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From www.bloodjournal.org by guest on November 20, 2014. For personal use only.
1999 94: 3694-3701
A Randomized, Double-Blind, Placebo-Controlled Study With Pegylated
Recombinant Human Megakaryocyte Growth and Development Factor
(PEG-rHuMGDF) as an Adjunct to Chemotherapy for Adults With De Novo
Acute Myeloid Leukemia
Eric Archimbaud, Oliver G. Ottmann, John A. Liu Yin, Klaus Lechner, Herve Dombret, Miguel A. Sanz,
Gerhard Heil, Pierre Fenaux, Wolfram Brugger, Alan Barge, Caroline O'Brien-Ewen, James Matcham and
Dieter Hoelzer
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
A Randomized, Double-Blind, Placebo-Controlled Study With Pegylated
Recombinant Human Megakaryocyte Growth and Development Factor
(PEG-rHuMGDF) as an Adjunct to Chemotherapy for Adults
With De Novo Acute Myeloid Leukemia
By Eric Archimbaud†, Oliver G. Ottmann, John A. Liu Yin, Klaus Lechner, Herve Dombret,
Miguel A. Sanz, Gerhard Heil, Pierre Fenaux, Wolfram Brugger, Alan Barge,
Caroline O’Brien-Ewen, James Matcham, and Dieter Hoelzer
To determine the safety, biologic, and clinical benefits of
pegylated recombinant human megakaryocyte growth and
development factor (PEG-rHuMGDF; Amgen, Thousand Oaks,
CA) after myelosuppressive chemotherapy in acute myeloid
leukemia (AML), 108 adult patients with de novo AML were
randomized to receive either PEG-rHuMGDF (2.5 mg/kg/d or
5 mg/kg/d) for up to 21 doses (group A), a single dose of 2.5
mg/kg PEG-rHuMGDF, 7 daily doses of 2.5 mg/kg PEGrHuMGDF (group B), or placebo. The greatest biologic activity was seen in group A with a median peak platelet count of
1,084 3 109/L, occurring at a median 9 days after the last
dose of study drug, compared with 517 3 109/L and 390 3
109/L in group B and placebo group, respectively. Thrombo-
cytosis (platelets G1,000 3 109/L) was seen at rates of 52%,
8%, and 9% in groups A, B, and placebo, respectively, but
were not associated with any adverse event. There was no
effect on median time to transfusion independent platelet
recovery (H20 3 109/L). The median time to neutrophil
recovery (H500/µL) and red blood cell transfusion requirements were similar in all groups, and there was no apparent
stimulation of leukemia. PEG-rHuMGDF was biologically
active and well tolerated. Further investigation of dose and
scheduling is required, specifically earlier dosing before and
during chemotherapy.
r 1999 by The American Society of Hematology.
A
counts fall below 20 3 109/L or 10 3 109/L.6,7 Recent
randomized studies have shown that increasing intensity of
induction and consolidation therapy in young patients with
AML leads to increased disease-free and overall survival.2,5
Such increases in treatment intensity are likely to result in more
severe, prolonged thrombocytopenia, with higher associated
morbidity rates. Reducing the duration of severe thrombocytopenia could potentially reduce morbidity and mortality rates and
the cost of AML therapy.8 Prophylactic platelet transfusions are
routinely administered during periods of thrombocytopenia and
to treat bleeding events. However, platelet transfusions are
expensive and subject to the risks of acute transfusion reactions,
alloimmunization, and transmissible disease.9
The recent identification and cloning of thrombopoietin by a
number of groups has lead to considerable interest in the
application of this agent in the setting of AML.10-16
Polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF;
Amgen, Thousand Oaks, CA) is a polypeptide related to
thrombopoietin, which includes the receptor-binding N-terminal
domain. The polypeptide has 163 amino acids and is conjugated
with polyethylene glycol on the N-terminal by reductive
alkylation. In vitro, PEG-rHuMGDF is a growth and development factor for megakaryocytes.17,18 Administration of PEGrHuMGDF to normal animals increases megakaryocyte mass
and platelet counts.19,20 After myelosuppressive treatment, animals treated with PEG-rHuMGDF recover their platelet counts
more quickly than controls.21-23
Early human studies indicate that PEG-rHuMGDF will
produce rises in the platelet counts of patients before receiving
chemotherapy and will accelerate platelet recovery after myelosuppressive chemotherapy.24,25 The platelets produced in response to PEG-rHuMGDF appear to be morphologically and
functionally normal.26 PEG-rHuMGDF appeared to be well
CUTE MYELOID LEUKEMIA (AML) is characterized
