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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 68-75
Treatment of Anemia in Myelodysplastic Syndromes
With Granulocyte Colony-Stimulating Factor Plus Erythropoietin:
Results From a Randomized Phase II Study and Long-Term Follow-Up
of 71 Patients
By
Eva Hellström-Lindberg,
Tomas Ahlgren,
Yves Beguin,
Magnus Carlsson,
Jan Carneskog,
Inger Marie Dahl,
Ingunn Dybedal,
Gunnar Grimfors,
Lena Kanter-Lewensohn,
Olle Linder,
Michaela Luthman,
Eva Löfvenberg,
Herman Nilsson-Ehle,
Jan Samuelsson,
Jon-Magnus Tangen,
Ingemar Winqvist,
Gunnar Öberg,
Anders Österborg, and
Åke Öst
From the Department of Hematology, Huddinge University Hospital,
Huddinge, Sweden; Department of Pathology, Karolinska University
Hospital, Stockholm, Sweden; Department of Hematology, University of
Liège, Liège, Belgium; The Scandinavian MDS Group, Sweden
and Norway.
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ABSTRACT |
Treatment with erythropoietin (epo) may improve the anemia of
myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of
granulocyte colony-stimulating factor (G-CSF) and epo may increase this
response rate. In the present phase II study, patients with MDS and
anemia were randomized to treatment with G-CSF + epo according to one
of two alternatives; arm A starting with G-CSF for 4 weeks followed by
the combination for 12 weeks, and arm B starting with epo for 8 weeks
followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts
[RARS], and 27 refractory anemia with excess blasts
[RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The
overall response rate to G-CSF + epo was 38%, which is identical to
that in our previous study. The response rates for patients with RA,
RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates
were identical in the two treatment groups indicating that an initial
treatment with G-CSF was not neccessary for a response to the
combination. Nine patients in arm B showed a response to the combined
treatment, but only three of these responded to epo alone. This
suggests a synergistic effect in vivo by G-CSF + epo. A long-term
follow-up was made on 71 evaluable patients from both the present and
the preceding Scandinavian study on G-CSF + epo. Median survival was
26 months, and the overall risk of leukemic transformation during a
median follow-up of 43 months was 28%. Twenty patients entered
long-term maintenance treatment and showed a median duration of
response of 24 months.The international prognostic scoring system
(IPSS) was effective to predict survival, leukemic transformation, and
to a lesser extent, duration of response, but had no impact on primary
response rates.
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INTRODUCTION |
APPROXIMATELY 90% of patients with
myelodysplastic syndromes (MDS) present with anemia at diagnosis and
the majority of the patients develop with time a requirement for
transfusions of packed red blood cells (RBC).1 In low-risk
MDS, the anemia is often the only or major clinical problem and may
give rise to significant morbidity.2 Quality of life is
reduced due to the low hemoglobin level and in older patients,
conditions such as congestive heart failure and angina pectoris are
often aggravated. Moreover, repeated transfusions may with time cause
secondary hemochromatosis.
The cytopenia in MDS may in some cases be ameliorated or improved by
treatment with hematopoietic growth factors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) are
relatively effective in increasing the number of
neutrophils,3-6 but have in randomized studies failed to
show a positive effect on survival. Moreover, both drugs have
demonstrated an overall negative effect on the platelet
counts.7,8 The risk for leukemic transformation did not
seem to be changed in actively treated patients. Erythropoietin (epo)
is a potent stimulator of normal erythropoiesis and may also improve
the anemia in patients with MDS.9-11 The efficacy of epo
alone is relatively low, around 20%, and mainly confined to patients
without the need for pretreatment transfusion.12 In a
recent meta-analysis the response rate in patients with ring
sideroblastic anemia (RARS), who generally show a relatively good
median survival, was only 8%, while it was 21% in patients with
refractory anemia (RA) and refractory anemia with excess blasts
(RAEB).12 Other predictors of response were absence of the
need for an initial transfusion and a serum epo level of <200 U/L.
