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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2191-2195
Prospective Randomized Multicenter Study Comparing Cyclosporin Alone
Versus the Combination of Antithymocyte Globulin and Cyclosporin for
Treatment of Patients With Nonsevere Aplastic Anemia: A Report From the
European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia
Working Party
By
J. Marsh,
H. Schrezenmeier,
P. Marin,
O. Ilhan,
P. Ljungman,
S. McCann,
G. Socie,
A. Tichelli,
J. Passweg,
J. Hows,
A. Raghavachar,
A. Locasciulli, and
A. Bacigalupo on behalf of the EBMT Severe
Aplastic Anaemia Working Party
From the Department of Haematology, St George's Hospital Medical
School, London, UK.
 |
ABSTRACT |
We report the results of the first prospective randomized
multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a
neutrophil count of at least 0.5 × 109/L and transfusion
dependence. Patients were randomized to receive cyclosporin (CSA) alone
or the combination of horse antithymocyte globulin
([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint
of the study was the hematologic response at 6 months. One hundred
fifteen patients were randomized and assessable with a median follow-up
period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA
group, the percentage of complete and partial responders was 23% and
23%, respectively, for an overall response rate of 46%. A
significantly higher overall response rate of 74% was found in the ATG
and CSA group, with 57% complete and 17% partial responders
(P = .02). Compared with CSA alone, the combination of ATG
and CSA resulted in a significantly higher median hemoglobin level and
platelet count at 6 months. Fewer patients required a second course of
treatment before 6 months due to a nonresponse. In the CSA group, 15 of
61 (25%) patients required a course of ATG before 6 months because of
disease progression, compared with only 3 of 54 (6%) in the ATG and
CSA group. The survival probabilities for the two groups were
comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which
excluded patients requiring second treatment because of nonresponse,
death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P = .001). We conclude that
the combination of ATG and CSA is superior to CSA alone in terms of the
hematologic response, the quality of response, and early mortality, and
a second course of immunosuppression is less frequently required.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE OUTCOME of patients with severe
aplastic anemia (AA) treated with immunosuppressive therapy or
allogeneic bone marrow transplantation (BMT) has improved with time. In
the early 1980s, antithymocyte globulin (ATG) was shown to
significantly improve the survival of patients with AA in comparison to
supportive care alone.1 It was initially uncertain whether
there was any benefit to be gained by combining androgens with ATG, but
a prospective randomized study later demonstrated that androgens
improved the response rate to ATG therapy, although they had no impact
on survival.2 Furthermore, the virilizing side effects of
androgens were often unacceptable to female patients, in addition to
the known hepatotoxicity.
The addition of cyclosporin (CSA) to ATG treatment has also improved
the response rate, as demonstrated by Frickhofen et al3 in
a multicenter randomized study. Although there was a trend for improved
survival using the combination of ATG and CSA compared with ATG alone,
with longer follow-up evaluation of patients, the survival advantage
disappeared, since patients who did not respond to ATG alone could
achieve rescue by a second course of immunosuppression with ATG and
CSA.4 A direct comparison of ATG and CSA was reported by
Gluckman et al5 in a French multicenter randomized study.
At 3 months, if patients in either treatment arm showed no response to
ATG or CSA, they were switched (crossover) to the other therapy (ATG or
CSA). This study suggested that CSA alone may be as effective as ATG,
but the number of responses in either study arm was low and the early
crossover precluded further analysis of the response. A potential
practical advantage of CSA alone would be that it can be administered
to outpatients, reducing the cost of treatment. In contrast, hospital
admission is required for ATG treatment.
