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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1175-1179
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Effect of recombinant human erythropoietin combined with
granulocyte/ macrophage colony-stimulating factor in the
treatment of patients with myelodysplastic syndrome
John A. Thompson,
D. Gary Gilliland,
Josef T. Prchal,
John M. Bennett,
Kay Larholt,
Richard A. Nelson,
Esther H. Rose,
Margaret H. Dugan, and
the GM/EPO MDS Study Group
From the Division of Oncology, University of Washington, Seattle,
WA; Hematology/Oncology Research, Howard Hughes Medical Institute,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
Division of Hematology/Oncology, University of Alabama, Birmingham, AL;
Cancer Center, University of Rochester, Rochester, NY; RW Johnson
Pharmaceutical Research Institute, Raritan, NJ; and Schering Plough
Research Institute, Kenilworth, NJ.
 |
Abstract |
This randomized, placebo-controlled trial was designed to assess the
efficacy and safety of therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (epoetin alfa) in
anemic, neutropenic patients with myelodysplastic syndrome. Sixty-six
patients were enrolled according to the following
French-American-British classification: refractory anemia (20),
refractory anemia with excess blasts (35), refractory anemia with
ringed sideroblasts (9), and refractory anemia with excess blasts in
transformation (2). Patients were stratified by their serum
erythropoietin levels (less than or equal to 500 mU/mL, n = 37;
greater than 500 mU/mL, n = 29) and randomized, in a 2:1 ratio, to
either GM-CSF (0.3-5.0 µg/kg·d) + epoetin alfa (150 IU/kg 3 times/wk) or GM-CSF (0.3-5.0 µg/kg·d) + placebo (3 times/wk). The
mean neutrophil count rose from 948 to 3831 during treatment with
GM-CSF ± epoetin alfa. Hemoglobin response (increase greater than or
equal to 2 g/dL, unrelated to transfusion) occurred in 4 of 45 (9%)
patients in the GM-CSF + epoetin alfa group compared with 1 of 21 (5%) patients with GM-CSF + placebo group
(P = NS). Percentages of patients in the
epoetin alfa and the placebo groups requiring transfusions of red blood
cells were 60% and 92%, respectively, for the low-endogenous erythropoietin patients and 95% and 89% for the high-endogenous erythropoietin patients (P = NS). Similarly,
the average numbers of units of red blood cells transfused during the
12-week study in the epoetin alfa and the placebo groups were 5.9 and
9.5, respectively, in the low-endogenous erythropoietin patients and
9.7 and 8.6 in the high-endogenous erythropoietin patients
(P = NS). GM-CSF ± epoetin alfa had no
effect on mean platelet count. Treatment was well tolerated in most
patients, though 10 withdrew from the study for reasons related
predominantly to GM-CSF toxicity.
(Blood. 2000;95:1175-1179)
© 2000 by The American Society of Hematology.
| |
Introduction |
Myelodysplastic syndrome (MDS) is a heterogeneous group
of disorders characterized by the abnormal proliferation and
differentiation of hematopoietic precursor cells, ineffective
hematopoiesis, and, in some patients, evolution to acute leukemia. The
disorders are of varying severity, with some patients having chronic,
mild anemia whereas others have severe abnormalities in the production
of all cell types.
There is, at present, no standard therapy for MDS. Aggressive
chemotherapy or radiotherapy followed by allogeneic bone marrow transplantation may induce durable complete remission, but many patients are not eligible for transplantation because of age or lack of a suitable donor.1 Because pancytopenia,
anemia, and thrombocytopenia are common in patients with
MDS,2,3 the potential role of hematopoietic
growth factors in the management of hematologic disorders in patients
with MDS is under investigation.
