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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2491-2501
A Randomized Phase 3 Study of Peripheral Blood Progenitor Cell
Mobilization With Stem Cell Factor and Filgrastim in High-Risk Breast
Cancer Patients
By
Elizabeth J. Shpall,
Catherine A. Wheeler,
Stewart A. Turner,
Saul Yanovich,
Randy A. Brown,
Andrew L. Pecora,
Thomas C. Shea,
Kenneth
F. Mangan,
Stephanie F. Williams,
C. Fred LeMaistre,
Gwynn D. Long,
Roy Jones,
Mark W. Davis,
Robyn Murphy-Filkins,
William R.L. Parker, and
John A. Glaspy
From the Bone Marrow Transplant Programs, University of Colorado
Health Sciences Center, Denver, CO; Beth Israel Hospital/Dana-Farber
Cancer Institute, Boston, MA; Amgen Inc, Thousand Oaks, CA; Medical
College of Virginia Hospitals, Richmond, VA; Washington University
School of Medicine, St Louis, MO; Hackensack University Medical Center,
Hackensack, NJ; UNC Lineburger Cancer Center, Chapel Hill, NC; The
Temple University Cancer Center, Philadelphia, PA; the University of
Chicago Medical Center, Chicago, IL; South Texas Cancer Institute, San
Antonio, TX; Stanford Medical Center, Stanford, CA; and Bowyer Oncology
Center, UCLA School of Medicine, Los Angeles, CA.
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ABSTRACT |
This randomized study compared the number of leukaphereses required
to collect an optimal target yield of 5 × 106
CD34+ peripheral blood progenitor cells/kg, using either
stem cell factor (SCF) at 20 µg/kg/d in combination with Filgrastim
at 10 µg/kg/d or Filgrastim alone at 10 µg/kg/d, from 203 patients
with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the
target yield of CD34+ cells had been reached or a maximum
of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the
patients treated with SCF plus Filgrastim (n = 100) compared with
47% of those receiving Filgrastim alone (n = 103) reached the
CD34+ cell target yield. There was a clinically and
statistically significant reduction (P < .05) in the number
of leukaphereses required to reach the target yield for the patients
receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with
patients receiving Filgrastim alone (median, 6 or more leukapherses;
ie, <50% of patients reached the target in 5 leukaphereses). All
patients receiving SCF were premedicated with antihistamines,
albuterol, and pseudoephedrine. Treatment was safe, generally well
tolerated, and not associated with life-threatening or fatal toxicity.
In conclusion, SCF plus Filgrastim is a more effective peripheral blood
progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In
addition to the potential for reduced leukapheresis-related morbidity
and costs, SCF offers additional options for obtaining cells for
further graft manipulation.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
OVER THE PAST DECADE, peripheral blood
progenitor cells (PBPCs) have replaced marrow as the major source of
hematopoietic support, resulting in significantly faster rates of
platelet and neutrophil engraftment after high-dose therapy for
malignant diseases.1-3
The criteria defining an adequate or optimal leukapheresis product are
of substantial interest to clinicians performing PBPC transplants.
Although the number of mononuclear cells and/or colony-forming units
granulocyte-macrophage (CFU-GM) were used previously to assess the
adequacy of a PBPC product, the CD34+ cell content has
recently evolved as the most consistent and clinically relevant measure
available for this purpose.3-10 The methods for
CD34+ cell analysis are variable, but published studies
suggest that the vast majority of patients receiving PBPC autografts
containing  5 × 106 CD34+ cells/kg
experience prompt and durable platelet engraftment, whereas those
receiving less than 1 to 2 × 106 CD34+
cells/kg are at risk for delayed engraftment or, rarely, engraftment failure.3,6-10 Consequently, 5 × 106
CD34+ cells/kg has been identified as an optimal target
yield, associated with a high probability of rapid multilineage
engraftment.3,6-8
Filgrastim (r-metHuG-CSF) is frequently used to mobilize hematopoietic
progenitors from the marrow into the peripheral blood.1,2,4 Patients then undergo leukaphereses until sufficient PBPCs for hematopoietic reconstitution are collected. The yields of
CD34+ cells are adversely affected by factors including
age, prior chemotherapy, prior radiation therapy, and tumor involvement
in the bone marrow.3,4,6 To obtain sufficient
CD34+ cells, multiple leukaphereses collections are often
required. The morbidity and expense associated with leukapheresis have
stimulated clinicians to develop strategies to improve PBPC
mobilization and thereby reduce the number of leukaphereses performed.
