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Therapy

Long-term survival data from a phase 3 study of Filgrastim as an adjunct to chemotherapy in adults with de novo acute myeloid leukemia

Abstract

We previously reported the results of a double-blind, placebo-controlled study of Filgrastim in patients with de novo AML undergoing induction and consolidation chemotherapy. The study demonstrated that Filgrastim was effective and well tolerated and had no impact on complete remission or survival. We now report follow-up data on these patients, assessing long-term effects with emphasis on prognostic indicators. After a median follow-up of 7 years, 434 (83%) patients were dead, 73 (14%) were alive, and 14 (3%) were lost to follow-up. The proportions of deaths were similar in the Filgrastim (83%) and placebo (84%) groups. No differences in median time to death (1.04 years Filgrastim, 1.13 years placebo; P=0.97) or median disease-free survival (0.86 years Filgrastim, 0.79 years placebo; P=0.52) were evident. Proportional hazard modeling identified age, performance status, and French-American-British subtype as independent predictors for survival (P<0.001, P=0.005, and P=0.036, respectively), whereas cytogenetic status was not (P=0.118). Filgrastim had no effect on overall survival in any of these subgroup analyses as none of the treatment comparisons were statistically significant. These findings indicate that Filgrastim can be effectively used to support patients with AML undergoing induction and consolidation chemotherapy without worsening long-term disease outcome.

Introduction

Acute myeloid leukemia (AML) is a clonal disorder of the early hematopoietic progenitors, which leads to a progressive failure of normal hematopoiesis and may cause death within 6–8 weeks if untreated.1, 2 AML is usually treated with chemotherapy; however, resulting myelosuppression is associated with neutropenia and infectious complication, one of the major causes of death among AML patients during the initial phase of chemotherapy.3 Hematopoietic growth factors such as recombinant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage-colony-stimulating factor are used to stimulate early granulopoiesis and reduce the duration of neutropenia and associated complications in patients with solid tumors and hematological malignancies.4, 5, 6, 7 However, hematopoietic growth factors have been shown to promote the growth of AML blasts in vitro, which has cast uncertainty on their safety in patients with AML.

Over the last decade, several randomized trials have analyzed whether recombinant growth factors can reduce the duration of chemotherapy-induced neutropenia in patients with AML without compromising the clinical outcome.4 These studies varied in methodology, assessed varied patient populations in terms of refractory or de novo AML, and produced somewhat inconsistent results. Generally, these studies did show that the use of growth factors significantly shortened the duration of severe neutropenia, which also reduced the need for hospitalization and intravenous antibiotic use.

We previously reported the results of a double-blind, placebo-controlled study of Filgrastim (recombinant G-CSF) in patients with de novo AML undergoing induction and consolidation chemotherapy.7 This study is the largest (n=521) single study of G-CSF in de novo AML and demonstrated that Filgrastim was effective and well tolerated and had no impact on achieving complete remission (CR) or on short-term survival during a mean follow-up of 24 months (range, 5–40 months). Patients were subsequently followed annually, and we now report long-term follow-up data (median 7 years, range 0.5–8.3 years).

Methods

The ethics committee of each country or hospital, as appropriate, approved the protocol, and all patients provided written informed consent before any study-specific procedures were performed. The study was conducted in accordance with the version of the Declaration of Helsinki that was in effect at the time the study took place.

Patients

Patients 16 years or older with de novo AML, as defined by the French-American-British (FAB) classification system, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 were eligible for study participation. Patients with previously diagnosed myelodysplastic syndromes or with a blast crisis of chronic myeloid leukemia were excluded, as were patients who had received previous treatment for AML and those who had had a previous malignancy.

