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ORIGINAL ARTICLE
AMD3100 plus G-CSF can successfully mobilize CD34 þ cells from
non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma
patients previously failing mobilization with chemotherapy and/or
cytokine treatment: compassionate use data
G Calandra
1
, J McCarty
2
, J McGuirk
3
, G Tricot
4
, S-A Crocker
1
, K Badel
1
, B Grove
1
, A Dye
1
and
G Bridger
1
1
AnorMED Corp of Genzyme Corp, Langley, British Columbia, Canada;
2
Department of Internal Medicine, Hematology/Oncology,
Virginia Commonwealth University, Richmond, VA, USA;
3
Blood and Bone Marrow Transplant Clinic, Kansas City Cancer Center,
Kansas City, MO, USA and
4
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock,
AR, USA
AMD3100 given with G-CSF has been shown to mobilize
CD34 þ cells in non-Hodgkin’s lymphoma (NHL), multi-
ple myeloma (MM), and Hodgkin’s disease (HD) patients
who could not collect sufficient cells for autologous
transplant following other mobilization regimens. These
poor mobilizers are usually excluded from company-
sponsored trials, but have been included in an AMD3100
Single Patient Use protocol, referred to as a Compassio-
nate Use Protocol (CUP). A cohort of 115 data-audited
poor mobilizers in CUP was assessed, with the objective
being to collect X2 10
6
CD34 þ cells per kg following
AMD3100 plus G-CSF mobilization. The rates of success-
ful CD34 þ cell collection were similar for patients who
previously failed chemotherapy mobilization or cytokine-
only mobilization: NHL—60.3%, MM—71.4% and
HD—76.5%. Following transplant, median times to
neutrophil and PLT engraftment were 11 days and 18
days, respectively. Engraftment was durable. There were no
drug-related serious adverse events. Of the adverse events
considered related to AMD3100, two (1.6%) were severe
(one patient—headache, one patient—nightmares). Other
AMD3100-related adverse events were mild (84.8%) or
moderate (13.6%). The most common AMD3100-related
adverse events were gastrointestinal reactions, injection site
reactions and paresthesias. AMD3100 plus G-CSF offers a
new treatment to collect CD34 þ cells for autologous
transplant from poor mobilizers, with a high success rate.
Bone Marrow Transplantation (2008) 41, 331–338;
doi:10.1038/sj.bmt.1705908; published online 12 November 2007
Keywords:
stem cells; autologous transplant; PBSC
Introduction
It has been shown that interaction of the chemokine SDF-1
with the CXCR4 receptor is an important component of
the mechanism of retention of stem cells in the bone
marrow.
1,2
SDF-1 also upregulates the expression of
adhesion molecules, such as VLA-4, which mediate the
adhesion of stem cells to bone marrow stroma.
3,4
The
mechanism of stem cell mobilization using the growth
factor G-CSF involves stimulation of CD34 þ stem cell
production within the bone marrow and proteolytic
cleavage of VCAM-1, the ligand for VLA-4.
5
It has been
proposed that CXCR4/SDF-1 interaction is also necessary
for G-CSF-mediated mobilization of stem cells.
6
AMD3100
mobilizes CD34 þ cells
7,8
via a proposed mechanism of
inhibition of the SDF-1/CXCR4 interaction responsible for
stem cell homing and retention. Furthermore, the synergis-
tic effect of AMD3100 and G-CSF observed in CD34 þ
progenitor cell mobilization is consistent with their
respective mechanisms of action. A recent review including
the mechanisms of stem cell mobilization has been
published by Cashen et al.
9
AMD3100 has been effective in mobilizing CD34 þ cells
for autologous transplant in a number of diseases,
including non-Hodgkin’s lymphoma (NHL),
10
multiple
myeloma (MM)
10
and Hodgkin’s disease (HD).
11
Clinical
studies show that AML cells may be mobilized by
AMD3100 via CXCR4 inhibition, and preclinical studies
suggest the same for CLL cells.
12–14
Recent clinical
experience also shows that plasma cell leukemia (PCL)
cells can be mobilized by AMD3100 (AnorMED, unpub-
lished data, 2006). Due to these concerns, AML, CLL and
PCL patients are excluded from AMD3100 trials.
AMD3100 trials have generally excluded patients who
could not mobilize or collect sufficient cells for transplant
(poor mobilizers), with the exception of two early phase 2
AMD3100 trials: AMD3100-2101
10
and AMD3100-2102.
15
In the study AMD3100-2101, 9/25 patients failed mobili-
zation with G-CSF alone but proceeded to collect a
Received 24 August 2007; revised 21 September 2007; accepted 25
September 2007; published online 12 November 2007
Correspondence: Dr G Calandra, Clinical Development, AnorMED
(Genzyme) Corporation, 200-20353, 64th Avenue, Langley, British
Columbia, Canada V3Y 1N5.