Erythropoietin regulates erythropoiesis, particularly of mature red
blood cells (RBCs). Endogenous erythropoietin levels vary widely among
patients with MDS, even those with similar hemoglobin levels, but
overall there is an inverse relationship between the severity of anemia
and the level of endogenous erythropoietin.4 Clinical
studies evaluating the efficacy of recombinant human erythropoietin
(epoetin alfa) as a treatment for MDS have produced variable
results.5 Responses, defined as a reduction in transfusion requirement (more than or equal to 30% to 50%), increases in
hemoglobin levels (1 to 2 g/dL), or both have been reported in 0% to
56% of patients. Various predictors of response have been proposed, including low endogenous erythropoietin levels before therapy and the
need for RBC transfusion.6-9
The limited therapeutic use of epoetin alfa in MDS may be attributed to
a deficiency in these patients of the burst-forming unit-erythroid
(BFU-E) pool, the most immature erythroid progenitor cells, leading to
insufficient influx of epoetin alfa-sensitive cells. Multi-lineage
growth factors such as granulocyte-macrophage colony-stimulating factor
(GM-CSF) are needed for optimal growth of BFU-E cells in vitro. GM-CSF
has been shown to expand this pool in the bone marrow of patients with
MDS.10 Treatment of MDS with GM-CSF may increase the pool
of BFU-E, which could potentially be further stimulated by
erythropoietin. An open-label study involving 13 patients with MDS
examined the effects of administering GM-CSF for 6 weeks, followed by
epoetin alfa plus GM-CSF for 12 weeks.11 Combined therapy
appeared to stimulate erythropoiesis and to correct or improve anemia
in some patients. A double-blinded, placebo-controlled, randomized
study to assess the safety of combination therapy with GM-CSF and
epoetin alfa after autologous bone marrow transplantation found that
the combination treatment was well tolerated in patients with MDS and
that it caused no severe or unexpected toxicities and no withdrawals
from adverse effects.12
We investigated the use of combined therapy with low doses of GM-CSF
and epoetin alfa in patients with MDS. The objective of the study was
to assess 3 primary aspects: (1) the efficacy and clinical benefit of
combined GM-CSF-epoetin alfa therapy in the restoration of normal
hematopoiesis in these transfusion-dependent patients; (2) the safety
of the combination therapy in anemic, neutropenic patients with MDS;
and (3) the effect of patients' pretreatment endogenous erythropoietin
levels on their responses to the combination therapy.
| |
Patients and methods |
This was a multicenter, randomized, double-blinded,
placebo-controlled, parallel-group study in patients with a diagnosis of MDS and refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB). At
the screening examination, patients provided written informed consent
and full medical histories, and they underwent physical examinations
that included hematologic assessment. Eligible patients were
neutropenic (absolute neutrophil count [ANC] less than 1500 cells/mL)
and anemic (hemoglobin less than or equal to 10 g/dL), and they had
platelet counts (unrelated to transfusion) greater than or equal to
15,000/mL. Patients had to be transfusion dependent (requiring at least
4 U RBC in the previous 3 months) and older than 17 years of age, and
they had to have a performance status less than or equal to 2 (on the
Zubrod scale) and normal renal and hepatic function. Patients were not
to have undergone cytotoxic treatment for MDS for at least 30 days
before the study. Criteria for exclusion included history of malignancy
(except basal or squamous cell skin cancer or cervical carcinoma in
situ); recent (within 1 year) history of thromboembolic disease; acute
leukemia or classification of chronic myelomonocytic leukemia; more
than 20% bone marrow blasts or more than 5% blasts in peripheral
blood or Auer rods on histologic examination of the bone marrow;
serious bacterial or fungal infection within 30 days before the study; receipt of more than 10 mg/d corticosteroid or androgen therapy within
the preceding 30 days; evidence of folate or vitamin B12 deficiency or untreated iron deficiency; exposure to any cytokine or
any experimental drug within the preceding 30 days.
Sixty-six patients were enrolled at 13 centers in the United States.
Patients were stratified at entry according to their endogenous serum
erythropoietin levels (less than or equal to 500 mU/mL or more than 500 mU/mL) and were randomly assigned, in a 2:1 ratio, to receive by
subcutaneous injection either GM-CSF (Schering Plough, Kenilworth, NJ)
(0.3-5.0 mg/kg·d) plus epoetin alfa (PROCRIT) (supplied
by Ortho Biotech, Raritan, NJ) (150 IU/kg 3 times/wk) or GM-CSF
(0.3-5.0 mg/kg·d) plus placebo (3 times/wk). Treatment was
administered in a double-blinded fashion for 12 weeks. GM-CSF and
epoetin alfa or placebo were injected at different sites to allow the
differentiation of site reactions. The initial dose of GM-CSF was
dependent on the ANC: 0.3 mg/kg·d with ANC more than or equal to 500 cells/mL or 1.0 mg/kg·d with ANC less than 500 cells/mL. The dose was
increased as necessary by a maximum of 0.5 mg/kg·wk so as to achieve
and maintain an ANC of 2000-5000 cells/mL. The maximum permissible dose
was 5.0 mg/kg·d. If the hemoglobin level reached 13.0 g/dL (unrelated
to transfusion), no further doses of epoetin-alfa/placebo were given
until it returned to 12.0 g/dL.