One such strategy involves the administration of chemotherapy plus cytokines, resulting in the collection of greater numbers of
CD34+ cells than with either modality
alone.11,12 Another approach is the use of multiple
cytokines, such as Filgrastim combined with recombinant human stem cell
factor (SCF; STEMGEN; US-adopted name,
Ancestim)13-16; recombinant human Mpl
ligands17,18; flt-3 ligand19; or interleukin-3
receptor ligands.20
The most extensively studied of these combinations is SCF plus
Filgrastim. SCF is a cytokine that acts on primitive multilineage hematopoietic progenitor cells.21-23 In rats, dogs, and
baboons the addition of species-specific SCF to granulocyte
colony-stimulating factor (G-CSF) increases PBPC mobilization compared
with G-CSF alone.24-28 In these animal models, the infusion
of increased PBPC numbers resulted in more rapid engraftment after
myeloablation.24,27,29
Recombinant human SCF has been shown in controlled clinical trials to
enhance the Filgrastim-induced mobilization of CD34+ cells
with and without chemotherapy.13,15,16 In a large, randomized phase 2 study of patients with breast cancer, Glaspy et
al13 defined the optimal dose and schedule of SCF and
Filgrastim when used in combination to mobilize PBPCs. The combination
of SCF at 20 µg/kg/d plus Filgrastim at 10 µg/kg/d doubled the
number of CD34+ cells that could be collected on days 5, 6, and 7 of cytokine administration, compared with Filgrastim alone. This
study also supported 5 × 106 CD34+
cells/kg as an optimal target yield. A central laboratory was used to
determine CD34+ cell numbers, because standardization of
target PBPC yields has been complicated by variation between
laboratories performing CD34+ cell
quantification.30 Infusion of greater than 5 × 106 CD34+ cells/kg resulted in rapid platelet
engraftment (within 15 days) for all patients, whereas 23% of patients
infused with less than 2 × 106 CD34+
cells/kg experienced delayed platelet engraftment (28 days).
We report here a randomized phase 3 trial of breast cancer patients
designed to determine whether the optimal target of 5 × 106 CD34+ cells/kg could be achieved with fewer
leukaphereses when a combination of SCF plus Filgrastim was used for
mobilization compared with Filgrastim alone.
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MATERIALS AND METHODS |
Patients.
The study protocol was approved by the Institutional Review Boards of
the participating institutions, and all patients gave written informed
consent before study enrollment. Patients with stage II or III breast
cancer involving 10 or more axillary lymph nodes or
chemotherapy-responsive metastatic disease were eligible for this
study. Normal vital organ function and a Karnofsky performance status
of 80% were required for study entry. Patients were excluded if
breast cancer represented more than 10% of the overall cellularity of
bilateral bone marrow biopsy specimens, as assessed by standard histological techniques. Patients were also excluded if they had received more than 12 cycles of prior chemotherapy, had documented brain metastases, or had a history of asthma or other significant IgE-mediated hypersensitivities.
Study design Collection phase.
Eligible patients were randomized to receive either Filgrastim at 10 µg/kg/d alone or the combination of SCF at 20 µg/kg/d and
Filgrastim at 10 µg/kg/d. The cytokine(s) was administered subcutaneously starting on day 1 and continued for up to 9 consecutive days (Fig 1). In the group that received
both SCF and Filgrastim, the two cytokines were injected separately.
Because of the potential for direct mast cell stimulation, all patients
treated with SCF were to receive a premedication regimen consisting of
diphenhydramine (50 mg orally every 6 hours), ranitidine (150 mg orally
every 12 hours), two puffs of albuterol metered-dose inhaler before each injection, and pseudoephedrine (120 mg sustained release before
each injection). Administration of diphenhydramine and ranitidine began
12 to 24 hours before the first dose of SCF and was timed so that a
dose of all four medications was delivered approximately 1 hour before
each injection of SCF. Diphenhydramine and ranitidine were administered
for 48 hours after the last injection of SCF.
Patients eligible for study had baseline hematology and serum chemistry
evaluations. Complete blood counts were evaluated daily until the final
leukapheresis was performed. Leukapheresis began on day 5 of cytokine
administration and was performed daily until either the optimal target
of 5 × 106 CD34+ cells/kg was collected
or a maximum of 5 leukaphereses was performed. Each leukapheresis
processed approximately 10 L of blood using a Cobe Spectra apheresis
device (COBE Laboratories, Lakewood, CO). The leukapheresis product was
processed and cryopreserved on the day it was collected. If, after 5 leukaphereses, the cumulative CD34+ cell content of the
PBPC graft was  1 × 106 CD34+ cells/kg,
the patient was classified as a mobilization failure and withdrawn from
the study.
Progenitor cell assays.
The CD34+ cell quantification was performed at a central
laboratory (Cytometry Associates Inc, San Diego, CA) that was blinded to patient cytokine regimen. Samples obtained from each leukapheresis product were shipped immediately by courier to the central laboratory, where they were labeled with phycoerythrin (PE)-conjugated anti-CD34 (HPCA-2; Becton Dickinson, Mountain View, CA) and then analyzed for
expression of CD34 using a FACScan (Becton Dickinson).
A bivariate plot of forward angle light scatter (FALS; ordinate) and
orthogonal light scatter (SSC; abscissa) was created from the list mode
data. A region was drawn on that plot that included all cells with the
combined characteristics of lymphocytes. Within this region, the
majority of cells with increased FALS and decreased SSC signal were
included. A gate was then created from this region and applied to a
bivariate plot of PE signal (ordinate) and SSC signal (abscissa). The
cluster of the brightest CD34-staining cells was considered positive.
