A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Leukine Pharmacology, Pharmacokinetics, Studies, Metabolism - Sargramostim
Leukine Pharmacology, Pharmacokinetics, Studies, Metabolism - Sargramostim
CLINICAL PHARMACOLOGY
General
GM-CSF belongs to a group
of growth factors termed
colony stimulating factors
which support survival,
clonal expansion, and
differentiation
of hematopoietic progenitor
cells. GM-CSF induces partially committed progenitor cells to divide
and differentiate in the granulocyte-macrophage pathways.
GM-CSF is also capable of activating mature
granulocytes and macrophages. GM-CSF is a multilineage factor
and in addition
to dose-dependent effects on the myelomonocytic lineage, can promote
the proliferation
of megakaryocytic and erythroid
progenitors.1
However, other factors are required to induce complete maturation
in these two lineages. The various cellular
responses (i.e., division, maturation, activation) are induced
through GM-CSF binding to specific
receptors expressed on the cell
surface of target
cells.2
In vitro Studies of Leukine in Human Cells
The biological activity
of GM-CSF is species-specific. Consequently, in vitro studies have
been performed on human
cells to characterize
the pharmacological activity
of Leukine. In vitro exposure
of human bone
marrow cells to Leukine at concentrations ranging from 1-100 ng/mL
results in the proliferation
of hematopoietic
progenitors and in the formation
of pure granulocyte,
proof macrophage
and mixed granulocyte-macrophage
colonies.3 Chemotactic,
anti-fungal and anti-parasitic4
activities of granulocytes and monocytes are increased by exposure
to Leukine in vitro. Leukine increases the cytotoxicity of monocytes
toward certain neoplastic cell
lines5 and activates
polymorphonuclear
neutrophils to inhibit the growth
of tumor cells.
In vivo Primate Studies of Leukine
Pharmacology/toxicology studies of Leukine were performed in cynomolgus
monkeys. An acute
toxicity study revealed
an absence of treatment-related
toxicity following a single IV
bolus injection
at a dose of 300 mcg/kg.
Two subacute studies
were performed using IV injection
(maximum dose 200 mcg/kg/day
x 14 days) and subcutaneous
injection (maximum
dose 200 mcg/kg/day x 28
days). No major visceral
organ toxicity
was documented. Notable histopathology findings included increased
cellularity in hematologic organs, and heart and lung
tissues. A dose-dependent increase in leukocyte
count, which consisted primarily of segmented neutrophils, occurred
during the dosing period; increases in monocytes, basophils, eosinophils
and lymphocytes were also noted. Leukocyte counts decreased to pretreatment
values over a 1-2 week recovery period.
Pharmacokinetics
Pharmacokinetic profiles have been analyzed in controlled studies
of 24 normal male
volunteers. Liquid and lyophilized Leukine, at the recommended dose
of 250 mcg/m2, have been determined to be bioequivalent
based on the statistical evaluation
of AUC.5 When Leukine (either liquid
or lyophilized) was administered IV
over 2 hours to normal
volunteers, the mean beta
half-life was approximately 60 minutes. Peak concentrations of GM-CSF
were observed in blood
samples obtained during or immediately after completion of Leukine
infusion. For Leukine Liquid, the mean
maximum concentration
(Cmax) was 5.0 ng/mL, the mean
clearance rate
was approximately 420 mL/min/m2 and the mean
AUC (0-inf) was 640 ng/mL.min.
Corresponding results for lyophilized Leukine in the same subjects
were mean Cmax of 5.4 ng/mL,
mean clearance rate of
431 mL/min/m2, and mean
AUC (0-inf) of 677 ng/mL.min.
GM-CSF was last detected in blood
samples obtained at 3 or 6 hours. When Leukine (either liquid or
lyophilized) was administered SC to normal
volunteers, GM-CSF was detected in the serum
at 15 minutes, the first sample
point. The mean beta half-life
was approximately 162 minutes. Peak levels occurred at 1 to 3 hours
post injection,
and Leukine remained detectable for up to 6 hours after injection.