Epo in combination with several other early-acting or myeloid cytokines
has shown synergistic effects on erythropoiesis in vitro.13,14 The combination of G-CSF and epo has been
administered in five clinical studies aiming at improving the anemia in
MDS. These studies have mainly comprised patients with RA, RARS, and RAEB. Two of the studies15,16 showed response rates of 42% and 38%, respectively, which suggested that the response rate was
better than with epo alone. Recently, Negrin et al17
published additional data from the American study, showing that around
50% of the patients with a response to the combination therapy lost their response when G-CSF was withdrawn, and some of these patients also regained a response when G-CSF was reintroduced. This strongly supports the hypothesis of a synergistic effect in vivo of G-CSF and
epo.
The present study was designed as a randomized phase II trial to allow
an unbiased selection of patients to one of two treatment alternatives.
It had the following aims: to try to verify the response rate from the
first Scandinavian study16 in an independant cohort of
patients with MDS, to study whether a need for priming with G-CSF
before epo was necessary, to study whether in vivo synergy between
G-CSF and epo on erythroid response could be proven, and finally to
study duration of response and long-term outcome. The answers to the
first three questions were given by the results from the present study,
while the fourth was approached using data from both the first and the
second Scandinavian study.
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MATERIALS AND METHODS |
Patients.
Patients in the randomized study were included from October 1992 to
January 1995. All participating centers used uniform diagnostic criteria18 and the diagnosis was confirmed with two bone
marrow samples over a period of at least 2 months. Disease duration was calculated from the date of the confirmatory bone marrow sample. Central pathologic review of bone marrow samples before the start of
treatment and at the end of the study was performed by Chief Pathologist, Dr Å. Öst and copathologist, Dr L. Kanter-Lewensohn. All patients signed consent forms and
the studies followed guidelines of the investigation review boards of
Sweden and Norway.
Inclusion criteria were diagnosis of RA, RARS, or RAEB with either
hemoglobin levels <100 g/L in combination with symptoms of anemia or
transfusion-dependent anemia. Patients with active ongoing bleeding or
transfusion-dependent thrombocytopenia were excluded from the trial.
The long-term follow-up included in addition all evaluable patients
from the first Scandinavian study, which has been previously
described.16
Treatment.
Patients were randomized to one of two alternatives; arm A started with
G-CSF (filgrastim; Roche Pharmaceutical, Stockholm, Sweden) for 4 weeks
and continued with the combination of G-CSF + epo (erythropoietin beta;
Boehringer Mannheim, Stockholm, Sweden) for 12 weeks; arm B started
with epo for 8 weeks and continued with the combination for 10 weeks.
G-CSF and epo were self-administered subcutaneously (SC) and given
daily. Treatment was started at the lowest dose and dose escalation was
performed every 2 weeks, if necessary. In contrast to the previous
Scandinavian study, doses were fixed and not given per kilogram body
weight. Three dose levels of G-CSF (30 to 75 to 150 µg/d, SC) and two
dose levels of epo (5,000 to 10 000 U/d) were used. A patient was
considered evaluable for a response to G-CSF and epo if the combination
was given for 6 weeks or more.
Sampling.
Baseline hematologic parameters, lactate dehydrogenase, serum ferritin,
serum epo, and soluble transferrin receptor were analyzed before and
after treatment. Serum epo and transferrin receptor levels (serum tfr)
were analyzed according to methods described by Wide et
al19 and Beguin et al.20 Bone marrow sampling
was performed before and after treatment and a cytogenetic analysis was
made before treatment in all patients and after treatment in nine of
these patients. The international prognostic scoring system (IPSS2) was used and a score was estimated for each patient.
Response criteria.