by an uncontrolled proliferation of a clone of immature
myeloid cells in the bone marrow, leading to profound myelosuppression. Anemia, neutropenia, and thrombocytopenia are
present in most patients at presentation. Intensive induction
chemotherapy is the first step of any curative therapy and
usually consists of a combination of daunorubicin and cytarabine (Ara-C).1,2
Therapy-related deaths are mainly related to infection.3
Nevertheless, hemorrhagic events are the source of significant
mortality and morbidity both before treatment due to diseaserelated coagulation disorders and thrombocytopenia4 and as a
result of chemotherapy-induced thrombocytopenia. Thrombocytopenia after chemotherapy may last for 3 weeks or more2-5 and
prophylactic platelet transfusions are usually used when platelet
From the Hoˆpital Edouard Herriot, Lyon, France; University of
Frankfurt, Frankfurt, Germany; Manchester Royal Infirmary, Manchester, UK; University of Vienna, Vienna, Austria; Hoˆpital Saint-Louis,
Paris, France; Hospital Universitario Le Fe, Valencia, Spain; Hannover Medical School, Hannover, Germany; CHU Lille, France; University of Tu¨bingen, Tu¨bingen, Germany; and Amgen Ltd, Cambridge, UK.
†This paper is dedicated to Prof Eric Archimbaud, Hoˆpital Edouard
Herriot, Lyon, France, who died in March 1998.
Submitted April 6, 1999; accepted July 26, 1999.
Supported by Amgen Ltd, Cambridge.
Address reprint requests to Dieter Hoelzer, MD, PhD, Klinikum der
JWG-University of Frankfurt, Med. Klinik III/Haematologie/Onkologie, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
r 1999 by The American Society of Hematology.
0006-4971/99/9411-0036$3.00/0
3694
Blood, Vol 94, No 11 (December 1), 1999: pp 3694-3701
From www.bloodjournal.org by guest on November 20, 2014. For personal use only.
PEG-rHuMGDF AND CHEMOTHERAPY IN AML
tolerated at the doses used in these studies. We conducted a
study to determine the safety and biologic activity of PEGrHuMGDF in patients undergoing remission induction and
consolidation treatment for de novo AML.
MATERIALS AND METHODS
Patients
The study protocol was approved by the institutional review board of
the participating centers, and all patients gave written informed consent
before the study. Patients aged 16 and over with de novo AML as
defined by the French-American-British (FAB) classification system
and an Eastern Cooperative Oncology Group (ECOG) performance
score of 0, 1, 2, or 3 were eligible. Patients with FAB subtypes M3 and
M7, in blast transformation of chronic myeloid leukemia, or with a
history of clinically relevant coagulation disorders within the previous 6
months were excluded.
Study Design
Patients were registered for the trial at the start of the 7-day
chemotherapy regimen (day 1) and were randomized on days 5, 6, or 7
to receive PEG-rHuMGDF or placebo. In the first series, patients were
randomized to receive either 2.5 µg/kg/d PEG-rHuMGDF subcutaneously (sc), 5 µg/kg/d PEG-rHuMGDF sc, or placebo (1:1:1) from 24
hours after the last dose of chemotherapy until a transfusionindependent platelet count greater than or equal to 50 3 109/L. In the
second series, patients were randomized to receive 2.5 µg/kg PEGrHuMGDF sc either as a single dose administered on day 7, or for a
duration of 7 days (day 8 to day 14), or placebo (1:1:1). Patients were
stratified by age (,60 years and $60 years). The nomenclature for
patient groups adopted for analysis was as follows: patients receiving
PEG-rHuMGDF in the first series were referred to as group A, patients
receiving PEG-rHuMGDF in the second series were referred to as group
B, and all patients from both series receiving placebo were combined
into a single placebo group. Investigators, study site staff, and monitors
were blind to treatment assignment. The first induction chemotherapy
was administered from day 1 to day 7. A further 2 courses of
chemotherapy could be adminstered within the protocol, with study
drug administered after each course as originally randomized. Tests,
including diagnostic bone marrow, cytogenetics, full blood count, and
blood chemistry were obtained at baseline. Full blood counts were
measured daily from the start of study drug, and blood chemistry was
obtained at weekly intervals. Remission status was assessed from a
bone marrow examination after hematologic recovery. Serum was taken
for measurement of antibodies to PEG-rHuMGDF at baseline and at the
end of the study.
