Colony‐stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

Ronit Gurion; Yulia Belnik‐Plitman; Anat Gafter‐Gvili; Mical Paul; Liat Vidal; Isaac Ben‐Bassat; Ofer Shpilberg; Pia Raanani

doi:10.1002/14651858.CD008238.pub3

. 2012 Jun 13;2012(6):CD008238. doi: 10.1002/14651858.CD008238.pub3

Colony‐stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

Ronit Gurion ¹, Yulia Belnik‐Plitman ¹, Anat Gafter‐Gvili ², Mical Paul ³, Liat Vidal ², Isaac Ben‐Bassat ⁴, Ofer Shpilberg ¹, Pia Raanani ^1,^✉

Editor: Cochrane Haematological Malignancies Group

PMCID: PMC7390444 PMID: 22696376

Abstract

Background

Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony‐stimulating factors (CSFs) are frequently administered during and after chemotherapy to reduce complications. However, their safety with regard to disease‐related outcomes and survival in AML is unclear. Therefore, we performed a systematic review and meta‐analysis to evaluate the impact of CSFs on patient outcomes, including survival.

Objectives

To assess the safety/efficacy of CSFs with regard to disease‐related outcomes and survival in patients with AML.

Search methods

We conducted a comprehensive search strategy. We identified relevant randomized clinical trials by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7), MEDLINE (January 1966 to July 2010), LILACS (up to December 2009), databases of ongoing trials and relevant conference proceedings.

Selection criteria

Randomized controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML. We excluded trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g. before and/or only for the duration of chemotherapy).

Data collection and analysis

Two review authors appraised the quality of trials and extracted data. For each trial, we expressed results as relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. We analyzed time‐to‐event outcomes as hazard ratios (HRs).

Main results

The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all‐cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival (HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates (RR 1.03; 95% CI 0.99 to 1.07), relapse rates (RR 0.97; 95% CI 0.89 to 1.05) and disease‐free survival (HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias (RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections (RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm (RR 1.33; 95% CI 1.00 to 1.56).

Authors' conclusions

In summary, colony‐stimulating factors should not be given routinely to acute myelogenous leukemia patients post‐chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections.

Keywords: Humans; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Granulocyte Colony‐Stimulating Factor; Granulocyte Colony‐Stimulating Factor/therapeutic use; Granulocyte‐Macrophage Colony‐Stimulating Factor; Granulocyte‐Macrophage Colony‐Stimulating Factor/therapeutic use; Induction Chemotherapy; Induction Chemotherapy/methods; Infections; Infections/drug therapy; Infections/etiology; Leukemia, Myeloid, Acute; Leukemia, Myeloid, Acute/complications; Leukemia, Myeloid, Acute/drug therapy; Leukemia, Myeloid, Acute/mortality

Plain language summary

The use of colony‐stimulating factors in the supportive care of patients with acute myelogenous leukemia (AML)

Acute myelogenous leukemia (AML) is an aggressive, rare type of blood cancer manifested by infections, bleeding and a high rate of mortality. It requires immediate treatment with intensive chemotherapy and sometimes also with bone marrow transplantation. Infections are a major cause of mortality in AML patients since intensive chemotherapy lowers the white blood cell (WBC) count and disrupts the immune system. Colony‐stimulating factors (CSFs) are agents administered in order to increase the WBC count, in the hope that this will decrease the rate of infections. However, it has not been established whether their administration might adversely affect other outcomes related to the disease, such as the achievement of remission or the relapse rate. Most importantly, it is unknown whether their administration affects the survival of AML patients. Therefore, we conducted a systematic review assessing the influence of CSFs on disease and infection‐related outcomes. Our review showed that the addition of CSFs to chemotherapy in AML patients affected neither overall survival, nor the achievement of disease remission or the rate of relapse. Importantly, they did not affect the rate of infections in this population. We concluded that CSFs post‐chemotherapy should not be given routinely in AML patients. However, their administration could be considered on an individual basis.