A complete erythroid response was defined as an increase in hemoglobin
to at least 115 g/L. A partial response (PR) was defined as an increase
in hemoglobin with 15 g/L or more in patients with nontransfused anemia
and a 100% reduction of transfusion need in combination with stable
hemoglobin level for  4 weeks in those with pretreatment transfusion
need. The aim of the G-CSF treatment was to obtain a neutrophil count
of 6 to 10 × 109/L and values within this range were
considered a complete response (CR). In patients who did not reach this
range, the neutrophil counts were considered as PRs (3 to 6 × 109/L), minor responses (1 to 3 × 109/L),
or no response (<1 × 109/L).
Maintenance treatment and long-term follow-up.
Twenty-one evaluable patients were included in the first Scandinavian
study on G-CSF + epo in MDS between November 1990 and 1992.16 Inclusion criteria were identical with those in the present study. A follow-up with regard to duration of response, survival, and progression to acute leukemia from start of treatment was
made on these 21 patients and the 50 evaluable patients from the
present study by the first of January 1997. Patients in the follow-up
analysis were thus included from November 1990 to January 1995, and the
median follow-up from start of treatment was 43 months. All patients
with an erythroid response in the second study were offered maintenance
treatment with G-CSF and epo, while maintenance treatment in the first
study was given on an individual basis.
Statistical analysis.
Student's t-test, Mann-Whitney U-test, and analysis of
variance (ANOVA) were used for comparison of continuous variables, whenever appropriate.  2 analysis was used to compare
categories. Kaplan-Meyer plots were used to describe survival,
evolution to acute myeloid leukemia (AML), and duration of response.
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RESULTS |
Patient description.
Fifty-six patients with a diagnosis of MDS were included in the study;
43 from Sweden and 13 from Norway. There were 30 men and 26 women. Median age was 69 years with a range from 48 to 87 years. Twenty-eight patients were randomized to each arm. Four patients
were withdrawals; two developed acute myeloid leukemia during the
interval between randomization and start of treatment, one patient was
diagnosed with AML within 1 week from start of treatment (arm B), and
one patient (arm B) was diagnosed as having pyoderma gangrenosum after
4 weeks of combined treatment. Two patients were dropouts; one
experienced a deterioration of a previously known depression within 2 weeks and refused further treatment and another one, living far from
the hospital, refused to come to visits. Thus, 50 patients (26 men)
were evaluable for a response to treatment and clinical characteristics
of these patients are shown in Table 1. The
median age in this group was 69.5 years (range, 48 to 87). Ten of these
patients had RA, 13 RARS, and 27 RAEB. Fifteen patients had stable
anemia and 35 were transfusion-dependent. The degree of transfusion
need (units per month) was estimated over a period of 6 months in those
with a disease duration over 6 months. In the rest, the minimum time
for observation of transfusion need was 3 months. Each patient was
transfused at the same hemoglobin level during the course of the study,
but there was an interindividual variation between patients. Iron stain
was positive in all patients. Serum creatinine was normal in all but
three patients; one responder had a serum creatinine of 8% above the
upper normal limit and two nonresponders had increases of 10% and
32%, respectively. A cytogenetic analysis was done in 46 of the
patients, 24 had a normal karyotype and 22 showed aberrations. Seven
patients had deletion 5q-, with six as single abnormality. Ten patients
had poor prognosis chromosomal patterns according to the risk score described by Greenberg et al.2 There were 46 patients
evaluable for a IPSS score. Eleven had a low score, 19 an
intermediate-1 score, 14 an intermediate-2 score, and two a high score.
Three patients in arm B received only the epo and was thus not
evaluable for a response to the combination treatment. These three
patients were all nonresponders. Two of these, both with known heart
disease, died of heart failure after 8 weeks of treatment and one
patient showed disease progression and was withdrawn from treatment
after 10 weeks. Thus, 47 patients were evaluable for a response to
treatment with the combination of G-CSF and epo.
The absolute majority of the patients managed to self-administer, while
the rest needed support either with dosing or with dosing plus the
injections.
Clinical results of treatment.