Chemotherapy
The first induction chemotherapy consisted of daunorubicin (45
mg/m2) for 3 days, Ara-C (100 mg/m2) twice a day for 7 days, and
etoposide (100 mg/m2) for 5 days (DAV 31715). The second course of
chemotherapy was determined by age and by remission status. Patients
younger than 60 years old received a second course of DAV 31715, if
in remission, and Ara-C (1 g/m2) for 4 days and mitoxantrone (12
mg/m2) for 3 days (MiDAC) if not in remission. All patients greater than
or equal to 60 years old, regardless of remission status, received a
second course consisting of daunorubicin (45 mg/m2) for 2 days, Ara-C
(100 mg/m2) twice a day for 5 days, and etoposide (100 mg/m2) for 5
days (DAV 21515). Patients not in complete remission (CR) after a
second induction were considered to have completed the study. After
CR, patients aged less than 60 years old received Ara-C (3 g/m2) for 6
days and daunorubicin (30 mg/m2) for 2 days; patients older than or
equal to 60 years old received DAV 21515 followed by the study drug.
3695
All chemotherapy courses were followed by the study drug as randomized.
Transfusion Policy
Prophylactic platelet transfusions were given in the absence of other
clinical indications when the morning platelet count was less than 20 3
109/L. Therapeutic transfusions were administered when clinically
indicated according to institutional policy. Packed red blood cell (RBC)
transfusions were given when the hemoglobin level was less than 8 g/dL
or when clinically indicated.
Statistical Analysis
All patients who received at least 1 dose of the study drug were
included in the analyses. The time to transfusion-independent platelet
recovery, neutrophil recovery, and peak platelet count were compared
between the treatment groups by using the log-rank test. The days of
platelet transfusion and of RBC transfusion were compared between
groups by using the Kolmogorov-Smirnov test. The number and types
of transfusion and reasons for transfusion were tabulated by treatment
group. All statistical tests have been performed with a two-sided
alternative hypothesis and the a 5 0.05 (5%) level of significance.
Estimates of treatment difference have also been calculated along with
associated 95% confidence intervals.
RESULTS
Patients
One hundred eleven patients were registered in the trial,
however, only 108 were randomized because 3 patients withdrew before randomization through ineligibility, death, and
withdrawal of consent. In the first series, 24 patients were
randomized to each of the PEG-rHuMGDF dose-to-target
cohorts and 22 were randomized to placebo. In the second
series, 12 patients were randomized to the single dose group, 14
to the 7-day dose group, and 12 to the placebo group. Patients
treated with PEG-rHuMGDF in the first and second series are
referred to as groups A and B, respectively, and the 2 placebo
groups have been combined. There were no significant differences between the groups with respect to age or other baseline
characteristics (Table 1).
The number of patients starting each course of chemotherapy
is shown in Table 2. There were 8 deaths during the study (3
patients in groups A/B, 5 patients in placebo); of the 8 deaths, 7
occurred during induction treatment and 1 after the second
consolidation treatment. Eight patient withdrawals were due to
adverse events (5 patients in groups A/B, 3 patients in placebo)
and 1 was due to withdrawal of consent (group B). Five patients
proceeded to alternative chemotherapy after completion of the
first induction course (4 patients from groups A/B, 1 patient
from the placebo group).
Disease Outcome
The remission rates for the individual patient cohorts are
given in Table 3. The overall remission rate in the study
population was 60% after 1 course of chemotherapy and 76%
after 2 courses. There was no evidence of an effect of
PEG-rHuMGDF on remission rate.