The survival of patients with severe AA after immunosuppressive therapy
is determined largely by the absolute neutrophil count. Patients with a
neutrophil count >0.5 × 109/L have a significantly
better survival rate than patients with a neutrophil count <0.5 × 109/L.6,7 In a recent analysis by the European
Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia (SAA)
Working Party in 1,765 patients treated from 1974 to 1996,8
an even more striking difference in survival was found when comparing
neutrophil counts of greater or less than 0.2 × 109/L,
although single centers have failed to show any difference in the
survival of such patients.9,10
There have been no prospective randomized studies of immunosuppressive
treatment in patients with nonsevere AA (neutrophils  0.5 × 109/L and transfusion dependence). The
objective of this prospective randomized multicenter European study was
to determine whether CSA alone is as effective as the current best
treatment for severe AA, that is, the combination of ATG and CSA. The
main study outcome parameter is the response at 6 months, as it was
predicted that there would be no significant difference in the
short-term outcome in the absence of severe neutropenia
and with provision of intensive supportive care for both groups.
| |
SUBJECTS AND METHODS |
Patients.
This multicenter study was organized by the EBMT SAA Working Party and
involved 54 centers from eight countries. Eligibility criteria were as
follows: no specific prior treatment for the disease, a neutrophil
count of at least 0.5 × 109/L, hypocellular bone marrow,
and red blood cell and/or platelet transfusion dependence.
Patients were excluded if they had congenital AA, paroxysmal nocturnal
hemoglobinuria with evidence of significant hemolysis, a clonal
cytogenetic abnormality, and severe uncontrolled infection or
unexplained fever higher than 38°C. Consecutive patients meeting the
above criteria for nonsevere AA were randomized and treated, and no
patients were excluded from the analysis.
Treatment protocol.
Patients were randomized to receive either CSA alone or the combination
of ATG and CSA. CSA was administered orally from day +1 to day +180 at
a dose of 5 mg/kg/d in two divided doses, with subsequent adjustment
according to weekly whole-blood CSA and serum urea, creatinine, and
bilirubin levels. The aim was to maintain trough whole-blood CSA levels
between 75 and 200 ng/mL. CSA was continued in all patients, but if the
blood cell count continued to increase at 6 months, CSA was continued
at the therapeutic dose until the blood cell count plateaued, and then
the dose was reduced gradually to help prevent a relapse of the
aplasia. The rate of CSA dose reduction was decided by the individual
physician in charge. Horse ATG (Lymphoglobuline; Merieux, Lyon, France) was administered at a dose of 1.5 vials/10 kg/d for 5 days (equivalent to 15 mg/kg/d) as an intravenous infusion. For prevention of serum sickness, prednisolone 1 mg/kg/d was administered orally from day +5,
continued for 9 days, and then reduced to zero over 1 week.
Endpoint of study.
The endpoint of the study was the hematologic response at 6 months. A
complete response was defined as a neutrophil count >2.0 × 109/L, a platelet count >100 × 109/L, and
transfusion independence; a partial response was defined as a
neutrophil count >1.0 × 109/L, a platelet
count >30 × 109/L, and transfusion independence; and
patients who remained transfusion-dependent were classified as
nonresponders regardless of the neutrophil and platelet count.
Failure-free survival was defined as survival with response. Death,
nonresponse by 6 months, disease progression requiring a second course
of immunosuppressive treatment or a stem-cell transplant, and relapse
were considered treatment failures. Follow-up evaluation was continued
on these patients; however, they were excluded from the analysis of
hematologic response and failure-free survival.
Statistical methods and data analysis.
The study hypothesis was that there is no difference in the response
rates between the two treatment groups. It was estimated that the
required number of patients is 225 for each treatment arm to detect a
difference in the response rate of about 10% with an expected response
of 70% to 80%, with 95% confidence. Interim analyses were planned
for every 100 patients randomized in case one group showed an
unexpected significant difference in response, survival, and
failure-free survival compared with the other group. The outcome
parameters were the hematologic response and failure-free survival at 6 months after treatment, overall response, survival, and failure-free
survival. The chi-square test was used to compare categoric variables,
and the Mann-Whitney U test (nonparametric) or Student
t-test (parametric) were used to compare continuous variables.