E-mail: gcalandra@anormed.com
Bone Marrow Transplantation (2008) 41, 331–338
& 2008 Nature Publishing Group All rights reserved 0268-3369/08 $30.00
www.nature.com/bmt
transplantable dose of CD34 þ cells when remobilized with
AMD3100 plus G-CSF. Obtaining cells for transplant from
poor mobilizers is a significant medical need and the results
from trials AMD3100-2101 and 2102 led to the conclusion
that the drug should be made available to these patients via
a Single Patient Use (SPU) protocol. The SPU protocol
was subsequently expanded for multiple patient use and
termed the Compassionate Use Protocol (CUP). Both the
SPU protocol and CUP were approved by the US Food
and Drug Administration (FDA) for patients who had
previously failed other mobilization regimens. CUP was
initiated first in the United States and then in Australia and
Canada allowing requests for AMD3100 treatment to be
addressed in an urgent manner, such as when a patient
required remobilization within 1–2 weeks. Access
to AMD3100 treatment through CUP was available to
patients at sites regardless of involvement in AMD3100
research trials.
SPU protocols allow patients who do not qualify for
ongoing trials to have access to unlicensed drugs.
16
The AMD3100 SPU protocol and CUP conform to
regulatory standards, but the data may be limited both in
amount sent by the site and the quality. However, these
data may be valuable to assess the outcomes of patients
treated with less common laboratory abnormalities or
unusual disease states not evaluated otherwise. While the
design of CUP does not include a comparative group as a
control, the patients enrolled had previously received
a conventional mobilization regimen, which resulted in
mobilization of insufficient CD34 þ cells for transplant.
This report evaluates the outcome of proven poor
mobilizers whose prior history and outcomes were verified
by auditing of data at the enrolling sites in the United
States. Approximately 70% of these patients were success-
fully mobilized resulting in a total of X2 10
6
CD34 þ
cells per kg being collected by apheresis. The safety profile
of AMD3100 was similar to that seen in previous studies.
Following transplant, patients engrafted durably.
Materials and methods
Enrollment into CUP
Physicians were required to complete regulatory documents
including informed consent and agree to follow the FDA-
approved protocol. Entry into the protocol was limited to
patients who had previously failed to proceed to apheresis
due to low peripheral blood (PB) CD34 þ cell counts
(usually 10 cells per ml or less) or based on apheresis yield
were unlikely to collect the minimum number for a single
transplant, usually 2 10
6
CD34 þ cells per kg. In almost
all cases this assessment was made from the first apheresis
following the mobilization.
Protocol inclusions/exclusions
Patients were required to meet the criteria listed below for
treatment in CUP. Inclusion criteria included: age of 18 to
70 years, failure of prior mobilization or collection, ability
to undergo transplant, WBC count 43.0 10
9
per liter,
ANC 41.5 10
9
per liter, PLT count 4100 10
9
per liter,
serum creatinine p1.5 mg/dl, liver function tests within
2 upper limit of normal, Eastern Cooperative Oncology
Group performance status of 0 or 1, recovery from acute
toxic effects of prior chemotherapy, left ventricle ejection
fraction 445%, Forced Expiratory Volume in the first
second 460% of predicted or carbon monoxide diffusing
capacity X45% of predicted and negative test for HIV
infection. Exclusions included brain metastases, acute
infection, active infection with hepatitis B or C, fever
(438 1 C/100.4 1F), hypercalcemia (41 mg/dl above the
upper limit of normal) and pregnancy. Exemptions, after
careful consultation, were given to a number of patients for
criteria including: age as low as 8 and up to 78 years; WBC,
ANC or PLT counts lower than those stated above and
elevated creatinine.
Protocol design, administration of G-CSF and AMD3100
The sequence of events for treatment in CUP is shown in
Figure 1. Patients underwent history, physical examination,
chest X-ray, electrocardiogram and laboratory evaluations.
They were given G-CSF as per site preference, typically as a
subcutaneous dose of 10 mg/kg each morning for 4 days. At
approximately 2200 on the fourth day of treatment they
were given a subcutaneous dose of 240 mg/kg AMD3100.
On the morning of the fifth day G-CSF was administered
and apheresis (blood volumes as per site preference) began
at approximately 10 h after the AMD3100 dose. Adminis-
tration of G-CSF, apheresis and administration of
AMD3100 were repeated daily until the patient collected
sufficient cells for transplantation (minimum 2 10
6
G-CSF mobilization (Days 1-4)
10 µg/kg/day G-CSF (morning)
Treatment/Apheresis (Starting Day 4)
240 µg/kg/day AMD3100 (evening)
10 µg/kg/day G-CSF (following morning)
Apheresis begins 10 hours after AMD3100
Myeloablative chemotherapy
Transplantation
Follow-up
Engraftment
3 and 6 month post transplant follow-up
Graft durability at 12 months post-transplant
Eligible patients
Repeated daily, or until
>_
2 × 10
6
CD34+ cells
collected
CUP screening
Document failure of mobilization due to
Low PB CD34+ counts
or
Inadequate apheresis collection
•
•
•
•
•
•
•
•
•
Figure 1 Study design.
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
332
Bone Marrow Transplantation
CD34 þ cells per kg). Treatment was discontinued at
the investigator’s discretion if the patient failed to collect
enough cells to warrant continuation. The number of
CD34 þ cells collected during each apheresis session was
recorded. After myeloablative chemotherapy using the
standard regimen at each site, patients received a transplant
of the cells collected. If insufficient cells were collected from
mobilization with AMD3100 plus G-CSF, cells could be
pooled for transplant with those from other collections.
