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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3607-3615
A Double-Blind Placebo-Controlled Trial of Granulocyte
Colony-Stimulating Factor in Elderly Patients With Previously Untreated
Acute Myeloid Leukemia: A Southwest Oncology Group Study (9031)
By
John E. Godwin,
Kenneth J. Kopecky,
David R. Head,
Cheryl L. Willman,
Catherine P. Leith,
Harry E. Hynes,
Stanley P. Balcerzak, and
Frederick R. Appelbaum
From the Loyola University Chicago, Maywood, IL; the Southwest
Oncology Group Statistical Center, Seattle, WA; St Jude Children's
Research Hospital, Memphis, TN; the University of New Mexico,
Albuquerque, NM; the Wichita CCOP, Wichita, KS; the Ohio State
University Health Center, Columbus, OH; and the Puget Sound Oncology
Consortium, Seattle, WA.
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ABSTRACT |
Older age is a poor prognosis factor in acute myeloid leukemia
(AML). This double-blind trial was designed to test the hypothesis that
granulocyte colony-stimulating factor (G-CSF) used as supportive care
could improve the treatment of elderly AML patients. Two hundred
thirty-four patients 55 or more years of age with a morphologic diagnosis of de novo or secondary AML, French-American-British (FAB)
M0-M7, excluding M3, were randomly
assigned to a standard induction regimen (daunorubicin at 45 mg/m2 intravenously [IV] on days 1 through 3 and Ara-C at
200 mg/m2 IV continuous infusion on days 1 through 7) plus
either placebo or G-CSF (400 µg/m2 IV over 30 minutes
once daily). Results are reported here for 211 centrally confirmed
cases of non-M3 AML. The two groups were well balanced in
demographic, clinical, and hematological parameters, with median ages
of 68 years in the G-CSF and 67 years in the placebo groups. The
complete response (CR) rate was not significantly better in the G-CSF
group: 50% in the placebo and 41% in the G-CSF group (one-tailed
P = .89). Median overall survival was also similar, 9 months
(95% confidence interval [CI], 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in the G-CSF arms (P = .71).
We found a significant 15% reduction in the time to neutrophil
recovery in the G-CSF group (P = .014). G-CSF had no impact
on recovery from thrombocytopenia (P = .80) or duration of
first hospitalization (P = .27). When infection complications were evaluated, G-CSF had a beneficial effect on the duration but not
on incidence of infection. G-CSF patients had fewer days with fever and
shorter duration of antibiotic use. However, there was no difference in
the frequency of total documented infections or in the number of fatal
infections (19% placebo v 20% G-CSF). In this study of
elderly AML patients, G-CSF improved clinical parameters of duration of
neutropenia and antibiotic use, but did not change CR rate or survival
or shorten hospitalization.
| |
INTRODUCTION |
APPROXIMATELY 60% of all acute myeloid
leukemia (AML) cases in the United States are in patients greater than
60 years of age.1 Although progress has been made in the
treatment of AML in the younger patient using aggressive therapy such
as marrow transplantation2 or high-dose cytosine
arabinoside,3-5 older patients have not benefited.
Treatment decisions in elderly patients with AML are difficult and
remain controversial.6-8 When intensive chemotherapy is
administered for newly diagnosed AML, age has been repeatedly shown to
be a poor prognostic factor. With each decade above age 50, there is a
decrease in complete remission (CR) rate caused both by an increase in
induction deaths associated with infection and other toxicities, as
well as by an increase in leukemia resistance.9 For
example, the CR rate using a standard induction regimen of daunorubicin
and cytosine arabinoside in a recent trial reported by Mayer et
al3 was 75% in patients less than 40 years of age, but
only 47% in those greater than 60 years of age. Resistant disease was
seen in 16% of those less than 40 years of age but increased to 22%
in those more than 60 years of age.3 In recent reports of
several modern AML treatment trials, expected induction deaths ranged
from 6% to 10% for those less than 40 years of age, but from 20% to
30% for those greater than 60 years of age.1,10,11 Thus,
treatment of AML in the elderly patient presents special problems and,
because the median age in the United States at diagnosis is 64 years,
this is a major clinical challenge.
One approach to improve the treatment of AML in the elderly patient has
been the use of a myeloid growth factor as supportive care.12-14 Myeloid growth factors have been shown to
significantly reduce the incidence of infection associated with
intensive chemotherapy in some solid tumor patients and to accelerate
hematopoietic recovery after bone marrow
transplantation.15-17 However, neither the benefits nor the
risks of the use of myeloid growth factors in the treatment of AML have
been entirely defined. Recently published randomized studies of myeloid
growth factors in AML treatment have shown earlier myeloid recovery in
the growth factor arms when administered after chemotherapy, but no
major improvement has been seen in complete response rates or
disease-free survival.12,13,18 Although there is legitimate
concern that a myeloid growth factor could accelerate the regrowth of
leukemia, clinical studies to date do not suggest that this is a major
problem, especially if administered after leukemia cells are reduced by
chemotherapy.12,13,18,19
To better define the role of myeloid growth factors in the treatment of
AML in the elderly, we performed a double-blind placebo-controlled trial of recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) administered after standard induction
chemotherapy-induced marrow aplasia in elderly AML patients. Our goals
were to determine the safety of this treatment and its impact on the
complete response rates and duration of survival in patients 56 years
of age or older. We also examined, as secondary endpoints, the duration of neutropenia and thrombocytopenia, the total number of febrile days,
the number of days of antibiotic therapy, the number and type of
infection episodes, and the number of hospital days.
