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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1556-1564
A Randomized Controlled Trial of Filgrastim During Remission
Induction and Consolidation Chemotherapy for Adults With Acute
Lymphoblastic Leukemia: CALGB Study 9111
By
Richard A. Larson,
Richard K. Dodge,
Charles A. Linker,
Richard M. Stone,
Bayard L. Powell,
Edward J. Lee,
Philip Schulman,
Frederick R. Davey,
Stanley R. Frankel,
Clara D. Bloomfield,
Stephen L. George, and
Charles A. Schiffer
From the University of Chicago, IL; the Cancer and Leukemia Group B
Statistical Center, Durham, NC; the University of California in San
Francisco, CA; the Dana Farber Cancer Institute, Boston, MA; Wake
Forest University School of Medicine, Winston-Salem, NC; the University
of Maryland, Baltimore, MD; North Shore University Hospital, Manhasset,
NY; the State University of New York Health Science Center at Syracuse,
NY; the Roswell Park Cancer Institute, Buffalo, NY; the Ohio State
University, Columbus, OH; and the Cancer and Leukemia Group B (CALGB),
Chicago, IL.
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ABSTRACT |
Recombinant human granulocyte colony-stimulating factor (G-CSF;
filgrastim) shortens the time to neutrophil recovery after intensive
chemotherapy, but its role in the treatment of adults with acute
lymphoblastic leukemia (ALL) is uncertain. We randomly assigned 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) to
receive either placebo or G-CSF (5 µg/kg/d) subcutaneously, beginning
4 days after starting intensive remission induction chemotherapy and
continuing until the neutrophil count was  1,000/µL for 2 days. The
study assignment was unblinded as individual patients achieved a
complete remission (CR). Patients initially assigned to G-CSF then
continued to receive G-CSF through 2 monthly courses of consolidation
therapy. Patients assigned to placebo received no further study drug.
The median time to recover neutrophils 1,000/µL during the
remission induction course was 16 days (interquartile range [IQR], 15 to 18 days) for the patients assigned to receive G-CSF and 22 days
(IQR, 19 to 29 days) for the patients assigned to placebo (P
< .001). Patients in the G-CSF group had significantly shorter
durations of neutropenia (<1,000/µL) and thrombocytopenia
(<50,000/µL) and fewer days in the hospital (median, 22 days
v 28 days; P = .02) compared with patients receiving
placebo. The patients assigned to receive G-CSF had a higher CR rate
and fewer deaths during remission induction than did those receiving
placebo (P = .04 by the chi-square test for trend). During
Courses IIA and IIB of consolidation treatment, patients in the G-CSF
group had significantly more rapid recovery of neutrophils
1,000/µL than did the control group by approximately 6 to 9 days.
However, the patients in the G-CSF group did not complete the planned
first 3 months of chemotherapy any more rapidly than did the patients
in the placebo group. Overall toxicity was not lessened by the use of
G-CSF. After a median follow-up of 4.7 years, there were no significant
differences in either the disease-free survival (P = .53) or
the overall survival (P = .25) for the patients assigned to
G-CSF (medians, 2.3 years and 2.4 years, respectively) compared with
those assigned to placebo (medians, 1.7 and 1.8 years, respectively).
Adults who received intensive chemotherapy for ALL benefited from G-CSF
treatment, but its use did not markedly affect the ultimate outcome.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
INTENSIVE MULTI-AGENT chemotherapy
programs produce complete remissions (CR) in the majority of adults
with acute lymphoblastic leukemia (ALL). The major cause of
treatment-related morbidity and mortality is infection due in part to
bone marrow suppression by cytotoxic therapy. In a recent Cancer and
Leukemia Group B (CALGB) trial using five chemotherapy drugs in
combination, 84% of adult ALL patients achieved a CR, but 9% died
during remission induction.1 This myelosuppressive regimen
caused, on average, 21 days of severe granulocytopenia (<500
neutrophils/µL) and 19 days of thrombocytopenia (<50,000/µL)
during the initial remission induction course. Therefore, the CALGB
designed a study to test the effectiveness of filgrastim (granulocyte
colony-stimulating factor [G-CSF]) in reducing the complications of
treatment by potentially shortening the time to neutrophil recovery
following courses of remission induction chemotherapy and postremission consolidation treatment.
The primary objectives of this randomized, double-blind, clinical trial
were to compare the time to bone marrow recovery, the incidence of
infections, the days of hospitalization, and the side effects of
treatment after intensive chemotherapy for ALL in patients treated
either with G-CSF or with placebo. In addition, we determined the
effect of G-CSF on the rate and duration of CR and the incidence of
death during treatment. We also compared the dose intensity of
chemotherapy that was delivered to patients assigned to receive G-CSF
or placebo during the first 3 months of treatment. Finally, we
continued to investigate the prognostic significance of disease and
patient entry characteristics for disease-free survival (DFS) using
this treatment program.