PMN and PLT recovery were measured as per site practices
and patients were monitored for graft durability up to 1
year post-transplant. All laboratory evaluations were
performed at local site laboratories.
Outcome criteria
Successful mobilization was defined as collection of a total
of X2 10
6
CD34 þ cells per kg during mobilization with
AMD3100 plus G-CSF. Prospective criteria for PMN and
PLT engraftment were not given. The majority of sites
defined PMN engraftment as the first of 3 consecutive days
with a PMN count X0.5 10
9
per liter or the first day
X1.0 10
9
per liter. PLT engraftment was typically defined
as the first day where the PLT count was X20 10
9
per
liter without PLT transfusion.
Adverse event reporting
Any adverse events (AEs) were reported to the sponsor if
they occurred from the time of the first dose of AMD3100
until 30 days after the last apheresis or until the first dose
of myeloablative chemotherapy (whichever occurred first).
Serious adverse events (SAEs) were reported to the
sponsor if they occurred from the time of the first dose of
AMD3100 until 6 months post-transplant. All AEs
and SAEs were graded by the investigator in terms of
severity and potential relationship to AMD3100. Graft
failure up to 12 months post-transplant was reported as
an SAE.
Data audit, definition of study population
Records submitted to the sponsor for MM, NHL and HD
patients enrolled in CUP were audited against source
documents at sites meeting the following criteria:
most patients enrolled in CUP, more than three patients
enrolled in each disease group and/or sites conducting
a company-sponsored AMD3100 study. Data audits
included all patients at a site, regardless of success or
failure of outcome. The primary focus of the audit was to
confirm safety, documentation of the prior mobilization
failure, the outcome of AMD3100 mobilization, the
outcome of transplantation and graft durability. Data
audit visits were performed between 23 January 2006 and
16 May 2006.
Results
At the time of the data audit more than 200 patients were
enrolled in CUP, including both adult and pediatric with
AML and solid tumors. This report comprises audited
outcomes and safety data for a subgroup of 115 patients
with NHL, MM or HD at 22 sites who met the criteria for
data audit as described. These 115 patients represent over
80% of the total NHL, MM and HD patients enrolled
in CUP at the time of the data audit. A total of 17 sites
contributed p6 patients each, the remaining 5 sites
contributed 7, 9, 10, 14 and 15 patients each. The original
CUP contained a statement allowing physicians judgment
as to a patient’s inability to mobilize cells for transplant.
The protocol was later amended to require documented
failure of a prior mobilization. Two patients (one NHL and
one HD, both previously given cytokines only for
mobilization) who had not failed prior mobilization
according to the CUP criteria were identified in the audit.
Both patients required five or more aphereses to collect the
minimum number of cells and are included in this report as
they were considered to be poor mobilizers. One additional
NHL patient included in this report failed prior chemo-
therapy mobilization and did not proceed to apheresis
following mobilization on CUP. This patient was consid-
ered a mobilization failure.
Patient characteristics are shown in Table 1, including
laboratory values at screening and the weight used for
calculation of AMD3100 dose. The majority of patients
were Caucasian and male. Regimens used for prior
mobilization were separated into two groups: chemother-
apy with or without cytokines and cytokines only. The
distribution of chemotherapy mobilization versus cytokine
mobilization was NHL—29/34, MM—24/11 and HD—8/9.
Where pre-mobilization PB CD34 þ cell counts were
available, 475% were o10 cells per ml; and the remainder
were in the range 10.1–16.3 cells per ml. In all disease
groups, patients had received a median number of 2 prior
to chemotherapy regimens. The median value and range of
CBC results for patients at entry to CUP are shown in
Table 1, PLT count was o100 10
9
per liter for 19% of all
patients.
Waivers for specific entry requirements were granted
to very ill patients who it was felt would benefit from
enrollment in CUP. A number of patients had a PLT count
less than 50 10
9
per liter, ANC as low as 0.4 10
9
per
liter, and liver function tests up to 2.5 times beyond the
upper limit of normal (data not shown). In addition, several
patients had creatinine clearance as low as 30 cc/min (data
not shown). The G-CSF dose administered was 10 mg/kg
for the majority of patients with a range of 5–16 mg/kg and
a median dose of 10.2 mg/kg. G-CSF was administered in
the morning between 0400 and 1100 for the majority of
patients. A small number of patients (o10) received at least
one dose of G-CSF as late as 2200. The dose of 240 mg/kg
AMD3100 was typically administered between 2100 and
2300. Ten patients received at least one dose of AMD3100
as late as 0000 (midnight) and one received doses as early as
2000. Apheresis typically began between 0700 and 1000 the
following morning.