| |
PATIENTS AND METHODS |
Eligibility
Eligibility was limited to patients 56 years of age or older with AML,
French-American-British (FAB) class M0-M7, that
was morphologically confirmed by bone marrow aspiration, biopsy, and cytochemical staining.20 Patients with acute promyelocytic
leukemia, AML M3, and blastic transformation of chronic
myelogenous leukemia were excluded. Patients who received prior
chemotherapy for acute leukemia were not eligible, although
administration of hydroxyurea to control high cell counts was
permitted. Patients with AML after a previous diagnosis of
myelodysplastic syndrome (MDS) or after prior chemotherapy or
radiotherapy were eligible. A history of prior treatment of MDS with
low-dose cytosine arabinoside was permitted, but 30 days must have
elapsed from prior treatment and all toxicities must be
resolved. Patients who received prior treatment with
erythropoietin, G-CSF, granulocyte-macrophage colony-stimulating factor
(GM-CSF), or other myeloid growth factors were eligible. Patients had
normal liver, renal, and cardiac function as indicated by (1) a
bilirubin less than two times the institutional upper limits of normal,
(2) serum creatinine less than two times the institutional upper limits
of normal, and (3) an ejection fraction  50% as measured by mutigated
cardiac blood pool (MUGA) scan. Patients with unstable
cardiac arrhythmia or unstable angina and pregnant or lactating women
were not eligible.
Study Design
This was a double-blind placebo controlled study. After granting
informed consent, patients were randomly assigned to one of two
remission induction treatment arms: cytosine arabinoside (Ara-C) and
daunorubicin plus placebo or Ara-C and daunorubicin plus G-CSF. The
randomization was stratified by age (56 to 64 v 65+ years of
age) and by onset of leukemia (secondary v de novo) and
dynamically balanced using the method of Pocock and Simon21 to assure nearly equal numbers of patients within levels of the stratifying factors. All patients received induction chemotherapy, with
daunorubicin at 45 mg/m2 intravenously (IV) on days 1 through 3 and Ara-C at 200 mg/m2/d as a continuous IV
infusion on days 1 through 7. On day 10, a bone marrow
biopsy was performed. If the day-10 marrow was
hypocellular with blasts less than 5%, either G-CSF or placebo
treatment was begun on day 11. Patients randomized to G-CSF received
Escherichia coli-derived recombinant human G-CSF (r-metHuG-CSF;
Neupogen; Filgrastim; Amgen, Inc, Thousand Oaks, CA) at 400 µg/m2 IV over 30 minutes once daily. The G-CSF was
continued until the absolute neutrophil count (ANC) was
1,000/µL, and then tapered over 3 days. If the day-10 marrow showed
blasts 5%, a marrow biopsy was repeated on day 14. If
the day-14 marrow showed residual leukemia, a second induction using
the identical chemotherapy was adminstered. After the second induction,
patients received either G-CSF or placebo, depending on initial
randomization, when the bone marrow blasts were less than 5%. If
leukemic regrowth occurred after a second induction, the patient was
removed from protocol treatment. Leukemic regrowth was defined as a
marrow with 30% blasts after a prior marrow with less than 5% blasts. After induction therapy, patients who achieved CR were registered to
receive two courses of postremission therapy consisting of daunorubicin
at 30 mg/m2 IV on days 1 and 2 and Ara-C at 200 mg/m2/d as a continuous IV infusion on days 1 through 7, and patients received the same treatment assignment, G-CSF or placebo,
during postremission therapy starting on day 8 after chemotherapy.
Guidelines for supportive care stipulated that neutropenic patients
with a temperature of 38°C on more than one occasion within a
single (24 hours) day or a single temperature greater than 38.5°C should be treated with empiric antibiotics, including an aminoglycoside and semisynthetic penicillin or cephalosporin. Fungal prophylaxis was
determined by local practice, and patients with documented fungal
infections or fevers unresponsive to broad spectrum antibiotics after
72 hours were treated with amphotericin B. Platelet transfusions were
adminstered for bleeding manifestations and invasive procedures, and
prophylactically when the platelet count was less than 20,000/µL.
