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© 2000 American Society for Clinical Oncology Granulocyte Colony-Stimulating Factor After Intensive Consolidation Chemotherapy in Acute Myeloid Leukemia: Results of a Randomized Trial of the Groupe Ouest-Est Leucémies Aigues MyeloblastiquesFrom the Departments of Hematology of University Hospital, Nantes; University Hospital, Nancy; University Hospital, Strasbourg; University Hospital, Angers; University Hospital, Amiens; University Hospital, Tours; University Hospital, Poitiers; University Hospital, Rennes; University Hospital, Brest; University Hospital, Besançon; University Hospital, Saint-Etienne; University Hospital, Reims; University Hospital, Bobigny; University Hospital, Clermont-Ferrand; Centre Hospitalier, Colmar; and University Hospital, Dijon, France. Address reprint requests to J.L. Harousseau, MD, Department of Hematology, 1 Place Alexis Ricordeau, 44035 Nantes cedex 1, France; email jlharousseau{at}sante.univ_nantes.fr
PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 µg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 x 109/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P < .001) and after ICC 2 (20 v 28 days, P < .001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P < .001; 29 v 34 days after ICC 2, P < .001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.
THREE STRATEGIES are currently used to prevent relapse in younger patients with acute myeloid leukemia (AML): allogeneic bone marrow transplantation (BMT), autologous stem-cell transplantation (ASCT), or intensive consolidation chemotherapy (ICC).1 Up to the age of 50 to 55 years, patients with HLA-identical siblings are generally offered allogeneic BMT, whereas the remaining patients receive either ASCT or ICC. In patients 60 years of age or younger, ICC with repeated courses of high-dose cytarabine significantly increased disease-free survival (DFS) rate.2 As compared with ICC, ASCT could reduce relapse rate but is associated with higher treatment-related mortality because of poor hematologic reconstitution.1,3 Recently completed randomized studies have prospectively compared ASCT and ICC.4-8 Although two studies have reported better long-term DFS after ASCT,4,5 other studies of adults or children6-8 have failed to show any improvement with ASCT. In these studies, after complete remission (CR) was achieved, patients received two to four courses of ICC or at least one course of ICC followed by myeloablative therapy with ASCT. Because of the toxicity of such intensive strategies, a high treatment-related mortality rate was reported in some series, mainly after ASCT. Moreover, 33% to 50% of patients in first CR were removed from study and could not receive the entire assigned treatment.8 The majority of withdrawals were due to complications of ICC. The use of hematopoietic growth factors could partly resolve these problems by reducing the morbidity and mortality related to hematopoietic toxicity of ICC. A number of placebo-controlled studies have shown that the use of myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) in AML is not harmful.9-12 Therefore, the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) has initiated a prospective randomized study to test the impact of G-CSF administered after ICC in patients with AML in first CR.
Design of the Study This study was part of the GOELAM 2 trial. The main objective of this randomized open trial was to assess the impact on the event-free survival (EFS) rate of quinine given as a multidrug resistance modifyer. Patients 15 to 60 years of age with de novo AML were eligible for entry onto this trial. Patients with AML3 subtype, transformation of myelodysplastic syndromes, or blast crisis of myeloproliferative disorders were not eligible. Patients with clinical or electrocardiographic signs of heart failure or coronary disease and patients with hepatic or renal failures were also excluded. Each case was classified according to the French-American-British (FAB) system.13 Cytogenetic abnormalities were classified as follows: favorable, inv(16) and t(8;21); unfavorable, abnormalities of chromosomes 5 and/or 7 and abnormalities involving 11q23 and complex abnormalities; intermediate, all other abnormalities.14,15 Allogeneic BMT was proposed for patients in CR after one or two courses of induction treatment if they were 45 years of age or younger and if they had an HLA-identical sibling. All other patients in CR and in good clinical condition were to receive two courses of ICC without stem-cell transplantation. Ineligibility criteria for ICC were as follows: cardiac, hepatic, or renal contraindications and/or severe infectious complications that arose during induction treatment (including invasive aspergillosis). Before the first course of ICC (ICC 1), patients were randomly assigned to receive or not receive G-CSF throughout the two courses of ICC. G-CSF (filgrastim; Neupogen; Amgen and Roche Laboratories, Neuilly, France) was administered subcutaneously at a daily dose of 5 µg/kg starting the day after the end of chemotherapy and until granulocyte recovery (> 1 x 109/L or > 0.5 x 109/L on three consecutive days). The study was approved by the institutional ethics committees, and the patients gave informed consent.