Eighteen of the 47 fully evaluable patients (38%) showed an erythroid
response to treatment. Ten patients had a CR and eight a PR
(Table 2). All nonresponders were exposed
to the highest epo dose. Responses were not correlated to dose/body
weight (P > .5). Figure 1 shows
hemoglobin levels during treatment in patients with a CR. The response
rates in the different subgroups of MDS were 20%, 46%, and 37% for
RA, RARS, and RAEB, respectively. The overall difference in response
rate between subgroups was not statistically significant (Table 2).
Only one response was observed in seven patients with 5q-. Forty-eight
percent of the patients showed a complete neutrophil response to
treatment (increase in absolute neutrophil count [ANC] to 6 × 109/L) and 6% and 15%, respectively, showed partial and
minor reponses. Thirty-one percent of the patients were by definition
nonresponders to G-CSF; 9% showed a decrease in neutrophil counts
after treatment and 22% an increase less than 1 × 109/L. Responses were not correlated to dose/body weight
(P > .5). All evaluable patients who were nonresponders to
G-CSF received the highest dose. There were two patients with a minor
response to G-CSF (ANC after treatment <3 × 109/L)
who received only the low and intermediate G-CSF doses, respectively. Both of these patients showed increased thrombocytopenia during treatment, as well as an increase of bone marrow blasts at the final
evaluation. No erythroid responses were seen in the group with
decreased neutrophil counts after treatment, but otherwise the change
in ANC was not associated with an erythroid response to
treatment. Thirteen of 18 patients with an erythroid
response to treatment received 70,000 U of epo per week and five 35,000 U/week. One patient had a PR on the lower dose, but improved to a CR
when the epo dose was increased after the study period. There was no
correlation between the G-CSF dose and response to treatment; seven,
three, and eight patients received the low, middle, and high dose,
respectively.
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| Fig 1.
Hemoglobin levels in patients with a CR to treatment.
Before, before start of treatment; after, at the end of the study
period (16 weeks in arm A and 18 weeks in arm B); Max, maximum
hemoglobin level during the maintenance phase.
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There was no significant differences between the two randomization
arms, apart from a significantly higher proportion of male patients in
arm B (Table 1). The response rate was identical in the two arms. Nine
of 24 patients (38%) responded in arm A (6 CR, 3 PR) and 9 of 23 (39%) in arm B (4 CR, 5 PR). There was clear evidence of in vivo
synergy between G-CSF and epo in a proportion of the patients. Only 3 of the 9 responders in arm B showed any response to epo alone (1 CR, 2 PR). An erythroid response induced by the addition of G-CSF was thus
seen in 6 patients. Time from start of combination treatment to
response did not differ between the two arms, but the study was not
designed to analyze signs of early response.
Morphologic and laboratory parameters.
All differences in percentages are given as percentage points.
Treatment induced an overall increase in bone marrow cellularity (+7%
in nonresponders (P = .06) and +9% in responding patients (P = .06). The percentage of erythropoietic cells was generally reduced,  9% in nonresponding and 10% in responding
patients (P = .0009 and .001, respectively). The percentage of
bone marrow blasts was unchanged in both groups of patients
(1.3% in responders, P = .25 and +0.4% in
nonresponders, P = .8, Fig 1). Serum ferritin was
significantly increased in nonresponders (+582 µg/L, P = .0001), but slightly increased also in the responding patients (+214
µg/L, P = 0.10). Serum epo was increased after treatment in
all patients (responders +1,135 U/L, P = .22 and nonresponders
+867 U/L, P = .05). Mean corpuscular volume (MCV)
was slightly increased in responding patients (+4.2 fL, P = .07), while no change was seen in nonresponding patients (P = .53). Patients with RARS had higher serum soluble transferrin receptor
levels (tfr) than the other subgroups (P = .09 with ANOVA for
all three groups and P = .05 with t-test comparing RA
and RARS). There was also a weak inverse correlation (P = .049)
between serum epo and serum tfr. Tfr levels were reduced in
nonresponding patients (936 µg/L, P = .3), while it
was increased in the responding population (+2,582 µg/L). However, because there was a large heterogeneity in the tfr response, this difference was not significant (P = .34). Clonal evolution
during treatment was observed in three patients in whom posttreatment karyotypic analyses were performed. Two patients with normal karyotype pretreatment showed 6p deletion and add 18p in a small
proportion of the cells after treatment. One patient with 5q- before
treatment showed, in addition, +8 in a few cells after treatment.