Effect of PEG-rHuMGDF on Platelet Recovery
Induction. The median daily platelet count for each individual treatment schedule, at the first induction, is shown in Fig
From www.bloodjournal.org by guest on November 20, 2014. For personal use only.
3696
ARCHIMBAUD ET AL
Table 1. Demographics and Disease Characteristics
Group B
Group A
PEG-rHuMGDF
2.5 µg/kg/d to Target (%)
No. of patients
Age
,60 yr
$60 yr
Median (yr)
Range
Sex
Male
Female
ECOG status
0
1
2
3
FAB subtype
M0
M1
M2
M4
M5
M6
Not assessed
Cytogenetic status
Normal
Abnormal*
Good
Intermediate
Poor
Not assessed
PEG-rHuMGDF
5 µg/kg/d to Target (%)
PEG-rHuMGDF
2.5 µg/kg/d Single Dose
[Day 8 only] (%)
PEG-rHuMGDF
2.5 µg/kg/d
[Days 8 to 14] (%)
Placebo
(%)
24
24
12
14
34
17 (71)
7 (29)
49
19-71
16 (67)
8 (33)
48
20-77
8 (67)
4 (33)
55
21-78
7 (50)
7 (50)
60
17-71
23 (68)
11 (32)
52
20-75
11 (46)
13 (54)
14 (58)
10 (42)
5 (42)
7 (58)
11 (79)
3 (21)
16 (47)
18 (53)
2 (8)
17 (71)
4 (17)
1 (4)
10 (42)
10 (42)
4 (17)
0 (0)
3 (25)
7 (58)
2 (17)
0 (0)
6 (43)
7 (50)
1 (7)
0 (0)
6 (18)
20 (59)
6 (18)
2 (6)
1 (4)
6 (25)
6 (25)
6 (25)
3 (13)
1 (4)
1 (4)
0 (0)
4 (17)
12 (50)
5 (21)
3 (13)
0 (0)
0 (0)
1 (8)
4 (33)
2 (17)
2 (17)
1 (8)
1 (8)
1 (8)
1 (7)
2 (14)
3 (21)
1 (7)
4 (29)
1 (7)
2 (14)
0 (0)
9 (26)
9 (26)
8 (24)
6 (18)
2 (6)
0 (0)
11 (46)
12 (50)
2 (8)
1 (4)
9 (38)
1 (4)
9 (38)
12 (50)
3 (13)
6 (25)
3 (13)
3 (13)
6 (50)
6 (50)
2 (17)
3 (25)
1 (8)
0 (0)
5 (36)
7 (50)
1 (7)
4 (29)
2 (14)
2 (14)
12 (35)
20 (59)
7 (35)
5 (25)
8 (40)
2 (6)
*Good: t(15,17), t(8,21), inv(16); Intermediate: abnormal; Poor: monosomy 5, 7, 7q-, 5q-, trisomy 8, 11q 23 abnormalities, complex abnormalities.
1. On subsequent grouping of patients from the 4 MGDF
treatment schedules into groups A and B, group A patients
showed a dose-dependent stimulation of platelet count peaking
a median of 9 days after stopping the study drug and a median of
20 days and 13 days in group B and placebo patients,
respectively. Taken from the start of chemotherapy, the median
time to peak platelet count was 29, 27, and 28 days in the 3
groups, respectively. Table 4 shows the platelet parameters; the
median peak platelet count in group A was 1,084 3 109/L,
compared with 517 3 109/L and 390 3 109/L in group B and
placebo patients, respectively. In addition, platelet counts rose
to greater than or equal to 1,000 3 109/L in 52%, 8%, and 9% of
patients in the 3 groups. The stimulation of platelet production
in group A did not translate into a significant shortening of the
time to transfusion-independent platelet recovery to greater than
or equal to 20 3 109/L. Figure 2 shows that there was no
difference in the median time to transfusion-independent platelet recovery between all patient groups. There was no signifiTable 2. Number of Patients Undergoing Chemotherapy Courses
Induction 1
Induction 2
Consolidation 1
Consolidation 2
Group A
Group B
Placebo
48
16
28
3
26
6
12
3
34
9
19
4
cant difference in the number of days on which a platelet
transfusion was required (4, 5, and 5.5 days in groups A, B, and
placebo, respectively; group A v placebo, P 5 .41; group B v
placebo, P 5 .44). Remission status was not an influencing
factor as time to platelet recovery for patients with persistent
disease was similar to those achieving CR. There was no effect
of PEG-rHuMGDF administration on time to neutrophil recovery to greater than or equal to 500 3 109/L (24.5, 28, and 26
days in groups A, B, and placebo, respectively). Granulocyte
colony-stimulating factor (G-CSF) usage was balanced between
the groups.
