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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Stem Cell Factor in Combination With Filgrastim After Chemotherapy Improves
Peripheral Blood Progenitor Cell Yield and Reduces Apheresis Requirements in
Multiple Myeloma Patients: A Randomized, Controlled Trial
By Thierry Facon, Jean-Luc Harousseau, Frédéric Maloisel, Michel Attal, Jesus Odriozola, Adrian Alegre,
Wilfried Schroyens, Cyrille Hulin, Rik Schots, Pedro Marin, François Guilhot, Albert Granena, Marc De Waele,
Arnaud Pigneux, Valérie Méresse, Peter Clark, Josy Reiffers, and the SCF-Multiple Myeloma Study Group
Stem cell factor (SCF) has been shown to synergize with
filgrastim to mobilize CD34ⴙ cells into the peripheral blood.
To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve
a target yield of 5 ⴛ 106 CD34ⴙ cells/kg, 102 patients with
multiple myeloma were randomized to receive mobilization
chemotherapy with cyclophosphamide (4 g/m2) and either
SCF (20 ␮g/kg/d) combined with filgrastim (5 ␮g/kg/d) or
filgrastim alone (5 ␮g/kg/d), administered daily until leukaphereses were completed. After collection, patients were
treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and
filgrastim (5 ␮g/kg/d). There was a significant difference
between the treatment groups in the number of leukaphereses required to collect 5 ⴛ 106 CD34ⴙ cells/kg (median of 1 v
2 for SCF ⴙ filgrastim and filgrastim alone, respectively, P ⴝ
.008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 ⴛ 106 CD34ⴙ
cells/kg in a single leukapheresis compared with patients
mobilized with filgrastim alone. The median CD34ⴙ cell yield
was significantly increased for the SCF group in the first
leukapheresis (11.3 v 4.0 ⴛ 106/kg, P ⴝ .003) and all leukaphereses (12.4 v 8.2 ⴛ 106/kg, P ⴝ .007). Total colony-forming
unit–granulocyte-macrophage (CFU-GM) and mononuclear
cell counts were also significantly higher in the SCF group in
the first leukapheresis and in all leukaphereses. As expected
for patients mobilized to an optimal CD34ⴙ cell yield, the
time to engraftment was similar between the 2 treatment
groups. Cells mobilized with the combination of SCF plus
filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim
was well tolerated, with mild to moderate injection site
reactions being the most frequently reported adverse events.
There were no serious allergic-like reactions to SCF. The
addition of SCF to filgrastim after cyclophosphamide for
PBPC mobilization resulted in a significant increase in CD34ⴙ
cell yield and a concomitant reduction in the number of
leukaphereses required to collect an optimal harvest of 5 ⴛ
106 CD34ⴙ cells/kg.
r 1999 by The American Society of Hematology.
I
CD34⫹ cells/kg results in rapid and consistent engraftment in a
large proportion of patients.10,11 Conversely, high-dose chemotherapy is usually not administered to patients with CD34⫹ cell
yields less than 1 to 2 ⫻ 106/kg.
Stem cell factor (SCF) is a glycoprotein growth factor that
acts on hematopoietic blood cell progenitors.12 Whereas SCF
alone exerts little colony-stimulating activity on normal human
bone marrow cells in vitro, the combination of recombinant
SCF and other recombinant hematopoietic cytokines results in a
synergistic increase in the numbers of colonies.13 The addition
of SCF to recombinant G-CSF (filgrastim) synergistically increases
PBPC mobilization compared with filgrastim alone.14-17 Several
clinical trials have reported the ability of the combination of SCF
with filgrastim to mobilize PBPC in patients with lymphoma,
multiple myeloma, and breast and ovarian cancers.18-24 Combination
of SCF with filgrastim has been observed to improve CD34⫹ cell
mobilization in heavily pretreated lymphoma20,25 or myeloma21
patients, who are known to be at risk of poor mobilization.
We report here the results of a large randomized and
controlled trial evaluating the addition of SCF to filgrastim for
the mobilization of PBPC in the chemotherapy-based mobilization setting. The study was conducted in patients with multiple
myeloma, most of whom were newly diagnosed. The primary
objective was to determine whether the addition of SCF could
reduce the number of leukaphereses required to achieve a target
yield of 5 ⫻ 106 CD34⫹ cells/kg.