Treatment Plan ICC 1 consisted of a combination of cytarabine and mitoxantrone as in the second induction course. ICC 2 consisted of amsacrine administered as a 1-hour infusion on 5 consecutive days at a daily dose of 150 mg/m2 and etoposide administered as a 2-hour infusion on 5 consecutive days at a daily dose of 100 mg/m2. In those patients who were randomly assigned to receive quinine, quinine was administered during ICC 1 on days 4 through 6 and during ICC 2 starting 12 hours before etoposide and ending 12 hours after the last infusion of etoposide. In all centers, patients were hospitalized for the entire ICC courses. Prophylaxis and treatment of fever and infection were administered according to the protocols used in each center. Broad-spectrum antibiotics were started empirically in case of fever greater than 38°C. Systemic antifungal therapy was initiated in patients with documented or suspected fungal infections or with fever persisting for 48 hours despite broad-spectrum antibiotics.
Objectives of the Study
Secondary end points were the incidence of septicemia and toxic deaths, the duration of IV antibacterial and antifungal therapy, and the duration of hospitalization after ICC 1 and ICC 2. Septicemia was defined as one positive blood culture (or two positive cultures for Staphylococcus epidermidis). The duration of hospitalization was calculated as the time from the first day of ICC to the date of discharge from the hospital. Other parameters were analyzed as well: the number of microbiologically documented infections, the number of days on which patients experienced fever, the duration of thrombocytopenia, and the number of RBCs and platelet transfusions. The duration of thrombocytopenia was defined as the number of days from the first day on which a patient had a platelet count of less than 30 x 109/L until the first day on which that patient had a platelet count
Statistical Analysis
Patients From February 1995 to June 1998, 349 eligible patients were enrolled in 16 GOELAM centers, and 283 patients (81%) achieved CR. Of these patients, 64 who were 45 years of age or younger had an HLA-identical sibling and were offered an allogeneic BMT. Twenty-five patients were considered ineligible or unassessable for ICC (death, five patients; relapse, six; toxicity of induction treatment, seven; infection, six; and protocol violation, one). Thus 194 patients in first CR were randomized at the time of ICC 1 (100 patients in the G-CSF group and 94 patients in the control group). The initial characteristics of the patients are listed in Table 1. There was no significant difference between the two treatment groups in terms of sex, performance status, FAB subtype, initial WBC and platelet counts, initial hemoglobin level, and cytogenetic analysis. The only difference was the median age (47.5 years in the G-CSF group v 45 years in the control group; P = .03).
The percentage of patients having achieved CR with only one course of induction treatment was 88% (88 of 100) in the G-CSF arm and 87% (82 of 94) in the control arm (P = .95). The median interval between CR achievement and the first day of ICC 1 was 17 days in the G-CSF arm and 17.5 days in the control arm (P = .79). In the absence of stratification according to the first randomization (quinine or no quinine), there was a slight imbalance between the two groups regarding treatment with quinine. Of 100 patients in the G-CSF arm, 54 received quinine versus 40 of 94 patients (43%) in the control arm (P = .15). However, the duration of neutropenia was not influenced by the administration of quinine during induction treatment (median, 25 days in the two groups; P = .92) during ICC 1 (median, 15 v 14 days; P = .15) and during ICC 2 (median, 22 v 25 days; P = .22). The median duration of G-CSF treatment was 15 days after ICC 1 (range, 5 to 47 days) and 21 days after ICC 2 (range, 7 to 47 days). No patient discontinued G-CSF treatment because of side effects.
Feasibility of the Protocol
Hematologic Recovery
After ICC 2, the median duration of neutropenia was 20 days (range, 7 to 56 days) for patients in the G-CSF group as compared with 28 days (range, 10 to 100 days) for patients in the control group (P < .001) (Fig 2). The median duration of thrombocytopenia was 30.5 days for patients in the G-CSF group and 30 days for patients in the control group (P = .47).
These results are listed in Table 2. For individual patients, the cumulative duration of neutropenia was also significantly reduced in the G-CSF group (median, 33 days; range, 16 to 66 days) as compared with that of the control group (median, 46 days; range, 26 to 118 days) (P < .001). Faster neutrophil recovery was observed for whichever treatment arm was allocated by the first randomization (quinine v no quinine; Table 3).
Duration of Hospitalization The criteria for authorizing hospital discharge were not defined in the protocol and might have varied from one center to another. However, one can assume that they were homogeneous within each center and were not influenced by G-CSF administration. After ICC 1, the median duration of hospitalization was 24 days for patients on the G-CSF arm (range, 17 to 100 days) versus 27 days (range, 16 to 61 days) for patients on the control arm (P < .001). After ICC 2, the median duration of hospitalization was 29 days for patients on the G-CSF arm (range, 19 to 62 days) versus 34 days (range, 21 to 100 days) for patients on the control arm (P < .001). These results are listed in Table 2. For individual patients, the median cumulative duration of hospitalization was 53 days (range, 36 to 94 days) in the G-CSF arm as compared with 61 days (range, 37 to 128 days) in the control arm (P < .001). After stratification for the use of quinine, the duration of hospitalization was significantly shorter with G-CSF, except after ICC 2 for patients who did not receive quinine (Table 3).