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MATERIALS AND METHODS |
Eligibility.
Patients 15 years or older with previously untreated ALL were eligible
for entry onto the trial. To support the diagnosis, cytochemistry and
immunophenotyping studies performed at each institution had to be
consistent with the diagnosis of ALL as defined by the
French-American-British (FAB) classification system.2,3 Emergency treatment of rapidly progressive hyperleukocytosis with hydroxyurea for up to 72 hours before entry on the study or the emergency use of leukapheresis was permissible. A single dose of
cranial irradiation for central nervous system (CNS) leukostasis was
also permissible. Unless directly attributable to leukemia, patients
were required to have a total bilirubin concentration and serum
creatinine level of less than 1.5 times the upper limits of normal at
each institution.
Study entry.
Written informed consent was obtained from all patients before entry on
the study. Patients were registered and randomly assigned to one of the
two treatment groups via a telephone call to the CALGB Statistical
Center before treatment. The diagnosis of ALL was confirmed by central
review of pretreatment blood smears and bone marrow specimens for
cytological and cytochemical features according to the FAB criteria. It
was recommended that pretreatment blood and marrow specimens be
submitted for cytogenetic analysis, including central review of the
karyotypes (CALGB study 8461). A lumbar puncture for spinal fluid
examination was performed only when there was clinical suspicion of CNS
disease.
Immunophenotyping (CALGB study 8364) was performed by multiparameter
flow cytometry in a central CALGB laboratory, using a panel of
monoclonal antibodies and indirect immunofluorescence.1 The
criterion for surface marker positivity was expression by at least 20%
of the leukemia blast cell population. B-lineage was defined as CD19 or
CD20 positivity. T-lineage was defined by CD2 or CD7 expression
together with CD1, CD3, CD4, CD5, or CD8 reactivity. Myeloid (My)
antigen expression included CD13 or CD33. Expression of the common ALL
antigen was assessed by CD10 reactivity. Cases coexpressing lymphoid
and myeloid antigens (BMy or TMy) were generally classified according
to their lymphoid lineage (B- or T-cell, respectively). Cases
expressing combinations of both B- and T-lineage antigens were
classified as BT, BTMy, or miscellaneous. Cases expressing surface
membrane immunoglobulin were considered FAB-L3 (Burkitt-type ALL) and
were not included among the other B-lineage cases in subsequent
analyses. Patients diagnosed with L3 ALL at the treating institution
were not excluded from this trial but were recommended for entry onto a
different CALGB trial running concurrently. Patients with
myeloperoxidase negative blasts that expressed only myeloid antigens
(and not B- or T-lymphoid antigens) were considered acute myeloid
leukemia (AML), subtype M0, and were classified as ineligible.
Treatment protocol.
Drugs and dosages used in the induction (Course I), consolidation
(Courses IIA and IIB), late intensification (Course IV), and
maintenance (Courses III and V) phases of treatment are listed in
Table 1. A complete report of the outcome
of 214 patients treated with this same chemotherapy regimen in a prior
study (CALGB study 8811) has been previously published.1
The total duration of treatment was 24 months. Testicular biopsies were
not required at the end of therapy, and testicular radiation was not
administered prophylactically. Patients who had an isolated CNS relapse
while continuing in marrow remission were counted as relapses. However,
they continued to receive systemic chemotherapy on protocol after
treatment with additional intrathecal chemotherapy. Patients with
unfavorable cytogenetic features [ie, the Philadelphia (Ph)
chromosome, t(9;22), t(4;11), t(8;14), or a variant] were recommended
to be withdrawn from this trial in first remission and undergo
allogeneic bone marrow transplantation, if it were feasible.
The use of oral nonabsorbable antibiotics, the management
of febrile episodes and transfusions, and the criteria for
hospitalization were not prescribed by the protocol, but rather were
left to institutional guidelines. Prophylactic systemic antibacterial
antibiotics were not permitted during Courses I and II of treatment,
but oral nonabsorbable antifungal drugs could be used prophylactically.
Co-trimoxazole or aerosolized pentamidine were recommended for
pneumocystis prophylaxis, starting in Course III.
No hematopoietic growth factors were permitted for supportive care
except as specified as part of the chemotherapy treatment on this
protocol.