The mean Cmax was 1.5 ng/mL.
For Leukine Liquid, the mean
clearance was 549
mL/min/m2 and the mean
AUC (0-inf) was 549 ng/mL.min.
For lyophilized Leukine, the mean
clearance was 529
mL/min/m2 and the mean AUC (0-inf) was 501 ng/mL.min.
Antibody Formation
Serum samples collected before and after Leukine treatment
from 214 patients with a variety
of underlying diseases have been examined for the presence of antibodies.
Neutralizing antibodies were detected in 5 of 214 patients (2.3%)
after receiving Leukine by continuous IV
infusion (3 patients)
or subcutaneous
injection (2 patients)
for 28 to 84 days in multiple
courses. All 5 patients had impaired hematopoiesis
before the administration
of Leukine and consequently the effect
of the development
of anti-GM-CSF antibodies on normal
hematopoiesis
could not be assessed. Drug-induced neutropenia, neutralization
of endogenous GM-CSF
activity and diminution
of the therapeutic effect of Leukine secondary
to formation of neutralizing
antibody remain a theoretical
possibility.
CLINICAL EXPERIENCE
Acute Myelogenous Leukemia
The safety and efficacy
of Sargramostim in patients with AML
who are younger than 55 years of age
has not been determined. Based on phase
II data suggesting the best therapeutic
effects could be achieved in patients at highest risk
for severe infections and mortality
while neutropenic, the phase
III clinical trial
was conducted in older patients. The safety and efficacy
of Leukine in the treatment
of AML were evaluated in
a multi-center, randomized, double-blind placebo-controlled trial
of 99 newly diagnosed adult patients, 55-70 years of age, receiving
induction with or
without consolidation.6
A combination of standard
doses of daunorubicin (days 1-3) and ara-C (days 1-7) was administered
during induction and
high dose ara-C was administered
days 1-6 as a single course of consolidation, if given. Bone-marrow
evaluation was performed
on day 10 following induction
chemotherapy. If hypoplasia
with <5% blasts was not achieved, patients immediately received
a second cycle of induction
chemotherapy. If the bone
marrow was hypoplastic
with <5% blasts on day 10 or 4 days following the second cycle
of induction chemotherapy,
Leukine (250 mcg/m2/day) or placebo
was given IV over 4 hours
each day, starting 4 days after the completion of chemotherapy.
Study drug was continued
until an ANC 31500/mm3
for three consecutive days was attained or a maximum
of 42 days. Leukine or placebo
was also administered after the single course of consolidation chemotherapy
if delivered (ara-C 3-6 weeks after induction
following neutrophil recovery). Study drug
was discontinued immediately if leukemic
regrowth occurred.
Leukine significantly shortened the median
duration of ANC
<500/mm3 by 4 days and <1000/mm3
by 7 days following induction (see table
below). 75% of patients receiving Leukine achieved ANC >500/mm3
by day 16 compared to day 25 for patients receiving placebo. The
proportion of patients receiving 1 cycle
(70%) or 2 cycles (30%) of induction
was similar in both treatment groups; Leukine significantly shortened
the median times to neutrophil
recovery whether one cycle
(12 versus 15 days) or two cycles (14 versus 23 days) of induction
chemotherapy was
administered. Median times to platelet (>20,000/mm3)
and RBC transfusion
independence were not significantly different between treatment
groups.
During the consolidation
phase of treatment,
Leukine did not shorten the median
time to recovery
of ANC to 500/mm3
(13 days) or 1000/mm3 (14.5 days)
compared to placebo. There were no
significant differences
in time to platelet
and RBC transfusion
independence.