Definitions of Outcomes
Response was evaluated according to Southwest Oncology Group (SWOG)
criteria, as modified from National Cancer Institute
guidelines.20 CR was defined as a marrow with greater than
20% cellularity, with maturation of all cell lines, less than 5%
blasts, and no Auer rods; peripheral blood with neutrophils 1,500/µL,
platelets greater than 100,000/µL, and no leukemic blasts; and no
extramedullary disease. Overall survival (OS) was measured from the day
of randomization until death from any cause, with observation censored
for patients last known alive. Relapse-free survival (RFS) was measured
from the date CR was established until relapse or death from any cause with observation censored for patients last known alive without report
of relapse.
Treatment failures.
Patients who failed to achieve CR after induction were classified
according to the type of failure (resistant disease, death during
aplasia, or indeterminate).
Toxicity criteria.
The criteria used to determine severity of toxicity were those of the
SWOG.22
Neutropenia.
The duration of neutropenia was defined as the number of days from the
start of chemotherapy until the first day that the ANC was 500/µL
for 2 consecutive days.
Thrombocytopenia.
The duration of thrombocytopenia was defined as the number days from
the start of chemotherapy until the first day that the platelet count
remained 30,000/µL and was sustained without transfusion for 7 consecutive days or more.
Febrile days.
The number of febrile days was defined as the total number of days of
fever (oral or core body temperature of >38°C) from the start of
chemotherapy until first hospital discharge.
Antibiotic days.
The total number of days of IV antibiotic and/or antifungal
therapy from the start of chemotherapy until first hospital discharge was defined as antibiotic days. In addition, any use of amphotericin B
was tabulated as administered or not administered (see Table 3).
Numbers of infection.
Each infection was defined by the first occurrence with a culture
documented pathogen and a clinically evident focus. Any culture
documented infection, including oral thrush, or herpes viral infection
was included in the total number of infections (see Table 3). Fever of
unknown source did not constitute an infection. The presence or absence
of a documented fungal infection other than oral thrush was also
separately tabulated. In addition, the occurrence of pneumonia (defined
as chest infiltrates and clinical diagnosis) or documented sepsis
(bacteremia or fungemia) was recorded as present or absent.
Hospital days.
The number of hospital days was calculated from the start of
chemotherapy until first hospital discharge.
Statistical Methods
This study design called for randomization of 182 evaluable patients
(91 per arm), providing statistical power of 82% to detect an increase
in the CR rate from 40% to 60% (one-tailed test at critical level of
 = .05). This number of patients, accrued over 2 years and with 1 additional year of follow-up, would also provide 82% power to detect a
hazard ratio (placebo:G-CSF) of 1.5 in the analysis of OS, assuming a
median OS with placebo of 7 months for 56 to 64 years of age (45% of
patients) and 1.4 months for 65+ years of age (55%). Demographic and
clinical data for patients in this study were collected with quality
control review according to standard procedures of the SWOG. This study
was monitored throughout its accrual and follow-up phases by a Data
Monitoring Committee of which the investigators were not members. One
preplanned interim analysis was performed, but its results did not
require early termination of the study.
Treatment comparisons were based on assigned treatments, ie, G-CSF
patients who did not in fact receive G-CSF were retained in the G-CSF
arm. CR rates were analyzed using logistic regression models.23 Distributions of OS and RFS were estimated by the method of Kaplan and Meier.24 The effects of treatment,
patient, and disease characteristics on OS and RFS were analyzed using the proportional hazards regression model of Cox.25 Because neutropenia or thrombocytopenia may increase the risk of death, the
primary statistical analyses of neutrophil and platelet recovery were
not based on simple Kaplan-Meier estimates. It is well known that, when
the outcome of interest (eg, neutrophil recovery) is subject to
censoring by a nonindependent competing outcome (eg, death), the simple
Kaplan-Meier estimate is biased, and effects of a covariate, such as
treatment assignment, on the two outcomes are
nonidentifiable.26 The primary comparisons of endpoints for
neutrophil and platelet recovery were based on the procedure described
by Lin et al27 to control for dependent censoring. If OS is
similar in the two treatment arms, the problem of dependent censoring
may have little impact on the comparison between arms. For this reason
and for the comparability with prior studies that did not account for
dependent censoring, Kaplan-Meier plots were also calculated for time
to neutrophil and thrombocyte recovery. Numbers of febrile days,
antibiotic days, numbers of infection, and hospital days were compared
using the Wilcoxon rank sum test. Quantitative factors were treated as
continuous variables in regression analyses, but grouped when necessary
for descriptive tables or figures. In all analyses, statistical
significance of differences between treatment arms is expressed in
terms of one-tailed P values for improvement with G-CSF. All
other test results are reported as two-tailed P values. Results
are based on data available September 23, 1996.
