-versus-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
Blood.
1988;72:546-554[Abstract/Free Full Text].
4.
Witherspoon RP, Sullivan KM, Lum LG, et al.
Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years follow up.
Bone Marrow Transplant.
1988;3:425-435[Medline]
[Order article via Infotrieve].
5.
Sullivan KM, Storek J, Kopecky KJ, et al.
A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery.
Biol Blood Marrow Transplant.
1996;2:44-53[Medline]
[Order article via Infotrieve].
6.
Storb R, Deeg HJ, Whitehead J, et al.
Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.
New Engl J Med.
1986;314:729-735[Abstract].
7.
Storb R, Leisenring W, Anasetti C, et al.
Methotrexate and cyclosporine for graft-vs.-host disease prevention: what length of therapy with cyclosporine?
Biol Blood Marrow Transplant.
1997;3:194-201[Medline]
[Order article via Infotrieve].
8.
Ruutu T, Volin L, Elonen E.
Low incidence of severe acute and chronic graft-versus-host disease as a result of prolonged cyclosporine prophylaxis and early aggressive treatment with corticosteroids.
Transplant Proc.
1988;20:491-493[Medline]
[Order article via Infotrieve].
9.
Lönnqvist B, Aschan J, Ljungman P, Ringden O.
Long-term cyclosporin therapy may decrease the risk of chronic graft-versus-host disease.
Br J Haematol.
1990;74:547-548[Medline]
[Order article via Infotrieve].
10.
Bacigalupo A, Maiolino A, Van Lint MT, et al.
Cyclosporine A and chronic graft-versus-host disease.
Bone Marrow Transplant.
1990;6:341-344[Medline]
[Order article via Infotrieve].
11.
Sullivan KM, Shulman HM, Storb R, et al.
Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression.
Blood.
1981;57:267-276[Abstract/Free Full Text].
12.
Gooley TA, Leisenring W, Crowley J, Storer BE.
Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.
Stat Med.
1999;18:695-706[CrossRef][Medline]
[Order article via Infotrieve].
13.
Kaplan EL, Meier P.
Nonparametric estimation from incomplete observations.
J Am Stat Assoc.
1958;53:457-481[CrossRef].
14.
Wagner JL, Flowers MED, Longton G, Storb R, Schubert M, Sullivan KM.
The development of chronic graft-versus-host disease: an analysis of screening studies and the impact of corticosteroid use at 100 days after transplantation.
Bone Marrow Transplant.
1998;22:139-146[CrossRef][Medline]
[Order article via Infotrieve].
Top
Abstract
Introduction