Study designTransplant and follow-up.
Within 2 to 10 days of completing the leukapheresis procedures,
patients were admitted to the hospital and treated with high-dose cyclophosphamide at 1,875 mg/m2/d administered
intravenously over 1 hour on each of 3 days (days  5 through
3), cisplatin at 55 mg/m2/d administered by
continuous intravenous infusion for 3 days (days 5 through
3), and carmustine at 600 mg/m2/d administered
intravenously over 2 hours on day 2. After a 48-hour rest
period, patients received an intravenous infusion of their PBPCs on
days 0, 1, and 2, depending on their number of cryopreserved PBPC
products. Patients received two PBPC products daily on
days 0 and 1, and the fifth product was administered on day 2. Beginning on day 0, all patients received Filgrastim at 10 µg/kg/d,
either by subcutaneous injection or intravenous infusion. Filgrastim
therapy was continued until the absolute neutrophil count (ANC) was 5 × 109/L for 3 consecutive days or 10 × 109/L on one determination. Antibiotics, blood
products, and intravenous fluids were administered according to
institutional protocols. Complete blood counts were obtained daily
until the ANC was 5 × 109/L and the
platelet count (PLT) was 20 × 109/L and were
obtained three times per week thereafter until the PLT was 50 × 109/L on two determinations separated by a minimum of 48 hours. All patients were eligible for discharge from the hospital when
their ANC was 0.5 × 109/L and they were able to
maintain adequate oral intake.
Study end-points and statistical analyses.
Primary end-points for this study included the number of leukaphereses
required to reach an optimal target of 5 × 106
CD34+ cells/kg, the number of days from the first day of
PBPC infusion to neutrophil engraftment (0.5 × 109/L), and the number of days until
transfusion-independent platelet engraftment (20 × 109/L). The safety profile of patients receiving SCF in
combination with Filgrastim was compared with that of patients
receiving Filgrastim alone.
The primary data set used for the analysis of this study included all
patients who were randomized and underwent at least 1 leukapheresis
(intent-to-treat). An efficacy-evaluable data set, from which patients
with protocol violations were excluded, was also defined.
Efficacy analyses were performed on both the intent-to-treat and
efficacy-evaluable data sets. All hypothesis testing and confidence
interval estimates were two-sided and performed at a 5% significance
level. All analyses were completed using SAS version 6.11 (SAS
Institute Inc, Cary, NC) on a Sun Sparc Station, running under UNIX.
A Cox proportional hazards analysis was used to compare the number of
leukaphereses required to reach the optimal target of 5 × 106 CD34+ cells/kg between treatment groups
while controlling for a prospectively determined covariate, the number
of cycles of prior chemotherapy. Values for patients whose
leukapheresis schedule deviated from that of the protocol due to an
adverse event were censored at 6 leukaphereses, regardless of the
number of procedures performed. Values for all other patients who did
not reach the target were censored at their last recorded leukapheresis.
The cumulative number and proportion of patients reaching the target
yield were calculated by day using Kaplan-Meier methods. Odds ratios
were calculated from the Kaplan-Meier event rates by day. The z-test
was used to compare the total proportion of patients reaching the
target by day 5 between the treatment groups. The rate of decrease in
CD34+ cell yield over time was calculated for each
treatment group to observe the comparative sustained yield. Also, for
descriptive purposes, the total CD34+ cell yields were
compared between treatment groups using the Wilcoxon rank sum test.
The number of days until neutrophil and platelet engraftment were
assessed using Kaplan-Meier methods. Values for patients who failed to
engraft were censored at their last recorded day or at day 100, whichever came first. Equivalence of engraftment was demonstrated using
the Hodges-Lehmann median difference estimator and its corresponding
95% confidence interval estimate. The proportion of patients failing
to achieve platelet engraftment within 14 days (and 28 days) of
transplant was assessed, censoring all times greater than 14 days (and
28 days). These proportions are presented for patients transplanted
with 1 to 2, 2 to 5, and greater than 5 × 106
CD34+ cells/kg. The generalized Wilcoxon test was used to
evaluate whether there was a significant difference between the
proportion of patients failing to achieve platelet engraftment within
14 days (and 28 days) for those who yielded 2 to 5 × 106 CD34+ cells/kg versus those who yielded
greater than 5 × 106 CD34+ cells/kg.
Safety.
During the collection phase, assessment of the safety profiles of SCF
plus Filgrastim and Filgrastim alone included daily evaluation of vital
signs, hematology laboratory values, and adverse events. Blood
chemistry values were obtained before and upon completion of the
collection phase.
During the treatment phase, assessment of safety after infusion of
PBPCs mobilized by SCF plus Filgrastim or by Filgrastim alone included
daily evaluation of vital signs during hospitalization, weekly
monitoring of blood chemistry values until day 30 posttransplant, and
frequent determination of hematology laboratory values (see section
above entitled "Study designTransplant and follow-up"). Long-term engraftment and patient survival were recorded at 60 and 100 days posttransplant.