On day 4, approximately 12 to 24 hours after the third dose of
daunorubicin, patients received the first subcutaneous injection of the
study drug (either G-CSF at 5 µg/kg/d or placebo). The subcutaneous
injections continued once daily for at least 7 days and until the
absolute neutrophil count (ANC) was 1,000/µL for two consecutive
determinations more than 24 hours apart. If the patient were otherwise
eligible for earlier discharge from the hospital, he or she was allowed
to self-administer the study drug subcutaneously at home. Once the
study drug was discontinued, it was not restarted again during that
particular treatment course, even if the neutrophil count fell below
1,000/µL.
After evaluation of the bone marrow exam on day 29 of the initial
induction course, the study drug assignment was unblinded by the
treating physician and pharmacist. Patients who had been randomly
assigned to placebo during Course I no longer received study drug
injections during Course II. Patients who had been randomly assigned to
receive G-CSF in a blinded fashion during Course I continued to receive
G-CSF at the same dose (5 µg/kg/d) in an unblinded, open-label
fashion during Course II. Patients or family members were taught to
administer daily subcutaneous injections at home.
During Courses IIA and IIB, the G-CSF injections began on day 2, ie,
the day after the cyclophosphamide dose. The G-CSF treatment continued
concurrently with the chemotherapy daily for at least 14 days after
which time it was discontinued if the ANC were 5,000/µL for two
consecutive determinations more than 24 hours apart. In every case the
G-CSF was stopped at least 2 days before the next cyclophosphamide
treatment. Priority was given to starting the cyclophosphamide
treatment in Course IIB on schedule, ie, 29 days after starting Course
IIA. Thus, for patients receiving G-CSF who had recovered 1,000
neutrophils/µL and 50,000 platelets/µL, the cyclophosphamide for
Course IIB was administered on day 29 of Course IIA even if the ANC had
not yet reached 5,000/µL by day 27.
Data quality control.
All data on this study were required to be submitted to the CALGB Data
Management Center on specified forms. CALGB central data management
personnel were responsible for quality assurance of the submitted data.
Eligibility criteria were verified for all patients and an evaluation
of treatment, response, and toxicity was made by the study chair
(R.A.L.). In addition, as part of the group data-monitoring program,
members of the CALGB Data Audit Committee made periodic site visits to
all institutions to verify compliance with federal regulations and
protocol requirements, including eligibility, treatment, response data,
and follow-up.4 A random subset of 54 patients (27%)
treated on this study had such an on-site review of their medical
records.
Criteria for response.
Patients were considered to be in CR when the neutrophil count was
1,500/µL, the platelet count was 100,000/µL, the results of a
bone marrow examination were normal (with <5% blasts), and all
extramedullary disease had resolved. Patients with >25% lymphoblasts remaining in the marrow after Course I were removed from this protocol.
All patients were required to have achieved CR by the end of
Course IIA to remain on the study. Relapse was confirmed by the
reappearance of >25% lymphoblasts in the bone marrow or blood or the
presence of leukemia cells in the spinal fluid after remission.
Randomization.
Patients were stratified by institution and randomly assigned in a
double-blinded fashion at the time of registration on the study to
treatment with either G-CSF or placebo. At each institution only one
investigational drug pharmacist who was not directly involved in the
patient's care was aware of the treatment assignment.
Statistical methods.
The primary analyses in this study followed the intention-to-treat
principle, which requires all patients who are randomized to be
included in the analysis regardless of eligibility status or the
treatment actually received. Because all enrolled patients were
randomized, no patients were excluded from the primary analyses.
The primary outcome measure was the number of days from the start of
treatment until the neutrophil count exceeded 1,000/µL during the
induction course and was maintained. Additional outcome measures were
the number of days from the start of treatment in Courses IIA and IIB
until the neutrophil count exceeded 1,000/µL, the duration of
neutropenia (the number of days with an ANC <1,000/µL), the number
of days from the start of treatment until the platelet count exceeded
50,000/µL, and the duration of thrombocytopenia (<50,000/µL)
during each of the first three treatment courses (I, IIA, and IIB). In
addition, we measured the number of days of hospitalization during each
treatment course, the number of febrile days (>38.5°C), and the
number of days required to complete the planned induction and
consolidation therapy courses (ideally, 85 days). We also compared the
nonhematologic toxicity observed in the two treatment groups.
For the primary endpoint, the recovery date was the first day after day
1 of chemotherapy with an ANC 1,000/µL when a sustained recovery
was documented; that is, the ANC continued to increase steadily
thereafter and did not drop again during that course to <1,000/µL.