NTENSIVE TREATMENT with autologous hematopoietic
support has become the treatment of choice for multiple
myeloma patients up to 65 years of age.1,2 Peripheral blood
progenitor cells (PBPC) are currently preferred for transplantation, because a hematopoietic recovery after transplantation is
faster than with bone marrow transplants.3-5 In multiple myeloma, mobilization of stem cells in the peripheral blood is
usually achieved with repeated daily injections of cytokines
(granulocyte colony-stimulating factor [G-CSF] or granulocytemacrophage colony-stimulating factor [GM-CSF]) after VAD6
(vincristine, adriamycin, dexamethasone) or cyclophosphamide.7,8 After PBPC transplantation, the time to hematopoietic
recovery is correlated with the number of CD34⫹ progenitor
cells infused.9 Recent studies suggest that infusion of ⱖ5 ⫻ 106
From the Departments of Hematology of Lille, France; Nantes,
France; Strasbourg, France; Toulouse, France; Madrid, Spain; Antwerpen, Belgium; Vandoeuvre-les-Nancy, France; Brussels, Belgium; Barcelona, Spain; Poitiers, France; L’Hospitalet, Spain; Pessac, France;
Amgen, Paris, France; and Cambridge, UK.
Submitted March 5, 1999; accepted April 19, 1999.
Supported by a clinical grant (950114 study) from Amgen Inc
(Thousand Oaks, CA).
Address reprint requests to Thierry Facon, MD, Service des Maladies
du Sang, Hôpital Claude Huriez, 59037 Lille Cedex, France; e-mail:
[email protected].
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.
r 1999 by The American Society of Hematology.
0006-4971/99/9404-0006$3.00/0
1218
PATIENTS AND METHODS
Patient Eligibility
The study was reviewed and approved by the relevant institutional
ethics committees and all patients gave written informed consent before
Blood, Vol 94, No 4 (August 15), 1999: pp 1218-1225
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STEM CELL FACTOR IN MULTIPLE MYELOMA
study entry. Patients were eligible if they were between 18 and 65 years
of age and if they had either newly diagnosed symptomatic stage I, II, or
III (Durie and Salmon staging) multiple myeloma or chemosensitive
myeloma in relapse eligible for autologous transplantation. Eligible
patients had to have an ECOG performance status of 0-2; a life
expectancy with treatment of at least 6 months; an absolute neutrophil
count (ANC) ⱖ1.5 ⫻ 109/L ; a platelet count ⱖ100 ⫻ 109/L; and
adequate major organ function as defined by serum creatinine ⱕ150
mmol/L, bilirubin, asparate aminotransferase (AST), and alanine aminotransferase (ALT) less than twice the upper limit defined at the
investigating laboratory.
Patients were not included if they had received prior high-dose
chemotherapy with autologous progenitor cell support or had presented
with another malignancy within the preceding 5 years, with the
exception of surgically cured basal cell carcinoma of the skin or in situ
carcinoma of the cervix. Because of the possibility of systemic
allergic-like reactions, patients with severe allergic history (seasonal/
recurrent asthma, anaphylactic-type events, angioedema/recurrent urticaria, and allergy to insect venoms) were not included. Other exclusion
criteria included active infection or fever, human immunodeficiency
virus seropositivity, known allergy to Escherichia coli-derived products, or significant nonmalignant disease. The concurrent use of
␤-adrenergic blocking agents was prohibited due to potential interactions with the SCF premedications.
Study Design
This was a randomized, open-label, multicenter study. It consisted of
a collection phase, a treatment phase, and a 90-day follow-up (Fig 1).