Summary of findings

Summary of findings for the main comparison. All cause mortality for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

All cause mortality for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings: inpatients   Intervention: All cause mortality
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	All cause mortality
All cause mortality ‐ 30 days   Follow‐up: 30 days	Study population		RR 0.97   (0.8 to 1.18)	3319   (11 studies)	⊕⊕⊝⊝   low^1,2
	109 per 1000	105 per 1000   (87 to 128)
	Moderate
	95 per 1000	92 per 1000   (76 to 112)
All cause mortality ‐ End of follow up   Follow‐up: 3‐7 years	Study population		RR 1.01   (0.98 to 1.05)	4029   (14 studies)	⊕⊕⊝⊝   low^1,3
	729 per 1000	736 per 1000   (715 to 766)
	Moderate
	758 per 1000	766 per 1000   (743 to 796)
All cause mortality subgroup analysis age>60   Follow‐up: 3‐7 years	Study population		RR 1.01   (0.97 to 1.06)	2035   (7 studies)	⊕⊕⊝⊝   low^1,2
	775 per 1000	782 per 1000   (751 to 821)
	Moderate
	852 per 1000	861 per 1000   (826 to 903)
All‐cause mortality subgroup analysis age< 60   Follow‐up: 3‐7 years	Study population		RR 1.08   (0.97 to 1.2)	1079   (5 studies)	⊕⊕⊝⊝   low^1,2
	533 per 1000	576 per 1000   (517 to 640)
	Moderate
	493 per 1000	532 per 1000   (478 to 592)
All‐cause mortality ‐ sensitivity analysis   Follow‐up: 3‐7 years	Study population		RR 1.03   (0.99 to 1.07)	3405   (10 studies)	⊕⊕⊕⊕   high
	710 per 1000	731 per 1000   (703 to 760)
	Moderate
	680 per 1000	700 per 1000   (673 to 728)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Some of the trials were not allocation concealed. Most studies were unblinded   ² The CI is very wide up to 20%   ³ Range of follow‐up is wide

Summary of findings 2. Overall survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Overall survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patientswith acute myelogenous leukemia   Settings:inpatients   Intervention: Overall survival
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Overall survival
Overall survival   Follow‐up: 3‐5 years	722 per 1000	722 per 1000   (696 to 749)	HR 1   (0.93 to 1.08)	3335   (11 studies)	⊕⊕⊝⊝   low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; HR: Hazard ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Some of RCTs are lack of allocation concealment. Only four RCTs are double blinded.   ² The CI is wide regarding OS ‐ There is 7% chance that CSFs can improved survival and also there is 8% that CSFs cannot improved survival.

Summary of findings 3. Complete remission for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Complete remission for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings:inpatients   Intervention: Complete remission
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Complete remission
complete response	Study population		RR 1.03   (0.99 to 1.07)	4774   (17 studies)	⊕⊕⊕⊝   moderate¹
	642 per 1000	661 per 1000   (635 to 687)
	Moderate
	612 per 1000	630 per 1000   (606 to 655)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Some of the studies lack allocation concealement

Summary of findings 4. Disease free survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Disease free survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings:inpatients   Intervention: Disease free survival
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Disease free survival
Disease free survival	Study population		OR 1   (0.9 to 1.13)	1639   (7 studies)	⊕⊕⊝⊝   low^1,2
	728 per 1000	728 per 1000   (706 to 751)
	Moderate
	722 per 1000	722 per 1000   (700 to 746)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Part of the studies were not blinded and allocation was not concealed   ² The CI was wide

Summary of findings 5. Relapse rate for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Relapse rate for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings:   Intervention: Relapse rate
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Relapse rate
Relapse rate	Study population		RR 0.97   (0.89 to 1.05)	2189   (10 studies)	⊕⊕⊝⊝   low^1,2
	513 per 1000	498 per 1000   (456 to 539)
	Moderate
	547 per 1000	531 per 1000   (487 to 574)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Not in all studies was allocation concealed   ² CI interval is not narrow

Summary of findings 6. Bacteremias for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Bacteremias for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patientswith acute myelogenous leukemia   Settings:inpatients   Intervention: Bacteremias
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Bacteremias
Bacteremia	Study population		RR 0.96   (0.82 to 1.12)	1638   (7 studies)	⊕⊕⊕⊝   moderate¹
	267 per 1000	256 per 1000   (219 to 299)
	Moderate
	272 per 1000	261 per 1000   (223 to 305)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Very wide CI

Summary of findings 7. Invasive fungal infections for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Invasive fungal infections for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patientswith acute myelogenous leukemia   Settings:   Intervention: Invasive fungal infections
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Invasive fungal infections
Invasive fungal infection	Study population		RR 1.4   (0.9 to 2.19)	929   (4 studies)	⊕⊕⊝⊝   low^1,2
	62 per 1000	87 per 1000   (56 to 136)
	Moderate
	53 per 1000	74 per 1000   (48 to 116)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Most studies were not allocation concealed or blinded   ² Very wide CI