The study was designed to provide an 80% power to detect a 7-day
difference in the time to recover an ANC 1,000/µL during the
induction course (eg, a median of 14 days in the experimental group
v 21 days in the placebo group) with a significance level of 0.05. A total of 76 patients per treatment group (total, 152 patients) was
the target. The duration of neutropenia was measured by counting each
interval day from the first recorded date in each chemotherapy course
when the ANC fell below 1,000/µL up to, but not including, the first
recorded date with a sustained ANC 1,000/µL. Actual dates of
recovery were used, and no data were derived from interpolation.
Complete blood counts were required at least three times per week
during Course I and weekly thereafter. In practice, blood counts were
generally obtained daily while patients were hospitalized and at least
once per week while they were outpatients. Estimations of the
distributions of time to recovery of hematologic endpoints were
performed via the Kaplan-Meier method,5 where patients who
died before the endpoint was reached were censored. The variation in
these trials was expressed in terms of the interquartile range (IQR,
25th to 75th percentiles).
The rate of CR and the duration of DFS and length of survival were
additional outcome measures. Differences in proportions of CRs among
patient subgroups were analyzed using Fisher's exact test. In
addition, for the analysis of CR rate and death rate during induction,
the chi-square test for trend was used where the qualitative ordering
was CR > alive with refractory disease > death.6 The
duration of DFS was defined to be the time from achieving a CR to
relapse (bone marrow, blood, CNS, or testicular), death, or date of
last follow-up. Patients still at risk or lost to follow-up were
censored for the analysis of DFS. Survival was defined as the time from
study entry to the date of last follow-up. Probabilities of surviving
and remaining in CR were estimated by the Kaplan-Meier
method.5 Ninety-five percent confidence intervals (CI) for
these probabilities were obtained using the method of Simon and
Lee.7 Median follow-up time was estimated as the median
survival time of all patients still at risk. Differences in survival or
DFS between patient subgroups were tested using the log-rank
statistic.8
In accordance with the study objectives, the prognostic significance of
age, white blood cell (WBC) count, platelet count, mediastinal mass,
organomegaly, lymphadenopathy, FAB classification, immunophenotype, and
cytogenetics (presence or absence of the Ph chromosome) were assessed
with respect to CR rate and duration and survival. For the joint
analysis of these variables, regression analyses were used. The Cox
proportional hazards model was used to estimate hazard ratios with
respect to CR duration and survival for the randomized treatment
groups, as well as to test for an age-treatment interaction in time to
hematologic recovery.9,10 All reported P values are
nominal, two-sided values unless otherwise stated. The analyses were
based on all data available as of January 1998.
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RESULTS |
Conduct of the study.
Between June 24, 1991, and July 30, 1993, 198 patients were registered
on CALGB study 9111 from 25 main member institutions and their
affiliated hospitals. No single institution enrolled more than 10% of
the total patients.
Before starting induction chemotherapy, 102 patients were randomly
assigned to receive G-CSF and 96 to receive placebo. The groups were
comparable with respect to pretreatment characteristics (Table 2). The median age was 35 years
(range, 16 to 79), and the median WBC count was 16,800/µL (range, 200 to 373,000).
There were major protocol violations involving 24 patients. These
included 13 patients who were considered to be ineligible after central
review of all pretreatment data; 10 were determined to have had AML, 2 had lymphocytic lymphoma, and 1 had T-cell lymphoma. Nevertheless,
these patients were all treated according to the protocol and were
evaluated for response. One patient withdrew consent before receiving
the study drug. Because of errors in the treatment assignments at four
institutions, one patient randomized to receive G-CSF actually received
placebo during the induction course and then no study drug during the
consolidation courses. Three patients who received G-CSF in an
appropriately blinded fashion during the induction course did not
receive any further study drug during their consolidation courses. Five
patients who correctly received placebo injections during the induction
course were incorrectly treated with G-CSF during the two consolidation courses. Regardless of these variations, the analysis of the responses reported here includes all enrolled patients according to
intention-to-treat principles. A secondary analysis that excluded
ineligible patients and those who received the incorrect study drug was
also performed to determine whether these exclusions changed the
conclusions.
Remission induction.
Data on the time required to recover an ANC 1,000/µL, the primary
outcome measure, were available for 195 of the 198 patients (Table 3). The median times to recover an
ANC 1,000/µL were 16 days (IQR, 15 to 18) for the 102 patients
assigned to receive G-CSF and 22 days (IQR, 19 to 29) for the 93 patients assigned to the placebo (P < .001)
(Fig 1). The duration of severe neutropenia (ANC < 1,000/µL) was also significantly shorter for those in the G-CSF group (median, 13 days [IQR, 10 to 16] v 20 days [IQR,
15 to 27] for the placebo group; P < .001). The median
number of days with fever >38.5°C was 3 days (IQR, 1 to 5) for
the G-CSF group and also 3 days (IQR, 2 to 7) for the placebo group
(P = .44). Patients randomized to receive G-CSF had a median
hospitalization of 22 days (IQR, 18 to 29) compared with 28 days (IQR,
22 to 33) for the placebo group (P = .02).