Treatment plan

A detailed report of the treatment plan was described previously.7 Briefly, patients with de novo AML received either one or two courses of induction chemotherapy, followed by one or two courses of consolidation therapy if their disease went into CR. At 6 days after the start of the induction chemotherapy, patients were randomized to receive either Filgrastim or placebo. Blinded study drug (i.e., 5 μg/kg/day Filgrastim or placebo) was given subcutaneously from 24 h after the last dose of chemotherapy until neutrophil recovery (defined as absolute neutrophil count 1.0 × 109/l for 3 consecutive days or 10 × 109/l for 1 day), or up to a maximum of 35 days. Patients continued to receive their blinded study drug following all courses of chemotherapy. After completion of the study termination visit, patients were followed for survival and disease status.

Statistical methods

The first patient was randomized on 4 March 1992, and the last patient completed the double-blind phase of the study on 9 May 1995. The study censor date for follow-up data was 30 June 2000. The duration of follow-up was defined for each patient according to his or her survival status. For patients who died, the length of the follow-up period was counted as the number of years from randomization until the study censor date. For patients who remained alive, this time was counted as the number of years from randomization until either the date they were last known to be alive or the study censor date, whichever was earlier.

Overall survival was calculated as the number of years from randomization until death or study censor. Patients who were lost to follow-up or who were still alive at the study censor date had their time to death censored at these times. Disease-free survival was defined as the number of days from documented CR until disease relapse, death without evidence of disease recurrence, or study censor. Survival rates at 3 and 5 years postrandomization were estimated using the Kaplan-Meier method.

Cox proportional hazard modeling was used to assess the effect of prognostic factors on overall survival. Prognostic factors considered in the analysis included center, age, sex, ECOG performance status, FAB type, cytogenetic status, evidence of pre-existing myelodysplastic syndrome determined from central review of bone marrow aspirate slides, use of prophylactic IV antibiotics at baseline, baseline fever, baseline infection, baseline neutropenia, baseline IV antibiotic use, baseline WBC count, administration of high-dose cytarabine and daunorubicin in the second consolidation chemotherapy, and Filgrastim use. Cytogenetic status was classified as very unfavorable (monosomies 5, 7, complex and multiple abnormalities), unfavorable (trisomy 8, 11q[23]), intermediate (normal karyotype), and favorable (t[15;17], t[8;21], inv[16]). Each covariate was assessed in a univariate manner and considered a predictor for survival if the effect was significant at the α=0.05 level. Multiple logistic regression models were developed to evaluate the effect of significant univariate predictors on overall survival and the impact of Filgrastim treatment on overall survival among predictor subgroups.

Results

Patients

A total of 521 patients were randomized (Filgrastim, n=259; placebo, n=262). The treatment groups were well balanced with respect to demographic and disease characteristics (Table 1). The median length of follow-up was 7 years (Table 2).

Table 1 Demographics and disease characteristics
Table 2 Duration of follow-up and survival

Overall survival and disease-free survival

At the study censor date (30 June 2000) survival and disease-free survival were similar across the treatment groups (Table 2). Overall survival was similar for patients who received Filgrastim and those who received placebo (P=0.97, hazard ratio=1.0 [95% CI, 0.83–1.21]; Figure 1). A total of 355 patients (178 Filgrastim, 177 placebo) achieved CR following chemotherapy induction. Among patients who attained CR, the median disease-free survival (defined as time from remission until death or disease progression) was also similar (P=0.52, hazard ratio=1.08 [95% CI, 0.86–1.35]) (Figure 2).

Figure 1
figure1

Overall survival. Overall survival was similar for patients who received Filgrastim and those who received placebo. Median time to death was 1.04 years for the Filgrastim group compared with 1.13 years for the placebo group.

Figure 2
figure2

Disease-free survival. Filgrastim had no effect on disease-free survival. Median time to disease progression or death while in remission was 0.86 years for the Filgrastim group and 0.79 years for the placebo group.

Predictors of survival

Age, ECOG performance status, FAB type, and cytogenetic status were identified as predictors for overall survival in univariate assessment (Table 3). After fitting terms into a multivariate model, age, ECOG performance status, and FAB type remained significantly associated with overall survival (P<0.001, P=0.005, and P=0.036, respectively), whereas cytogenetic status was not (P=0.118). In assessments of disease-free survival, age and ECOG performance status were identified as significant predictors in univariate analysis (P<0.001 and P=0.045, respectively); however, the association remained significant only for age in the multivariate model (P=<0.001). As shown in Table 4, worse survival outcomes were associated with the two upper age quartiles, higher ECOG score, FAB type M5, and very unfavorable cytogenetic status.