Quality of life (QOL) study.
A companion study was conducted along with the clinical trial to assess
patient QOL during PBPC mobilization and transplantation for both
treatment groups. The total QOL study period for each patient was 160 days from the time of randomization. The QOL questionnaire consisted of
questions selected from two generic instruments (SF-3631 and EuroQOL32) and two disease-specific instruments
(FACT-G33 and FACT-BMT34). The questionnaires
were administered throughout the collection phase, during
hospitalization, and at regular intervals during follow-up for a total
of up to 20 planned assessments. Areas for assessment included general
health perceptions, physical well-being, social well-being, functional
well-being, emotional well-being, and relationship with physicians. In
addition, questions specific to morbidity symptoms associated with bone
marrow transplantation were included. The area under the curve (AUC)
method was used for computing cumulative quality of life (AUC-QOL)
scores over the entire study duration; these scores were divided by 160 days to obtain the daily QOL scores over the study
duration.35,36
Study drug.
The SCF used in this trial was produced using genetically engineered
Escherichia coli, with retention of the initiating N-terminal methionine residue (Amgen Inc, Thousand Oaks, CA). The SCF was provided
as a lyophilized powder that, after reconstitution, was administered at
a concentration of 1.5 or 2.0 mg/mL. Filgrastim also was provided by
Amgen Inc.
| |
RESULTS |
Collection phaseGroups analyzed.
Fourteen transplant centers participated in the study. A total of 203 breast cancer patients were randomized, received a cytokine(s), and
underwent at least one leukapheresis (intent-to-treat data set); 103 received Filgrastim alone and 100 received the cytokine combination.
The demographic and baseline disease characteristics are provided in
Table 1. The two groups were evenly
balanced for stage of disease, bone marrow involvement, and extent of
prior treatment. There were protocol violations related to the primary end-points of the study for 28 patients. These patients were evenly balanced between the two treatment groups. Nine of the protocol violations were errors in patient enrollment (eg, recent or excessive prior chemotherapy), 14 were errors in following the protocol at study
sites or at the central laboratory after patient enrollment (eg,
leukapheresis stopped before target yield reached), and 5 were caused
by logistical difficulties (eg, bad weather preventing further
leukaphereses). When the protocol violations were excluded, 175 patients were evaluable for the primary study end-points
(efficacy-evaluable data set), 90 in the Filgrastim alone group and 85 in the SCF plus Filgrastim group.
Progenitor cell harvests.
The daily median CD34+ cell yields for the intent-to-treat
population are illustrated in Fig 2A.
Patients receiving the combination of SCF plus Filgrastim had higher
median yields of CD34+ cells on each day of leukapheresis
compared with patients receiving Filgrastim alone; this difference was
statistically significant (P < .01) on days 7, 8, and 9 of
cytokine therapy (leukapheresis days 3, 4, and 5). Although patients in
the SCF plus Filgrastim group underwent fewer leukaphereses than those
in the Filgrastim alone group, the median total CD34+ cell
yield was nevertheless higher for the SCF plus Filgrastim group (5.3 × 106/kg v 4.8 × 106/kg,
P = .067). Note, as indicated in Fig 2A, that the
patient numbers decreased with successive days as those who
successfully reached the target yield no longer required leukapheresis;
this decrease accounts for the decrease in medians cell yields across days of leukapheresis. It can be seen in Fig 2A that the rate of
decrease in cell yield across days of leukapheresis was markedly lower
in the SCF plus Filgrastim combination group compared with the
Filgrastim alone group, indicating that CD34+ cell yields
were sustained to a greater degree. This is further illustrated in Fig
2B, which shows CD34+ cell yield values, only for the
patients remaining on each successive day, as a percentage of their day
1 yields. For patients who underwent 5 leukaphereses, the median day-5
yield was 84% of the day-1 yield for the SCF plus Filgrastim group but
only 38% for the Filgrastim alone group.
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| Fig 2.
(A) Intent-to-treat population. Median
CD34+ cell yield (×106/kg) by day of
leukapheresis. (B) Intent-to-treat population. Median daily
CD34+ cell yields (only for those patients remaining on
each successive day) as a percentage of the day 1 values, which are
shown as 100%.
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Proportion of patients reaching target yield and number of
leukaphereses.
Table 2 shows the proportion of patients
reaching the target yield of 5 × 106
CD34+ cells/kg within 5 leukaphereses and the median number
of leukaphereses required to reach the target by treatment group for
the intent-to-treat and efficacy-evaluable data sets. For the
intent-to-treat data set, 63% of the patients receiving SCF plus
Filgrastim reached the target yield compared with 47% of patients
receiving Filgrastim alone (P < .05). The number of
leukaphereses required to reach the optimal target yield showed a
clinically and statistically significant reduction (P < .05)
for the cytokine combination group (median, 4 leukaphereses) compared
with the Filgrastim alone group (median, 6 or more leukaphereses; ie,
<50% of patients receiving Filgrastim alone reached the target in 5 leukaphereses). Thus patients mobilized with the cytokine combination
required at least 2 fewer procedures to reach the target, compared with
those receiving Filgrastim alone. Analyses of the 175 patients in the
efficacy-evaluable data set yielded similar results. Sixty-seven
percent of patients receiving SCF plus Filgrastim reached the target
yield within 5 leukaphereses compared with 48% of patients receiving
Filgrastim alone (P < .01). The median number of
leukaphereses required to reach the target was 3 for efficacy-evaluable
patients receiving SCF plus Filgrastim and 6 for the patients
receiving Filgrastim alone (P < .01).