Summary of findings 8. Episodes of febrile neutropenia for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Episodes of febrile neutropenia for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: patients with prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings:inpatients   Intervention: Episodes of febrile neutropenia
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Episodes of febrile neutropenia
Episodes of febrile neutropenia	Study population		RR 0.98   (0.94 to 1.03)	2140   (9 studies)	⊕⊕⊕⊝   moderate¹
	710 per 1000	696 per 1000   (667 to 731)
	Moderate
	731 per 1000	716 per 1000   (687 to 753)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ In half of the studies allocation was not concealed and were not blinded

Summary of findings 9. Adverse events requiring discontinuation of CSFs for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Adverse events requiring discontinuation of CSFs for prevention and treatment of infectious complications in patients with acute myelogenous leukemia
Patient or population: Prevention and treatment of infectious complications in patients with acute myelogenous leukemia   Settings:inpatients   Intervention: Adverse events requiring discontinuation of CSFs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Adverse events requiring discontinuation of CSFs
Adverse events requiring discontinuation of CSFs	Study population		RR 1.33   (1 to 1.76)	770   (4 studies)	⊕⊝⊝⊝   very low^1,2
	156 per 1000	207 per 1000   (156 to 274)
	Moderate
	21 per 1000	28 per 1000   (21 to 37)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

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¹ Very wide CI   ² Allocation of most studies was not concealed and generally studies were not blinded

Background

Description of the condition

Acute myeloid leukemia (AML) is a group of neoplastic disorders characterized by the proliferation and accumulation of immature hematopoietic cells in the bone marrow and blood. These malignant cells gradually replace and inhibit the growth and maturation of normal erythroid, myeloid and megakaryocytic precursors (Hoffman 2008). Acute myelogenous leukemia results from sporadic acquired somatic mutations in hematopoietic progenitors that confer a proliferative and/or survival advantage, impair hematopoietic differentiation and confer properties of limitless self‐renewal. Approximately 8000 new cases of AML in the USA occur per year and the incidence has remained stable over the last decade. AML is a disease of adults with a median age at diagnosis of 65 years. AML represents approximately 90% of all acute leukemias in adults. The age‐specific incidence is 3.5:100,000, 15:100,000 and 22:100,000 in individuals 50, 70 and 80 years, respectively (Hoffman 2008).

The classification and diagnosis of AML has evolved from the primarily morphologic and cytochemical system proposed by the French American British (FAB) Co‐operative Group in 1976 (Bennet 1976) to the current World Health Organization (WHO) 2008 classification (Vardiman 2009), which includes clinical information, cytogenetics and molecular abnormalities. The FAB co‐operative group classified the acute leukemias according to the resemblance of the predominant leukemic cell type to a normal differentiating hematopoietic precursor cell. The FAB group divided the myeloid leukemias into eight broad categories based on morphology, cytochemical staining and immunologic phenotype of the predominant cell type, based on Wright‐Giemsa stained blood and marrow smears or biopsies. The WHO classification defines unique clinical and biologically important subgroups. A change introduced by the WHO classification reduces the defining blast threshold for the diagnosis of AML from 30% blasts to 20% blasts. The WHO classification has now replaced the FAB classification of AML (Hoffman 2008).

Infiltration of the bone marrow by leukemic blasts is a major cause of morbidity and mortality in AML patients due to neutropenia, anemia and thrombocytopenia. Chemotherapy used for the treatment of AML is highly suppressive and thus worsens myelosuppression. Moreover, it is more frequently associated with infectious complications than regimens used to treat solid tumors. Almost all AML patients suffer from prolonged grade 4 neutropenia during induction and intensive consolidation chemotherapy and the incidence of neutropenic fever ranges between 50% and 90%, depending on the phase of the disease and the intensity of chemotherapy (Ottmann 2007). Bacterial and fungal infections are the major causes of morbidity and mortality in AML patients. Overall, there are about 10% infectious deaths during induction chemotherapy, with an even higher rate in patients older than 60 years of age (Bennett 1999; Bennett 2001). Allogeneic hematopoietic stem cell transplantation is the treatment of choice for many patients with AML. The major complications of allogeneic HSCT are infections, the need for red blood cell and platelet transfusions, organ damage, graft versus host disease (GVHD) and graft rejection (Bernstein 1998; Blume 2004; Goker 2001; Lee 2003; Nichols 2003; Smith 2006).