Collection phase. Patients were randomized in a 1:1 ratio to 1 of the
2 stem cell mobilization regimens. The mobilization regimen consisted
of 4 g/m2 cyclophosphamide administered by intravenous (IV) infusion
to all patients followed 24 hours later by either 20 µg/kg/d SCF
(r-metHuSCF; Amgen Inc, Thousands Oaks, CA) subcutaneously (SC)
plus 5 µg/kg/d filgrastim (Neupogen; Amgen Inc) SC (SCF group) or
5 µg/kg/d filgrastim alone SC (filgrastim group) administered daily, at
separate sites of the body, until all leukaphereses were completed. All
patients randomized to treatment with SCF were premedicated with H1
and H2 antihistamines (cetirizine and ranitidine, respectively) and an
inhaled bronchodilator (salbutamol). Leukaphereses were initiated
when the white blood count (WBC) was ⱖ4 ⫻ 109/L after the
cyclophosphamide-induced nadir. Leukaphereses were performed using
a Baxter Fenwall CS3000 (Baxter, Deerfield, IL) or a comparable
machine. A blood volume of approximately 10 L was processed at each
leukapheresis. An aliquot from each leukapheresis harvest was sent to a
central laboratory (Haematology Lab, AZ VUB, Brussels, Belgium) for
CD34⫹ cell enumeration using the HPCA2 anti-CD34⫹ fluorescein
isothiocyanate (FITC)-labeled monoclonal antibody (Becton Dickinson, Mountain View, CA). Daily leukapheresis continued until a total of
ⱖ5 ⫻ 106 CD34⫹cells/kg body weight were collected, based on the
central laboratory results, or until a total of 4 leukaphereses had been
performed. Patients with less than 5 ⫻ 106 CD34⫹ cells/kg proceeded to
treatment phase at the discretion of the investigator. No assessment of
CD34⫹ cell subsets or malignant clone cells was performed on the
leukaphereses product.
Treatment phase. After a rest period of a maximum of 8 weeks,
patients received myeloablative therapy followed by autologous PBPC
infusion and observation of hematopoietic recovery. Administration of
chemotherapy was allowed between the last day of leukapheresis and
the first day of conditioning therapy, at the discretion of the investigator.
The myeloablative treatment regimen consisted of either melphalan
alone (200 mg/m2, IV) or melphalan (140 mg/m2, IV) plus total body
irradiation (8 to 10 Gy). PBPC were infused on day 0, 24 hours after the
last dose of cytotoxic therapy. Filgrastim (5 µg/kg/day, IV or SC) was
administered from day 1 until neutrophil recovery.
1219
Follow-up phase. Patients were assessed on day 90 post-PBPC
infusion for maintenance of engraftment, disease status, and survival.
Patients continue to be observed for survival on a separate protocol.
Statistical Methods
The primary study endpoint was the number of leukaphereses
required to achieve a target yield of 5 ⫻ 106 CD34⫹ cells/kg body
weight. Secondary study endpoints were CD34⫹ cell, colony-forming
unit–granulocyte-macrophage (CFU-GM), and mononuclear cell (MNC)
numbers in the first leukapheresis product and over all required
leukaphereses in the collection phase; the time to the first of 3 days with
platelet count ⱖ20 ⫻ 109/L independent of platelet transfusions, time to
platelet transfusion independence, number of days and number of
platelet transfusions, number of days and number of red blood cell
(RBC) transfusions, and time to ANC ⱖ0.5 ⫻ 109/L in the treatment
phase.
The number of leukaphereses required to reach the target was
analyzed using Kaplan Meier analysis and the Gehan-Wilcoxon test.
The numbers of CD34⫹ cells, CFU-GM, and MNC and the number of
days of platelet and RBC transfusions were compared using the
Wilcoxon rank-sum test. Time to ANC recovery and time to platelet
recovery were analyzed using Kaplan-Meier analysis and the logrank
test.
The effect of SCF and melphalan and their interaction on CD34⫹ cell
yields were assessed using analysis of variance on the log CD34⫹ cell
yields (to satisfy the assumptions of normality and equal variances).
RESULTS
One hundred two patients (55 in the SCF group and 47 in the
filgrastim group) were enrolled and randomized from March
1996 to October 1997 at 15 sites in France (8 sites), Spain (4
sites), and Belgium (3 sites). All patients were included in the
intent-to-treat analysis.
