|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 68-75
By
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.
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.
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.
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.
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 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. 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.
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
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, 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).
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
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.
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.
Submitted December 8, 1997;
accepted February 27, 1998.
1.
Greenberg PL:
The myelodysplastic syndromes
, in Hoffman R,
Benz E,
Shattil S,
Furie B,
Cohen H
(eds):
Hematology: Basic Principles and Practice
New York, NY, Churchill Livingstone
, 1994
, p 1098
2.
Greenberg PL,
Cox C,
LeBeau M,
Fenaux P,
Morel P,
Sanz G,
Sanz M,
Vallespi T,
Hamblin T,
Oscier D,
Ohyashiki K,
Toyama K,
Aul C,
Mufti G,
Bennett J:
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood
89:2079,
1997
3.
Negrin R,
Haeuber D,
Nagler A,
Kobayashi Y,
Sklar J,
Donlon T,
Vincent M,
Greenberg P:
Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor.
Blood
76:36,
1990
4.
Yoshida Y,
Hirashima K,
Asano S,
Takaku F:
A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes.
Br J Haematol
78:378,
1991[Medline]
[Order article via Infotrieve]
5. (suppl 1)
Greenberg P,
Taylor K,
Larson R,
Koeffler P,
Negrin R,
Saba H,
Ganser A,
Jakubowski A,
Gabrilove J,
Mufti G,
Cruz J,
Hammond W,
Broudy V,
Langley GR,
Keating A,
Vardiman J,
Lamborn K,
Brown S:
Phase III randomized multicenter trial of G-CSF vs observation for myelodysplastic syndromes (MDS).
Blood
82:196a,
1993
6.
Vadhan-Raj S,
Keating M,
LeMaistre A,
Hittelman W,
McCredie K,
Trujillo J,
Broxmeyer H,
Henney C,
Gutterman J:
Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes.
N Engl J Med
317:1545,
1987[Abstract]
7.
Shuster MW,
Larson RA,
Thompson JA,
Coiffier B,
Bennett JM,
Israel RJ for the Shering-Plough/Sandoz MDS Study Group:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) for myelodysplastic syndrome (MDS): Results of a multi-center randomized controlled trial.
Blood
76:318a,
1990
8.
Shuster MW,
Thompson JA,
Larson RA,
Dugan,
:
Randomized phase II study of recombinant granulocyte-macrophage colony-stimulating factor (RGM-CSF) in patients with neutropenia secondary to myelodysplastic syndrome (MDS).
Blood
86:338a,
1995
9.
Bessho M,
Jinnai I,
Matsuda A,
Saito M,
Hirashima K:
Improvement of anaemia by recombinant eryhtropoietin in patients with myelodysplastic syndromes and aplastic anaemia.
Int J Cell Cloning
8:445,
1990[Abstract]
10.
Hellström E,
Birgegård G,
Lockner D,
Wide L,
Helmers C,
Öst Å:
Treatment of myelodysplastic syndromes with recombinant human erythropoietin.
Eur J Haematol
47:355,
1991[Medline]
[Order article via Infotrieve]
11.
Rose EH,
Abels RI,
Nelson RA,
McCullough DM,
Lessin L:
The use of r-HUEpo in the treatment of anaemia related to myelodysplasia (MDS).
Br J Haematol
89:831,
1995[Medline]
[Order article via Infotrieve]
12.
Hellström Lindberg E:
Efficacy of erythropoietin in the myelodysplastic syndromes. An analysis of 205 patients in 17 studies.
Br J Haematol
89:67,
1995[Medline]
[Order article via Infotrieve]
13.
Amano Y,
Koike K,
Nakahata T:
Stem cell factor enhances the growth of primitive erythroid progenitors to a greater extent than interleukin 3 in patients with aplastic anemia.
Br J Haematol
85:663,
1993[Medline]
[Order article via Infotrieve]
14.
Backx B,
Broeders L,
Löwenberg B:
Kit ligand improves in vitro erythropoiesis in myelodysplastic syndromes.
Blood
80:1213,
1992
15.
Negrin RS,
Stein R,
Doherty K,
Cornwell J,
Vardiman J,
Krantz S,
Greenberg P:
Treatment of the anaemia of myelodysplastic syndromes using human granulocyte-CSF in combination with erythropoietin.
Blood
82:737,
1993
16.
Hellström-Lindberg E,
Birgegård G,
Carlsson M,
Carneskog J,
Dahl IM,
Dybedal I,
Grimfors G,
Merk K,
Tangen JM,
Winqvist I,
Öst Å:
A combination of granulocyte-colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes.