Table 3 Univariate assessment of the effect of covariates on overall survival
Table 4 Effect of covariates on overall survival

Effect of filgrastim on predictors of time to death

Formal interaction tests were conducted to determine if there was any overall influence of Filgrastim on the effect of age, ECOG status, FAB type, or cytogenetic status. The analyses were conducted for both overall survival (Table 5) and disease free survival (Table 6). No significant interactions between Filgrastim treatment and these baseline parameters were observed for either overall or disease-free survival.

Table 5 Effect of treatment group on overall survival subgroup analysis
Table 6 Effect of treatment group on disease-free survival subgroup analysis

Discussion

This study is the first study designed to investigate the effect of Filgrastim on the long-term outcome of patients with de novo AML. After a median follow-up of 7 years, patients who received Filgrastim after induction and consolidation chemotherapy courses had a median time to death and rates of overall and disease-free survival that were comparable to those of patients who received placebo. Furthermore, Filgrastim had no detrimental interaction with factors having known prognostic significance in AML, such as age, ECOG performance status, FAB type, and cytogenetic status.

Patients diagnosed with AML have a relatively poor prognosis, with a 5-year survival rate of about 20%,8 although various prognostic factors affect the probability of response to chemotherapy and survival.2 Since the life expectancy for patients with AML is directly correlated to the time spent in CR,9 the goal of induction and consolidation treatment is to induce CR and prevent relapse. During induction chemotherapy, neutropenia-related infections are frequent and can be detrimental to the patient's outcome, not only by causing a potentially life-threatening condition but also by leading to delays in administration of subsequent chemotherapy.10 Thus, the ability to give chemotherapy with fewer complications and sequelae is highly desirable.

The results of the previously published phase of this study7 indicated that Filgrastim was effective and well tolerated among patients with AML receiving chemotherapy. During the first chemotherapy induction, patients receiving Filgrastim experienced neutrophil recovery 5 days earlier than those receiving placebo (P<0.001). The accelerated neutrophil recovery among patients treated with Filgrastim was accompanied by significant reductions in the duration of fever, use of parenteral antibiotics, and length of hospital stay. Similar reductions were seen after a second chemotherapy induction and the consolidation courses. Filgrastim also was associated with a significant reduction in the use of systemic antifungal therapy, which contributed to a reduced toxicity burden for the patients.

A considerable number of studies have investigated the use of growth factors in the treatment of AML.4, 11, 12, 13, 14, 15, 16 Although the methods and results have been somewhat variable, most of these studies have shown a benefit in terms of reducing the duration of neutropenia. Importantly, the majority of studies have shown growth factors to have no deleterious effect on duration of response or survival and little evidence for leukemic clone stimulation. Our long-term follow-up data (median 7 years) supports the contention that Filgrastim does not worsen the outcome of disease in patients with de novo AML and has no effect on the time to death when compared with placebo.

The survival data in our study compare well with survival data from studies conducted by the ECOG,17 which included patients who received chemotherapeutic agents similar to those used in our study. In the ECOG studies, 5-year overall survival rates ranged from 9 to 33% for patients <55 years old and from 6 to 13% for those 55 years and older. By comparison, our estimated 5-year survival rates ranged from 27 to 28% for the age quartiles that included patients under 54 years, and from 3 to 17% for the age quartiles that included patients 54 years and older. Previous studies have reported 4-year survival rates of about 50% in younger adults (i.e., patients under 60 years of age) with AML who received intensive chemotherapy as consolidation treatment.18, 19, 20 In contrast, our estimated 3-year survival rate is about 30% for patients less than 54 years of age. Our lower survival rate for younger adults may be due to the small number of patients in our study who received an intensive postremission therapy with high-dose cytarabine (47 patients)7 and the small number who presented with favorable cytogenetics (19 patients), both of which contribute to improved outcomes.