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Table 2.
Proportion of Patients Reaching the Target
CD34+ Cell Yield and the Median Number of Leukaphereses
Required to Reach the Target Yield for Each Treatment Group
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The number of prior cycles of chemotherapy was confirmed to be a
statistically significant covariate for PBPC mobilization (P < .001); there was a direct positive correlation between the number
of leukaphereses required to reach the target yield and the number of
cycles of prior chemotherapy. Therefore, this prospectively identified
covariate was included in the statistical analysis of the primary
end-point.
A retrospective stepwise multiple regression was performed to look at
factors that may affect PBPC mobilization (response variable = average
CD34+ cell yield per leukapheresis) and to determine
whether any subgroup of patients identified in terms of these factors
benefit most from SCF. Thirty-three demographic factors, including age,
stage of disease, prior chemotherapy, prior radiotherapy, baseline
laboratory values, and treatment center, were evaluated. None of the
factors, other than prior therapy, influenced the extent of PBPC
mobilization, and there was no interaction between prior therapy and
effect of SCF, indicating that SCF increases CD34+ cell
yields in both the heavily and less heavily treated patients who
received, respectively, greater than 5 or less than 5 cycles of prior therapy.
The median number of prior chemotherapy cycles for both treatment
groups was 5. In patients with less than 5 cycles of prior chemotherapy, the median CD34+ cell yields per
leukapheresis were 2.31 × 106/kg for the SCF plus
Filgrastim group and 1.83 × 106/kg for the Filgrastim
alone group. In patients with 5 cycles of prior chemotherapy, the
corresponding values were 0.99 × 106/kg and 0.68 × 106/kg.
Seven patients (3 treated with SCF plus Filgrastim and 4 treated with
Filgrastim alone) failed to achieve a CD34+ cell yield of
1.0 × 106/kg with 5 leukaphereses. They were deemed
mobilization failures and were ineligible for transplant on study, as
specified in the protocol. The 3 mobilization failures in the SCF plus
Filgrastim group had all received 6 cycles of chemotherapy prior to
enrollment on study, and 2 had received prior radiotherapy. Their mean
baseline ANC and PLT were 3.91 (SD, 1.35) × 109/L and
192 (SD, 30) × 109/L, respectively. The 4 mobilization failures in the Filgrastim alone group had received 22, 7, 7, and 3 prior cycles of chemotherapy, respectively. The patient who
had received 22 prior chemotherapy cycles, and 1 of the patients who
had received 7 prior chemotherapy cycles, had also received prior
radiotherapy. The mean baseline ANC and PLT for the 4 patients were
4.26 (SD, 1.67) × 109/L and 186 (SD, 48) × 109/L, respectively. With the small number of mobilization
failures, their prior chemotherapy, prior radiotherapy, and baseline
ANC and PLT did not differ significantly from those for the total study
populations (Table 1).
Treatment phaseGroups analyzed.
One hundred eighty-nine (97 in the Filgrastim alone group and 92 in the
SCF plus Filgrastim group) of the 203 patients underwent PBPC infusion
and were included in the analysis for the transplant phase
(intent-to-treat data set). Fourteen patients (6 in the Filgrastim
alone group and 8 in the SCF plus Filgrastim group) were withdrawn
before PBPC infusion on study, but after completing the leukapheresis
schedule. Seven of these patients (mentioned in preceding section: 4 treated with Filgrastim alone and 3 treated with SCF plus Filgrastim)
failed to achieve a CD34+ cell yield of 1.0 × 106/kg with 5 leukaphereses and were withdrawn as required
by the protocol. The high-dose chemotherapy was not administered to 3 patients who had developed disease progression, 2 patients who had
developed unrelated medical conditions, and 1 patient who voluntarily
withdrew from study. One patient died during high-dose chemotherapy administration.
The efficacy-evaluable data set for the transplant phase excluded 28 patients with protocol violations (essentially the same 28 patients who
incurred protocol violations in the collection phase; see section above
entitled "Collection phaseGroups analyzed"), such that this
data set was composed of 161 patients (85 in the Filgrastim alone group
and 76 in the SCF plus Filgrastim group).
Engraftment.
Engraftment was equivalent for the two intent-to-treat groups with
respect to ANC and PLT recovery (Fig 3).