Adverse events.
General side effects were few. Eight of the patients experienced minor
flu-like side effects, which in the majority of cases, diminished after
a couple of weeks. Irritation at local injection sites was observed in
a few patients. Two patients developed increased splenomegaly. One of
these had a long history of RARS with previous massive transfusion need
and secondary hemochromatosis. The other had also RARS, and in addition
to this, alcohol-induced liver cirrhosis and secondary splenomegaly.
There was no general tendency of disease progression in the patient
group, but three patients developed a significant increase in their
bone marrow blasts (Fig 2).
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| Fig 2.
Bone marrow blasts (%) before start of treatment and at
the end of the treatment period in (A) responding patients and (B) nonresponding patients.
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The most important side effect was an overall decrease in platelet
counts (Fig 3). This decrease was most
pronounced in nonresponding patients (-32 × 109/L,
P = .004) and was a problem in patients with preexisting
thrombocytopenia. Fourteen of 17 patients with pretreatment platelet
counts of < 100 × 109/L showed a further decrease
in their values after treatment. A reduction in platelet counts was
also observed in the responding group (Fig 3), but this was mainly due
to a decrease in patients with supranormal platelet levels before
treatment.
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| Fig 3.
Platelet count (×109/L) before start of
treatment and at the end of the treatment period in (A) responding
patients and (B) nonresponding patients.
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Variables associated with a response to treatment.
Table 3 shows continuous variables and
Table 4 category variables in responding
and nonresponding patients. Serum epo showed the strongest association
with a response to treatment. A cut-off level of 500 U/L was more
informative than 100 U/L. The degree of RBC transfusion need was
significantly associated with a response to treatment. The response
rate in patients with 2 U of RBC transfusions per month was 21.7%
compared with 50% in those with less than 2 U/month. Three variables
showed borderline significance; pretreatment platelet counts, MCV, and
soluble transferrin receptor levels were higher in responding patients.
The IPSS score showed no correlation with response rate. The response
rates in the low, intermediate-1, and intermediate-2 risk groups were
45%, 32%, and 43%, respectively. One of the two patients with a high
risk score responded to treatment.
Long-term follow up and duration of response.
Survival and time to progression to acute leukemia were calculated from
start of treatment. The median time from final diagnosis to start of
treatment was 6.5 months (range, 1 to 79 months). This variable had no
association at all with response to treatment (P > .5), response duration (P > .5), or survival (P > .5). However, the median time from diagnosis to treatment was shorter
in patients developing AML during or after treatment (4.5 v 8.5 months, P = .03). The median survival time of the 71 evaluable
patients in both studies was 26 months. Four patients were not scored
according to IPSS due to missing cytogenetic data and thus 67 patients
were given an IPSS score. Patients with a low risk score showed a
survival of 68% at 5 years, while the median survival of patients with intermediate-1 and intermediate-2 risk score was 27 and 14 months, respectively. There were only two patients with a high score. Time to
progression to AML was measured from start of treatment. Only one
patient progressed to overt AML during the treatment period, but four
additional patients developed AML within 2 months from the end of the
study. Altogether 19 patients (28%) progressed to AML during the
observation period with a median time from start of treatment to
progression of 11 months (range, 4 to 31 months). The frequency of
leukemic progression was 12% (2 of 17) in the low-risk group, 21% (6 of 28) in the intermediate-1 group, 45% (9 of 20) in the
intermediate-2 group, and 100% (2 of 2) in the high-risk group.