Toxicity of Intensive Consolidation Chemotherapy
After ICC 2, the incidence of microbiologically documented infections was also lower in the G-CSF group (40.5% v 55.5%), but the difference was only of borderline significance (P = .07). There were 21 episodes of septicemia in the G-CSF group (S epidermidis, nine; other gram-positive, three; E coli, three; other gram-negative, three; and Candida, three) and 25 in the control group (S. epidermidis, 12; streptococcus, four; other gram-positive, three; E coli, two; other gram-negative, three; and Candida, one). In the G-CSF group, nine patients (11%) remained afebrile during the entire course of ICC 2 versus six (7.5%) in the control group (P = .53). Four patients had confirmed invasive aspergillosis in the G-CSF group (three patients after ICC 1, one after ICC 2) versus four in the control group (two after ICC 1, two after ICC 2). The median number of days on which patients had fever was identical in the two arms after both ICC courses. The median duration of IV antibiotics was significantly reduced in the G-CSF group after both ICC courses. The median duration of antifungal therapy was significantly reduced after ICC 1. The number of patients who received antifungal therapy was lower in the G-CSF group, although this difference did not reach statistical significance (after ICC 1, 39% v 51%, P = .12; after ICC 2, 44% v 56%, P = .16). The numbers of RBC transfusions and platelet transfusions were identical in the two groups.
DFS and OS
Ten years after the first clinical studies, the use of G-CSF or GM-CSF in AML remains a controversial issue. Many investigators have shown that AML blast cells may have G-CSF and GM-CSF receptors and that these myeloid growth factors may increase the in vitro leukemia cell growth.9-12 Therefore, G-CSF and GM-CSF have been used in AML with two objectives: first, to reduce the duration of neutropenia after intensive chemotherapy, and second, to recruit leukemia cells into the cell cycle to increase the number of blasts that are susceptible to cycle-specific cytotoxic agents. The first issue has been addressed in a number of randomized placebo-controlled studies.17-25 In these studies, the growth factor was generally administered after chemotherapy17-22 or during and after chemotherapy.22-25 In a great majority of these studies, the CR rate, the number of treatment failures or early relapses, and the remission duration were not different in the group of patients who received the growth factor as compared with patients who received the placebo, which indicates that the use of G-CSF or GM-CSF is not harmful to AML patients. In most studies, the duration of neutropenia was significantly reduced in patients who received the growth factor. However, the impact of G-CSF or GM-CSF administration on treatment outcome remains unclear. Whereas some studies showed an increase of the CR rate17,18 and even of the OS,18 in other studies, the only significant difference was the reduction of time to neutrophil recovery, without clinical benefit for the patients. It should be noted that in all these trials, the impact of the growth factor was studied exclusively or mainly during induction treatment. It is conceivable that the inability of growth factors to significantly improve the treatment outcome is determined by the intrinsicly poor risk of the disease in some individuals. Moreover, the main cause of failure after induction treatment in AML is currently not infection but failure to eradicate the leukemic clone. Therefore, it could be easier to demonstrate a clinical benefit of myeloid growth factors in patients who have achieved CR. Few studies have focused on the role of myeloid growth factors given after consolidation chemotherapy in patients with AML. In a large placebo-controlled multicenter trial, Heil et al20 demonstrated that patients who received G-CSF had a significantly reduced duration of neutropenia. This was observed not only after induction treatment but also after consolidation courses. However, two of the three consolidation courses used in this study were moderately myelotoxic. Only 47 randomized patients received a highly myelosuppressive regimen that included high-dose cytarabine. After this type of ICC, the administration of G-CSF reduced the duration of neutropenia by 5.5 days. Similarly, Moore et al26 showed a dramatic decrease in the duration of neutropenia in 61 patients who received G-CSF after an aggressive combination regimen with aziridinyl benzoquinone and mitoxantrone as compared with 51 patients who did not receive G-CSF. However, this study was not randomized. Conversely, in the Eastern Cooperative Oncology Group study that tested GM-CSF in elderly patients, Rowe et al18 failed to show a significant decrease in the duration of neutropenia after consolidation chemotherapy. In this particular study, after 12 doses of high-dose cytarabine, the growth factor was first administered only 5 days after completion of consolidation chemotherapy. The present study confirms that the administration of G-CSF in patients with AML in first CR dramatically reduces the duration of neutropenia after each of the two courses of ICC. When given after the first course, with eight doses of high-dose cytarabine plus mitoxantrone, G-CSF induced a 7-day decrease in the median duration of neutropenia (from 19 days to 12 days). The second course of ICC was even more myelotoxic, and the addition of G-CSF also reduced the median duration of neutropenia by 8 days (from 28 days to 20 days). For an individual patient, the median cumulative duration of neutropenia after ICC 1 and ICC 2 was reduced from 46 days to 33 days. The incidence of septicemia and microbiologically documented infections was not significantly reduced among patients on the G-CSF arm. However, due to the shortening of neutropenia, patients who were treated with G-CSF received significantly less antibacterial therapy after both ICC 1 and ICC 2 and less antifungal therapy after ICC 1. The most obvious benefit for patients was the significant reduction of hospitalization duration. The median gain was 3 days after ICC 1 and 5 days after ICC 2. When adding ICC 1 and ICC 2, the median duration of hospitalization was reduced from 61 days in the control group to 53 days in the G-CSF group. Until now, this reduction of the number of days spent in hospital was observed in only one of the published placebo-controlled studies that tested the impact of myeloid growth factors on induction treatment of patients with AML (Table 5). For patients on the G-CSF arm, the median interval between ICC 1 and ICC 2 was only slightly reduced and the number of patients undergoing ICC 2 was not increased. The toxic death rate was the same in both arms. Therefore, the use of G-CSF did not seem to facilitate the feasibility of the protocol.