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| Fig 1.
The number of days from the start of chemotherapy until
the recovery of an ANC >1,000/µL during Course I is shown according
to treatment assignment. The medians were 16 days for the G-CSF group
and 22 days for the placebo group (P < .001).
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Platelet recovery was also more rapid in the patients receiving G-CSF
(Fig 2). The median times to recover
platelets 50,000/µL were 16 days (IQR, 14 to 20) for the G-CSF
group and 19 days (IQR, 15 to 23) for the placebo group (P = .003). The median durations of thrombocytopenia <50,000/µL were 14 days (IQR, 9 to 17) and 17 days (IQR, 11 to 22), respectively
(P = .008). A secondary analysis that excluded the 13 ineligible patients and the 2 who either received the wrong study drug
treatment or withdrew from the study before receiving the study drug
yielded similar results, both for neutrophil recovery and for platelet
recovery (data not shown).
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| Fig 2.
The number of days from the start of chemotherapy until
the recovery of platelets >50,000/µL during Course I is shown
according to treatment assignment. The medians were 16 days for the
G-CSF group and 19 days for the placebo group (P = .003).
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Of the 102 patients randomly assigned to receive G-CSF, 89 (87%)
achieved a CR, 8 (8%) had refractory disease, and 5 (5%) died during
the induction course (Table 4). Of the 96 patients assigned to placebo, 74 (77%) achieved a CR, 11 (11%)
survived treatment but had refractory disease, and 11 (11%) died
early. Using the chi-square test for trend for these three outcomes
between the two treatment groups, there is a higher than expected
proportion of CR patients in the G-CSF group and a higher than expected
proportion of deaths in the placebo group (P = .04). Using the
chi-square test for proportions, the P value is .07 for the
comparison of CR with no CR in favor of the G-CSF treatment.
Considering only the 185 eligible ALL patients by the treatment
actually received, the CR rate was 87 of 97 patients (90%) with G-CSF
versus 71 of 88 patients (81%) with placebo (P = .10). The CR
rates for these 185 eligible patients according to pretreatment
clinical and biological characteristics of ALL are shown in
Table 5. The CR rate was 87% for patients
<60 years old and 77% for patients 60 years old (P = .18).
The impact of G-CSF on hematologic recovery in older patients (60
years old) and younger patients (<60 years old) was analyzed by
testing for an age-treatment interaction in a Cox regression model.
There were no detectable treatment effects for the ANC endpoints or
hospitalization in the two age groups. However, there was a significant
interaction with respect to recovery of platelets (P = .04).
Older patients who received placebo had a median time to platelet
recovery of 26 days, whereas the older patients who received G-CSF had
a median time to recovery of 17 days. The younger patients had median
times to recovery of 16 days in each treatment group. A similar
relationship was found for duration of thrombocytopenia.
For the 21 patients 60 years old assigned to G-CSF treatment, the CR
rate was 81%, and 2 patients (10%) died during induction. For the 20 patients 60 years old assigned to placebo, the CR rate was 55%, and
5 patients (25%) died during induction. These differences were not
statistically significant (P = .10 and .24, respectively). For patients <60 years old, the CR rate was 89% with
G-CSF and 83% with placebo (P = .36), whereas the induction death rates were 4% and 8%, respectively (P = .32).
Remission consolidation courses.
Data on neutrophil recovery after consolidation chemotherapy are
available on 146 of the 154 patients who entered Course IIA and 129 of
the 143 patients who entered Course IIB. During course IIA, the median
times to recover an ANC 1,000/µL were 20 days (IQR, 6 to 25) with
G-CSF and 29 days (IQR, 22 to 31) for the placebo group (P < .001) (Fig 3A). The duration of neutropenia was also significantly shorter with G-CSF: a median of 5 days (IQR, 0 to 12) for G-CSF and 13 days (IQR, 6 to 18) for placebo (P < .001). Of the patients receiving G-CSF, 35% never had an ANC
<500/µL during this course compared with 19% of those on the control arm. The median times to recover platelets 50,000/µL were
not different: 20 days (IQR, 17 to 22) with G-CSF and 20 days (IQR, 18 to 22) for placebo (P = .53). Forty-six percent of the patients
receiving G-CSF had a fever >38.5°C compared with 45% of those
on the control arm (P = 1.0). There were no
significant differences in the number of days of hospitalization: a
median of 7 days with G-CSF and 3 days for the placebo group (P = .32). Of the patients receiving G-CSF, 35% did not require
hospitalization during this course compared with 40% of those on the
control arm.