Given the uncertainty in the literature, several systematic reviews and meta‐analyses have previously assessed the efficacy of hematopoietic CSFs among cancer patients. These reviews can be divided into two groups: those looking at CSFs for the prevention of febrile neutropenia and those looking at CSFs for the treatment of febrile neutropenia. Both groups concentrated on infection‐related outcomes. Patients with AML were included in these reviews, although not always separately. For example, Dekker 2006 conducted a meta‐analysis including 34 trials to estimate the efficacy of CSFs in stem cell transplantation. The results of this meta‐analysis showed that CSFs reduced the risk of documented infections and duration of parenteral antibiotics but did not reduce infection‐related or treatment‐related mortality. Of note, this meta‐analysis included only AML patients undergoing hematopoietic stem cell transplantation (HSCT) and not AML patients receiving induction or consolidation treatment. Furthermore, the study population included all patients undergoing HSCT for any indication and not only for AML. Sung 2004 published a meta‐analysis on the role of prophylactic CSFs in the reduction of the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection‐related mortality in children with cancer. They showed that CSFs were associated with a 20% reduction in febrile neutropenia and a shorter duration of hospitalization but did not reduce infection‐related mortality. Unlike the present meta‐analysis, Sung 2004 included only children and the patients included in this meta‐analysis had all types of cancer and not only AML. Only one trial included in the meta‐analysis conducted by Sung included AML patients (Channa 2002).

Our review addresses AML patients only, compiling trials that assessed the use of growth factors during and after chemotherapy, regardless of the indication. Thus, our review offers the opportunity to assess endpoints related to the primary disease and overall survival and concentrate on safety issues.

Description of the intervention

Hematopoietic CSFs are a class of cytokines that regulate proliferation, differentiation and functions of hematopoietic cells. More than 20 different molecules of CSFs have been identified. Among them, granulocyte colony‐stimulating factor (G‐CSF) and the granulocyte macrophage colony‐stimulating factor (GM‐CSF) have been studied in cancer patients. G‐CSF regulates the production of neutrophil lineage. The administration of G‐CSF to humans results in a dose‐dependent increase in circulating neutrophils. GM‐CSF stimulates the growth of granulocyte, macrophage and eosinophil colonies. Administration of GM‐CSF to humans results in a dose‐dependent increase in blood neutrophils, eosinophils, macrophages and sometimes lymphocytes. Different types of G‐CSF and GM‐CSF have been tested in clinical trials (De Vita 2001).

CSFs may be administered in the context of AML in three scenarios:

Before and/or during chemotherapy in a priming strategy, in order to recruit leukemic cells into the cell‐cycle and enhance cell susceptibility to the cytotoxic effects of chemotherapy, especially by cell‐cycle specific agents like cytarabine.
After chemotherapy and/or allogeneic HSCT in order to accelerate myeloid regeneration and decrease the incidence and severity of neutropenia‐associated infectious complications.
During febrile neutropenia with or without documented infections in order to enhance recovery and resolution of infection.

In the present systematic review and meta‐analysis we included only those trials reporting on patients treated with CSFs started with or after chemotherapy (induction therapy, consolidation therapy, salvage treatment or conditioning for HSCT) and continued for more than 24 hours, in order to accelerate myeloid regeneration and decrease the incidence and severity of neutropenia‐associated infectious complications. We excluded trials assessing the role of CSFs for priming.

How the intervention might work

In most studies, shortening of neutropenia duration has been accompanied by reduced duration of fever, less use of antibiotics and antifungal drugs and a shorter duration of hospitalization. However, the incidence and severity of infections remained largely unchanged and mortality was unchanged. In a systematic review and meta‐analysis, which included 1518 patients with febrile neutropenia from 13 trials assessing all types of cancer, patients randomized to receive CSFs experienced a shorter time to neutrophil recovery (hazard ratio (HR) 0.32; 95% CI 0.23 to 0.46), a shorter length of hospitalization (HR 0.63; 95% CI 0.49 to 0.62), marginally less infection‐related mortality (HR 0.56; 95% CI 0.26 to 1.0) and no significant difference in overall mortality (HR 0.68; 95% CI 0.43 to 1.08) (Clark 2000).