On days 1 (the first day of medication administration), 3, and 5 and
weekly for 12 weeks, hematologic variables, vital signs, concurrent
therapy, transfusion information, adverse events, febrile events, and
infections were recorded. Patients were weighed weekly before the
administration of study medication, and blood chemistry, serum iron
profiles, and liver and spleen size evaluations were repeated monthly
(days 29, 57, and 85). On the last day of the study (day 85), bone
marrow aspirates and biopsy procedures were repeated. Transfusions were
given to patients whose hematocrit was less than or equal to 25% and,
at the investigator's discretion, to patients whose hematocrit was
between 25% and 30%. Serum erythropoietin levels were measured using
a modified competitive radioimmunoassay with a limit of quantitation of
5 mU/mL.
Criteria for withdrawal included a World Health Organization grade 3 adverse event13 attributable to GM-CSF and the development of acute leukemia or refractory anemia with excess blasts in
transformation (RAEB-t). Two patients (1 from each treatment group)
with French-American-British classifications (FAB) of RAEB-t were
allowed to continue in the study because their conditions remained
stable for a considerable time.
Primary efficacy measures were change in hemoglobin from
baseline to endpoint (last value recorded), RBC transfusion rate in
months 2 and 3, and proportion of patients requiring RBC transfusion during study. Secondary measures included determining the proportion of
patients showing increases in hemoglobin (unrelated to transfusion) greater than or equal to 2 g/dL above the baseline value (hemoglobin responders), the proportion of patients becoming ANC correctors (ANC
greater than or equal to 2000 cells/mL), and a change in platelet count
from baseline to endpoint.
Significance was set at 0.05, and most tests were
1-sided. Tests of interaction were 2-sided and had a significance level of 0.10. Linear model analyses (least-squares mean) were performed to
assess the effects of possible covariables (baseline hemoglobin, baseline RBC transfusion rate, and FAB classification of MDS at diagnosis) for hemoglobin level, RBC cumulative transfusion rate, platelet cumulative transfusion rate, and RBC transfusion rate in
months 2 and 3. Two-sample t tests were used to test
differences in monthly platelet transfusion rates. Differences in the
proportion of patients transfused with RBCs and platelets were assessed
using the 1-sided Fisher exact test. For the secondary variables,
summary statistics were provided for weekly ANC and white blood cell
counts, and 2-sample t tests were used to analyze changes in
hemoglobin and platelet count. Proportions of patients showing
increased (greater than or equal to 2 g/dL) hemoglobin or becoming ANC
correctors were compared using the 1-sided Fisher exact test. Analysis
of efficacy was based on the intent-to-treat population. Analysis of
safety included data from all patients who received study medication.
| |
Results |
Of the 66 patients enrolled, 45 received epoetin alfa and 21 received placebo. Demographic and baseline characteristics were similar
in both treatment groups (Tables 1 and
2). Thirty-seven patients (25 epoetin
alfa, 12 placebo) had baseline endogenous erythropoietin levels less
than or equal to 500 mU/mL. Baseline endogenous erythropoietin
levels were greater than 500 mU/ml in 29 patients (20 epoetin alfa and
9 placebo). Mean baseline hemoglobin levels for both baseline
endogenous erythropoietin groups (treatment groups combined) were 9.4 and 8.6 g/dL, respectively. Forty-eight patients completed the study
(34 in the epoetin alfa group and 14 in the placebo group).
Efficacy analyses
Changes in hemoglobin levels over the course of the study
are shown in Table 3. In patients treated
with GM-CSF and placebo, hemoglobin levels tended to decrease during
the study despite transfusion, whereas hemoglobin levels were
maintained at approximately baseline levels in patients on GM-CSF and
epoetin alfa. For patients with more than 500 mU/mL endogenous
erythropoietin, the mean change in hemoglobin level from baseline to
endpoint was greater in the epoetin alfa group than in the placebo
group. The adjusted mean change in hemoglobin level was 0.07 g/dL in
patients who received epoetin alfa compared with  0.96 g/dL in
those who received placebo (P = .048).
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Table 3.