Hematological Recovery: Induction
|
Dataset
|
Sargramostim N=52*
Median (25%, 75%)
|
Placebo N=47 Median (25%, 75%)
|
p-value**
|
| ANC>500mm3 a |
13 (11, 16)
|
17 (13, 25)
|
0.009
|
| ANC>1000mm3 b |
14 (12, 18)
|
21 (13, 34)
|
0.003
|
| PLT>20,000mm3 c |
11 (7, 14)
|
12 (9, >42)
|
0.10
|
| RBCd |
12 (9, 24)
|
14 (9, 42)
|
0.53
|
* Patients with missing data censored.
a 2 patients on Sargramostim and
4 patients on placebo
had missing values.
b 2 patients on Sargramostim and
3 patients on placebo
had missing values.
c 4 patients on placebo
had missing values.
d 3 patients on Sargramostim and
4 patients on placebo
had missing values.
** p=Generalized Wilcoxon
The incidence of
severe infections and deaths associated with infections was significantly
reduced in patients who received Leukine. During induction or consolidation,
27 of 52 patients receiving Leukine and 35 of 47 patients receiving
placebo had at least
one grade 3, 4 or 5 infection
(p=0.02). Twenty-five patients receiving Leukine and 30 patients
receiving placebo experienced severe and fatal
infections during induction
only. There were significantly fewer deaths from infectious
causes in the Sargramostim arm (3 versus 11, p=0.02). The majority
of deaths in the placebo
group were associated
with fungal infections with pneumonia
as the primary infection.
Disease outcomes were not adversely affected by the use of Leukine.
The proportion of patients achieving complete remission
(CR) was higher in the Leukine group
(69% as compared to 55% for the placebo
group), but the difference was not significant
(p=0.21). There was no significant
difference in relapse
rates; 12 of 36 patients who received Leukine and 5 of 26 patients
who received placebo
relapsed within 180 days of documented CR
(p=0.26). The overall median
survival was 378 days
for patients receiving Leukine and 268 days for those on placebo
(p=0.17). The study was not sized to assess the impact of Leukine
treatment on response
or survival.
Mobilization and Engraftment of PBPC
A retrospective review was conducted of data from patients with
cancer undergoing collection of peripheral
blood progenitor
cells (PBPC) at a single transplant
center. Mobilization of PBPC and myeloid
reconstitution post-transplant were compared between four groups
of patients (n=196) receiving Leukine for mobilization
and a historical control
group who did not receive
any mobilization
treatment [progenitor
cells collected by leukapheresis without mobilization
(n=100)]. Sequential cohorts received Leukine. The cohorts differed
by dose (125 or 250 mcg/m2/day),
route (IV over 24 hours or SC) and use of Leukine post
transplant . Leukaphereses
were initiated for all mobilization
groups after the WBC reached
10,000/mm3. Leukaphereses continued
until both a minimum
number of mononucleated
cells (MNC) were collected (6.5 or 8.0 x 108/kg
body weight) and a minimum
number of phereses (5-8)
were performed. Both minimum requirements varied by treatment
cohort and planned conditioning
regimen. If subjects failed to reach a WBC
of 10,000 cells/mm3 by day 5 another
cytokine was substituted
for Leukine; these subjects were all successfully leukapheresed
and transplanted. The most marked mobilization and post
transplant effects
were seen in patients administered the higher dose of Leukine (250
mcg/m2) either IV (n=63) or SC (n=41).
PBPCs from patients treated at the 250 mcg/m2/day
dose had significantly higher number
of granulocyte-macrophage colony-forming units (CFU-GM) than those
collected without mobilization. The mean
value after thawing was 11.41 x 104
CFU-GM/kg for all Leukine mobilized patients, compared to 0.96 x
104/kg for the non-mobilized group.
A similar difference was observed in the mean number of erythrocyte
burst-forming units (BFU-E) collected (23.96 x 104/kg
for patients mobilized with 250 mcg/m2
doses of Leukine administered SC vs. 1.63 x 104/kg
for non-mobilized patients).
After transplantation, mobilized subjects had shorter times to
myeloid engraftment, and fewer days between transplantation
and the last platelet transfusion compared to non-mobilized subjects.