Of the 102 patients randomized, 101 had at least 1 leukapheresis. Ninety-seven patients (95%) completed the collection
phase and entered the treatment phase of the study and 95
patients (93%) completed the study according to protocol. Five
patients withdrew during the collection phase: 2 patients died of
progressive disease, 1 before undergoing any leukapheresis, and
3 patients were withdrawn due to reported poor CD34⫹ cell
yields (2 in the SCF group and 1 in the filgrastim group; CD34⫹
cell yields: 2.9, 0.12, and 0.26 ⫻ 106/kg, respectively). In the
treatment phase, 2 patients withdrew: 1 died during autotransplantation of multiple organ failure and the other was lost to
follow-up after autotransplantation.
Treatment groups were balanced for demographics, disease
stage, ECOG score, number of prior therapy cycles, and prior
radiotherapy (Table 1) and for all key hematology and biochemistry parameters (data not shown). Twenty-three patients (24%;
11 in the SCF group and 12 in the filgrastim group) were
administered chemotherapy between the collection and the
treatment phase: 18 patients received 1 cycle, 3 patients
received 2 cycles, 1 patient received 3 cycles, and 1 patient
received 4 cycles. The number of cycles of chemotherapy
administered during this period was balanced between treatment groups.
Number of Leukaphereses to Achieve the Target Stem Cell
Yield (Primary Endpoint)
The median number of leukaphereses to reach the target yield
of 5 ⫻ 106 CD34⫹ cells/kg was 1 in the SCF group versus 2 in
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1220
FACON ET AL
Fig 1. Study design and treatment flow chart.
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STEM CELL FACTOR IN MULTIPLE MYELOMA
1221
Table 1. Patient Demographics and Baseline Disease Characteristics
SCF ⫹
Filgrastim
n
Sex (%)
Male
Female
Age (yrs)
Median
Range
Stage (DS) at diagnosis (%)
I
II
IIIA
IIIB
ECOG score (%)
0
1
2
Prior cycles of chemotherapy
Median
Range
No. of patients receiving prior
radiotherapy (%)
Filgrastim
Table 2. Cumulative Number and Proportion of Patients Reaching a
CD34ⴙ Cell Yield of 5.0 ⴛ 106/kg According to Day of Leukapheresis
Total
55
47
102
36 (65)
19 (35)
24 (51)
23 (49)
60 (59)
42 (41)
60
38-66
59
37-65
59
37-66
1 (2)
10 (18)
42 (76)
2 (4)
3 (6)
10 (21)
33 (70)
1 (2)
4 (4)
20 (20)
75 (74)
3 (3)
19 (35)
32 (58)
4 (7)
21 (45)
23 (49)
3 (6)
40 (39)
55 (54)
7 (7)
3
1-38
3
3-19
3
1-38
12 (22)
13 (28)
25 (25)
the filgrastim group (P ⫽ .008, Gehan-Wilcoxon test; Fig 2).
The proportion of patients reaching the target yield of 5 ⫻ 106
CD34⫹ cells/kg after a single leukapheresis was 65% (36/55)
versus 40% (19/45) in the SCF and filgrastim alone groups,
respectively (P ⫽ .011; odds ratio, 2.79; 95% confidence
interval [CI], 1.25 to 6.25; Table 2). Although not an endpoint of
the study, we also analyzed the proportion of patients reaching a
yield of 2 ⫻ 106 CD34⫹ cells/kg in a single leukapheresis. This
cell yield was reached in a single leukapheresis in 80% (44/55)
versus 62% (29/47) of patients in the SCF and filgrastim groups,
respectively (P ⫽ .041; odds ratio, 2.48; 95% CI, 1.04 to 6.16).
PBPC Yields
The median number of CD34⫹ cells collected in the first
leukapheresis was significantly higher in the SCF group (11.3 ⫻
106 CD34⫹ cells/kg) than in the filgrastim group (4.0 ⫻ 106
CD34⫹ cells/kg; P ⫽ .003). Numbers of CFU-GM and MNC
were also significantly higher (Table 3). Over all leukaphereses,
Day 1
Day 2
Day 4
Values are the number of patients, with percentages in parentheses.