| |
RESULTS |
Patient and Disease Characteristics
A total of 234 patients (116 randomized to G-CSF and 118 to placebo)
were registered on SWOG-9031 from 68 institutions between January 1992 and February 1994. Diagnoses of AML (non-M3) were confirmed
by central morphology review for 211 patients (90%; 106 G-CSF and 105 placebo). The other 23 patients included 10 with central review
diagnoses other than non-M3 AML: 4 RAEB, 1 M3
AML, 2 M0/L2 or
M0/M7/L2, and 3 with too few blasts
to meet the protocol definition of AML. For the other 13 patients,
adequate materials were not submitted for eligibility review. The
following analyses are based on intent to treat and include the 211 patients with centrally confirmed diagnoses of AML. Nine of these 211 cases failed to meet other eligibility criteria. Results from all 234 registered patients or the 202 fully eligible patients were separately analyzed and found to be similar to these results. Infection
complications, duration of hospitalization, and hematologic recovery
analysis are based on the numbers of patients evaluable for these
outcomes (see below). The 211 centrally confirmed cases were also the
basis for a prognostic factor analysis reported in detail
separately.28
The two treatment groups were well balanced with respect to
demographic, clinical, and hematologic factors
(Table 1). The median age was 67 years in
the placebo and 68 years in the G-CSF arm. About one fourth of the
patients in each arm had secondary AML (ie, reported prior MDS, prior
chemotherapy, or radiotherapy). Histories of treatment with
myelosuppressive therapy for other diseases before the diagnosis of AML
were reported for 11 patients in each treatment arm. Central nervous
system (CNS) involvement was reported for only 1 patient (on the G-CSF
arm), and prior exposure to myeloid growth factors was reported for 4 patients (1 G-CSF and 3 placebo).
Treatment
Three of the 211 patients (1 G-CSF and 2 placebo) did not receive
induction therapy according to the protocol: 1 patient refused, 1 received doxorubicin rather than daunorubicin, and 1 received induction
therapy for ALL. Including these 3, 51 patients (24%) did not receive
blinded drug: 10 (6 G-CSF and 4 placebo) died before the earliest
possible start of drug and 41 others (22 G-CSF and 19 placebo) never
received the study drug for other reasons, most frequently because they
had residual blasts in the marrow and never met the treatment
requirement of a marrow with less than 5% blasts (15 in each arm).
Three other patients, all randomized to G-CSF, received open label
G-CSF rather than blinded drug. Among the 160 patients (78 G-CSF and 82 placebo) who received blinded drug or open label G-CSF, 145 (91%)
completed all possible treatment: 116 (57 G-CSF and 59 placebo) were
treated until ANC recovery and 29 (18 G-CSF and 11 placebo) died or had
progression of leukemia while on blinded drug. The remaining 15 patients stopped receiving blinded drug early for a variety of reasons.
Reasons identified for more than 1 patient included prolonged
neutropenia (1 G-CSF and 3 placebo), patient refusal (2 placebo), and
decision to attempt other induction therapy (2 placebo).
Response to Induction Therapy
Ninety-five (45%) of the 211 patients achieved CR. Eighty-six patients
(41%) achieved CR after the first induction attempt. Of the remaining
125 patients, 48 received the second induction attempt, and 9 of these
48 patients (19%) achieved CR. Of the 116 patients who did not achieve
CR, the responses of 5 patients were not evaluated: these included 3 patients who did not receive induction therapy and 2 who were removed
from study by their institutions. The remaining 111 patients who did
not achieve CR had treatment failure classified according to standard
criteria as follows: 73 (35% of the 211) due to resistant disease; 19 (9%) due to complications of aplasia; and 19 (9%) due to treatment
failure of indeterminate cause.20
Table 2 summarizes CR rates by the
stratification factors, AML onset and age, and treatment assignment.
The CR rate was not significantly better in the G-CSF arm (41%
[43/106] v 50% [52/105] for placebo; one-tailed P = .89, with adjustment for stratification). The estimated regression
coefficient for the effect of G-CSF relative to placebo was  0.36
(95% confidence interval [CI], 0.92 to 0.21). In univariate
analyses, the CR rate did not vary significantly between age strata 65 years of age or older versus 56 to 64 years of age (two-tailed
P = .59), but did differ between the two AML onset groups
(two-tailed P = .0005). The CR rate was significantly lower for
patients with secondary AML 24% (12/50) compared with de novo 52%
(83/161). The CR rate appeared particularly low among secondary AML
patients in the G-CSF arm (12% [3/26]; Table 2). However, estimation
of the CR rate based on this small number of patients is imprecise: the
corresponding 95% CI is wide (2% to 30%) and substantially overlaps
that for the CR rate of 38% observed in the placebo patients (95% CI,
19% to 59%). In a multivariate analysis of response (reported by
Leith et al28), three independent prognostic factors were
identified: secondary AML, cytogenetic status, and MDR1 expression. The
CR rate was significantly worse for patients with secondary AML
(two-tailed P = .0035) or unfavorable cytogenetic status
(two-tailed P = .0031). MDR1 expression was evaluated by the
MDR1 specific antibody MRK16 and quantified by the Kolmogorov-Smirnov
(KS) statistic. The CR rate decreased with increasing expression of
MDR1:MRK16 negative (67% CR); dim (45% CR); and bright/moderate (34%
CR) (two-tailed P = .0041). (For more details, see Leith et
al.28) After accounting for these effects, none of the
other factors considered retained significant independent prognostic
association with CR, including age (treated as a continuous variable,
two-tailed P = .51). There was no evidence of higher CR rate in
the G-CSF arm in the multivariate analysis (one-tailed P = .97).