Neutrophil recovery
(ANC >500/mm3) was more rapid
in patients administered Leukine following PBPC transplantation
with Leukine-mobilized cells (see table
below). Mobilized patients also had fewer days to the last platelet
transfusion and
last RBC transfusion, and
a shorter duration of hospitalization
than did non-mobilized subjects.
|
Route for Mobilization
|
Post-transplant Leukine
|
ENGRAFTMENT (median value
in days)
|
|
ANC>500/mm3
|
Last platelet
transfusion
|
| No mobilization |
-
|
no
|
29
|
28
|
Leukine
250 mcg/m2 |
IV
|
no
|
21
|
24
|
|
IV
|
yes
|
12
|
19
|
|
SC
|
yes
|
12
|
17
|
A second retrospective review of data from patients undergoing PBPC
at another single transplant
center was also conducted.
Leukine was given SC at 250 mcg/m2/day
once a day (n=10) or twice a day (n=21) until completion of the
phereses. Phereses were begun on day 5 of Leukine administration
and continued until the targeted MNC count of 9 x 108/kg
or CD34+ cell count of
1 x 106/kg was reached. There was
no difference in CD34+ cell
count in patients receiving
Leukine once or twice a day. The median
time to ANC>500/mm3
was 12 days and to platelet
recovery (>25,000/mm3)
was 23 days.
Survival studies comparing mobilized study patients to the non-mobilized
patients and to an autologous
historical bone marrow
transplant group
showed no differences in median
survival time.
Autologous Bone Marrow Transplantation7
Following a dose-ranging Phase I/II trial in patients undergoing
autologous BMT for lymphoid
malignancies,8,9
three single-center, randomized, placebo-controlled and double-blinded
studies were conducted to evaluate the safety and efficacy
of Leukine for promoting hematopoietic
reconstitution
following autologous
BMT. A total of 128 patients (65 Leukine, 63 placebo) were enrolled
in these 3 studies. The majority of the patients had lymphoid
malignancy (87 NHL,
17 ALL), 23 patients had Hodgkin's disease,
and 1 patient had acute
myeloblastic leukemia (AML). In
72 patients with NHL or
ALL, the bone marrow
harvest was purged prior to storage with one of several monoclonal
antibodies. No chemical
agent was used for in
vitro treatment
of the bone marrow. Preparative
regimens in the 3 studies included cyclophosphamide
(total dose 120-150 mg/kg) and total body
irradiation (total
dose 1,200-1,575 rads).
Other regimens used in patients with Hodgkin's disease
and NHL without radiotherapy
consisted of 3 or more of the following in combination (expressed
as total dose): cytosine
arabinoside (400 mg/m2) and carmustine
(300 mg/m2), cyclophosphamide (140-150
mg/kg), hydroxyurea
(4.5 gm/m2) and etoposide (375-450
mg/m2).
Compared to placebo,
administration
of Leukine in 2 studies (n=44 and 47) significantly improved the
following hematologic and clinical
endpoints: time to neutrophil
engraftment, duration
of hospitalization
and infection experience or antibacterial
usage. In the third study
(n=37) there was a positive
trend toward earlier myeloid
engraftment in favor of Leukine. This latter study differed from
the other 2 in having enrolled a large number of patients with Hodgkin's
disease who had also
received extensive radiation and chemotherapy
prior to harvest of
autologous bone
marrow. A subgroup analysis
of the data from all 3 studies revealed that the median time to
engraftment for patients with Hodgkin's disease,
regardless of treatment, was 6 days longer when compared to patients
with NHL and ALL, but that
the overall beneficial Leukine treatment
effect was the same.
In the following combined analysis
of the 3 studies, these 2 subgroups (NHL and ALL
vs. Hodgkin's disease) are presented separately.
Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma
and Acute Lymphoblastic Leukemia): Myeloid engraftment (absolute
neutrophil count
[ANC] 3500 cells/mm3) in 54 patients
receiving Leukine was observed 6 days earlier than in 50 patients
treated with placebo (see table
below). Accelerated myeloid
engraftment was associated with significant clinical
benefits. The median
duration of hospitalization
was 6 days shorter for the Leukine group
than for the placebo
group. Median duration of infectious
episodes (defined as fever
and neutropenia; or 2 positive cultures of the same organism; or
fever >38C and
1 positive blood culture; or clinical
evidence of infection)
was 3 days less in the group treated with Leukine. The median
duration of antibacterial
administration in the post-transplantation period
was 4 days shorter for the patients treated with Leukine than for
placebo-treated patients. The study was unable to detect a significant
difference between the treatment
groups in rate of disease
relapse 24 months post-transplantation.
As a group, leukemic subjects
receiving Leukine derived less benefit
than NHL subjects. However,
both the leukemic and
NHL groups receiving Leukine
engrafted earlier than controls.
Autologous BMT: Combined Analysis from Placebo-
Controlled Clinical Trials of Responses
in Patients with NHL and
ALL Median Values (days)
| |
ANC 3500/mm3
|
ANC 31000/mm3
|
Duration of Hospitalization
|
Duration of Infection
|
Duration of Antibacterial Therapy
|
|
Leukine (n=54)
|
18*#
|
24*#
|
25*
|
1*
|
21*
|
|
Placebo (n=50)
|
24
|
32
|
31
|
4
|
25
|
* p <0.05 Wilcoxon or CMH ridit chi-squared
# p <0.05 Log rank
Note: The single AML patient
was not included.
Patients with Hodgkin's Disease: If patients with
Hodgkin's disease are analyzed separately, a trend
toward earlier myeloid
engraftment is noted. Leukine-treated patients engrafted earlier
(by 5 days) than the placebo-treated patients (p=0.189, Wilcoxon)
but the number of patients
was small (n=22). Studies are in progress
to confirm statistically the trend toward earlier engraftment with
Leukine in patients with Hodgkin's disease.
Allogeneic Bone Marrow Transplantation
A multi-center, randomized, placebo-controlled, and double-blinded
study was conducted to evaluate the safety and efficacy
of Leukine for promoting hematopoietic reconstitution
following allogeneic
BMT. A total of 109 patients (53 Leukine, 56 placebo) were enrolled
in the study. Twenty-three patients (11 Leukine, 12 placebo) were
18 years old or younger. Sixty-seven patients had myeloid
malignancies (33 AML, 34 CML), 17 had lymphoid
malignancies (12 ALL, 5 NHL), 3 patients had Hodgkin's disease,
6 had multiple myeloma,
9 had myelodysplastic disease,
and 7 patients had aplastic anemia. In
22 patients at one of the seven study sites, bone
marrow harvests were
depleted of T cells. Preparative regimens included cyclophosphamide,
busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids,
and asparaginase. Some patients also received total body, splenic,
or testicular irradiation.
Primary graft-versus-host disease
(GVHD) prophylaxis
was cyclosporine
A and a corticosteroid.
Accelerated myeloid
engraftment was associated with significant
laboratory and clinical
benefits. Compared to placebo,
administration
of Leukine significantly improved the following: time
to neutrophil engraftment,
duration of hospitalization,
number of patients with bacteremia
and overall incidence
of infection (see
table below).
Median time to myeloid
engraftment (ANC 3500 cells/mm3)
in 53 patients receiving Leukine (Sargramostim) was 4 days less
than in 56 patients treated with placebo
(see table below). The
number of patients with
bacteremia and infection
was significantly lower in the Leukine group compared to the placebo
group (9/53 versus 19/56
and 30/53 versus 42/56, respectively). There were a number
of secondary laboratory
and clinical endpoints. Of these, only the incidence
of severe (grade 3/4) mucositis was significantly improved in the
Leukine group (4/53) compared
to the placebo group (16/56)
at p<0.05. Leukine treated patients also had a shorter median
duration of post-transplant
IV antibiotic
infusions, and shorter median
number of days to last
platelet and RBC
transfusions compared to placebo
patients, but none of these differences reached statistical significance.