Consolidation. The median daily platelet count for each
individual treatment schedule at the first consolidation is shown
in Fig 3; the platelet parameters are summarized in Table 5, and
time to platelet recovery is shown in Fig 4. There was no
significant difference between any of the curves presented in
Figs 3 and 4. Thus, none of the patient groups undergoing
consolidation and treated with PEG-rHuMGDF behaved differently from other groups nor from placebo treated subjects in
terms of platelet response, which reflects the response found at
induction.
Adverse Events
The nature and incidence of reported adverse events were
similar in all treatment groups for all phases of the study. In
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PEG-rHuMGDF AND CHEMOTHERAPY IN AML
3697
Table 3. Outcome of Induction Chemotherapy
Group A
Group B
PEG-rHuMGDF
2.5 µg/kg/d to Target
PEG-rHuMGDF
5 µg/kg/d to Target
PEG-rHuMGDF
2.5 µg/kg/d Day 8
PEG-rHuMGDF
2.5 µg/kg/d Days 8 to 14
All PEG-rHuMGDF
Patients
Placebo
24
16
8
0
67%
24
13
10
1
54%
12
8
3
1
67%
14
7
6
0
50%
74
44
27
2
59%
34
21
9
4
62%
7
3
4
0
43%
9
4
4
1
44%
2
1
0
1
50%
4
2
2
0
50%
22
10
10
2
45%
9
7
2
0
78%
79%
71%
75%
64%
73%
82%
Induction 1
No. of patients
Complete remission
Persistant disease
Induction 1 deaths
Remission rate after induction 1
Induction 2
No. of patients
Complete remission
Persistant disease
Not assessed
Remission rate after induction 2
Overall remission rate
Remission rate odds ratio (all PEG-rHuMGDF patients v placebo patients). Induction 1: 0.91 (0.40, 2.09); Induction 2: 0.23 (0.04, 1.35).
induction 1, the most frequently reported events considered
related to the study drug were fever (PEG-rHuMGDF 4%,
placebo 0%) and thrombocytosis (.1,000 3 109/L) (PEGrHuMGDF 13%, placebo 0%). All other events reported as
treatment related were single patient reports. In consolidation,
the overall incidence of treatment-related adverse events was
8% in PEG-rHuMGDF treated patients and 4% in the placebo
group, for which all were single patient reports (1 case each of
colitis, rash, and thrombophlebitis in the active groups and 1
case of venous thrombosis in the placebo group). There were 4
reports of thrombotic events during the study period, 2 in
PEG-rHuMGDF and 2 in placebo patients (Table 6); the platelet
counts at the time of each event do not show an association with
the administration of the study drug. There were no differences
between the treatment groups in the nature, frequency, or
severity of events. Overall, PEG-rHuMGDF was well tolerated.
No neutralizing antibodies to MGDF were detected in serum
samples obtained from 103 patients before and after the study
drug was administered with a solid phase screening radioimmunoassay.
DISCUSSION
This is the first reported experience of the use of PEGrHuMGDF after chemotherapy for AML and suggests that daily
sc doses of 2.5 µg/kg/d and 5 µg/kg/d administered to recovery
of a target platelet count stimulate platelet production and are
well tolerated. These results are consistent with observations
made in other recently published studies of PEG-rHuMGDF in
patients with solid tumors.24,25,27
The doses and schedule of PEG-rHuMGDF administered to
the first series of patients led to marked thrombocytosis after
recovery, peaking 9 days after discontinuing the cytokine.