Leuk Lymphoma
11:221,
1993
17.
Negrin RS,
Stein R,
Doherty K,
Cornwell J,
Vardiman J,
Krantz S,
Greenberg P:
Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: Evidence for in vivo synergy.
Blood
87:4076,
1996
18.
Bennett JM,
Catovsky D,
Daniel MT,
Flandrin G,
Galton DAG,
Gralnick HR,
Sultan C,
The French-American-British (FAB) Group:
Proposals for the classification of the myelodysplastic syndromes.
Br J Haematol
51:189,
1982[Medline]
[Order article via Infotrieve]
19.
Wide L,
Bengtsson C,
Birgegård G:
Circadian rythm of human serum erythropoietin.
Br J Haematol
51:189,
1989
20.
Beguin Y,
Clemons G,
Pootrakul P,
Fillet G:
Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin.
Blood
81:1067,
1993
21.
Hellström-Lindberg E,
Robèrt KH,
Gahrton G,
Forsblom AM,
Lindberg G,
Kock Y,
Öst Å:
A predictive model for the clinical response to low dose ara-C: A study of 102 patients with myelodysplastic syndromes or acute leukemia.
Br J Haematol
81:503,
1992[Medline]
[Order article via Infotrieve]
22.
Miller KB,
Kyungman K,
Morrison FS,
Winter JN,
Bennett JM,
Neiman RS,
Head DR,
Cassileth PA,
O'Connell MJ:
The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: A phase-III intergroup study.
Ann Hematol
65:162,
1992[Medline]
[Order article via Infotrieve]
23.
Ganser A,
Maurer A,
Contzen C,
Seipelt G,
Ottmann OG,
Schadeck-Gressel C,
Kolbe K,
Haas R,
Zander C,
Reutzel R,
Hoelzer D:
Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol.
Ann Hematol
72:237,
1996[Medline]
[Order article via Infotrieve]
24.
Imamura M,
Kobayashi M,
Kobayashi S,
Yoshida K,
Mikuni C,
Ishikawa Y,
Matsumoto S,
Sakamaki S,
Niitsu Y,
Hinoda Y,
Yachi A,
Kudoh T,
Chiba S,
Kasai M,
Oka T,
Okuno A,
Maekawa I,
Sakurada K,
Miyazaki T:
Failure of combination therapy with granulocyte colony-stimulating factor and erythropoietin in myelodysplastic syndromes.
Ann Hematol
68:163,
1994[Medline]
[Order article via Infotrieve]
25.
Musto P,
Falvone A,
Carotenuto M:
Granulocyte colony-stimulating factor and erythropoietin for the anemia of myelodysplastic syndromes: A real improvement with respect to EPO alone?
Blood
84:1687,
1994
26.
Cazzola M,
Mercuriali F,
Brugnara C:
Use of recombinant human erythropoietin outside the setting of uremia.
Blood
89:4248,
1997
27.
Stenke L,
Wallvik J,
Celsing F,
Hast R:
Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes.
Leukemia
7:1324,
1993[Medline]
[Order article via Infotrieve]
28.
Hellström-Lindberg E,
Negrin R,
Stein R,
Krantz S,
Lindberg G,
Vardiman J,
Öst Å,
Greenberg P:
Erythroid response to treatment with G-CSF plus erythropoietin for the anemia of patients with myelodysplastic syndromes: Proposal for a predictive model.
Br J Haematol
99:344,
1997[Medline]
[Order article via Infotrieve]
29.
May SJ,
Smith SA,
Jacobs A,
Williams A,
Bailey-Wood R:
The myelodysplastic syndromes: Analysis of laboratory characteristics in relation to the FAB classifiacation.
Br J Haematol
59:311,
1985[Medline]
[Order article via Infotrieve]
30.
Hellström-Lindberg E,
Kanter-Lewensohn L,
Öst Å:
Morphological changes and apoptosis in bone marrow from patients treated with granulocyte-CSF and erythropoietin.
Leuk Res
21:415,
1997[Medline]
[Order article via Infotrieve]
31.
Bowen DT,
Culligan D,
Beguin Y,
Kendall R,
Willis N:
Estimation of effective and total erythropoiesis in myelodysplasia using serum transferrin receptor and erythropoietin concentrations, with automated reticulocyte parameters.
Leukemia
8:151,
1994[Medline]
[Order article via Infotrieve]
This article has been cited by other articles:
|
Abstract
Introduction
Abstract
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).
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.
9% in nonresponding and 