Another potential benefit of G-CSF administration after ICC could be to enhance peripheral-blood progenitor-cell collection when autologous transplantation is scheduled. As in other hematologic malignancies, the use of peripheral blood instead of bone marrow for ASCT in patients with AML results in faster hematopoietic reconstitution and possibly less transplantation related morbidity.27,28 G-CSF has been used safely with or without chemotherapy to collect peripheral-blood hematopoietic progenitors in patients with AML who are in first CR.29,30 However, until now, there has been no evidence of significant survival benefit of peripheral-blood progenitors as compared with bone marrow.3 Finally, the 2-year DFS and OS were not affected by G-CSF therapy, which confirms previously published data showing that the use of myeloid growth factors in AML is not dangerous. We conclude that G-CSF should be administered routinely after ICC in patients with AML. The benefit of G-CSF administration is not only a reduction of time to neutrophil recovery but also a significant reduction of time to hospital discharge and a reduction of antibacterial and antifungal therapy. The impact of these results on hospital costs should be evaluated in a pharmacoeconomic analysis. The regimen that we used contained only two courses of ICC, and G-CSF did not increase the feasibility of this program. Whether G-CSF could facilitate the timely administration of ICC with more courses remains to be determined.
Supported in part by Amgen France, Neuilly, France, and by a major grant from Programme Hospitalier de Recherche Clinique. We thank Caroline Even for technical assistance and Benedicte Petard for editing the manuscript.
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Zittoun RA, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332:217-223, 1995 5. Burnett A, Goldstone AH, Stevens RMF, et al: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial. Lancet 351:700-707, 1998[Medline]
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Rowe JM, Andersen JW, Mazza JJ, et al: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: A study of the Eastern Cooperative Oncology Group. Blood 86:457-462, 1995
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Zittoun R, Suciu S, Mandelli F, et al: Granulocyte macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: A randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 14:2150-2159, 1996
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Moore JO, Dodge RK, Amrein PC, et al: Granulocyte colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoguinone and mitoxantrone: Cancer and Leukemia Group B Study 9022. Blood 89:780-788, 1997 27. Reiffers J, Korbling M, Labopin M, et al: Autologous blood stem cell transplantation versus autologous bone marrow transplantation for acute myeloid leukemia in first remission. Int J Cell Cloning 10:111-113, 1992
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Sanz MA, de La Rubia J, Sanz GF, et al: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients in first complete remission: A report from a single institution. J Clin Oncol 11:1661-1667, 1993 29. Demirer T, Petersen FB, Bensinger WI, et al: Autologous transplantation with peripheral blood stem cells collected after granulocyte colony-stimulating factor in patients with acute myelogenous leukemia. Marrow Transplant 18:29-34, 1996 30. Martin C, Torres A, Leon A, et al: Autologous peripheral blood stem cell transplantation mobilized with G-CSF in AML in first complete remission: Role of intensification therapy in outcome. Bone Marrow Transplant 21:375-382, 1998[Medline] Submitted May 3, 1999; accepted October 19, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30 x 109/L without transfusion. 
2 test for binary variables and the Wilcoxon rank sum test for continuous variables. DFS was calculated from the time of first CR until the date of first relapse or the date of death from any cause. Overall survival (OS) was defined as the time of diagnosis to the time of death. Survival curves were plotted using the Kaplan-Meier method and differences were analyzed with the log-rank test. Central randomization was stratified by center. Because the use of quinine did not significantly increase the duration of neutropenia in a previous placebo-controlled study,