The safety profile showed that of the AMD3100-related
AEs, 2 (1.6%) were severe, 17 (13.6%) were moderate and
106 (84.8%) were mild. The most common AEs related
to AMD3100 were gastrointestinal (diarrhea—17.4%,
nausea—9.6%), injection site (erythema—15.7%) and
nervous system (paresthesia and oral paresthesia—6.9%)
(Table 2). Two severe AEs were AMD3100 related; these
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
333
Bone Marrow Transplantation
Table 1 Patient characteristics
NHL MM HD All
N (%) 63 (54.8) 35 (30.4) 17 (14.8) 115 (100.0)
Age (years)
Mean (s.d.) 58.4 (10.3) 58.6 (9.75) 42.5 (15.0) 56.1 (12.3)
Median 60 61 40 59
Min, Max 23, 77 37, 70 21, 70 21, 77
Sex N (%)
Female 25 (39.7) 14 (40.0) 8 (47.1) 47 (40.9)
Male 38 (60.3) 21 (60.0) 9 (52.9) 68 (59.1)
Ethnic group N (%)
African American 0 (0.0) 2 (5.7) 4 (23.5) 6 (5.2)
Asian 1 (1.6) 1 (2.9) 0 (0.0) 2 (1.7)
Caucasian 58 (92.1) 30 (85.7) 12 (70.6) 100 (87.0)
Hispanic/Latino 4 (6.3) 2 (5.7) 1 (5.9) 7 (6.1)
Weight (kg)
N 59 30 17 106
Mean (s.d.) 77.4 (16.2) 79.1 (18.0) 87.6 (16.4) 79.5 (17.0)
Median 79.0 78.1 91.2 79.7
Min, Max 42.6, 116.0 45.0, 128.0 60.3, 120.0 42.6, 128.0
Median (range) PMN Count 10
9
per liter 4 (0.4–45.3) 3 (0.9–13.8) 2 (1.2–29.6) 3 (0.4–45.3)
Median (range) PLT Count 10
9
per liter 135 (55.0–302) 157 (82.0–302) 201 (103–402) 154 (55.0–402)
Median (range) Hemoglobin (g/dl) 11 (8.7–16.0)) 12 (8.7–15.6) 11 (9.0–13.3) 11 (8.7–16.0)
Abbreviations: NHL ¼ non-Hodgkin’s lymphoma; MM ¼ multiple myeloma; HD ¼ Hodgkin’s disease.
Table 2 Summary of adverse events considered possibly, probably or definitely related to AMD3100 occurring in X1% of patients per disease
group
Adverse event NHL MM HD All
Total patients in group N (%) 63 (54.8) 35 (30.4) 17 (14.8) 115 (100.0)
Anemia 0 (0.0) 1 (2.9) 2 (11.8) 3 (2.6)
Thrombocytopenia 3 (4.8) 2 (5.7) 2 (11.8) 7 (6.1)
Abdominal discomfort, distension and/or pain 3 (4.8) 2 (5.7) 0 (0.0) 5 (4.3)
Diarrhea 13 (20.6) 6 (17.1) 1 (5.9) 20 (17.4)
Frequent bowel movements and/or loose stools 2 (3.2) 0 (0.0) 0 (0.0) 2 (1.7)
Flatulence 1 (1.6) 3 (8.7) 1 (5.9) 5 (4.3)
Nausea 8 (12.7) 2 (5.7) 1 (5.9) 11 (9.6)
Vomiting 2 (3.2) 1 (2.9) 1 (5.9) 4 (3.5)
Asthenia and/or fatigue 1 (1.6) 0 (0.0) 1 (5.9) 2 (1.7)
Peripheral edema and/or fluid retention 1 (1.6) 1 (2.9) 0 (0.0) 2 (1.7)
Injection site burning 1 (1.6) 1 (2.9) 1 (5.9) 3 (2.6)
Injection site edema 0 (0.0) 2 (5.7) 0 (0.0) 2 (1.7)
Injection site erythema 10 (15.9) 7 (20.0) 1 (5.9) 18 (15.7)
Injection site pain 1 (1.6) 0 (0.0) 1 (5.9) 2 (1.7)
Injection site pruritus 1 (1.6) 2 (5.7) 0 (0.0) 3 (2.6)
Injection site reaction 1 (1.6) 0 (0.0) 1 (5.9) 2 (1.7)
Injection site urticaria 0 (0.0) 2 (5.7) 0 (0.0) 2 (1.7)
Contusion 2 (3.2) 0 (0.0) 0 (0.0) 2 (1.7)
Blood alkaline phosphatase increased 0 (0.0) 2 (5.7) 2 (11.8) 4 (3.5)
Arthralgia and/or joint stiffness 2 (3.2) 0 (0.0) 0 (0.0) 2 (1.7)
Bone pain 1 (1.6) 1 (2.9) 0 (0.0) 2 (1.7)
Dizziness 1 (1.6) 2 (5.7) 0 (0.0) 3 (2.6)
Headache 3 (4.8) 1 (2.9) 1 (5.9) 5 (4.3)
Paresthesia 3 (4.8) 2 (5.7) 1 (5.9) 6 (5.2)
Paresthesia oral 1 (1.6) 0 (0.0) 1 (5.9) 2 (1.7)
Anxiety and/or nightmare 0 (0.0) 1 (2.9) 1 (5.9) 2 (1.7)
Flushing and/or hot flush 2 (3.2) 2 (5.7) 0 (0.0) 4 (3.5)
Abbreviations: NHL ¼ non-Hodgkin’s lymphoma; MM ¼ multiple myeloma; HD ¼ Hodgkin’s disease.