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| Fig 3.
The number of days from the start of chemotherapy until
the recovery of an ANC >1,000/µL is shown for Course IIA (A) and
for Course IIB (B) according to treatment assignment. The medians were
20 days for the G-CSF group and 29 days for the placebo group for
Course IIA (P < .001) and 25 days and 31 days, respectively,
for Course IIB (P < .001).
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During course IIB, the median times to recover an ANC 1,000/µL were
25 days (IQR, 15 to 32) with G-CSF and 31 days (IQR, 27 to 39) for the
placebo group (P < .001) (Fig 3B). The duration of
neutropenia was also significantly shorter with G-CSF: a median of 11 days (IQR, 4 to 17) for G-CSF and 14 days (IQR, 10 to 25) for placebo
(P = .001). Of the patients receiving G-CSF, 28% never had an
ANC <500/µL compared with 24% on the control arm. The median times
to recover platelets 50,000/µL were 24 days (IQR, 21 to 31) with
G-CSF and 22 days (IQR, 0 to 28) for placebo (P = .03), and the
duration of thrombocytopenia was also significantly different: a median
of 10 days (IQR, 7 to 20) with G-CSF and 7 days (IQR, 0 to 15) for
placebo (P = .02). There was no obvious explanation for the
delay in platelet recovery observed on the G-CSF arm during this
course. Forty-eight percent of the patients receiving G-CSF had a fever
>38.5°C compared with 55% of those on the control arm (P
= .73). There were no significant differences in the number of days
of hospitalization: a median of 4 days with G-CSF and 2 days for the
placebo group (P = .17). Of the patients receiving G-CSF, 38%
did not require hospitalization during this course compared with 44%
of those on the control arm.
Effects of G-CSF on treatment toxicity.
The G-CSF treatment itself was very well tolerated. Unfortunately,
there was no evidence that the G-CSF significantly reduced the
nonhematologic complications that occur during intensive chemotherapy treatment of ALL. The incidence of severe, life-threatening, and fatal
toxicities (grades 3, 4, and 5) according to treatment assignment is
shown in Table 6. Infectious complications
were not different in the two groups. Probably as a consequence, the
patients who were assigned to receive G-CSF were not able to complete
the first 3 months of planned chemotherapy any more rapidly than those
assigned to placebo. A median of 106 days (IQR, 96 to 117) was required by the G-CSF group to complete the first three courses of treatment compared with 108 days (IQR, 103 to 117) for the placebo group (P
= .60) (Fig 4).
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| Fig 4.
The interval in days required from the start of
chemotherapy until the beginning of Course III is shown according to
treatment assignment. The medians were 106 days for the G-CSF group and
108 days for the placebo group (P = .60).
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DFS.
The median DFS for the 158 eligible ALL patients who achieved a CR on
this study was 23 months; 40% (95% CI, 33% to 48%) were estimated
to remain in continuous CR longer than 3 years. The DFS results for
various clinical and biological subsets of patients are shown in Table
5. There were no significant differences in the DFS according to
treatment assignment: a median of 2.3 years for those assigned to G-CSF
and 1.7 years for placebo (P = .53) (Fig 5). Treatment with G-CSF did not
affect the DFS for patients who had coexpression of myeloid markers on
their lymphoblasts. The median DFS is 4.0 years for the 20 patients
with a BMy or TMy immunophenotype assigned to the G-CSF treatment and
1.3 years for the 12 similar patients assigned to placebo (P = .21). Similarly, the DFS was not different between the 11 patients who
had Ph+ ALL and were assigned to G-CSF (median, 0.8 years)
and the 11 similar patients who were assigned to placebo (median, 1.1 years; P = .98).
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| Fig 5.
There was no difference in the DFS between the patients
assigned to G-CSF (median, 2.3 years) and those assigned to placebo
(median, 1.7 years) (P = .53).
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Survival.
The median overall survival for the 185 eligible ALL patients enrolled
on this study was 23 months; 43% (95% CI, 36% to 50%) of patients
were estimated to be alive longer than 3 years (Table 5). Survival was
not different according to treatment assignment: a median of 2.4 years
for patients assigned to G-CSF and 1.8 years for placebo (P =
.25) (Fig 6). Similarly, survival did not
differ among the 39 patients with a BMy or TMy immunophenotype or the 26 patients known to have Ph+ ALL according to treatment
assignment (data not shown). The median follow-up time for these
analyses was 4.7 years (range, 2.0 to 6.4 years).
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| Fig 6.