because collections were preplanned on the basis of reaching a
target yield of 5.0 ⫻ 106 CD34⫹ cells/kg and because patients
exposed to SCF underwent fewer leukaphereses, the difference
in yields was smaller, but was also significantly improved with
SCF. The increase in the number of CD34⫹ cells/kg collected
after exposure to the combined cytokines was also observed in
the subgroups of patients with and without prior treatment with
melphalan (Table 4). The analysis of variance on log CD34⫹
cell yields obtained from the first leukapheresis showed no
significant interaction between SCF and melphalan (F1,98 ⫽
1.33, P ⫽ .25), indicating that the effect of SCF was the
effectively same in both melphalan groups (and the effect of
melphalan was effectively the same in both SCF groups). The
effects of SCF and melphalan were both statistically significant
(melphalan: F1,98 ⫽ 26.91, P ⫽ .0001; SCF: F1,98 ⫽ 7.20, P ⫽
.009). The CD34⫹ cell yields were reduced by 84% in the
melphalan group (ratio of geometric means ⫽ 0.16; 95% CI,
0.08 to 0.31) and increased by 137% by 2.4-fold in the SCF
group (ratio of geometric means ⫽ 2.37; 95% CI, 1.25 to 4.48;
Table 5).
Median time to first leukapheresis from the first day of
mobilization was the same in both treatment groups (median of
12 days in both groups; ranges, 9 to 22 days v 10 to 21 days for
the SCF and filgrastim groups, respectively).
Engraftment and Transfusions
The median number of cells reinfused to the patient was
14.3 ⫻ 106 CD34⫹ cells/kg (range, 1.6 to 90.4 ⫻ 106) in the
SCF group and 8.4 ⫻ 106 CD34⫹ cells/kg (range, 0.6 to 65.9 ⫻
106) in the filgrastim group. Time to platelet recovery (median
Table 3. Median CD34ⴙ Cells, CFU-GM, and MNC Contents in the
Product of the First Leukapheresis and All Leukaphereses
SCF ⫹ Filgrastim
(n ⫽ 55)
Fig 2. Kaplan Meier plot of the probability of reaching the target
yield of 5 ⴛ 106 CD34ⴙ cells/kg according to the treatment group.
Day 3
SCF ⫹ filgrastim (n ⫽ 55) 36 (65.4) 45 (81.8) 45 (81.8) 47 (85.4)
Filgrastim (n ⫽ 47)
19 (40.4) 28 (59.6) 33 (70.2) 36 (76.6)
Odds ratio
2.79
3.05
1.91
1.80
95% CI
1.25-6.25 1.24-7.51 0.76-4.83 0.65-4.92
First leukapheresis
CD34⫹ cells (⫻106/kg)
Range
CFU-GM (⫻104/kg)
Range
MNC count (⫻108/kg)
Range
All leukaphereses
CD34⫹ cells (⫻106/kg)
Range
CFU-GM (⫻104/kg)
Range
MNC count (⫻108/kg)
Range
*Wilcoxon rank-sum test.
11.3
0.0-90.4
45.4
0.0-625.0
114.8
2.42-1719.7
12.4
0.0-90.4
45.2
0.0-625.0
177.5
5.2-3658.1
Filgrastim
(n ⫽ 47)
4.0
0.0-65.9
10.3
0.3-174.2
34.2
2.39-491.9
8.2
0.3-65.9
23.1
0.2-174.2
75.2
3.7-2183.6
P Value*
.003
.011
.0008
.007
.018
.043
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1222
FACON ET AL
Table 4. CD34ⴙ Cell Yields (ⴛ106/kg) in Patients With or Without
Prior Treatment With Melphalan
Without Melphalan
CD34⫹ cells (⫻106/kg)
Mean
All leukaphereses
Median
Range
With Melphalan
Filgrastim
(n ⫽ 34)
SCF ⫹
Filgrastim
(n ⫽ 19)
Filgrastim
(n ⫽ 13)
24.6
14.1
8.8
5.0
21.3
0.1-90.4
9.3
1.1-65.9
7.1
0.0-47.1
5.3
0.3-9.7
SCF ⫹
Filgrastim
(n ⫽ 36)
of 9 days and 10 days for the SCF and filgrastim groups,
respectively) or neutrophil recovery (median of 10 days in both
groups) was similar in patients having received PBPC collected
after mobilization by the combination or by filgrastim alone
(Figs 3 and 4). The time to platelet and RBC transfusion
independence was also similar in the 2 groups (platelets, median
of 8 days; RBC, median of 10 days). The median number of
days of platelet or RBC transfusions was 1 in both groups
(platelet transfusions: range, 0 to 19 in the SCF group and 0 to 7
in the filgrastim group; RBC transfusions: range, 0 to 9 in the
SCF group and 0 to 4 in the filgrastim group).