Age, performance status, and FAB type were identified as predictors for overall survival in our study. Although cytogenetic status was identified as a predictor for survival in univariate assessment, the relationship was not significant in multivariate assessment after adjustment for the effects of age, ECOG, and FAB type. Our lack of correlation between cytogenetic status and overall survival may be explained in part by the lack of availability of cytogenetic status results for 141 patients as well as the small number of patients in our study presenting with favorable (n=19) and very unfavorable (n=31) status. Nevertheless, the other prognostic factors identified in our study are compatible with previous reports2 and support the validity of our study results.

We previously demonstrated that Filgrastim was effective and well tolerated and had no effect on the incidence or duration of remission among patients with de novo AML receiving chemotherapy. After a median follow-up of 7 years, this is the first report to show that Filgrastim therapy had no detrimental effect on either disease-free survival or overall survival for these patients. These results continue to show that Filgrastim can be used to support chemotherapy induction and consolidation in this patient population.

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Acknowledgements

The following hospitals and investigators participated in the International AML study group: Derriford Hospital, Plymouth, UK (A Prentice); Manchester Royal Infirmary, UK (JA Liu Yin); Royal London Hospital, UK (A Newland); Addenbrooke's Hospital, Cambridge, UK (R Marcus); Musgrove Park Hospital, Taunton, UK (S Johnson); Guys Hospital, London, UK (S Schey); John Radcliffe Hospital, Oxford, UK (T Littlewood and C Bunch); University of Frankfurt, Germany (D Hoelzer and A Ganser); University of Ulm, Germany (G Heil and H Heimpel); University of Freiburg, Germany (R Mertelsmann and A Lindemann); Johannes-Guttenberg University, Mainz, Germany (C Huber and K. Kolbe); Ospedali Riuniti, Bergamo, Italy (T Barbui); Ospedale Regionale, Bolzano, Italy (P Coser); Ospedale San Bortoli, Vicenza, Italy (R Battista and F Rodeghiero); Ospedale S Eugenio, Roma, Italy (G Papa and A Venditti); University Eppendorf, Hamburg, Germany (D Hossfeld); Stuyvenberg Ziekenhuis, Antwerpen, Belgium (P Zachée); Ospedale Nuovo San Gerardo, Monza, Italy (G Corneo and E Pogliani); Hospital La Fe, Valencia, Spain (M Sanz and G Martín); Hospital de la Princesa, Madrid, Spain (J Fernández-Rañada and J Tomás); University of Vienna, Austria (K Lechner and K Geissler); Belfast City Hospital, UK (TCM Morris); University of Gent, Belgium (L Noens); Centre Hospitalier Sart Tilman, Liège, Belgium (G Fillet); Instituto Portugues de Oncologia (A Parreira); University Hospital of Lund, Sweden (PG Nilsson); and the Australian Leukaemia Study Group: Peter McCallum Cancer Institute, Melbourne (J Bishop); Royal Adelaide Hospital (C Juttner and J Ho); Royal Prince Alfred Hospital, Sydney (D Joshua); Westmead Hospital, Sydney (K Bradstock); Alfred Hospital, Melbourne (J Szer); Royal Melbourne Hospital (J Szer).

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Correspondence to G Heil.

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Sponsored by Amgen Ltd, Cambridge, UK and F Hoffmann-La Roche Ltd, Basel, Switzerland.

Presented at the 44th annual meeting of the American Society of Hematology, Philadelphia, PA, USA; December 6–10, 2002.

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Heil, G., Hoelzer, D., Sanz, M. et al. Long-term survival data from a phase 3 study of Filgrastim as an adjunct to chemotherapy in adults with de novo acute myeloid leukemia. Leukemia 20, 404–409 (2006). https://doi.org/10.1038/sj.leu.2404090

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Keywords

  • hematologic malignancies
  • granulocyte colony-stimulating factor
  • neutropenia

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