Patients are counted once only for each adverse event, although the patient may report the same event several times. Percentages are calculated using the
number of patients (N) in that group as the denominator.
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
334
Bone Marrow Transplantation
were headache experienced by one patient and nightmares
experienced by one other. Nine patients experienced
nonserious AMD3100-related decreases in PLT
count. These decreases occurred immediately following
apheresis, suggesting they may have been related to
the apheresis procedure. No AMD3100-related SAEs
were experienced by the group of 115 data-audited patients.
There were 15 deaths among the 115 patients, none
were related to AMD3100. Two deaths occurred within
30 days of the last dose of AMD3100. These deaths
were attributed to disease progression and multiple organ
failure due to chemotherapy. One AMD3100-related
SAE of worsening abdominal pain was experienced by a
patient entered in CUP during the time period studied,
although this patient was not among the 115 presented in
this report.
Data including apheresis yield, transplantation rates
and engraftment are shown in Table 3. The median time
between prior mobilization failure and treatment in CUP
was approximately 1 month. The success of patients
collecting X2 10
6
CD34 þ cells per kg was 466%
overall and was higher for patients previously failing
chemotherapy mobilization than for cytokine mobilization
in the NHL and MM groups, but not the HD group.
Success of mobilization could not be distinguished by any
difference in PMN, PLT or Hb baseline values. Interest-
ingly, some patients successfully mobilized with low PLT
counts. Overall, 475% of patients were able to proceed to
transplant. The median time to PMN engraftment post-
transplant was 11 days and the median time to PLT
engraftment was 18 days. Of the 87 patients who received a
transplant, 50 (21 NHL, 19 MM and 10 HD) patients
received cells mobilized only with AMD3100 plus G-CSF.
The remaining 37 patients (24 NHL, 8 MM and 5 HD)
received cells mobilized with AMD3100 plus G-CSF
pooled from cells from other mobilizations. Of the patients
who received pooled cells, all but one patient received cells
collected from mobilization with AMD3100 plus G-CSF
pooled with previously collected cells. One patient received
cells pooled with those collected by bone marrow harvest
subsequent to treatment on CUP. The times to PMN and
PLT engraftment were similar for patients who received
only cells mobilized with AMD3100 plus G-CSF, or pooled
cells.
The collection of follow-up data was subject to patient’s
consent to laboratory evaluations up to 12 months post-
transplant. For all patients graft failure was reported as an
AE up to 12 months post-transplant. Laboratory results to
assess graft durability up to 12 months after transplant
were available for 36 patients (23 NHL, 6 MM and 7 HD).
Of the 36 patients, 34 (94.4%) patients met the following
definition of graft durability: ANC 41.0 10
9
per liter and
PLTs 420 10
9
per liter. Of the two patients who did not
meet these criteria, one mobilized only 0.2 10
6
CD34 þ
cells per kg during CUP and was transplanted with cells
pooled from various collections. The remaining patient
experienced disease relapse resulting in death. An addi-
tional patient had a SAE of graft failure reported at the
time of death though PMN, hemoglobin and PLT counts
were found to be inconsistent with graft failure. No
additional reports of graft failure were made.
Discussion
AMD3100 provides additional benefit to G-CSF mobiliza-
tion in terms of the number of cells collected and the
number of days to collect X2 10
6
CD34 þ cells per kg,
10
both of which are beneficial to patients seeking to proceed
to autologous stem cell transplantation.
The benefit of AMD3100, compared to other mobili-
zation strategies is not straightforward to quantify.
A comparable study to AMD3100 CUP is difficult to
identify in terms of patient’s age, disease, prior treatment,
apheresis procedures, criteria for success and other factors.
For example, in a review by Boeve et al.,
17
the success
of a second mobilization following a failed mobilization
was based upon the ability to provide sufficient cells
for transplant by combining cells from both mobiliza-
tions. Using this definition, when high-dose G-CSF (32 mg/
kg per day) or a combination of G-CSF (10 mg/kg per day)
plus GM-CSF (5 mg/kg per day) was used, the success rate
was 73%. However, the median apheresis yield for the
high dose G-CSF group was 2.2 10
6
CD34 þ cells per kg
and that for G-CSF plus GM-CSF was 1.6 10
6
CD34 þ
cells per kg. These yields suggest the success rate
of collecting X2 10
6
CD34 þ cells per kg by remobiliza-
tion with G-CSF or G-CSF plus GM-CSF was approxi-
mately 50%. Lefrere et al.
18
reported in a letter to the
editor a success rate of 65% for remobilization using
G-CSF (10 mg/kg) 7 days after failure of mobilization
with chemotherapy plus G-CSF (5 mg/kg). Whether the
prior low dose of G-CSF or the short interval after
prior mobilization influenced the rate of success is
uncertain. Goterris et al.
19
recently reported a success rate
of 51% using either G-CSF (10 mg/kg) or chemotherapy
plus G-CSF (5 mg/kg) in 41 patients of which 19 had NHL,
HD or MM. This contrasts to a study from the late 1990s
20
where G-CSF (10–32 mg/kg) was successful in 24% of 50
patients. It appears that the success rate for a second
mobilization is 20–50% with the exception of the Lefrere
report of 65%.