Three-Month Follow-Up
Eighty-five patients were assessed for engraftment and
survival at 3 months. All patients had platelet and neutrophil
count recovery greater than 20 ⫻ 109/L and 0.5 ⫻ 109/L,
respectively. No death and no fulminant progression of multiple
myeloma occurred during this 3-month follow-up.
Safety
The number of days of exposure to cytokines during the
collection phase was similar between treatment (12 v 13 days
for SCF and filgrastim groups, respectively; Table 6). The
cumulative dose of cyclophosphamide was also similar (data
not shown).
Exposure to SCF was associated with manageable levels of
toxicity. It is noteworthy that there were no reports of serious
allergic-like reactions. The most commonly reported severe
adverse events were gastrointestinal events (nausea, vomiting,
and diarrhea) related to the associated chemotherapy, which
occurred in 8 patients (15%) in the SCF group versus 4 (9%) in
the filgrastim group.
Adverse events were reported as possibly, probably, or
Fig 3. Kaplan Meier plot of the time to platelet recovery (H20 ⴛ
109/L) according to treatment group. Median of 9 days versus 10 days
for SCF and filgrastim groups, respectively.
definitely related to the experimental cytokine treatment in 44
(80%) SCF recipients and 8 (17%) filgrastim recipients (Table
6). Application site reactions were the most frequent adverse
reactions reported as at least possibly related to cytokine and
were observed in 24 (44%) SCF recipients but in none of the
filgrastim alone recipients. They were mild to moderate in
severity and consisted primarily of injection site erythema.
Nonserious skin reactions distant from the injection site, also
reported as at least possibly related to cytokine, were also
observed mostly in the SCF group. They consisted of rash,
maculo-papular rash, erythema, pruritus, abnormal pigmentation, or urticaria and occurred in 25% of patients exposed to
SCF overall (2% to 13% for any individual reaction). Consistent
with the reported side effects of filgrastim, musculo-skeletal
pain was reported as at least possibly related to cytokines in 7
(13%) patients exposed to the combination of SCF and filgrastim and in 5 (11%) patients exposed to filgrastim alone. Seven
patients (13%) in the SCF group and none in the filgrastim
group experienced treatment-related asymptomatic elevations
in lactate dehydrogenase (LDH) levels. Cytokine-related fever
was reported in 6 patients (11%) versus 1 patient (2%) in the
SCF and filgrastim groups, respectively. Overall, 39 SCF
patients (71%) versus 29 filgrastim patients (62%) experienced
fever of any origin during the mobilization phase.
No clinically meaningful differences were observed between
Table 5. Geometric Means of the CD34ⴙ Cell Yields (ⴛ106/kg) From
the First Leukapheresis According to the Treatment Effects of Prior
Melphalan and SCF (Analysis of Variance)
Group
n
Mean CD34⫹
Cells (⫻106/kg)
(first leukapheresis)
Melphalan
Without melphalan
Ratio of melphalan/without melphalan
SCF ⫹ filgrastim
Filgrastim
Ratio of SCF ⫹ filgrastim/filgrastim
32
70
1.32
8.45
0.75-2.34
5.76-12.39
55
47
0.16
5.14
2.17
2.37
0.08-0.31
3.30-8.03
1.33-3.55
1.25-4.48
95% CI
Fig 4. Kaplan Meier plot of the time to neutrophil recovery
(H0.5 ⴛ 109/L) according to treatment group. Median of 10 days for
both groups.