Despite marked postrecovery thrombocytosis, PEGrHuMGDF had no effect on the time to transfusion independent
recovery of platelets to greater than or equal to 20 3 109/L. The
explanation for this is not clear, but may lie in the kinetics of
megakaryocyte differentiation and platelet production in response to PEG-rHuMGDF as indicated by in vitro studies.17
These suggest that there is a relatively fixed time period of 6 to 8
days from exposure of primitive progenitor cells to PEGrHuMGDF and the appearance of megakaryocytes and a further
4-day delay in platelet release. In this study, in the placebo
group, spontaneous platelet recovery occurred 14 days after the
initiation of the study drug, most likely stimulated by the higher
than normal levels of endogenous thrombopoietin in patients
with chemotherapy-induced thrombocytopenia.28 In retrospect,
it may have been unrealistic to expect PEG-rHuMGDF to
Table 4. Platelet Parameters—First Induction
Group A
Fig 1.
Median platelet counts —first induction.
No. of patients
Median peak platelet count (3109/L)
Range
Median time to peak platelet count after
last dose (days)
Range
Median time to peak platelet count after
start of chemotherapy (days)
Range
Percentage of patients with platelet
count .1,000 3 109/L
Median days to transfusion-independent platelet recovery .20 3 109/L
Range
Group B
Placebo
48
26
34
1,084
517
390
33-3,745 25-1,390 18-1,514
9
0-15
20
0-25
13
0-28
29
12-37
27
8-38
28
10-52
52%
21
13-43
8%
20.5
14-32
9%
21
12-36
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3698
ARCHIMBAUD ET AL
Table 5. Platelet Parameters—Consolidation
Group A
Group B
Placebo
No. of patients
31
15
23
416
498
409
Median peak platelet count (3109/L)
Range
73-2,425 49-1,041 66-1,101
Median time to peak platelet count after
last dose (days)
11
21
14
Range
7-28
12-42
7-32
Median time to peak platelet count after
start of chemotherapy (days)
29
28
29
Range
9-43
23-40
22-43
Percentage of patients with platelet
19%
6%
4%
count .1,000 3 109/L
Median days to transfusion-indepen17
19
19
dent platelet recovery .20 3 109/L
Range
14-48
15-34
15-42
Fig 2.
Time to platelet recovery (H 20 3 109/L)— first induction.
substantially shorten this period of severe thrombocytopenia.
As a consequence, there was little impact on the use of platelet
transfusions.
Although maximum platelet counts exceeding 1,000 3 109/L
were observed in approximately 50% of the patients, no excess
of thrombotic events was noted in the PEG-rHuMGDF–treated
patients. This may indicate that the platelets produced in
response to PEG-rHuMGDF function normally and do not
exhibit enhanced aggregation in vivo. This is consistent with the
observation of relatively modest effects on platelet aggregation
activation by PEG-rHuMGDF in vitro29-32 and the absence of
activation in vivo.20,26 Interestingly, we also observed platelet
counts of greater than 1,000 3 109/L in patients in the placebo
group, most likely because of the effects of endogenous
hematopoietic growth factors, including endogenous thrombopoietin, after intensive chemotherapy.
The most likely explanation for the observed thrombocytosis
is the time-dependent generation of megakaryocytes in response
to PEG-rHuMGDF, which in vitro takes a minimum of approximately 8 days. Since the maximum platelet counts occurred
approximately 8 days after cessation of PEG-rHuMGDF administration, it is likely that progenitor cells, present in the bone
marrow at the time of the last few doses, were stimulated to
Fig 3. Median platelet counts from start of chemotherapy—
consolidation.
begin differentiation into megakaryocytes and completed their
maturation approximately 8 days later. Another potential contributing factor may be the prolonged circulation of PEGrHuMGDF after discontinuation of therapy. The in vivo halflife of PEG-rHuMGDF in this population has not been evaluated.
However, it is estimated to be 30 to 36 hours in cancer patients
after conventional chemotherapy.33
The administration of 2.5 µg/kg PEG-rHuMGDF as a single
dose and 2.5 µg/kg for 7 days showed no difference from
placebo with respect to platelet recovery or transfusion requirement. Accordingly, there was no evidence of significant thrombocytosis after recovery, unlike that observed in the earlier
groups of patients who received the same daily doses of
PEG-rHuMGDF until platelet recovery.