Allogeneic BMT: Analysis of Data from Placebo-Controlled
Clinical Trial Median Values (days or number
of patients)
| |
ANC 3500/mm3
|
ANC 31000/mm3
|
Number of Patients with Infections
|
Number of Patients with Bacteremia
|
Days of Hospitalization
|
|
Leukine (n=53)
|
13*
|
14*
|
30*
|
9**
|
25*
|
|
Placebo (n=56)
|
17
|
19
|
42
|
19
|
26
|
* p <0.05 generalized Wilcoxon test
** p <0.05 simple
Chi-square test
Bone Marrow Transplantation Failure or Engraftment Delay
A historically-controlled study was conducted in patients experiencing
graft failure following
allogeneic or autologous
BMT to determine whether
Leukine improved survival
after BMT failure.
Three categories of patients were eligible for this study:
1) patients displaying a delay in engraftment (ANC £
100 cells/mm3 by day 28 post-transplantation);
2) patients displaying a delay in engraftment (ANC £
100 cells/mm3 by day 21 post-transplantation)
and who had evidence
of an active infection; and
3) patients who lost their marrow
graft after a transient
engraftment (manifested by an average
of ANC ³
500 cells/mm3 for at least one week
followed by loss of engraftment
with ANC < 500 cells/mm3
for at least one week beyond day 21 post-transplantation).
A total of 140 eligible patients from 35 institutions were treated
with Leukine and evaluated in comparison to 103 historical control
patients from a single institution. One hundred sixty-three patients
had lymphoid or myeloid
leukemia, 24 patients had non-Hodgkin's lymphoma,
19 patients had Hodgkin's disease
and 37 patients had other diseases, such
as aplastic anemia, myelodysplasia
or non-hematologic malignancy. The majority of patients (223 out
of 243) had received prior chemotherapy
with or without radiotherapy and/or immunotherapy
prior to preparation
for transplantation.
One hundred day survival
was improved in favor of the patients treated with Leukine after
graft failure
following either autologous
or allogeneic BMT. In addition,
the median survival
was improved by greater than 2-fold. The median
survival of patients
treated with Leukine after autologous
failure was 474 days versus 161 days for the historical patients.
Similarly, after allogeneic failure, the median
survival was 97 days
with Leukine treatment and 35 days for the historical controls.
Improvement in survival
was better in patients with fewer impaired organs.
Median Survival by Multiple Organ Failure (MOF)
Category Median Survival (days)
| |
MOF <2 Organs |
MOF >2 Organs |
MOF (Composite of Both Groups) |
| Autologous BMT |
|
|
|
| Leukine |
474 (n=58) |
78.5 (n=10) |
474 (n=68) |
| Historical |
165 (n=14) |
39 (n=3) |
161 (n=17) |
| Allogeneic BMT |
|
|
|
| Leukine |
174 (n=50) |
27 (n=22) |
97 (n=72) |
| Historical |
52.5 (n=60) |
15.5 (n=26) |
35 (n=86) |
The MOF score is a simple
clinical and laboratory
assessment of 7 major
organ systems: cardiovascular,
respiratory, gastrointestinal,
hematologic, renal, hepatic
and neurologic.10
Assessment of the MOF score
is recommended as an additional method
of determining the need
to initiate treatment
with Leukine in patients with graft
failure or delay in engraftment following autologous
or allogeneic BMT.
Factors that Contribute to Survival: The probability
of survival was relatively greater for patients with any one of
the following characteristics: autologous BMT
failure or delay in
engraftment, exclusion
of total body irradiation from the preparative regimen, a non-leukemic
malignancy or MOF
score < 2 (0,
1 or 2 dysfunctional organ
systems). Leukemic subjects derived less benefit
than other subjects.
top
