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Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2722-2730
By
From the Clinical Hematology Units of Centre Hospitalier
Universitaire de Nancy, Nancy, France; Centre Hospitalier Universitaire
de Poitiers, Poitiers, France; Centre Hospitalier Universitaire de
Saint Etienne, Saint Etienne, France; Centre Hospitalier Universitaire
de Brest, Brest, France; Hôpital Beaujon, Clichy, France; Centre
Hospitalier Universitaire de Besançon, Besançon,
France; Centre Hospitalier Universitaire de Strasbourg,
Strasbourg, France; Centre Hospitalier Universitaire
d'Angers, Angers, France; Centre Hospitalier Universitaire d'Amiens,
Amiens, France; Centre Hospitalier Universitaire de Reims, Reims,
France; Centre Hospitalier Universitaire de Rennes, Rennes,
France; Hôpital Pasteur, Colmar, France; Centre Hospitalier
Universitaire de Dijon, Dijon, France; Hôpital Avicenne, Bobigny,
France; Centre Hospitalier Universitaire de Tours, Tours, France;
Hôpital Bon Secours, Metz, France; Pharmacia Upjohn, Guyancourt,
France; and Centre Hospitalier Universitaire de Nantes, Nantes, France.
The complete remission (CR) rate after intensive chemotherapy for
acute myelogenous leukemia (AML) remains low in elderly patients,
mainly because of a higher infectious mortality rate related to
neutropenia and an increased incidence of adverse prognostic factors.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been
shown to potentially recruit leukemic blasts into cell cycle and
improve cytotoxic effects when given during chemotherapy, and to
shorten the duration of neutropenia when administered after chemotherapy. Two hundred forty patients aged 55 to 75 years who had
newly diagnosed AML were randomly assigned to receive placebo or
Escherichia coli-derived GM-CSF (5 µg/kg/d by 6-hour
intravenous infusion) starting during induction chemotherapy on day 1 and continued through and after chemotherapy until recovery of
neutrophils, or evidence of regrowth of leukemia, or up to day 28. Induction chemotherapy consisted of idarubicin (8 mg/m2/d
on days 1 to 5) and cytarabine (100 mg/m2/d on days 1 to
7). The study drug was not administered subsequent to the induction
course. Patients who achieved a CR received continuous maintenance
therapy for 1 year with four quarterly reinduction courses; in the 55- to 64-year age subgroup, patients were randomly assigned to receive or
not a consolidation course before maintenance therapy. The CR rate was
similar in the GM-CSF and placebo groups (63% and 60.5%,
respectively; P = .79). The mortality, rate of resistant
disease, and rate of regrowth of leukemia were also similar in both
groups. The time to neutrophil recovery was shorter in patients who
received GM-CSF (24 v 29 days; P = .0001), but the
incidence and characteristics of infectious events were not different.
The 2-year disease-free survival (DFS) rate was significantly improved
in the GM-CSF group (48% v 21% in the placebo group; P = .003). This effect was highly significant in the cohort
of patients aged 55 to 64, but only marginal in patients
THE INCIDENCE OF acute myelogenous
leukemia (AML) increases with age and more than half of the patients
are over 60 years at the time of the diagnosis.1,2
Treatment results after intensive chemotherapy remain disappointing in
elderly patients with AML3-5 for two main reasons: a high
rate of mortality during the neutropenic period, which is mainly due to
infection; and an increased incidence of adverse prognostic factors,
which explains the higher failure rate.
Therefore, the use of hematopoietic growth factors (HGFs), in
particular granulocyte-macrophage colony-stimulating factor (GM-CSF)
and granulocyte colony-stimulating factor (G-CSF), in combination with
intensive chemotherapy, has appeared to be a potentially highly
effective approach to improve outcome in older patients with AML. Two
separate mechanisms of HGFs have been shown in AML: (1) when given
before and/or during chemotherapy, HGFs can recruit leukemic
blast cells into cell-cycle, thus making them more susceptible for
killing by S-phase-specific agents, like cytarabine
(Ara-C)6-13; and (2) when given after chemotherapy, HGFs
may shorten the duration of neutropenia and therefore decrease the rate
of infections, particularly fatal infections.14,15
Here, we report the results of a multicenter, randomized,
placebo-controlled, double-blind clinical trial conducted by the Groupe Ouest Est Leucémies Aiguës Myéloblastiques
(GOELAM) and designed to evaluate the effects of GM-CSF given both
during and after intensive induction chemotherapy for de novo AML in elderly patients aged 55 to 75.