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STEM CELL FACTOR IN MULTIPLE MYELOMA
1223
Table 6. Exposure to Treatment and Incidence of Treatment-Related
Adverse Events During Collection Phase
SCF ⫹
Filgrastim
No. of patients
Median duration of cytokine exposure (d)
Range
Cumulative SCF dose (µg/kg)
Range
Cumulative filgrastim dose (µg/kg)
Range
No. (%) with treatment-related adverse
event
Filgrastim
55
12
2-26
239.2
39.3-520.0
59.8
15.7-131.4
47
13
9-29
—
—
65.2
45.0-143.4
44 (80%)
8 (17%)
Application site
Injection site erythema
Injection site reaction
24 (44%)
12 (22%)
8 (15%)
0 (0%)
0 (0%)
0 (0%)
Skin and appendages
Rash
Erythema
14 (25%)
7 (13%)
3 (5%)
1 (2%)
0 (0%)
1 (2%)
Fever
6 (11%)
1 (2%)
Metabolic/nutrition
LDH increased
7 (13%)
7 (13%)
0 (0%)
0 (0%)
Musculo-skeletal
Pain skeletal
Pain back
Myalgia
7 (13%)
4 (7%)
3 (5%)
0 (0%)
5 (11%)
1 (2%)
2 (4%)
2 (4%)
treatment groups regarding hematologic variables, although
platelet and neutrophil counts were higher in the SCF group
(data not shown).
DISCUSSION
In this controlled randomized study conducted in a large
number of myeloma patients, the addition of SCF to a stem cell
mobilization regimen consisting of cyclophosphamide and
filgrastim resulted in a 3-fold enhancement of the number of
PBPC collected in the first leukapheresis and a related decrease
in the number of leukaphereses required to collect 5.0 ⫻ 106
CD34⫹ cells/kg. These results are in line with those observed in
other trials of the combination of SCF and filgrastim to improve
PBPC collection.18-25
The use of SCF and filgrastim significantly reduced the
number of leukaphereses procedures needed. This is important,
because leukaphereses can be associated with adverse experiences related to anticoagulant therapy and central venous
catheter complications, such as infection or thrombosis.26 Even
in the absence of severe complications, the presence and
maintenance of a central venous catheter is a source of
discomfort and alters the quality of life of patients undergoing
high-dose therapy programs.26 Leukapheresis procedures are
also associated with significant costs.27
In the future, use of a combination of SCF and filgrastim
could reduce the length of the first leukapheresis required to
collect a target number of CD34⫹ in a substantial proportion of
patients. Indeed, in this study, cell yields reached a median of
11.3 ⫻ 106 CD34⫹ cells/kg in the first leukapheresis in patients
exposed to this combination, potentially allowing a 50%
reduction in apheresis blood volume in most patients.
A sufficient number of progenitor cells might also be
collected in a limited volume of whole blood. This would avoid
leukapheresis-associated morbidity altogether and would significantly reduce the costs of PBPC collections. Infusion of 1 L of
whole blood after filgrastim priming has already been reported
as capable of supporting high-dose melphalan therapy in
patients with lymphoma.28 In patients with ovarian cancer,
mobilization of progenitor cells into the peripheral blood using
a combination of chemotherapy and cytokines equivalent to the
present one (3 g/m2 cyclophosphamide, 20 µg/kg/d SCF, and 5
µg/kg/d filgrastim) resulted in a theoretical collection of 2 ⫻
106/kg CD34⫹ cells in a median volume of 512 mL of whole
blood.23 In a subset of patients from the present study, we have
quantified the number of circulating CD34⫹ cells in the
peripheral blood before harvesting. In 43% of the 30 patients
tested who had been exposed to the combination of SCF and
filgrastim, a blood volume of 500 mL would have contained at
least 2 ⫻ 106 CD34⫹ cells/kg. Such a yield would have been
obtained in only 15% of the 25 patients tested in the filgrastim
group.28
Combining SCF with filgrastim could also be of benefit for
patients with prior exposure to melphalan, who are known to be
at risk of failure to mobilize sufficient progenitor cells.29
Exposure to melphalan was also a predictor of lower PBPC
yields in the present study. As demonstrated in the ANOVA
analysis (Tables 4 and 5), the effect of SCF is consistent both in
patients without prior melphalan and in the subset of patients at
risk of insufficient mobilization due to prior melphalan.