Hodges-Lehmann estimates and distribution-free 95% confidence
intervals for median differences indicated that there was, at most, a
1-day difference in median time to ANC recovery and no difference in
PLT recovery between the two treatment groups. The median number of
days to engraftment of ANC 0.5 × 109/L for patients
mobilized with SCF plus Filgrastim and for patients mobilized with
Filgrastim alone was 10 days (range, 8 to 13 days) and 9 days (range, 8 to 15 days), respectively. Both treatment groups required 11 days
(range, 8 to 100+ days and 8 to 88+ days, respectively) to reach PLT
20 × 109/L. There was no difference in the
requirements for red blood cell and platelet transfusions between the
two treatment groups. Similar results were observed for the
efficacy-evaluable population.
Delayed platelet engraftment.
Figure 4 shows the proportion of patients
(overall in the top panel, and within each treatment group in the
bottom panel) that failed to engraft to PLT 20 × 109/L by day 14 or day 28 as a function of number of
CD34+ cells infused. Overall (top panel), for those
patients receiving greater than 5 × 106
CD34+ cells/kg, only 1% failed to recover by day 14, and
all recovered by day 28. For those patients receiving 2 to 5 × 106 CD34+ cells/kg, 13% failed to recover by
day 14, and 3% failed to recover by day 28. Thus, there were
significantly less (P < .05) patients failing to engraft by
day 14 or day 28 for the patients receiving greater than 5 × 106 CD34+ cells/kg compared with those
receiving 2 to 5 × 106 CD34+ cells/kg.
Similar engraftment results, as a function of CD34+ cells
per kilogram infused, were documented for each treatment group (bottom
panel); the differences in delayed engraftment between the two
treatment groups are not statistically significant.
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| Fig 4.
Proportion of patients from both groups failing to
engraft to PLT 20 × 109/L within 14 or 28 days after
transplant with respect to the number of CD34+ cells
infused, overall (top panel) and by treatment group (bottom panel).
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Safety.
As expected, peripheral white blood cell (WBC) counts increased in both
treatment groups during the collection phase, plateauing at about 40 to
50 × 109/L. There was no difference between the
treatment groups in this regard. Only one patient (combination group)
had a WBC greater than 100 × 109/L. This patient's
baseline WBC was 14 × 109/L, increased to 110 × 109/L on day 7 of the collection phase, and returned to
baseline after the cytokines were discontinued. There were no clinical sequelae associated with any level of leukocytosis.
Small increases from baseline were noted for several serum chemistry
values in both treatment groups (Table 3).
At the end of the collection phase, the increases in median values for
alkaline phosphatase, lactic dehydrogenase, and uric acid were greater for the SCF plus Filgrastim group than for the Filgrastim alone group.
These increases probably resulted from increased neutrophil production
and turnover, as reported previously for Filgrastim,37 and
may be further increased with the addition of SCF. None of the
increases in serum chemistries was considered clinically significant, because no adverse clinical symptoms were associated with these transient elevations.
Generally, adverse events reported in the collection phase were mild to
moderate in severity for both treatment groups. No fatal or
life-threatening events were reported. Severe events were reported for
17% (17/100) of patients in the SCF plus Filgrastim group and for 12%
(12/103) of patients in the Filgrastim alone group. Consistent with the
known side effects of Filgrastim, mild to moderate musculoskeletal
symptoms were reported at least possibly related to cytokine for 39%
of patients in both treatment groups.
Overall incidence of adverse events, including all severities and
relationships that were reported more frequently (5% difference) in
the SCF plus Filgrastim group than in the Filgrastim alone group are
provided in Table 4. These included
injection site reactions, dizziness, tachycardia, dyspnea,
hypocalcemia, and pruritus. The increased incidence of dizziness and
tachycardia (heart rate, 90 to 145 beats/min) in the SCF plus
Filgrastim group may be due to one or more of the premedications that
these patients received. In 1 patient, mild tachycardia was reported as
related to SCF. None of the other events of dizziness or tachycardia
was reported as related to cytokine, and all were reported as mild in
severity; no patients were treated for these symptoms. The highest
heart rate recorded was 145 beats/min in a patient who had a baseline
heart rate of 100 beats/min. Paresthesia, headache, and nausea were
reported more frequently in the Filgrastim alone group (Table 4).
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Table 4.
Adverse Events of All Severities and Treatment
Relationship With a Difference of 5% in Incidence Between the
Treatment Groups
|
|
Five patients (5%) who received SCF plus Filgrastim and no patients
who received Filgrastim alone experienced serious adverse events that
were considered at least possibly related to the cytokine. Three of
these 5 patients experienced systemic allergic-like reactions attributed to SCF: 1 experienced dyspnea (plus cough with angiodema); 1 experienced throat tightness; and 1 developed generalized urticaria and
pruritus. All symptoms resolved completely in these patients after SCF
was discontinued and antihistamine and/or steroid was administered. The
2 additional patients experienced events that were reported as possibly
related to SCF: 1 (who received multiple respiratory depressive
medications) developed hypoxia and confusion; the other developed a
dermatologic reaction manifested by edema and erythema of the hands,
which culminated in skin exfoliation 10 days after the cessation of
SCF. In both patients, the symptoms/clinical findings resolved completely.