Effects of PEG-rHuMGDF after consolidation chemotherapy
were similar to those observed after induction. Daily administration of PEG-rHuMGDF did not significantly affect the duration
of severe thrombocytopenia. Alternative schedules of 7-day or
single doses of PEG-rHuMGDF did not significantly change the
profile of platelet recovery, although postrecovery thrombocytosis was avoided.
There was no effect of PEG-rHuMGDF on the rate of
neutrophil recovery or the requirement for RBC transfusions,
indicating the lack of clinically important effects on other cell
lineages in this setting. The lack of effect on neutrophil recovery
observed in our patients is consistent with the majority of
animal studies,19,21,23,34 although some studies showed an accel-
Fig 4.
Time to platelet recovery (H 20 3 109/L)—consolidation.
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PEG-rHuMGDF AND CHEMOTHERAPY IN AML
3699
Table 6. Thrombotic Events
Event
Cerebral infarction
Subclavian vein thrombosis (catheter associated)
Thrombosis in mesenteric vein (operative
specimen)
Brachiocephalic/subclavian vein thrombosis
(catheter associated)
Platelet Count
(3109/L) at Time
of Event
8 3 109/L
3,174 3 109/L
73
109/L
546 3 109/L
Treatment
Arm
Placebo
PEG-rHuMGDF to target
(Gp A)
PEG-rHuMGDF to target
(Gp A)
Placebo
eration of neutrophil recovery by thrombopoietin.35,36 Phase 1
clinical studies also showed no evidence of significant stimulation of neutrophil recovery by PEG-rHuMGDF.24,25 Stimulation
of erythropoiesis may be anticipated in some settings, given the
known in vitro synergy between the 2 molecules37 as was
observed in some animal models35,38,39 but not in phase 1
studies.24,25
The overall CR rate observed in our PEG-rHuMGDF–treated
patients was 73%, not significantly different from the rate
observed in the placebo arm, indicating a lack of any marked
stimulation of leukemic cells by the administration of PEGrHuMGDF. Such a stimulation is theoretically possible, despite
exclusion of the rare subgroup of M7 AML from our study,
because it is known that leukemic cells from 20% to 60% of
patients with nonmegakaryoblastic AML express Mpl,40-43 and,
in some cases, show proliferative responses in vitro to PEGrHuMGDF.41,44 The safety of myeloid growth factors after
chemotherapy for AML (G-CSF45-48 and GM [granulocytemacrophage]-CSF49-51) has been well established.
This study has shown that PEG-rHuMGDF is biologically
active and well tolerated in patients undergoing induction and
consolidation therapy for AML. So far, no antibodies against
PEG-rHuMGDF have been detected in AML patients, including
the patients in this study. Despite clear evidence of lineagedominant activity, treatment with PEG-rHuMGDF at these
doses and schedules, after chemotherapy, produced no clinical
benefit. The explanation for this is not clear, but may reflect the
difficulty in influencing the apparently obligatory 8 to 12 days
required for progenitor cells to proliferate and mature into
megakaryocytes. After the end of induction chemotherapy,
platelet production in control patients recovered to 20 3 109/L
platelets in approximately 14 days. Because platelets appearing
in the circulation at that point are produced by megakaryocytes
whose maturation began at least 8 days earlier, this suggests that
there may be a very limited ‘‘window,’’ of perhaps only 6 days,
after chemotherapy, in which PEG-rHuMGDF may realistically
influence the number or differentiation of megakaryocyte
progenitors. To exert such an influence, the presence of
progenitors capable of responding to PEG-rHuMGDF in the
bone marrow would be essential during this early period after
the end of chemotherapy. In view of these considerations,
alternative, earlier dosing schedules of PEG-rHuMGDF may
need to be investigated. The scope for this in the context of
induction therapy may be limited by the disease and by the need
to initiate chemotherapy as quickly as possible. Such limitations
may not apply in consolidation, in which prospective expansion
of the megakaryocyte mass in the bone marrow, before chemotherapy, may offer the best opportunity of exploiting the
biologic effects of PEG-rHuMGDF.
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