PBPC collected after exposure to the combination of cytokines were equivalent to those obtained after mobilization with
filgrastim as far as short-term engraftment is concerned. Consistent published data have shown a clear dose-response relationship between the number of CD34⫹ cells reinfused and the
speed of platelet and granulocyte recovery.9 Although 1 to 2 ⫻
106 CD34⫹ cells/kg can still be considered adequate to prevent
graft failure, available data show that cell doses ⱖ5 ⫻ 106
CD34⫹ cells/kg are now considered as optimal, because they
are associated with rapid engraftment in a higher proportion of
patients. This translates in lower mean costs after the high-dose
chemotherapy.30 The present study was not designed to observe
differences in engraftment, because only the leukaphereses
totaling the target of 5 ⫻ 106 CD34⫹ cells/kg were to be
reinfused to the patient.
In this study, administration of the combination of SCF and
filgrastim was safe and well-tolerated. The adverse event profile
of the cytokine combination regimen was consistent with prior
observations, although no serious allergic-like reactions were
observed. Absence of such events in the present study might be
related to careful screening for allergy history, systematic
premedication, or relatively small patient numbers for detecting
low frequency events. In other large randomized studies, such
severe events were reported in 3% to 10% of patients.18,25
It would now be of interest to compare the combination of
SCF and filgrastim, without cyclophosphamide, with the cyclophosphamide and filgrastim regimen used as a control in the
present study. If equivalent or superior CD34⫹ cell collections
could be achieved with cytokines alone, the morbidity associated with cyclophosphamide use would be avoided.
The present study also suggests that, because high numbers
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1224
FACON ET AL
of CD34⫹ cells can be collected in a vast majority of patients,
several cycles of high-dose chemotherapy with autologous stem
cell support could be explored. Indeed, tandem autologous
transplantation has been reported as an encouraging therapeutic
option, at least for some young patients with myeloma.31
However, this option remains to be evaluated for the vast
majority of myeloma patients and some patients still have a very
poor outcome, even with tandem transplants.
The combination of SCF with filgrastim could also facilitate
exploration of the medical benefits of ex vivo manipulations of
progenitor cell products such as tumor cell purging32 or
expansion and maturation of progenitor cells in culture and, in
the future, gene therapy.
APPENDIX
SCF multiple myeloma study group. Prof Jean-Pierre Jouet, Dr
Florence Villard, Dr Marie-Odile Pétillon, and Dr Philippe Cabre
(Department of Haematology, Hôpital Claude Huriez, Lille, France); Dr
Claire de Cervens and Dr Chantal Adjou (Department of Haematology,
Hôtel Dieu Hospital, Nantes, France); Dr Alain Bohbot (Department of
Haematology, Strasbourg, France); Dr Anne Huynh, Dr Catherine
Payen, Dr Jean-Pierre Calot, and Dr Cécile Demur (Department of
Haematology, Toulouse, France); Dr Pierre Feugier, Dr François
Schooneman, and Dr Catherine Claise (Vandoeuvre-les-Nancy, France);
Dr Alain Sadoun and Dr Christine Giraud (Poitiers, France); Dr
Bouzgarrou (Department of Haematology, Pessac, France); Heleen
Denecker (Amgen, Brussels, Belgium); Gemma Hernandez (Amgen,
Barcelona, Spain); Mireille Mur and Anne-Marie Sainte-Beuve (Amgen, Paris, France).
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1999 94: 1218-1225
Stem Cell Factor in Combination With Filgrastim After Chemotherapy
Improves Peripheral Blood Progenitor Cell Yield and Reduces Apheresis
Requirements in Multiple Myeloma Patients: A Randomized, Controlled
Trial
Thierry Facon, Jean-Luc Harousseau, Frédéric Maloisel, Michel Attal, Jesus Odriozola, Adrian Alegre,
Wilfried Schroyens, Cyrille Hulin, Rik Schots, Pedro Marin, François Guilhot, Albert Granena, Marc De
Waele, Arnaud Pigneux, Valérie Méresse, Peter Clark, Josy Reiffers and the SCF-Multiple Myeloma
Study Group
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