There was no difference in the survival between the
patients assigned to receive G-CSF (median, 2.4 years) and those
assigned to placebo (median, 1.8 years) (P = .25).
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DISCUSSION |
G-CSF is a potent stimulator of granulopoiesis as well as early
hematopoietic progenitor cells.11 In this double-blinded, randomized, placebo-controlled clinical trial in adults with ALL, we
have shown that G-CSF significantly shortens the time required to
recover normal numbers of peripheral blood neutrophils after intensive
combination chemotherapy. The duration of neutropenia was significantly
shortened after each of three courses of treatment. The duration of
thrombocytopenia was also shortened significantly after the first
course but was no different after the second, and a modest delay in
platelet recovery was observed during the third course. We observed no
significant decreases either in the incidence or severity of
nonhematologic toxicity such as severe infections, mucositis, or
bleeding or in the number of febrile days during each course. This is
probably because these chemotherapy-induced complications generally
occur early in the treatment course at the nadir of the WBC count
before the marrow has had time to respond to growth factor stimulation.
Nevertheless, the more rapid recovery in the neutrophil count may have
led to more rapid resolution of toxicity because our patients receiving
G-CSF spent significantly fewer days in the hospital during the
remission induction course than did those receiving placebo.
A recently published randomized trial of G-CSF (10 µg/kg/d) in
children with ALL also reported on the accelerated rate of recovery of
granulocytes after myelosuppressive remission induction chemotherapy,
but this did not result in a decreased rate of hospitalization for
neutropenic fever, lower costs of supportive care, or a higher probability of event-free survival.12 However, the use of
G-CSF was significantly associated with a lower incidence of documented infections, shorter median hospital stays, and fewer delays in starting
the consolidation chemotherapy on schedule.
The impact of G-CSF treatment is likely to be most apparent on the
subsets of patients who otherwise have the slowest hematologic recovery. This includes elderly patients and may also include those
with infection or malnutrition and those receiving prolonged courses of
other myelosuppressive medications. In our study, fewer patients on the
G-CSF arm than on the placebo arm had very prolonged neutrophil
recovery times or very prolonged hospitalizations.
The ultimate clinical benefit of more rapid hematologic recovery is
less apparent. Patients who received G-CSF had a higher response rate
and fewer deaths during the remission induction course than did those
receiving placebo. However, patients in the G-CSF group were not able
to complete their first 3 months of prescribed chemotherapy any more
rapidly than those in the placebo group. Thus, we were not able to
increase the intensity of antileukemia therapy by shortening the time
required to deliver the treatment safely. The remission durations and
survival of the two treatment groups are not different after a median
follow-up time of 4.7 years, although the study was not designed to
detect significant differences in these two outcomes. If the apparent difference in the median survivals between the two treatment groups were true (Fig 6), we would need to have accrued 2.25-fold more patients to show statistical significance.
The German ALL study group has reported on a trial in which 76 adults
with ALL were randomly allocated to receive either G-CSF in an
open-label fashion or no growth factor during the last 4 weeks of an
8-week remission induction regimen.13 The median duration
of neutropenia (ANC < 1,000/µL) was 8 days in the G-CSF arm and
12.5 days in the control group (P < .002). There was no significant difference in the incidence of infections. However, prolonged interruptions of chemotherapy administration were less frequent; delays of 2 weeks or more occurred in only 24% of patients receiving G-CSF but in 46% of patients in the control arm (P = .01). For this reason, the planned chemotherapy was completed more
rapidly with the use of G-CSF (median, 39 v 44 days; P = .008), but this small interval is not likely to have clinical importance. No difference in the DFS was observed between the two
patient groups.
We did not detect any disadvantage from the use of G-CSF in any
subgroup of patients with ALL. It is known that some cases of
Ph+ ALL and some ALL cells that coexpress myeloid antigens
have surface receptors for G-CSF.14,15 However, neither the
rate of hematologic recovery nor the clinical outcomes were different
overall when Ph+ ALL patients were assigned to G-CSF or to
placebo. Two patients who had Ph+ ALL were observed to have
increasing numbers of lymphoblasts in the peripheral blood while
receiving G-CSF during the induction course. After the G-CSF was
discontinued, one patient entered a CR and one had residual ALL in the
marrow. There were also no significant differences observed according
to treatment assignment among patients who had myeloid antigens
expressed on the surface of their lymphoblasts. Table 5 shows the
treatment outcomes for the commonly used prognostic subsets of adults
with ALL. These data confirm the results previously reported with this
multiagent regimen.1
In this trial, the G-CSF treatment was begun only after the
administration of the most myelosuppressive chemotherapy drugs, ie, on
the fourth day of the induction course. Thus, we were able to avoid the
possible toxicity of concurrent administration of a hematologic growth
factor with weekly daunorubicin, a schedule widely used in other
treatment programs.16 Importantly, the use of G-CSF
concurrent with antimetabolite therapy (low doses of cytarabine and
daily 6-mercaptopurine) during Courses IIA and IIB did not lead to more
severe myelosuppression. Nor did the use of G-CSF in an earlier course
lead to greater cytopenia, lack of cytokine-responsiveness, or
"marrow exhaustion" in subsequent courses.
