Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1194-1196
CORRESPONDENCE
 |
To the Editor: |
Cyclosporine (CSP) or CSP plus methylprednisolone for
graft-versus-host-disease prophylaxis in patients with high-risk
lymphohemopoietic malignancies: long-term follow-up of a randomized
trial
Several randomized trials of
graft-versus-host-disease (GVHD) prophylaxis have included
methylprednisolone (MP),1-4 but in those studies MP was
administered in both study arms in combination with other agents. A
trial reported from this institution compared the effect of a
combination of methotrexate (MTX) plus cyclosporine (CSP) with the
3-drug combination MTX plus CSP plus MP and failed to show an overall
advantage of the addition of MP.5 The effects of the
addition of MP to a standard regimen of CSP had never been studied in a
randomized trial. In the early 1990s we conducted such a trial
comparing CSP as a single agent to CSP plus MP as GVHD prophylaxis. The
hypothesis was that the incidence of GVHD would be lower with the drug
combination, but there was also concern that the addition of MP might
increase the risk of infections6 and other
posttransplantation complications. Because of continued interest in the
role of MP for GVHD prophylaxis, we thought it would be important to
provide long-term follow-up on our study.
The study involved 122 patients with advanced
lymphohemopoietic malignancies who were considered to be at high risk
for posttransplantation complications and relapse.7 All
patients received marrow from HLA-identical sibling donors. Patient and transplantation
characteristics are summarized in Table 1.
Daily CSP was
started on day 
1 (5 mg/kg/d IV) and given at gradually reduced
doses until day 180. MP was started on day +7 at 0.5 mg/kg/d,
increased to 1 mg/kg/d on day 15, started on a taper schedule on day
29, and discontinued on day 72. In the initial publication, we reported
incidence rates of acute GVHD grades II-IV of 73% and 60% for
patients given CSP and CSP plus MP, respectively (P = .01).
Chronic GVHD, however, was more frequent among patients who received
CSP plus MP (44% vs 21%; P = .02). The conditional
probabilities of developing chronic GVHD were 94% and 51% for
patients receiving CSP plus MP or CSP, respectively (P = .03). There was a suggestion that the risk of relapse
was lower in patients who received CSP plus MP (P = .10).
While early overall survival did not differ between the 2 groups
(P = .44), there was a trend toward better relapse-free
survival in patients on CSP plus MP (P = .07). There was no
significant difference in the incidence of early posttransplantation
infections between both groups.
The minimum follow-up for surviving patients is now more than 3.6 years
(median 6.1; maximum 8.0). The probability for overall survival is 23%
among patients randomized to CSP prophylaxis and 26% among patients
who received CSP plus MP. Among patients who received CSP alone, 17 relapsed 42-657 (median 81) days after transplantation, compared with
15 patients on CSP plus MP, 57-1343 (median 217) days after
transplantation, for cumulative incidences of relapse of 28% and 24%
for the 2 respective groups (P = .19). Currently, 12 patients
in the CSP arm are surviving in remission (20%), compared with 16 patients (26%) in the CSP plus MP arm (P = .11) (Figure
1).
View larger version (12K):
[in this window]
[in a new window]
|
Leukemia-free survival in patients receiving GVHD prophylaxis
with CSP alone or with CSP plus MP. P = .11.
|
|
At the time of last contact, the Karnofsky performance scores were
80-100 (median 100) and 60-100 (median 100) for the CSP-treated and the
CSP-plus-MP-treated patients, respectively. One patient in the CSP arm
still requires immunosuppressive therapy, compared with 4 patients who
had received CSP-plus-MP prophylaxis. One patient in the CSP arm and 4 in the CSP-plus-MP arm developed chronic pulmonary disease. Three
patients in the CSP arm developed aseptic necrosis (involving 1-4 joints), requiring joint replacement surgery in 2, compared
with 5 patients (involving 1-3 joints) in the CSP-plus-MP arm,
requiring replacement surgery in 2.
Thus long-term observations in this randomized trial fail to show any
significant advantage to the addition of MP to CSP as GVHD
prophylaxis. Although there was a somewhat lower incidence of acute
GVHD (accounted for entirely by skin involvement7) in
patients who received the drug combination, the cumulative incidence of
chronic GVHD was significantly increased. Earlier trends toward a
reduced incidence of relapse and better relapse-free survival with the
drug combination have diminished since our initial report, and neither
difference is significant. At the same time, however, the lowest
current Karnofsky scores were seen among patients who had received CSP
plus MP, and there is a suggestion that more patients in this cohort
have developed complications such as aseptic necrosis of the bone and
chronic pulmonary disease and have required immunosuppressive therapy
for a longer duration.
Very few patients enrolled in this trial were able to avoid the use of
MP completely since MP was generally given as initial therapy when GVHD
developed. But considering the overall course of these patients, the
probability of developing delayed complications, and their current
performance status, there is no basis on which to recommend MP plus CSP
as a GVHD prophylactic regimen. Although these reuslts do not exclude
the possibility that MP may be beneficial when combined with other
drugs, data to support such a claim are lacking.
H. Joachim Deeg
Mary E. D. Flowers
Wendy Leisenring
Frederick R. Appelbaum
Paul J. Martin
Rainer F. Storb
Fred Hutchinson Cancer Research Center
University of
Washington
Seattle, WA
| |
References |
1.
Forman SJ, Blume KG, Krance RA, et al.
A prospective randomized study of acute graft-v-host disease in 107 patients with leukemia: methotrexate/ prednisone v cyclosporine A/prednisone.
Transplant Proc.
1987;19:26052607.
2.
Santos GW, Tutschka PJ, Brookmeyer R, et al.
Cyclosporine plus methylprednisolone versus cyclophosphamide plus methylprednisolone as prophylaxis for graft-versus-host disease: a randomized double-blind study in patients undergoing allogeneic marrow transplantation.
Clin Transplant.
1987;1:21-28.
3.
Chao NJ, Schmidt GM, Niland JC, et al.
Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease.
N Engl J Med.
1993;329:1225-1230[Abstract/Free Full Text].
4.
Ross M, Schmidt GM, Niland JC, et al.
Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host disease and long-term survival.
Biol Blood Marrow Transplant.
1999;5:285-291[Medline]
[Order article via Infotrieve].
5.
Storb R, Pepe M, Anasetti C, et al.
What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?
Blood.
1990;76:1037-1045[Abstract/Free Full Text].
6.
Sayer HG, Longton G, Bowden R, Pepe M, Storb R.
Increased risk of infection in marrow transplant patients given methylprednisolone for graft-versus-host disease prevention.
Blood.
1994;84:1328-1332[Abstract/Free Full Text].
7.
Deeg HJ, Lin D, Leisenring W, et al.
Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial.
Blood.
1997;89:3880-3887[Abstract/Free Full Text]