The overall success rates in this analysis of CUP data for
NHL, MM and HD patients were better than in most prior
reports at 60.3, 71.4 and 76.5%, respectively. The success
rates for patients who previously failed chemotherapy
mobilization were 65.5, 75.0 and 75.0% for NHL, MM and
HD, respectively. These rates exceed the success rate of the
Lefrere report for patients who initially failed chemo-
therapy mobilization.
Previous AMD3100 trials have shown the drug to be
generally safe.
11,21,22
The most common AEs considered
related to AMD3100 are diarrhea, injection site erythema
and nausea/vomiting. The safety profile of AMD3100 in
the CUP population was similar to that seen in patients in
two phase 2 trials
10,23
despite potentially more severe
background conditions. G-CSF was administered conco-
mitantly with AMD3100 and may have contributed to
some AEs including bone pain, general fatigue, headache,
nausea/vomiting, and changes in blood chemistry including
increased alkaline phosphatase.
9,24
The cells collected following mobilization with
AMD3100 plus G-CSF engrafted and the graft remained
durable. Median times to engraftment of 11 days
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
335
Bone Marrow Transplantation
Table 3 Mobilization and transplantation outcome
Disease NHL
a,b
MM HD
a
All
Previous mobilization regimen
c
Cytokines Chemotherapy All Cytokines Chemotherapy All Cytokines Chemotherapy All
N (%) 34 (29.6) 29 (25.2) 63 (54.8) 11 (9.6) 24 (20.9) 35 (30.4) 9 (7.8) 8 (7.0) 17 (14.8) 115 (100.0)
Days of apheresis
Median 3 3 33443233
Min, Max 1, 7 0, 7 0, 7 1, 5 1, 7 1, 7 2, 5 1, 5 1, 5 0, 7
Mean total CD34+ cell yield from all
aphereses 10
6
cells per kg (s.d.)
2.81 (2.27) 3.16 (2.79) 2.97 (2.51) 4.59 (4.67) 4.36 (3.25) 4.44 (3.68) 3.24 (2.14) 4.00 (1.72) 4.54 (4.22) 3.51 (2.90)
Patients collecting o1 10
6
CD34+
cells per kg (%)
b
7 (20.6) 5 (17.2) 12 (19.0) 2 (18.2) 3 (12.5) 5 (14.3) 2 (22.2) 0 (0.0) 2 (11.8) 19 (16.5)
Patients collecting 1–1.9 10
6
CD34+
cells per kg (%)
b
8 (23.5) 5 (17.2) 13 (20.6) 2 (18.2) 3 (12.5) 5 (14.3) 0 (0.0) 2 (25.0) 2 (11.8) 20 (17.4)
Patients collecting X2 10
6
CD34+
cells per kg (%)
b
19 (55.9) 19 (65.5) 38 (60.3) 7 (63.6) 18 (75.0) 25 (71.4) 7 (77.8) 6 (75.0) 13 (76.5) 76 (66.1)
Proceeded to transplantation (%)
d
25 (73.5) 19 (65.5) 45 (71.4) 6 (54.5) 21 (87.5) 27 (77.1) 7 (77.8) 8 (100.0) 15 (88.2) 87 (75.7)
Days to PMN engraftment
N 23 18 42 6 21 27 7 8 15 84
Median 12 11 11 13 11 11 13 11 11 11
Min, Max 8, 36 9, 16 8, 36 10, 20 9, 17 9, 20 8, 17 9, 25 8, 25 8, 36
Days to PLT engraftment
N 21 16 36 6 18 24 7 8 15 76
Median 20 18 18 20 21 21 15 15 15 18
Min, Max 10, 155 12, 37 10, 155 15, 25 12, 57 12, 57 10, 22 10, 56 10, 56 10, 155
Abbreviations: NHL ¼ non-Hodgkin’s lymphoma; MM ¼ multiple myeloma; HD ¼ Hodgkin’s disease.
a
One patient with NHL and one with HD did not have a prior history of failed mobilization and were entered on CUP at the physician’s discretion. These patients are included in ‘cytokines’ subgroup because of
their last procedure prior to CUP under their respective diseases in this summary.
b
One patient with NHL (prior chemotherapy mobilization failure) is included in this summary but did not undergo apheresis, no cells were collected, and is counted as a mobilization failure.
c
The mobilization regimen which failed prior to enrolment in CUP was classified as either ‘cytokines’ for cytokine-only mobilization or ‘chemotherapy’ for any regimen including mobilizing chemotherapy.
d
Of the patients to proceed to transplantation: 21 NHL, 19 MM and 10 HD patients received cells mobilized only with AMD3100+G-CSF. The remaining patients received cells mobilized with AMD3100+
G-CSF pooled from cells from other mobilizations.
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
336
Bone Marrow Transplantation
post-transplant for PMNs and 18 days post-transplant for
PLTs were similar to those seen in a previous study by
Flomenberg et al.,
10
where the median times post-trans-
plant to PMN and PLT engraftment were 10–11 days and
16 days, respectively. It should be noted that CUP patients
had fewer PMN and PLT measurements taken to docu-
ment the precise day of PLT engraftment than in other
AMD3100 trials.