The effect of myeloid growth factors on other outcomes, such as complete remission (CR) rate and disease‐free survival (DFS) or overall survival (OS) in AML patients, is not clear. AML cells, like their normal cellular counterparts, express functional growth factor receptors on their cell surface. The effect of having CSF receptors on leukemic cells has been evaluated in multiple clinical trials. Diverging results were reported (Griffin 1986; Inoue 1990; Lemoli 1991; Lowenberg 1988; Ohno 1990; Ohno 1993; Ohno 1994; Park 1989; Souza 1986; Vellenga 1987; Witz 1998; Zittoun 1996).

CSFs stimulate clonogenic leukemic colony‐forming units in vitro, therefore their clinical application in leukemia has been controversial. In vitro laboratory investigations have provided ample evidence to show that the effect of chemotherapy on leukemic cells can be amplified when they are simultaneously activated by CSFs stimulation. While this effect is positive, caution must be taken due to the risk that CSFs can cause leukemic cells to multiply (Griffin 1986; Inoue 1990; Lemoli 1991; Lowenberg 1988; Park 1989; Souza 1986; Vellenga 1987; Witz 1998 ; Zittoun 1996).

According to the American Society of Clinical Oncology (ASCO) recommendations, the use of CSFs following induction therapy is reasonable, although there has been no favorable impact on remission rate, remission duration or survival (Smith 2006).

According to the ASCO guidelines, when the risk of febrile neutropenia is approximately 20%, reduction in febrile neutropenia is an important clinical outcome that justifies the use of CSFs, regardless of the impact on other factors (Smith 2006). The use of CSFs following allogeneic blood HSCT has been shown to decrease the duration of absolute neutropenia but did not lead to shortened hospitalizations, cost savings or reduced antibiotic use (Smith 2006). The potential risks of CSFs in the management of AML remain inconclusive.

Why it is important to do this review

A systematic review and meta‐analysis assembling the current data might provide more conclusive evidence regarding the role and safety of CSFs in the management of patients with AML and might help in establishing the policy of treatment for patients with AML after induction, consolidation or salvage therapy and after HSCT. In the present systematic review and meta‐analysis we evaluate the safety of CSFs administered after these treatment phases.

Objectives

To evaluate the safety and efficacy of CSFs administered after induction, consolidation or salvage treatment and after HSCT in patients with AML.
To evaluate the safety of CSFs in young versus elderly patients as defined per study (usually older than 55 to 60 years).

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

Patients with AML of all six main WHO 2008 classification categories (AML with recurrent genetic abnormalities, AML with myelodysplasia‐related changes, therapy‐related myeloid neoplasms, AML not otherwise specified, myeloid sarcoma, myeloid proliferations related to Down syndrome) (Vardiman 2009)) at all stages of treatment after the administration of chemotherapy (induction, consolidation, salvage treatment and those undergoing HSCT). AML patients were included irrespective of age.

We included studies that assessed patients with AML as part of a cohort with other cancer patients or those undergoing HSCT and we tried to extract outcomes separately from the publications or through correspondence with the primary investigators. If separate data were unavailable, we excluded the study if the AML patients constituted less than 75% of the study cohort.

Types of interventions

Intervention

CSFs, including G‐CSF or GM‐CSF, administered either intravenously or subcutaneously, started with or after chemotherapy (induction, consolidation, salvage or conditioning for HSCT) and continued for more than 24 hours, compared with placebo or no treatment. We included both patients with and without neutropenia (absolute blood neutrophil count less than 0.5 x 10³/ml) and/or fever on admission. Fever was defined per study according to the definitions of neutropenic fever (usually, body temperature higher than 38.3 °C or 38.5 ºC on one occasion or higher than 38 °C on two or more occasions).

We excluded CSFs administered for the purpose of stem cell collection and/or priming, namely: CSFs administered before and/or only for the duration of chemotherapy.

Types of outcome measures

Primary outcomes

All‐cause mortality at the end of study follow up (number of deaths out of number evaluated).
Overall survival (hazard ratio (HR); 95% confidence interval (CI)).

Although both outcomes express the same meaning, the way of reporting is different and each outcome includes different RCTs.