OS and RFS
Of the 211 patients, 180 have died. The remaining 31 patients were last
known to be alive between 18 and 53 months (median, 33 months) after
entering the study. Figure 1 shows a
Kaplan-Meier plot of the OS experience for all patients by
randomization arm. There was no significant difference in survival
between the placebo and G-CSF arms (one-tailed P = .71). The
estimated relative risk of death (G-CSF relative to placebo) was 1.09 (95% CI, 0.81 to 1.46). The median survivals were 9 months (95% CI, 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in
the G-CSF arm. Comparing survival by disease onset, the median OS was 8 months (95% CI, 6 to 9 months) for patients with de novo AML and 7 months (95% CI, 3 to 8 months) for those with secondary AML. Despite
these similar median survival times, OS appeared markedly poorer among
patients with secondary AML by 12 to 18 months
(Fig 2). Consequently, in univariate
analysis, OS was significantly associated with disease onset
(two-tailed P = .030) as well as age (treated as a continuous
variable P = .0003). Although secondary AML was significantly
associated with a lower CR rate and with shorter OS in the univariate
model, AML onset was not an independent prognostic factor for OS. In
the multivariate analyses reported by Leith et al,28 three
factors were found to have independent prognostic significance for OS.
OS was significantly worse for patients with unfavorable cytogenetics
(P < .0001) and with increasing age (P = .014) and
increasing white blood cell count (P = .029). After accounting for these effects, none of the other factors considered in this study was significantly associated with OS, including AML onset (two-tailed P = .29) and treatment
assignment (one-tailed P = .80).
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| Fig 1.
Kaplan-Meier estimates of the distributions of survival
from day of study entry, by treatment arm, based on 211 patients with centrally confirmed diagnoses of non-M3 AML. Tickmarks
indicate censored data.
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| Fig 2.
Kaplan-Meier estimates of the distributions of survival
from day of study entry, by disease onset, based on 211 patients with centrally confirmed diagnoses of non-M3 AML. Tickmarks
indicate censored data.
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Of the 95 patients who achieved CR (52 placebo and 43 G-CSF), 41 of 52 (79%) and 33 of 43 (77%) of the placebo and G-CSF arms, respectively,
received protocol postremission therapy. Reasons for failure to receive
postremission therapy on study included impaired cardiac function (7),
other medical reasons (7), correct or mistaken diagnosis of progression
of AML (6), and patient refusal (1). Of the patients who achieved CR,
77 have relapsed (44 placebo and 33 G-CSF), and 5 others (2 placebo and
3 G-CSF) have died without report of relapse, all due to consolidation
toxicities: infection, CNS hemorrhage, and complications of surgery.
RFS was not significantly better in the G-CSF arm (one-tailed P = .38). The estimated relative risk of relapse or death (G-CSF relative to placebo) was 0.93 (95% CI, 0.59 to 1.47). The median RFS was 9 months for the placebo group (95% CI, 7 to 10 months) and 8 months for
the G-CSF group (95% CI, 4 to 10 months;
Fig 3). In multivariate analyses, RFS was
significantly worse for patients with unfavorable cytogenetics
(P = .028), but was not significantly associated with any other
factors, including AML onset (P = .42), age (P = .75), or treatment assignment (P = .38).
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| Fig 3.
Kaplan-Meier estimates of the distributions of RFS from
day of CR, by treatment arm, based on 95 patients with centrally
confirmed diagnoses of non-M3 AML who achieved CR.
Tickmarks indicate censored data.
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Overall Toxicity and Infection
Toxicity of induction therapy was evaluated in 207 patients (104 G-CSF
and 103 placebo). The remaining 4 include 3 who did not receive
protocol induction therapy and 1 who was removed from study due to
pre-existing insufficient cardiac function. Nonhematologic toxicities
were comparable in the two treatment groups. Bone pain was reported for
only 1 G-CSF patient, compared with 5 placebo patients. Fatal induction
toxicities occurred in 20% (21/104) of the G-CSF group and 19%
(20/103) of the placebo arm. There was no apparent increase in leukemic
relapse in the G-CSF arm, because, as indicated above, the RFS did not
differ by treatment assignment.