This is one of the largest prospective trials of a new
treatment for patients who mobilize poorly. However,
there are some potential limitations of the data set.
The standard of care of the patients was not monitored
and sites were not trained in the conduct of CUP. However,
the majority of sites were those conducting company-
sponsored trials and therefore had knowledge of the
conduct of AMD3100 trials and had experience with the
drug. This, hopefully, decreased the risk of treatment or
data collection errors. A more significant limitation was the
ability to retrieve case report form (CRF) pages from the
sites. Data collection was significantly improved for data-
audited patients as sites were encouraged to provide CRFs
to the sponsor prior to the audit visits. Long-term follow-
up data were limited as some patients had left their CUP
physician to return to their referring physician prior to data
being submitted. Another limitation was that the audit
reviewed only data reported on CRFs and with the
exception of principal data did not search patient records.
For the most part these limitations should not adversely
affect the report, but do limit the ability to analyze some
factors such as details of prior chemotherapy regimens or
past disease.
The reason for the superior response with AMD3100
plus G-CSF in patients who had previously failed a
chemotherapy mobilization is unclear. Assuming that
progenitors are held within the bone marrow via the
chemotactic effects of SDF-1 on CXCR4-expressing cells
(including CD34 þ cells), chemotherapy depletion of
progenitors and WBCs could significantly affect the
homeostasis, whereby the bone marrow contains an excess
of SDF-1.
25
This imbalance may inhibit the release of
progenitors, particularly in patients who have depleted
bone marrow (such as CUP patients) and is corrected by
administration of AMD3100.
There have been no comparative randomized trials in
poor mobilizers of AMD3100 plus G-CSF versus G-CSF
alone or other regimens. The comparative partially
randomized study reported by Flomenberg
10
where the
patient served as his/her own control did show a significant
benefit in poor mobilizers of AMD3100 plus G-CSF
compared to G-CSF alone. A comparative study of
AMD3100 plus G-CSF (10 mg/kg) versus G-CSF (10 mg/
kg) alone is being initiated in NHL and MM
patients failing prior chemotherapy mobilization with
G-CSF. This study should help to identify the better
mobilization strategy. Stiff
26
has proposed that the
best approach is to prevent poor mobilization by using
optimal combination treatment up front. Until such an
approach is widely adopted, the results from the
CUP program show that AMD3100 in conjunction with
G-CSF may be very beneficial for patients failing prior
mobilization.
References
1 Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC.
The chemokine SDF-1 is a chemoattractant for human
CD34+ hematopoietic progenitor cells and provides a new
mechanism to explain the mobilization of CD34+ progenitors
to peripheral blood. J Exp Med 1997; 185: 111–120.
2 Lapidot T. Mechanism of human stem cell migration and
repopulation of NOD/SCID and B2mnull NOD/SCID mice.
The role of SDF-1/CXCR4 interactions. Ann NY Acad Sci
2001; 938: 83–95.
3 Shen W, Bendall LJ, Gottlieb DJ, Bradstock KF. The
chemokine receptor CXCR4 enhances integrin-mediated in
vitro adhesion and facilitates engraftment of leukemic pre-
cursor-B cells in the bone marrow. Exp Hematol 2001; 29:
1439–1447.
4 Sanz-Rodriguez F, Hidalgo A, Teixido J. Chemokine stromal
cell-derived factor-1alpha modulates VLA-4 integrin-
mediated multiple myeloma cell adhesion to CS-1/fibronectin
and VCAM-1. Blood 2001; 97: 346–351.
5 Lapidot T, Petit I. Current understanding of stem cell
mobilization: the roles of chemokines, proteolytic enzymes,
adhesion molecules, cytokines, and stromal cells. Exp Hematol
2002; 30: 973–981.
6 Thomas J, Liu F, Link DC. Mechanisms of mobilization of
hematopoietic progenitors with granulocyte colony-stimulat-
ing factor. Curr Opin Hematol 2002; 9: 183–189.
7 Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K,
Cooper S et al. Mobilization of hematopoietic progenitor cells
in healthy volunteers by AMD3100, a CXCR4 antagonist.
Blood 2003; 102: 2728–2730.
8 Liles WC, Rodger E, Broxmeyer HE, Dehner C, Badel K,
Calandra G et al. Augmented mobilization and collection of
CD34+ hematopoietic cells from normal human volunteers
stimulated with granulocyte-colony-stimulating factor by
single-dose administration of AMD3100, a CXCR4 antago-
nist. Transfusion 2005; 45: 295–300.
9 Cashen AF, Lazarus HM, Devine SM. Mobilizing stem cells
from normal donors: is it possible to improve upon G-CSF?
Bone Marrow Transplant 2007; 39: 577–588.
10 Flomenberg N, Devine SM, DiPersio JF, Liesveld JL,
McCarty JM, Rowley SD et al. The use of AMD3100
plus G-CSF for autologous hematopoietic progenitor cell
mobilization is superior to G-CSF alone. Blood 2005; 106:
1867–1874.