Twenty patients of altogether 26 responders (8 in the previous and 18 in the present study) were given maintenance treatment. Three of the
responding patients in the first study and three from the second study
did not enter the maintenance phase. In the second study, one patient
(PR) showed an increase of bone marrow blasts shortly after the first
study period and was withdrawn from treatment, and two patients did not
want to continue with the injections. The median time for duration of
response was 24 months (range, 4 to 60 months)
(Fig 4). Six of nine patients with RARS had
a response duration of 18 months. All patients showing a response
duration of 12 months had either a low or an intermediate-1 IPSS, but
there was no difference between these two groups.
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| Fig 4.
Duration of response in the 20 patients with primary
response who entered maintenance phase. Median duration of response 24 months.
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DISCUSSION |
Treatment of anemia in MDS has so far been relatively discouraging. Epo
alone shows an overall response rate of 20%, with only around 10%
responses in patients with preexisting transfusion need. Other
treatment alternatives, such as low-dose cytosine arabinoside has shown
an erythroid response rate of 30% or less, but with more side effects
than the cytokines.21,22 The erythroid response rate in our
study, 38%, seems to be relatively high in comparison with other
treatment alternatives for anemia in MDS and deserves further
consideration.
The present study confirmed the response rate, 38%, from the first
Scandinavian study. These results are in accordance with another
relatively large phase II study17 using the same drugs and
also with a study using G-CSF and epo in combination with all-trans-retinoic acid (ATRA).23
The reason why two smaller studies have failed to show similar results
is not clear, but might be due to the lower epo dose used in these two
studies and maybe also the very high G-CSF dose used in the Japanese
study.24,25
The second aim of the study was to investigate whether G-CSF treatment
was needed as a primer before the addition of epo to obtain an optimal
erythroid effect. This was appearantly not the case, as response rates
in the two randomization arms were identical. The consequence of this
result is that treatment with G-CSF and epo are started simultaneously
in the ongoing third Scandinavian trial.
Third, the study aimed at showing evidence for in vivo synergy between
G-CSF and epo. The response pattern in arm B, starting with epo, showed
that six of nine responders to combination treatment did not show any
response to epo alone. Most responses to epo have been reported to
occur within the first 8 weeks of treatment,11,26,27 and it
is therefore not likely that all of these six patients would have
developed a late response to epo as monotherapy. Moreover, some
patients who maintained their transfusion need during the epo phase
developed a pronounced increase in hemoglobin (hemoglobin 150 g/L)
after the addition of G-CSF (Fig 1). Another argument for a true
synergistic effect of the drugs was the high response rate, 46%, in
patients with RARS, as this MDS subgroup has shown a poor response to
epo alone.12 Recently, additional evidence for a
synergistic effect was published. Approximately 50% of the responders
to G-CSF + epo in the American study17 lost their erythroid
response when G-CSF was withdrawn. In our study, the synergistic effect
seemed to be most pronounced in patients with RARS, even if patients
with RAEB also seemed to respond relatively well to the combination
(37%). The response in patients with RA was not as good, (20%), but
the size of the RA group (10 patients) was too small to allow
conclusions about the effect of the combination compared with epo
alone. Only one of the seven patients with 5q- aberration showed a
response to treatment. Four of these patients were found in the RA
subgroup, which might explain the response rate in this group. The
reason for the poor response rate in the 5q- group is unclear. Serum
epo levels and pretreatment transfusion need were comparable between
patients with and without 5q-, which suggests that the poor response
might be explained by the specific biology of this MDS subtype.
The fourth aim of the trial was to study clinical outcome and long-term
efficacy. The median response duration of 24 months was comparable and
even better than that described in the American study.17
Again, the most pronounced long-term efficacy was found in the RARS
group with six of nine patients responding for more than 18 months. The
observation that there are responses with a duration of more than 5 years is promising. Unfortunately, there are no data on long-term
efficacy with epo alone, so that comparison can at present not be done.
All patients, except one (data not shown), needed continuous
maintenance treatment to maintain their response. It was also found
that a relatively high epo dose (50,000 U/wk) was needed for the
majority of the responding patients, but also that a minority of the
responders managed to lower their epo dose to 30,000 U/wk. However,
dose reduction and titration of minimal effective doses were not a part
of the protocol, but is included in the ongoing Scandinavian trial.