To compare the infectious complications, several outcomes were measured
during the first hospitalization: the number of febrile days; the
duration of IV antibiotic therapy; the total number of documented
infectious episodes; the proportion of patients with fungal infections
other than oral Candida; the proportion requiring Amphotericin-B; the
proportion with pneumonia; the proportion with positive blood cultures;
and the frequency of infection-related deaths
(Table 3). The number of culture confirmed
infections during the first hospitalization was evaluated for 206 patients (103 G-CSF and 103 placebo). Twenty-eight (27%) of the G-CSF
patients had no documented infections during their first
hospitalization, whereas the other 75 (73%) had a total of 163 such
infections. In comparison, 37 (36%) of the placebo patients had no
documented infections, and the remaining 66 (64%) had a total of 141. The distribution of number of infections per patient was not
significantly lower on the G-CSF arm (P = .82), and there was
no evidence that G-CSF was associated with a reduced proportion of
patients with fungal infection, pneumonia, positive blood culture, or
treatment with Amphotericin-B (Table 3). Accounting for multiple
infections and varying lengths of hospitalization, it was noted that
the average rate of documented infection in the G-CSF arm (163 in 3,285 patient-days, or 1.5 per 30 patient-days) was not significantly different than the rate in the placebo arm (141 in 3,432 patient-days, or 1.2 per 30 patient-days). Infection was the most frequent cause of
induction death. However, the risk of fatal infections was not
significantly lower in the G-CSF arm, with 20 (19%) infection deaths,
compared with 14 (14%) in the placebo arm (P = .90).
However, some improvement was seen in the measures of infection
duration in the G-CSF arm. The number of febrile days during the first
hospitalization tended to be shorter for the G-CSF patients, with a
median of 8 days (range, 0 to 79 days), compared with 10 days (range, 0 to 34 days) for placebo patients (one-tailed P = .091), and the
number of days on IV antibiotics was decreased in the G-CSF arm, 22 days (range, 0 to 128 days), compared with 26 days (range, 0 to 69 days) for placebo patients, a marginally significant improvement
(one-tailed P = .053; Table 3).
Hematologic Recovery and Hospital Duration
The duration of neutropenia in the first induction course was evaluated
for 207 patients (104 G-CSF and 103 placebo). Neutrophil recovery was
observed in 149 patients (75 G-CSF and 74 placebo). Another 47 patients
(25 G-CSF and 22 placebo) died or relapsed without neutrophil recovery.
For the remaining 11 patients, hematologic follow-up was incomplete and
observation was therefore censored at the date of each patient's last
reported neutrophil count. On average, the duration of neutropenia was
15% shorter with G-CSF (95% CI, 3% to 27% shorter) compared with
placebo, which is a significant decrease (P = .014). For
comparison with results of previous studies, Kaplan-Meier curves were
calculated for time to neutrophil recovery. For reasons previously
discussed (see Statistical Methods), these curves should not be viewed
as unbiased estimates of the distributions of time to neutrophil
recovery. Nevertheless, it is apparent from
Fig 4 that the curves from our study are
similar to those reported previously. In particular, the median, ie,
the point at which the curve reaches 50%, was 24 days for the G-CSF
patients, 3 days less than the median for the placebo group. The fact
that our analysis, which is not based on the problematic assumptions
underlying the interpretation of the Kaplan-Meier curves and
corresponding log rank tests, found an effect consistent with those
reported earlier lends credence to the previous findings.
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| Fig 4.
Kaplan-Meier estimates of the distributions of time from
chemotherapy start until neutrophil recovery to greater than 500/µL, by treatment arm, based on 207 patients evaluated for this endpoint. Tickmarks indicate observations censored by death, relapse, or end of
follow-up.
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Recovery from thrombocytopenia was observed in 137 patients (64 G-CSF
and 73 placebo), whereas another 52 (29 G-CSF and 23 placebo) died
without platelet recovery. Observation was censored for the remaining
18 patients. There was no significant difference in the duration of
thrombocytopenia by treatment assignment (P = .80;
Fig 5). On average, duration of
thrombocytopenia was 7% longer with G-CSF; however, the 95% CI for
this difference included both longer and shorter durations of
thrombocytopenia, ranging from 12% shorter to 33% longer.
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| Fig 5.
Kaplan-Meier estimates of the distributions of time from
chemotherapy until platelet recovery to greater than 30,000/µL, by treatment arm, based on 207 patients evaluated for this endpoint. Tickmarks indicate observations censored by death, relapse, or end of
follow-up.
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The duration of hospitalization was evaluated for 207 patients (103 in
G-CSF and 104 placebo). Fifty-two patients died during their first
hospitalization (28 G-CSF and 24 placebo), and the remaining 155 were
discharged alive. The median length of the first hospitalization,
whether the patient was discharged alive or died in the hospital, was
29 days in each treatment arm (range, 4 to 155 days for G-CSF and 3 to
106 days for placebo). There was no difference in the length of
hospital stay in the G-CSF arm compared with placebo (one-tailed
P = .27). It must be stressed that there was no uniform
protocol for discharge criteria and that each investigation site had
different capabilities to provide G-CSF treatment or transfusions in
the outpatient setting.
| |
DISCUSSION |
This study demonstrates that G-CSF administered during induction
therapy for untreated AML in elderly patients, 56 years of age or
greater, significantly shortens the duration of neutropenia but does
not improve the rate of CR, OS, or disease-free survival. The use of
G-CSF in this elderly population reduced the duration of infection but
not its incidence, as evidenced by the decrease in febrile days and
days on intravenous antibiotics, but with no difference in the number
or type of documented infections or the number of fatal infections. The
use of G-CSF as a supportive care measure in this population was not
associated with an increase in toxicity or obvious evidence of leukemic
regrowth.