No toxicities reported as related to SCF were observed upon infusion of
PBPCs mobilized with SCF plus Filgrastim. In addition, through 100 days, no difference was noted in the incidence of disease progression
or death between the two groups (data not shown).
QOL study.
Ninety-three percent of the patients enrolled in this clinical trial
participated in the QOL study and patients in both groups completed
91% of the scheduled assessments. Table 5
summarizes the QOL study results. Although the study was not powered to
show a statistically significant difference in QOL end-points, patients receiving SCF plus Filgrastim had slightly higher QOL scores on all
nine scales.
| |
DISCUSSION |
The efficiency of PBPC mobilization may be quite variable, influenced
by the patient's underlying disease, by the amount of prior
chemotherapy and/or irradiation, and by the mobilization regimen
used.3,4,6 Correlations have been between particular PBPC
graft parameters and rate of hematopoietic engraftment; the number of
CD34+ cells in the PBPC harvest has emerged as the most
reliable predictor of engraftment kinetics (ANC and PLT
recovery).3-10
To avoid the risks of delayed or impaired hematopoietic engraftment,
clinicians generally will not initiate high-dose chemotherapy unless a
minimum number of CD34+ cells, ranging from 1 to 2.5 × 106 cells/kg, are available for infusion. Patients
yielding less than 1 × 106 CD34+ cells/kg
usually are considered mobilization failures and will typically not
receive high-dose chemotherapy until and unless more cells are
collected. Conversely, the infusion of 3 to 8 × 106 CD34+ cells/kg has been reported to be
necessary for rapid platelet recovery.3,4,7-9,38,39
In the present study, 5 × 106 CD34+
cells/kg was chosen as an optimal target yield for rapid engraftment,
based on studies by a number of investigators.3,6-8,13 A
central laboratory was used to standardize the determination of
CD34+ cell numbers, and the analysis of engraftment
kinetics as a function of CD34+ cell numbers infused
supports the choice of 5 × 106 CD34+
cells/kg as an optimal target. There were significantly fewer patients
failing to engraft to platelets 20 × 109/L by day
14 or day 28 overall for patients receiving greater than 5 × 106 CD34+ cells/kg compared with those
receiving 2 to 5 × 106 CD34+ cells/kg
(P < .05).
The proficiency of mobilization dictates the number of leukaphereses
required to achieve the desired PBPC yields. The use of Filgrastim
alone for mobilization often requires multiple leukapheresis procedures.3 However, it is difficult to determine
precisely from the literature how many leukaphereses are routinely
performed. As mentioned, the PBPC yield and number of leukaphereses
required to achieve the yield are influenced by mobilization regimen
(eg, cytokine with or without chemotherapy), tumor type, extent of prior therapy, and variability in CD34+ cell measurement
and leukapheresis procedures. However, in general, it would appear that
1 to 3 leukaphereses are routinely used for chemotherapy plus cytokine
mobilization and 2 to 8 for cytokine-alone mobilization. The
CD34+ cell yields for patients receiving Filgrastim alone
in the present study are similar to those in a previous clinical study
in breast cancer patients,13 and as we demonstrated, are
less than the optimal target of 5 × 106/kg in more
than half the patients.
Clinicians are interested in reducing the number of leukaphereses
required for reasons of associated morbidity (hypocalcemia, paresthesia, thrombocytopenia, and catheter-related complications), convenience (hospital visits and time undergoing leukaphereses), and
cost, but not at the risk of delayed engraftment. The cost of a single
leukapheresis has been estimated as $2,266 (US).40
In the present study, in comparison with Filgrastim alone, the
combination of SCF plus Filgrastim for PBPC mobilization resulted in
significant reductions in the number of leukaphereses required to
achieve CD34+ cell yields optimal for successful transplant
in patients with breast cancer. The reductions in leukaphereses
occurred because patients receiving SCF plus Filgrastim had higher
median yields of CD34+ cells on each day of leukapheresis,
such that the cumulative proportion of patients reaching the
CD34+ cell target over 5 days of leukapheresis was higher
in this group for both the intent-to-treat and efficacy-evaluable data
sets. Patients in the SCF plus Filgrastim group also had
CD34+ cell yields that were more sustained over the
leukapheresis period than the yields for patients in the Filgrastim
alone group. The CD34+ cell data suggested that patients
who required more than 2 leukaphereses benefited most from the use of
SCF along with Filgrastim.