A recently published joint study by the Scandinavian and American Study
Groups28 used multivariate analysis to study predictors of
response in a larger patient sample (including 34 of the patients in
the present study). Multivariate analysis was not repeated in the
present study, but it was evident that the two predictors of response
observed in the joint study, pretreatment serum epo levels and
transfusion need, were significant univariate variables also in the
present study. The most interesting additional finding was probably the
higher median MCV value in responding patients and the fact that MCV
actually increased during treatment in these patients. Macrocytosis has
been defined as a dysplastic sign in MDS29 and the reason
for an increase in responding patients is unclear. A previous study has
shown that an erythroid response to G-CSF + epo is paralleled by both a
reduced number of erythroid cells and a reduced number of apoptotic
cells in the bone marrow, but how this is linked to the MCV findings
remains to be investigated.30 Another finding was that
pretreatment soluble serum transferrin levels were somewhat higher
(P = .07) in responding patients and also tended to increase
more in responding than in nonresponding patients. This probably
reflects a previously described finding that patients with RARS showed
higher serum tfr values than other MDS subgroups.31
The IPSS score was not included as a variable in the previously
published multivariate analysis,28 but from the present study, it was clear that it did not predict for a response to treatment. Similar results have been published for low-dose
cytosine arabinoside (ara-C)21 and the
present results support the hypothesis that variables predicting for
survival are not always the same as those predicting for response to a
specific treatment. The survival times in the present study seemed
longer than those in the IPSS material.2 This could be
explained by the fact that any clinical study implies a selection of
patients and that our analysis included only evaluable patients.
Whether treatment with G-CSF + epo could have a favorable impact on
survival in certain patient groups remains to be investigated in a
controlled trial.
Treatment with G-CSF and epo is well-tolerated and from the present
study, there is no indication that it increases the number of bone
marrow blasts or causes progression to acute leukemia. The lack of such
a stimulating effect has previously been shown for G-CSF in a
randomized study.5 However, treatment-induced thrombocytopenia has to be considered. Even if the reduction of platelet counts in most patients were moderate and without clinical risk, there were also cases showing significant reduction. This problem
was basically only observed in nonresponding patients, which further
supports ongoing attempts to develop a functioning predictive model.
The erythroid response rate of 38% for the anemia in MDS is promising
in the aspect of previous treatment results. However, it is still a
disappointment that almost two thirds of the patients are not
responsive to this this type of treatment. A lack of response could
partly be due to reasons that are associated with advanced disease,
such as long-standing and high transfusion need or the finding of
complex karyotype. However, specific biologic reasons cannot be
excluded in some of the patients. Further studies on the biology of
different subgroups of MDS might help to develop new treatment
approaches.
In conclusion, the anemia associated with MDS of subtypes RA, RARS, and
RAEB may respond to treatment with G-CSF and epo. Scandinavian and
American data on hitherto 112 patients suggest that the response rate
of approximately 40% is stable and not depending on a temporaray good
selection of patients. There is a clear in vivo synergy between the two
drugs, at least in patients with RARS, and long-term efficacy is so far
promising. Considering the cost, it is necessary that ongoing studies
focus on the indication for this treatment. A proposed model for
selection of patients for this treatment has been recently
published,28 but the model has to be prospectively
validated before use outside clinical trials.
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FOOTNOTES |
Submitted December 8, 1997;
accepted February 27, 1998.
Supported by grants from the National Cancer Foundation, Stockholm,
Sweden.
Address reprint requests to Eva Hellström-Lindberg, MD, PhD,
Department of Hematology, Huddinge University Hospital, 141 86 Huddinge, Sweden; e-mail: Eva.Hellstrom-Lindberg{at}medhs.ki.se.
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.
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The myelodysplastic syndromes
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Abstract
Introduction
Abstract