Our overall CR rate of 52% in the de novo AML group is similar to
recent results in other randomized trials of myeloid growth factors in
elderly AML patients.12-14 Our study design differs from
these trials in that we included secondary AML patients. This group
made up approximately one fourth of our study population (24%; Table
1). Secondary AML is commonly seen in the elderly, and our study
population therefore may more closely reflect the overall population
pattern of AML in the older patient. Secondary AML patients are known
to have a significantly worse prognosis, and our study confirms this
observation, with only a 24% CR rate in this group. Multivariate
analysis of these data showed that secondary AML, unfavorable
cytogenetics, and increasing MDR expression are independently
associated with decrease in CR. Thus disease characteristics seem to
play a predominant role in achieving CR in a population already
consisting of elderly AML patients. Evaluating this multiple logistic
regression analysis of CR rates, a referee has suggested that the
one-tailed P value of .97 observed in the G-CSF arm, if
converted to a two-sided test with the resulting P = .064, might be viewed as marginally significant evidence of a decreased CR
rate with G-CSF. However, such a result must be interpreted with
particular caution, because it was obtained in an exploratory post hoc
analysis. The evidence for such a detrimental effect of the G-CSF is
not at all significant in the stratified comparison for which this
study was designed: the one-tailed P value of .89 obtained for
this designed comparison corresponds to a stratified analysis
two-tailed P = .21.
The survival duration and RFS were similar in our trial to other recent
AML studies in the elderly and remain significantly worse than those
seen in patients less than 50 years of age. Despite the negative effect
on CR rate, secondary AML status was not an independent predictor of OS
in our multivariate analysis. In this analysis, the disease factor
unfavorable cytogenetics was associated with decreased survival; in
addition, age emerged as an independent poor prognosis factor for
survival.
The effect of G-CSF on myeloid recovery in our study is notably
consistent with that reported in other recent randomized trials of
G-CSF in AML patients.14,18 We estimated a 15% reduction (95% CI, 3% to 27%) in the average time to neutrophil recovery with
G-CSF, using an analysis that does not rely on a questionable assumption of independent censoring. Other investigators have reported
the effect on neutrophil recovery in terms of changes in median time to
recovery, as estimated using the product-limit method of Kaplan and
Meier.24 Reported reductions in the estimated median times
to recovery from neutropenia with G-CSF have included 6 days in elderly
AML (Dombret et al14), 5 days in adult AML patients (Heil
et al18), and 8 days in relapsed or refractory adult AML
patients (Ohno et al29). Our results lend credence to the
previous claims that G-CSF reduces the duration of neutropenia, because
we obtained results similar to those in the earlier reports if we use
the same analytic methods. The Kaplan-Meier estimate of the time to
median recovery was 3 days shorter with G-CSF compared with placebo in
our study. This consistency of results in different studies was seen
despite the fact that the proportion of patients who actually received
drug differed in each study and the timing of the initiation of G-CSF
was different in each study: day 8 in the study of Heil et
al,18 day 9 in the study of Dombret et al,14
day 10 to 14 in the study of Ohno et al,29 and day 11 to 15 in our own study. The present study methodology is similar to the CALGB
study reported by Stone et al13 in that
patients were randomized to receive growth factor before starting
induction chemotherapy. Therefore, some patients did not receive
blinded drug, which began no sooner than day 8 for the CALGB and day 11 for the present study. In the CALGB study, 27 to 388 (7%) did not
receive blinded drug; the corresponding figure is 51 to 211 (24%) for
the present study. In the studies of Ohno et al,29 Dombret
et al,14 and Heil et al,18 patients were
randomized to growth factor shortly before starting drug treatment and
thus all patients received the drug. However, there is no evidence that
the timing of randomization influenced the treatment comparisons of
myeloid recovery in the present study. For example, we can attempt to
simulate the effect of delaying randomization until the start of
blinded drug by considering only the 160 patients who actually received
blinded drug. This of course risks the introduction of bias from the
uncontrolled effects that determined whether patients actually received
blinded drugs. However, if we ignore this possible bias, the
Kaplan-Meier estimate of the median time to neutrophil recovery was 4 days shorter in the G-CSF arm, essentially the same as the difference
of 3 days based on all 211 eligible patients.
Two prior randomized studies report no difference in the overall
incidence of infection in AML with the use of G-CSF as supportive care
after chemotherapy.14,18 However, the duration of infection as measured by the surrogates of fever and IV antibiotic use were decreased in the study by Heil et al18 as well as by our
own study. Duration of infection was not evaluated in the trial by Dombret et al.14 These data are consistent with the known
myeloablative effect of AML therapy and the period of absolute
neutropenia during which the majority of these infections occur.