11 Cashen AF, Calandra G, MacFarland R, Lopez S, DiPersio J.
A mobilizing regimen of AMD3100+G-CSF increases stem
cell collection in patients with Hodgkin’s disease, and PK is
similar to that of non-cancer patients. Blood (ASH Annual
Meeting Abstracts) 2006; 108: 869a; Abstract 3053.
12 Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H,
Fujii N et al. Small peptide inhibitors of the CXCR4
chemokine receptor (CD184) antagonize the activation,
migration, and antiapoptotic responses of CXCL12 in chronic
lymphocytic leukemia B cells. Blood 2005; 106: 1824–1830.
13 Nervi B, Holt M, Rettig MP, Bridger G, Ley TJ, DiPersio JF.
AMD3100 mobilizes acute promyelocytic leukemia cells from
the bone marrow into the peripheral blood and sensitizes
leukemia cells to chemotherapy. Blood (ASH Annual Meeting
Abstracts) 2005; 106: 127a; Abstract 246.
14 Andreeff M, Konoplev S, Wang R-Y, Zeng Z, McQueen T, Shi
Y-X et al. Massive mobilization of AML cells into circulation
by disruption of leukemia/stroma cell interactions using
CXCR4 antagonist AMD3100: first evidence in patients and
potential for abolishing bone marrow microenvironment-
mediated resistance. Blood (ASH Annual Meeting Abstracts)
2006; 108: 176a; Abstract 568.
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
337
Bone Marrow Transplantation
15 Fassas A, Fox M, Calandra G, Tricot G. Successful mobiliza-
tion of peripheral blood stem cells (PBSCs) with AMD3100
in patients failing to collect with hematopoietic growth
factors (HGF) and/or chemotherapy. J Clin Oncol (Meeting
Abstracts) 2004; 22 (14 Suppl): 591; Abstract 6643.
16 Calandra G, Garelik JP, Kohler PT, Brown KR. Problems and
benefits of an antibiotic compassionate therapy program. Rev
Infect Dis 1987; 9: 1095–1101.
17 Boeve S, Strupeck J, Creech S, Stiff PJ. Analysis of remobiliza-
tion success in patients undergoing autologous stem cell
transplants who fail an initial mobilization: risk factors, cytokine
use and cost. Bone Marrow Transplant 2004; 33: 997–1003.
18 Lefrere F, Levy V, Makke J, Audat F, Cavazzana-Calvo M,
Miclea JM. Successful peripheral blood stem cell harvesting
with granulocyte colony-stimulating factor alone after pre-
vious mobilization failure. Haematologica 2004; 89: 1532–1534.
19 Goterris R, Hernandez-Boluda JC, Teruel A, Gomez C, Lis
MJ, Terol MJ et al. Impact of different strategies of second-
line stem cell harvest on the outcome of autologous
transplantation in poor peripheral blood stem cell mobilizers.
Bone Marrow Transplant 2005; 36: 847–853.
20 Weaver CH, Tauer K, Zhen B, Schwartzberg LS, Hazelton B,
Weaver Z et al. Second attempts at mobilization of peripheral
blood stem cells in patients with initial low CD34+ cell yields.
J Hematother 1998; 7: 241–249.
21 Stiff P, Micallef I, McCarthy P, Magalhaes-Silverman M,
Flomenberg N, Weisdorf D et al. AMD3100 combined with
standard doses of G-CSF leads to rapid, consistent mobiliza-
tion of hematopoietic progenitor cells in patients with non-
Hodgkin’s lymphoma (NHL) and multiple myeloma. Blood
(ASH Annual Meeting Abstracts) 2004; 104: 778a; Abstract
2847.
22 Dugan MJ, Akard LP, Thompson JM, Nademanee A,
Maziarz RT, Bensinger WI et al. Treatment with AMD3100
in multiple myeloma or non-Hodgkin’s lymphoma patients to
increase the number of peripheral blood stem cells when given
with a mobilizing regimen of chemotherapy and G-CSF.
Proceedings of American Society of Hematology 2004; 104:
782a; Abstract 2860.
23 Ehninger G, Fruehauf S, Hubel K, Platzbecker U, Badel K,
Calandra G. Steady state mobilization of autologous blood
stem cells using G-CSF and AMD3100 in patients with
multiple myeloma (MM). Blood (ASH Annual Meeting
Abstracts) 2006; 108: 396b; Abstract 5219.
24 Murata M, Harada M, Kato S, Takahashi S, Ogawa H,
Okamoto S et al. Peripheral blood stem cell mobilization and
apheresis: analysis of adverse events in 94 normal donors. Bone
Marrow Transplant 1999; 24: 1065–1071.
25 Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ.
Disruption of the CXCR4/CXCL12 chemotactic interaction
during hematopoietic stem cell mobilization induced by GCSF
or cyclophosphamide. J Clin Invest 2003; 111: 187–196.
26 Stiff PJ. Management strategies for the hard-to-mobilize
patient. Bone Marrow Transplant 1999; 23 (Suppl 2): S29–S33.
AMD3100 þ G-CSF can successfully mobilize
G Calandra et al
338
Bone Marrow Transplantation