Change in mean hemoglobin level, percentage of patients
transfused during the study, and mean number of units of blood
transfused during months 2 and 3 of the study
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Hemoglobin responses occurred in 4 of 45 (9%) patients in the
GM-CSF + epoetin alfa group, compared to 1 of 21 (5%) patients in the
GM-CSF + placebo group (P = NS). All 5 hemoglobin responders had baseline endogenous erythropoietin concentrations less than or
equal to 500 mU/ml. All 4 hemoglobin responders who received epoetin
alfa had RAEB, whereas the hemoglobin responder who received placebo
had RARS. The durations of hemoglobin response were 9, 13, 13, 13, and
75 weeks.
The percentage of patients transfused during the study and the mean
number of units of blood transfused during months 2 and 3 are shown in
Table 3. In the less than or equal to 500 mU/mL endogenous
erythropoietin group, only 15 of 25 (60%) epoetin alfa patients were
transfused with RBCs compared with 11 of 12 (92%) placebo patients.
This difference approached statistical significance (P = .051). In the more than 500 mU/mL endogenous
erythropoietin group, 19 of 20 (95%) epoetin alfa patients and 8 of 9 (89%) placebo patients were transfused. Among patients who received
epoetin alfa, the percentage transfused with RBCs was significantly
lower in the less than or equal to 500 mU/mL endogenous erythropoietin group (60%) than in the more than 500 mU/mL endogenous erythropoietin group (95%), P = .0069.
For all treatment groups, the overall mean ANC rose from 948 cells/µL
at baseline to 3831 cells/µL by week 12. In the less than or equal to
500 mU/mL endogenous erythropoietin group, 83% of epoetin alfa
patients and 92% of placebo patients were classified as ANC
correctors. The corresponding values for the more than 500 mU/mL
endogenous erythropoietin subgroup were 80% and 75%, respectively.
Analysis of mean change in platelet count from baseline to endpoint
revealed no significant differences between the 2 treatment groups. The
mean pretreatment platelet count was 108 000/µL in the epoetin alfa
group and 120 000/µL in the placebo group. In the low endogenous
erythropoietin group, the mean change in platelet count from baseline
to endpoint was 14 640/µL in the epoetin alfa patients and
32 920/µL in the placebo patients (P = .12). In the
high endogenous erythropoietin group, the mean change in platelet count
from baseline to endpoint was 17 750/µL in the epoetin alfa
patients and 12 330/µL in the placebo patients
(P = .62).
Safety analyses
A total of 243 adverse events were reported, 165 in the 45 epoetin
alfa-treated patients and 78 in the 21 placebo-treated patients.
Injection site reactions were most common (62% epoetin alfa and 86%
placebo). Of the adverse events, 57 (36 epoetin alfa and 21 placebo)
were deemed to have a probable or definite relationship to study
medication (Table 4). Nine of the adverse
events were rated as severe 5 in the epoetin alfa patients (1 pain in
extremities, 3 thrombocytopenias, and 1 stroke) and 4 in the placebo
patients (1 myalgia, 1 erythema, and 2 injection-site reactions).
At the doses used, combination therapy with GM-CSF and epoetin alfa was
well tolerated in most patients. However, 18 of 66 patients withdrew
during the course of therapy. In 8 of these 18 patients, the reason for
withdrawal was thought to be disease related: infection (3), evolution
to acute leukemia (2), second malignancy (1), gait disturbance (1), and
asthenia (1). The other 10 patients who withdrew did so because of side
effects that were thought to be drug related: thrombocytopenia (3),
myalgia (2), skin erythema (2), fever (1), pericarditis (1), and stroke (1).
Changes in laboratory test values from baseline to endpoint were
similar for epoetin alfa-treated and placebo-treated patients. Systolic
and diastolic blood pressure values remained fairly constant in both
groups. Most patients did not experience changes in liver or spleen
size. Of the 36 patients on epoetin alfa who did not have liver
enlargement at baseline, 3 (8.3%) experienced liver enlargement during
the study. Three of 19 (15.8%) patients in the placebo group
experienced liver enlargement during the study (complete liver and
spleen data were available for all; none had liver enlargement at
baseline). Two of 38 (5.2%) patients in the epoetin alfa group with
normal spleens at baseline experienced spleen enlargement during the
study, in comparison with 4 of 19 (21.1%) patients on placebo; 1 patient on epoetin alfa who had an enlarged spleen at baseline
experienced a reduction in spleen size.
Transformation to acute leukemia occurred in 1 patient in the GM-CSF + epoetin alfa group and in 1 patient in the GM-CSF + placebo group.