The probability of response and survival was analyzed using the method
of Kaplan and Meier.11
Consent.
Informed written consent was obtained from all patients according to
established procedures at each center, and the study was approved by
the local hospital ethics committees.
| |
RESULTS |
Patient characteristics.
The study commenced in April 1993, and this interim analysis was
performed in March 1997, when 115 assessable patients were randomized.
Sixty-one patients were randomized to CSA therapy alone and 54 to ATG
and CSA. Patient characteristics are summarized in Table
1. Patients in the ATG and CSA group were
significantly younger (median age, 29 v 35 years,
P = .04) and had a lower median platelet count (15 v
20 × 109/L) compared with the CSA group. The median
follow-up period was similar, 343 days for the CSA group and 365 for
the ATG and CSA group, respectively.
Response.
A complete response to CSA alone was observed in 14 patients (23%) and
a partial response in 14 (23%), for an overall response rate of 46%
(28 of 61). In contrast, in the ATG and CSA group, 31 patients (57%)
had a complete response and 9 (17%) had a partial response for an
overall response rate of 74% (40 of 54) (Table 2). The difference in response between the
two groups was statistically significant (P = .02). At 6 months, patients in the ATG and CSA group had a significantly higher
median hemoglobin concentration of 11.8 g/dL as compared with 9.7 for
the CSA group (P = .03), and a strikingly higher median
platelet count of 84 × 109/L as compared with 29 × 109/L for the CSA group (P = .005). There was no
difference in the median neutrophil count between the two groups at 6 months. Figure 1 illustrates not only that
the probability of response at 6 months was higher in the ATG and CSA
group but also that these patients responded earlier than those
receiving CSA alone. Transfusion independence before 6 weeks was
observed in some patients in both treatment groups.
Significantly more patients in the CSA group had evidence of disease
progression before 6 months necessitating a second course of treatment
during this period. In the CSA group, 15 of 61 (25%) patients required
a second course of immunosuppression with ATG before 6 months, compared
with only three of 54 (6%) in the ATG and CSA group
(P = .005). A further 8 patients received an allogeneic stem-cell transplant before 6 months because of disease progression (5 in the ATG and CSA group and 3 in the CSA group). After censoring patients who received a second course of immunosuppression or a
stem-cell transplant before 6 months, the overall response rate between
the two groups remained significantly different, 87% for the ATG and
CSA group and 65% for the CSA group (P = .001) (Table 3).
The median interval from diagnosis to treatment was 28 days. There was
no significant difference between an interval of less than 28 days or
more than 28 days and the response (data not shown).
Survival and failure-free survival.
The overall probability of survival is 93% for the CSA group and 91%
for the ATG and CSA group (P = .5) with a median follow-up period of 343 days (range, 19 to 1,454) and 365 days (21 to 1,227), respectively (Fig 2). The probability of
failure-free survival was calculated by excluding not only deaths but
also cases requiring a second treatment for nonresponse to the first
course or for disease progression before 6 months, thus identifying
patients who are alive, transfusion-independent, completing 6 months
without crossover to a second course and/or responding to the
initial therapy, and not transplanted. There were 4 early deaths in the CSA group (2 infections, 1 hemorrhage, and 1 infection with hemorrhage) and 2 early deaths in the ATG and CSA group (both from infection). There were 2 late deaths in the ATG and CSA group (1 hemorrhage and 1 post-BMT) and 1 death in the CSA group (post-BMT). At 6 months, 49 of
54 patients (90%) in the ATG and CSA group were alive and
failure-free, compared with only 41 of 61 (67%) in the CSA group
(P = .001) (Table 2). The probability of failure-free survival at 1,454 days was 80% for the ATG and CSA group, compared with 51% for the CSA group (P = .0005) (Fig
3).
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| Fig 3.