Myeloid growth factors cannot reverse absolute neutropenia in AML, but
they can shorten its duration. Another variable to consider when
comparing different myeloid growth factor trials, and especially when
considering the possible economic impact of the study, is the dose of
growth factor. Our study used a relatively high dose of G-CSF (400 µg/m2 IV), corresponding roughly to 10 to 12 µg/kg. In
the studies of Dombret et al14 and Heil et
al,18 G-CSF was administered at a lower dose (5 µg/kg),
with similar results regarding acceleration of myeloid recovery. Prior
studies and our own report indicate no effect on recovery from
thrombocytopenia with the use of G-CSF. These studies as well as our
own suggest no increase in overall toxicity or leukemia
regrowth.30
There is no significant qualitative difference in these results when
GM-CSF is studied in AML.12,13,31 In the studies reported
by Stone et al13 and Rowe et al12
in elderly patients with AML, there was no difference in CR rate or
overall incidence of infection with the use of GM-CSF. Whether there is
any effect with the use of either G-CSF or GM-CSF on particular
subgroups of patients with infectious complications in AML is still
unclear. Rowe et al12 reported a decrease in pneumonia
associated death in the GM-CSF arm compared with placebo. Heil et
al18 reported a reduction in the total number of patients
requiring amphotericin B use in the G-CSF arm but no difference in the
total incidence of fungal infections. The present study shows no
difference between G-CSF and placebo arms in the frequency of
pneumonia, documented fungal infections, amphotericin B use, frequency
of septicemia, or infection-related mortality.
Of the recently published randomized trials of myeloid growth factors
in elderly AML,12-14,18,31 only the study reported by Rowe
et al12 showed a difference in overall median survival with
the use of yeast-derived GM-CSF. In that study, the observed median
survival of the placebo arm was shorter than that seen in all the other
trials of elderly AML: the median OS survival give by Rowe et
al12 in the placebo arm was 4.8 months; that of the placebo
arm in Stone et al13 was about 11 months; that of the
placebo arm in Dombret et al14 was approximately 7.5 months; and our report indicates a median OS in the placebo arm of 9 months. The survival in the GM-CSF-treated arm reported by Rowe et
al12 (10.6 months) was similar to growth factor treated arms in the other randomized trials. The 7+3 chemotherapy induction regimen in the trial reported by Rowe et al12 administered
daunorubicin at a dose of 60 mg/m2, whereas the other
trials in the elderly, including our own, used daunorubicin at 45 mg/m2. It is unclear what role this difference in treatment
played in the demonstrated effect of GM-CSF on median
survival.30
Our study was designed to have statistical power at a level
conventionally sought in phase III cancer studies, ie, at least 80%
power to detect the design alternative hypothesis of a difference of 20 percentage points in the response rate or a hazard ratio of 1.5 in the
analysis of survival. Therefore, this study cannot by itself
conclusively rule out the possibility that G-CSF is associated with
improvements in response or survival that, although smaller than the
design alternatives, might nevertheless be of clinical interest.
However, the accumulating evidence from this and the other reported
trials of G-CSF and GM-CSF in AML suggest that the myeloid growth
factors are not strongly beneficial with regard to the endpoints of CR
rate or survival when administered as supportive care.32,33
In summary, our results indicate that the use of G-CSF after induction
chemotherapy is safe and can shorten myeloid recovery in the elderly
patient with AML, but does not increase the CR rate or confer a
survival benefit. The use of G-CSF or other myeloid growth factor as
supportive care in elderly AML can positively affect infection duration
and related outcomes. The use of G-CSF may impact the costs of AML
treatment, because some measures of infection duration are
significantly shortened and this could affect the economics of
antibiotic use or hospitalization. However, although these are positive
clinical benefits, the recommendation for the routine use of myeloid
growth factors in AML therapy should await the outcome of careful
analyses of the economic impact of this therapy in AML.
| |
FOOTNOTES |
Submitted May 20, 1997;
accepted January 2, 1998.
Supported in part by the following Public Health Services
Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services (Grants No.
CA38926, CA32101, CA04920, CA35431, CA58416, CA20319, CA12644, CA46441,
CA58686, CA37981, CA35128, CA04919, CA58658, CA35117, CA13612, CA46282, CA16385, CA58861, CA35176, CA12213, CA22433, CA28862, CA58415, CA42028,
CA45377, CA46136, CA46113, CA35192, CA27057, CA35261, CA42777, CA52654,
CA45450, CA45807, CA35090, CA52757, and CA35281).
Address reprint requests to Southwest Oncology Group (SWOG-9031),
Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
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.
| |
ACKNOWLEDGMENT |
The authors are indebted to the efforts of all the institutions who
participated in the trial and their data management teams; to Dr D.Y.
Lin for his insightful suggestions; and to the personnel in the
Statistical Center and Operations Office of the SWOG who made this
study possible.
| |
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Abstract
Introduction
Abstract