There were 3 deaths on the study (all in the GM-CSF + epoetin alfa
group). The causes of death were pericarditis, stroke, and thrombocytopenia.
| |
Discussion |
The objectives of this randomized, double-blinded,
placebo-controlled study were to assess the efficacy (in terms of
restoring normal hematopoiesis) and tolerability of combined therapy
with GM-CSF and epoetin alfa in anemic, neutropenic patients with MDS and to assess the effect of pretreatment endogenous erythropoietin level on response to therapy. Hemoglobin response (an increase in
hemoglobin of at least 2 g/dL unrelated to transfusion) occurred in 4 of 45 (9%) patients in the GM-CSF + epoetin alfa group, compared with
1 of 21 (5%) patients in the GM-CSF + placebo group, a difference that
was not statistically significant. Although all the hemoglobin responders had levels of endogenous EPO less than or equal to 500 mU/mL, no statistically significant effect of endogenous EPO on
hemoglobin response was demonstrated. The median duration of hemoglobin response was 13 weeks.
GM-CSF in combination with epoetin alfa appeared to offer benefits over
GM-CSF and placebo in terms of maintaining hemoglobin levels and in
reducing transfusion requirements in patients with low baseline
endogenous erythropoietin levels. Low (less than or equal to 500 mU/mL)
endogenous erythropoietin levels have previously been suggested to be
predictive of response to epoetin alfa in patients with
MDS.6,7 This is consistent with our finding that, among
previously transfusion-dependent patients treated with GM-CSF and
epoetin alfa, those with low erythropoietin levels were less likely to
require RBC transfusion than those with high (more than 500 mU/mL)
endogenous erythropoietin levels. However, the apparent effect of
epoetin alfa was not observed solely in the low endogenous
erythropoietin group. The difference in mean hemoglobin over the course
of the study in the epoetin alfa versus placebo recipients
reached statistical significance only in the more than 500 mU/ml
endogenous erythropoietin group.
Other studies have shown that GM-CSF can increase leukocyte counts in
patients with MDS.14-16 In agreement with these findings, our study indicated that in anemic and neutropenic patients with MDS,
treatment with GM-CSF, with or without concurrent epoetin alfa,
increased the ANC approximately 3-fold. An ANC increase of this
magnitude may help overcome infection. Moreover, GM-CSF, with or
without epoetin alfa, had no apparent effect on mean platelet counts.
Eighteen patients withdrew from the study. Withdrawal was for
disease-related reasons in 8 of them. Withdrawal from the protocol for
disease-related reasons in 8 of 66 patients is not surprising in this
population of neutropenic, transfusion-dependent patients with MDS. The
other 10 patients who withdrew did so because of side effects,
including thrombocytopenia, myalgia, skin erythema, fever, and
pericarditis, that were thought to be drug related. The occurrence of
myalgia, skin erythema, fever, and pericarditis was likely to be
GM-CSF-related because they have been reported in other studies of
GM-CSF treatment and they not common side effects of epoetin alfa. The
thrombocytopenia observed was likely related to both GM-CSF and epoetin
alfa therapy. The 3 cases of treatment withdrawal because of
thrombocytopenia occurred in the GM-CSF + epoetin alfa group, whereas
there were no cases of treatment withdrawal because of thrombocytopenia
in the GM-CSF + placebo group. Six patients had documented
enlargement of the spleen during the study, a side effect that has
previously been reported with GM-CSF therapy. The development of
splenomegaly may contribute to worsening thrombocytopenia in this
patient population.
In conclusion, combination therapy with GM-CSF and epoetin alfa offers
benefit over GM-CSF alone with respect to maintenance of hemoglobin
levels and reduction of transfusion requirements in patients with MDS
who have less than or equal to 500 mU/mL baseline endogenous
erythropoietin levels. GM-CSF, with or without epoetin alfa, can also
substantially increase ANC in anemic, neutropenic patients with MDS.
For transfusion-dependent patients with MDS who are not candidates for
bone marrow transplantation, a therapeutic trial of GM-CSF and epoetin
alfa for 3 months may be indicated to determine the response
to cytokine therapy.
| |
Footnotes |
Submitted April 28, 1998; accepted October 4, 1999.
Reprints: John A. Thompson, Division of Oncology, University of
Washington Medical Center, Room ee122B, 1959 NE Pacific Street, Box
356043, Seattle, WA 98195-6043; e-mail: jat{at}u.washington.edu.
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.
| |
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Top
Abstract
Introduction