Patients
Study Design
Evaluation of Therapy The efficacy of induction therapy was evaluated after one course. Complete remission (CR) was defined as a normocellular bone marrow containing less than 5% blasts and peripheral blood counts showing greater than 1,000/µL neutrophils and greater than 100,000/µL platelets. Treatment failure was defined as resistant leukemia (partial response or no response) or death (early death during the 7 days of induction treatment or death during chemoinduced bone marrow hypoplasia). Leukemic cell regrowth was defined, after a clearance of circulating blast cells consecutive to chemotherapy, as a rapid increase of these cells between days 15 and 28 to greater than 1,000/µL. Relapse was defined as the reappearance of leukemic cells in the bone marrow or peripheral blood or evidence of extramedullary leukemia. Neutropenia-related infectious complications such as septicemias, pneumonias, and other significant clinically or microbiologically documented infections were registered and compared in the two treatment groups. Severity of treatment-related toxicity was graded according to the National Cancer Institute (NCI) common toxicity criteria.20Statistical Analysis The main objective of the study was to assess the ability of GM-CSF to improve the antileukemic effect of induction chemotherapy by increasing the CR rate and/or duration of disease-free survival (DFS). Assuming a 50% remission rate and a 20% DFS rate at 2 years in the placebo group, a total of 240 randomized patients were required to demonstrate either a 20% CR rate improvement or a 20% increase of DFS rate ( = 5%,  = 20%, unilateral test). The secondary
objectives were to evaluate the reduction of the time to neutrophil
recovery, to evaluate the reduction of neutropenia-related infectious
complications, and to detect an increase in overall survival (OS). All
eligible patients who received the randomly assigned treatment were
included in the analysis for comparison between the two treatment
groups whether the planned program was completed or the study drug
prematurely discontinued. Comparison between the two treatment groups
were performed with Fisher's exact test for binary variables and
Student's t test in case of normal distribution, for
continuous variables. Survival curves and time to neutrophil recovery
were estimated by the Kaplan-Meier method and comparison was made with
the log-rank test. OS was calculated from the date of random assignment
to the time of death. DFS was calculated from the date of first CR to
the date of first relapse. The time to neutrophil recovery was
calculated from the first day of chemotherapy. The duration of
hospitalization was calculated from the first day of induction
chemotherapy to the date of discharge from the hospital. The following
factors were analyzed for their impact on CR achievement, CR duration,
and survival with a logistic regression analysis (for the CR rate) and
the Cox model with the likelihood ratio test (for DFS and OS): age,
performance status, white blood cell count, FAB classification, and
cytogenetic features.
Between May 1992 and November 1994, 244 patients were registered in the study by 17 institutions. Four patients (one in the GM-CSF group and three in the placebo group) were considered not eligible for entry onto the study: one because of an inadequate diagnosis, one because of poor clinical status, and two for withdrawal consent before receiving the study medication. Characteristics of Patients Of 240 eligible patients, 114 were randomly assigned to receive GM-CSF and 126 to receive placebo. There was no significant difference between the two treatment groups at diagnosis in terms of age, sex, performance status, FAB subtype, blood cell counts, and cytogenetic analysis (Table 1). The incidence of unexplained cytopenia before diagnosis was also similar in both groups (8.5% in the GM-CSF group and 5% in the placebo group; P = .31) as was the incidence of morphologic features of myelodysplasia at the time of the diagnosis (23% and 15%, respectively; P = .09). Among 240 eligible patients included in the study, eight (four in each treatment group) were judged nonassessable for induction treatment: one because of death before the first administration of the study medication and seven because of major protocol violation (one never received the medication because of a supply problem, three did not receive the assigned medication, one received the medication only during induction treatment, one received the medication only after induction treatment, and one received chemotherapy with high-dose Ara-C).
Overall Results Of 232 patients assessable for induction treatment, 143 (62%) achieved a CR. There were 17 early deaths (7%), 22 deaths during marrow hypoplasia (9%), and 50 (22%) patients with resistant leukemia. The CR rate was not different in the two age subgroups (55 to 64 and 65 to 75 years) (Table 2).
Outcome According to Prognostic Factors Among the factors tested for their impact on CR rate, two were of significant predictive value: the initial white blood cell count (cut-off, 30,000/µL) and cytogenetic features (normal and favorable karyotype v intermediate or unfavorable) (P = .003 and P = .0003, respectively) (Table 2).
Outcome According to Treatment Group (GM-CSF v Placebo)
Extrahematologic toxicities.
GM-CSF treatment was discontinued due to intolerance in 13.5% of
patients (15 of 110), whereas the rate for placebo discontinuation was
only 4% (five of 122 patients) (P = .02). The main reasons for discontinuation of the study medication were flushing, hypotension, or fever (in four and two patients, respectively, of the GM-CSF and
placebo arms), fluid overload symptoms (in four and one patient, respectively), serious cardiopulmonary or renal events with or without
capillary leak syndrome (in seven and two patients), and bone pain in
one patient of the placebo group. Extrahematologic toxicities
attributable to the induction regimen or adjuvant therapies were
similar in both groups. Severe extrahematologic toxicities (grade Time to neutrophil recovery, neutropenia-related infectious complications, and transfusion support. The median time from the start of chemotherapy to the recovery of a neutrophil count greater than 500/µL was 24 days (95% confidence interval, 23 to 26 days) in the GM-CSF group compared with 29 days (95% confidence interval, 28 to 32 days) in the placebo group. Neutrophil recovery was significantly shorter in the GM-CSF group (P = .0001, log-rank test). The duration of febrile episodes higher than 38.5°C was similar among the two treatment groups, as were the incidence and characteristics of significant clinically or microbiologically documented infections (Table 4). Although the duration of intravenous antibiotic treatment was significantly reduced among the patients randomly assigned to GM-CSF (P = .018), the duration of hospitalization of these patients was only marginally decreased (P = .10) (Table 4). The shortening of neutropenia did not decrease the duration of systemic antifungal therapy in the GM-CSF group (P = .90), mainly because of frequent continuation of antifungal treatment beyond the end of neutropenia for persistence of either presumed or documented fungal infection. Median platelet and red blood cell transfusion requirements were not different in the two treatment groups (P = .67 and P = .10, respectively) (Table 4).