These findings of increased and sustained leukapheresis
CD34+ cell yields with SCF plus Filgrastim are consistent
with the preclinical biology of SCF21-23 and with a
previous clinical study in breast cancer patients in which the
increases in PBPCs were sustained when the cytokine combination was
administered for 7, 10, or 13 days.13 Similar results
showing increased CD34+ cell yields with SCF plus
Filgrastim have been obtained in patients with lymphoma, myeloma, and
ovarian cancer.14,15,41,42 The addition of SCF to regimens
using chemotherapy and Filgrastim for mobilization is also associated
with substantial increases in the number of PBPCs
harvested.15
The overall results show that approximately 20% more patients reached
the optimal target of 5 × 106 CD34+
cells/kg in 5 leukaphereses for the SCF plus Filgrastim group than for
the Filgrastim alone group. However, it is also clear that for patients
who did not reach the optimal target, those in the SCF plus Filgrastim
group nevertheless yielded more CD34+ cells than those in
the Filgrastim alone group, ie, median yields of CD34+
cells were higher on each day of leukapheresis for the SCF plus Filgrastim group. Thus, the use of SCF along with Filgrastim can be
expected to have a range of clinical benefits for patients, depending
on their underlying mobilization potential. For poor mobilizers (<1 × 106 CD34+ cells/kg), the likelihood of
reaching a minimum yield (1 to 2 × 106
CD34+ cells/kg) to allow transplant would be expected to
become greater.4,41 For medium mobilizers (2 to 5 × 106 CD34+ cells/kg), the likelihood of reaching
an optimal yield (>5 × 106 CD34+
cells/kg) would be expected to become greater. And for good mobilizers (>5 × 106 CD34+ cells/kg), there is a
likelihood of reaching the optimal yield with fewer leukaphereses.
Because leukapheresis to an optimal CD34+ cell target is
increasingly adopted in transplant centers, the combination of SCF plus
Filgrastim will have the added advantage, over Filgrastim alone, of
sustained mobilization beyond day 5 of leukapheresis, ie, continued
daily leukapheresis would be more feasible, decreasing the need for
second mobilizations or back-up bone marrow harvests.
Engraftment was equivalent for the two treatment groups in this study.
This result was expected because patients were mobilized to a target
CD34+ cell yield. As discussed, rapidity of engraftment was
directly related to the number of CD34+ cells infused.
The dosing of SCF in this study (ie, 20 µg/kg/d) was based on prior
dose-finding clinical studies performed in combination with
Filgrastim.13 The dosing of Filgrastim (ie, 10 µg/kg/d) was that most typical for mobilization with Filgrastim as a single agent and is in accordance with product labeling. Some
studies43,44 have suggested that higher doses of Filgrastim
as a single agent do not enhance mobilization, whereas other
studies45 have suggested that they do. However, studies in
baboons have shown that SCF in combination with Filgrastim enhances
mobilization relative to Filgrastim alone, regardless of the Filgrastim
dose.28 Thus, clinical trials of SCF in combination with
higher doses of Filgrastim may be warranted.
SCF at 20 µg/kg/d, when administered with premedication as in this
study, is safe and generally well tolerated. Three patients (3%)
receiving SCF developed systemic allergic-like reactions that were
considered to be related to the cytokine. These reactions were similar
in character and severity to those reported in other SCF clinical
trials and resolved completely with the administration of
antihistamines/steroids and cessation of SCF treatment.
Ancillary studies have shown that there was no difference in the
incidence of tumor contamination of the leukapheresis products of the
two groups46 or in immune reconstitution of the grafts after transplantation.47
In addition to the benefits for patients undergoing conventional or
multicycle PBPC transplant, an enhanced CD34+ cell yield
has potential benefits for the further therapeutic manipulation of PBPC
harvests. A number of procedures invariably result in loss of a
substantial fraction of hematopoietic progenitor cells; these include
CD34+ cell selection, tumor cell purging, and genetic
manipulation. Other procedures that would benefit from higher starting
cell numbers include ex vivo expansion of CD34+ cells,
which has the potential to further decrease the duration and severity
of myelosuppression after transplantation, and ex vivo manipulations to
increase the number of effector cells and cycling stem cells, thereby
facilitating immunotherapy and gene therapy, respectively.
| |
ACKNOWLEDGMENT |
The authors thank Angela Brame, Garinell Davis, Lisa Gaynes, Eric
Guempel, Lisa Hami, Sharon Heister, Betty Hinshaw, Randi Isaacs, Kathy
Jelaca-Maxwell, John Lu, Becky Malloy, Lisa Matta, Hillary O'Kelly,
Sheryl Oliversen, Joseph Rosenblatt, Carol Rush, Anne Sharpe, Jeffrey
Shogan, Sharon Taffs, Kate Tierney, Arianne Van Vliet, Jennifer Wang,
and Marianne Zblyski for their contributions towards this research. We
also thank Cheryl Garrison, Keith Langley, Melanie LaPolla, and MaryAnn
Foote, PhD, for their assistance in the finalization of the manuscript.
| |
FOOTNOTES |
Submitted February 20, 1998; accepted December 3, 1998.
Supported in part by National Institutes of Health/National Cancer
Institute Grant No. R01-CA61508 (to E.J.S.); by Grant No. M01-RR00865
from The Revlon/UCLA Women's Cancer Research Program (to J.A.G.); by
Grants No. M01RR00046 and 5-P30-CA16086-23 from the University of North
Carolina, Chapel Hill, NC (to T.C.S.); and by Amgen Inc.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Elizabeth J. Shpall, MD, Bone Marrow
Transplant Program, University of Colorado Health Sciences Center,
Denver, CO 80262.
| |
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ABSTRACT
INTRODUCTION