G-CSF is an expensive drug. The typical pharmacy cost for an adult is
$120 to $180 per day. An economic analysis was not an objective of this
trial, but we are now collecting these data retrospectively for
study.17 Despite its lack of significant benefit for
overall survival, the potential clearly exists for G-CSF to increase
the CR rate and to reduce the overall cost of care by reducing
hospitalization during remission-induction treatment for ALL. Although
the clinical benefits were found largely among older patients in this
trial, current CALGB trials for adults with ALL routinely use G-CSF for
all patients during the induction course. Because prolonged
hospitalization was rarely required during the consolidation
chemotherapy courses and because there has been no prolongation of
remission duration or survival, we are not routinely using G-CSF during
postremission treatment.
| |
FOOTNOTES |
Submitted February 26, 1998;
accepted May 5, 1998.
Supported in part by grants from the National Cancer Institute to the
CALGB (CA31946 and CA37027) and the CALGB Statistical Center (CA33601)
and from the Coleman Leukemia Research Fund.
Address reprint requests to Richard A. Larson, MD, University of
Chicago Medical Center, 5841 S Maryland Ave, MC2115, Chicago, IL
60637-1470; e-mail:ralarson{at}mcis.bsd.uchicago.edu.
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 |
We thank the many physicians, nurses, and data managers at each of the
CALGB institutions and their affiliated hospitals for their assistance
with the conduct of this clinical trial. We also thank Audrey McKinnon,
CALGB data coordinator for this study, for her expertise in central
data management and quality assurance. The study drug was supplied by
Amgen to the National Cancer Institute, Cancer Therapy Evaluation
Program.
| |
APPENDIX |
The following institutions (principal investigators) participated in
the study: Wake Forest University School of Medicine, Winston-Salem, NC
(M. Robert Cooper, MD; CA03927); Central Massachusetts Oncology Group,
Worcester, MA (F. Marc Stewart, MD); Dana-Farber Cancer Institute,
Boston, MA (George P. Canellos, MD; CA32291); Dartmouth Medical School
 Norris Cotton Cancer Center, Lebanon, NH (L. Herbert Maurer, MD;
CA04326); Duke University Medical Center, Durham, NC (Jeffrey Crawford,
MD; CA47577); Long Island Jewish Medical Center, New York, NY (Marc
Citron, MD; CA11028); Massachusetts General Hospital, Boston, MA
(Michael Grossbard, MD; CA12449); McGill Department of Oncology,
Montreal, Canada (Brian Leyland-Jones, MD; CA31809); Mount Sinai
Hospital, New York, NY (James F. Holland, MD; CA04457); New York
Hospital Cornell Medical Center, New York, NY (Ted Szatrowski, MD;
CA07968); North Shore University Hospital, Manhasset, NY (Daniel R. Budman, MD; CA 35279); Rhode Island Hospital, Providence, RI (Louis A. Leone, MD; CA 08025); Roswell Park Cancer Institute, Buffalo, NY (Ellis
Levine, MD; CA 59518); SUNY Health Science Center at Syracuse, NY
(Stephan Graziano, MD; CA 21060); University of Alabama, Birmingham, AL (Robert Diasio, MD; CA47545); University of California at San Diego, CA
(Stephen Seagren, MD; CA 11789); University of Chicago, Chicago, IL
(Nicholas Vogelzang, MD; CA41287); University of Iowa, Iowa City, IA
(Gerald Clamon, MD; CA 47642); University of Maryland Cancer Center,
Baltimore, MD (Ernest Borden, MD; CA 31983); University of Minnesota,
Minneapolis, MN (Bruce Peterson, MD; CA 16450); University of
Missouri/Ellis Fischel Cancer Center, Columbia, MO (Michael C Perry,
MD; CA 12046); University of North Carolina at Chapel Hill, NC (Thomas
Shea, MD; CA47559); Walter Reed Army Medical Center, Washington, DC
(Nancy Dawson, MD; CA26806); Washington University Barnes Hospital,
St Louis, MO (Daniel Ihde, MD; CA47546).
| |
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Abstract
Introduction
Abstract