Actuarial probability of failure-free survival following
treatment with CSA alone or CSA + ATG. Failure-free survival is
defined as survival with response. Death, nonresponse by 6 months,
disease progression requiring a second course of immunosuppressive
therapy or a stem-cell transplant, and relapse were considered
treatment failures.
|
|
Response to a second course of immunosuppression among nonresponders
at 6 months.
A total of 39 patients who failed to respond to either CSA alone or ATG
and CSA received a second course of immunosuppression with ATG, of whom
27 were in the CSA group and 12 in the ATG and CSA group. Nine of 27 (33%) patients in the CSA group responded to a second course of ATG,
and 6 of 12 (50%) in the ATG and CSA group responded to a second
course of ATG (either horse or rabbit ATG; Merieux). There was no
statistical difference in the response rate to the second course of
treatment between the two groups (P = .32).
Relapse and clonal disease.
To date, there have been no relapses, 2 cases of myelodysplasia (both
in the CSA group), no cases of acute myeloid leukemia, and 3 cases of
paroxysmal nocturnal hemoglobinuria (2 in the ATG and CSA group and 1 in the CSA group), but the follow-up period is too short to evaluate
the true risk of clonal evolution in this cohort of patients.
| |
DISCUSSION |
The results of this multicenter European study of nonsevere AA show
that compared with CSA alone, the combination of ATG and CSA results in
a significantly higher probability of hematologic response, an earlier
response, a significantly better quality of response, and fewer cases
of nonresponse and disease progression. The actuarial survival was
similar between the two groups (91% to 93%), but failure-free
survival was significantly higher in the ATG and CSA group (90%
v 67% in the CSA group). This reflects a larger proportion of
patients who failed to respond to CSA alone and a larger proportion who
showed evidence of disease progression before 6 months after CSA
therapy as compared with patients who received initial treatment with
ATG and CSA.
Since the actuarial survival of patients in the two groups is similar,
this study raises the question of whether an early response to
immunosuppression is important, because it was shown that patients who
fail to respond to CSA may respond later to ATG. Cost is a major factor
when considering the use of CSA alone as initial therapy. CSA can be
used for outpatients, thus avoiding inpatient hospital costs. Secondly,
if successful, it avoids the immediate and late side effects (serum
sickness) of ATG, in addition to the risk of early infective deaths
reported by several studies.2,5 However, the investigators
from one of these studies5 emphasize that if ATG is to be
administered to patients with AA, it should only be used by physicians
in centers who are familiar with the medication and its side effects.
Furthermore, in this study, there were four early infective deaths in
the CSA group, compared with only two in the ATG and CSA group,
suggesting no reduction in early mortality with CSA. A lower risk of
infective deaths is expected in patients with nonsevere AA versus
severe AA. The concern about delaying the use of ATG until after an
initial treatment with CSA is that patients would require a longer
period of transfusion support, which would increase the risk of HLA
alloimmunization antigens resulting in platelet transfusion
refractoriness.12,13 Sensitization to minor
histocompatibility antigens increases the risk of graft rejection after
HLA-identical sibling transplantation. Other potential risks include
transfusion-associated viral infection and, in the longer term,
transfusional hemosiderosis. The response rate to ATG as a secondary
therapy in this study appears to be lower than for ATG as an initial
therapy in previously reported studies,14,15 although a
larger number of patients would be required to confirm this trend.
Evidence of disease progression while the patient is on CSA therapy
would suggest a decreased chance of response to ATG
subsequently.8 Furthermore, we have demonstrated that
delaying ATG therapy after CSA does not compensate for the reduced
response, so we encourage the use of ATG combined with CSA as the
initial therapy for nonsevere AA.
It is possible that some of the early responses seen in both treatment
groups may have represented spontaneous recovery of the aplastic
anemia. In both groups, some patients became transfusion independent
before 6 weeks. Because it is unlikely that all these cases were caused
by spontaneous recovery, we suggest that this early transfusion
independence after immunosuppression may be a feature of AA patients
with nonsevere disease.