Results of induction therapy. Sixty-nine of 110 assessable patients (63%; 95% confidence interval, 54% to 72%) achieved a CR in the GM-CSF group, as compared with 74 of 122 assessable patients (60.5%; 95% confidence interval, 52% to 69%) in the placebo group. The CR rates were not different in the two treatment groups (P = .79). Table 5 gives the breakdown of the results after induction therapy. Adjustment for prognostic factors using the logistic regression model did not modify the result (P = .76, likelihood ratio test). The reasons for not achieving CR were similar in both treatment groups. The mortality rate during induction phase was 18% in patients receiving GM-CSF and 15.5% in patients receiving placebo; the rates of resistant leukemia (partial response or no response) were 19% and 24%, respectively (P = .70). Leukemic regrowth occurred in two patients in each group.
Postremission therapy. There were no significant differences between the two treatment groups considering chemotherapy administered after remission. Among patients aged 55 to 64, 10 of 32 (31%) in the GM-CSF group were randomly assigned to receive a consolidation course before maintenance treatment, as compared with 13 of 30 (43%) in the placebo group (P = .39). The proportion of patients in whom the intensity of maintenance chemotherapy had to be reduced at least once by more than 20% (in dose and/or in duration and/or by delay of therapy) was also similar in both treatment groups (47% and 54%, respectively, in the GM-CSF and placebo groups). DFS. DFS was affected by whether patients had received GM-CSF or placebo concomitantly with induction course. Among 69 patients who achieved a CR in the GM-CSF group, the median DFS duration was 23 months (95% confidence interval, 16 to 30) and the probability of remaining alive and free of disease at 2 years was 48% (95% confidence interval, 35% to 60%), as compared with 11 months (95% confidence interval, 8 to 15) and 21% (95% confidence interval, 11% to 30%), respectively, for patients randomly assigned to receive placebo (P = .003, log-rank test) (Fig 1A). Adjustment for prognostic factors did not modify this result (P = .007, likelihood ratio test). The impact of GM-CSF on DFS was significantly different according to age (P = .002 and P = .22, log-rank test, between DFS in the GM-CSF and placebo groups among younger and older age subgroups, respectively) (Fig 1B and C). A more beneficial impact of GM-CSF on DFS also appeared in patients with M1, M2, and M3 FAB subtypes (P = .013); initial leukocytosis less than 30,000/µL (P = .012); and in patients receiving maintenance therapy without prior consolidation as postremission treatment in the younger age subgroup (P = .0002, log-rank test) (Table 3).
OS. There was a trend toward an improvement in OS in the GM-CSF group (P = .082, log-rank test) (Fig 2). The estimated OS rate at 2 years was 39% in the GM-CSF group (95% confidence interval, 30% to 48%) and 27% in the placebo group (95% confidence interval, 19% to 35%). Among patients greater than 65 to 75 years of age, OS was similar in the two treatment groups (P = .97). In contrast, among patients aged 55 to 64, the positive impact of GM-CSF on OS was significant (P = .014) and, in this age subgroup, the use of GM-CSF during the induction course appeared to be a predictive factor for survival independent of the other predictive factors (initial white blood cell count, karyotype, and consolidation therapy before maintenance) (P = .039, likelihood ratio test).
The aim of this randomized trial was to assess the ability of recombinant E coli-derived GM-CSF to improve the outcome of induction therapy and the DFS in elderly patients with AML when administered simultaneously with chemotherapy and thereafter. Our study confirms the positive result of most other controlled trials on the use of myeloid growth factors for supportive care in AML with a reduction of the median neutrophil recovery by 5 days in patients assigned to receive GM-CSF. However, this faster recovery did not result in a substantial reduction of the incidence of documented infections or mortality during hypoplasia or length of hospitalization. The shortening in duration of intravenous antibiotic requirement was the only benefit observed according to neutropenia-related morbidity.
Submitted July 14, 1997;
accepted December 2, 1997.
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© 1998 by The American Society of Hematology.
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| Copyright © 1998 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Abstract
Introduction
65 years of
age. There was a trend toward a longer overall survival (OS) in the
GM-CSF group (P = .082). In summary, the administration of
GM-CSF, concomitantly with chemotherapy and thereafter during induction
course in AML, shortened the time to neutrophil recovery, but did not
improve the CR rate in patients aged 55 to 75. Nonetheless, DFS and OS
were significantly prolonged in patients aged 55 to 64 treated with
GM-CSF. These results are promising and further evaluation of myeloid
growth factors in AML is warranted.
Abstract
t(8;21),
t(15;17), and inv(16); unfavorable