For patients with severe AA and who are ineligible for allogeneic BMT,
intensive immunosuppression is now recommended.9,10,16-18 In contrast, patients with nonsevere AA may not require such intensive immunosuppression and treatment with ATG alone, for example, may be
sufficient. This study did not examine the use of ATG alone, but this
could be evaluated in future studies. It has been suggested that two or
more courses of ATG may increase the risk of later clonal
disorders.19,20
Because of the significant difference in response rate at 6 months
between the two groups in this study, the study was closed at this
initial interim analysis stage according to the original study plan.
From this study we recommend that patients with nonsevere AA who are
transfusion dependent are treated with ATG and CSA to achieve an
earlier and higher chance of response. We believe it is important to
follow up this cohort of patients over a long period of time, not only
to assess later clonal disease and relapse but also to compare the
incidence of HLA alloimmunization and transfusional hemosiderosis
between the two groups.
At present, we conclude that there is not a good reason to use CSA
alone as the initial therapy for nonsevere AA, given the lower
response, poorer blood cell counts, and lack of reduction in early
mortality as compared with the combination of ATG and CSA.
| |
ACKNOWLEDGMENT |
We are indebted to physicians from the following centers who entered
patients into this study. Italy; P. Leoni, Ancona; D. de Mattia, Bari;
R. Bassan, Bergamo; C. Finelli, P. Rosito, Bologna; P. Coser, Bolzano; T. Izzi, F. Porta, Brescia; G. Broccia, Cagliari; A. Gallamini, Cuneo; A. Lippi, Firenze; A. Bacigalupo, P. Mori, M. Gobbi,
Genova; P. Foa, Milano; A. Locasciulli, E. Pogliania, Monza; L. Pinto,
B. Rotoli, Napoli; A. Gabbas, Nuoro; I. Majolino, Palermo; F. Locatelli, P. Allesandro, Pavia; P. di Bartolomeo, Pescara; F. Caracciolo, Pisa; P. Iacopino, Calabria; W. Arcese, G. de Rossi, Roma;
M. Carotenuto, S.G. Rotondo, P. Saracco, Torino; M. Baccarani, Udine;
G. Todeschini, Verona; D. Bona, Vicenza; United Kingdom: D. Milligan,
Birmingham; J. Hows, Bristol; S. McCann, I. Temperley, Dublin, Ireland;
F. Matthey, East Surrey; A. Parker, Edinburgh; M. Lewis, Kidderminster;
J. Marsh, E.C. Gordon-Smith, D. Samsom, E. Kanfer, A. Newland, London;
J. Keidan, Norfolk; T. Littlewood, Oxford; F. Booth, Reading; S. Rassam, Sidcup; S. Roath, Southampton; Germany: V. Schillin, A. Neubauer, Berlin; M. Burk, Dusseldorf; W. Heit, Essen-Werden; Sonnen,
Hamburg; Mengfelder, Homburg; Fischer, Karlsruhe; Hoffken, Jena; Wolf, Magdeburg; Lengfelder, Mannheim; H. Schrezenmeier, A. Raghavachar, Ulm;
Turkey: O. Ilhan, K. Halluk, Ankara; Sweden: P. Ljungman, Huddinge; F. Celsing, Stockholm; E. Forestier, Umea; I. Nilsson, Karlstad; Finland:
L. Volin, Helsinki; Spain: P. Marin, Barcelona; and The Netherlands: G. den Ottolander, Leiden.
| |
FOOTNOTES |
Submitted August 3, 1998; accepted November 17, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to J. Marsh, MD, Department of Haematology, St
George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE.
e-mail: jmarsh{at}sghms.ac.uk.
| |
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M. Teramura, A. Kimura, S. Iwase, Y. Yonemura, S. Nakao, A. Urabe, M. Omine, and H. Mizoguchi
Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan
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TOP
ABSTRACT
INTRODUCTION