Secondary outcomes

All‐cause mortality at 30 days (number of deaths/number evaluated) (mortality at 30 days usually parallels mortality related to AML induction treatment).
Number of patients achieving complete remission (CR) defined according to the International Working Group at the time point as defined per study (Cheson 1990).
Disease‐free survival (DFS) (HR; 95% CI) and number of patients with relapse.
Neutropenia duration from randomization (mean or median).
Episodes of febrile neutropenia per patient and per patient‐day (number of patients and number of episodes).
Episodes of invasive fungal infections (IFI), defined as probable or proven IFI according to acceptable guidelines (Ascioglu 2002; De Pauw 2008).
Number of bacteremias per patient.
Duration of hospital stay (mean or median) (only inpatients were included for the evaluation of hospitalization duration).
Any adverse events.
Adverse events requiring discontinuation of CSFs including: bone pain, allergic reaction (rash, urticaria, facial edema, respiratory (wheezing, dyspnea), and cardiovascular (hypotension, tachycardia), splenic rupture, acute respiratory distress syndrome (ARDS).
Secondary leukemia according to new chromosomal aberrations or a different type of leukemia.

Search methods for identification of studies

Electronic searches

We conducted a comprehensive search strategy to identify both published and unpublished trials, with no restriction on language or study years. We identified relevant randomized clinical trials by searching the Cochrane Review Group (CRG), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7) (Appendix 1), MEDLINE (January 1966 to July 2010) (Appendix 2), LILACS (up to December 2009), and references of all included studies and major reviews. In addition, we searched the following conference proceedings (2002 to June 2010):

European Group for Bone and Marrow Transplantation (available at: http://www.ebmt.org/);
Annual Meeting of the European Hematology Association (available at: http://www.ebmt.org/);
Annual Meeting of the Society for Hematology and Stem Cells (available at: http://www.exphem.org/); and
The Center for International Blood and Marrow Transplant Research (CIBMTR) (http://www.cibmtr.org/).

Searching other resources

We inspected all identified studies for references to further trials.

Data collection and analysis

Selection of studies

YB and RG independently inspected each reference identified by the search and applied the inclusion criteria. For possibly relevant articles, or in cases of disagreement between the two review authors, we obtained the full article and the two review authors inspected it independently.

Data extraction and management

Two review authors independently extracted the data from the included trials. In case of any disagreement, a third review author extracted the data. We discussed the data extraction, documented our decisions and, where necessary, contacted the study authors for clarification.

Trials were identified by the name of the first author and year in which the trial was first published and ordered chronologically.

We extracted the following data from the included studies:

Characteristics of trials

Date (defined as recruitment initiation year); location (country); centre (single centre or multi‐centre); setting of trial (inpatients or outpatients)(if inpatients ‐ isolation single room, laminar air flow room, positive pressure room).
Publication status: published; published as abstract; unpublished.
Design of trial: sources of bias: sequence generation and allocation concealment; blinding; incomplete outcome data; selective reporting.
Sponsor of trial (specified, known, unknown).
Duration of follow up: duration of planned CSFs administration; duration of follow up after the intervention and actual duration of follow up in the study.
Case definitions used (inclusion and exclusion criteria defined by each trial).
Inclusion criteria as defined by study: age; type of AML (morphology criteria according to the FAB classification); leukemia type (de novo AML, secondary AML, refractory AML, relapsed AML); white blood cell count; platelet count; treatment stage (induction, consolidation, relapse).

Characteristics of participants

Number of participants in each group.
FAB subtype (M0 to M7, not assessed).
Disease stage (newly diagnosed AML, primarily refractory AML, relapsed AML, relapsed and refractory AML).
Type of treatment (induction, consolidation, salvage). We recorded specifically for each treatment the chemotherapy protocol administered including the type of chemotherapy, dose intensity and schedule.
Age.
Gender.
Eastern Co‐operative Oncology Group (ECOG) status.
Cytogenetics (favorable, normal, unfavorable, not assessed).
Infection at diagnosis (number of patients) (none, FUO (fever of unknown origin, i.e.>38.3°C on several occasions, duration of >3 weeks and failure to reach diagnosis despite 1 week of inpatient investigation, documented infection, severe infection at diagnosis).
White cell count at diagnosis (number of patients).
Mean marrow blast infiltration (in %).
Fever at diagnosis.
Prophylactic antibiotics.

Characteristics of interventions

Type of CSF.
Dose of CSF.
Schedule of administration.
Total duration of intervention.

Characteristics of outcome measures as defined above

We extracted outcomes preferably by intention‐to‐treat, including all individuals randomized in the outcome assessment.

Assessment of risk of bias in included studies

Two review authors assessed the trials fulfilling the review inclusion criteria for methodological quality. We extracted information about randomization and allocation concealment, blinding, sample size, exclusions after randomization, and different lengths of follow up. We used the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) and ‘Risk of bias’ tables. The standard ‘Risk of bias’ table includes assessments for sequence generation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting and ‘other issues’. For each item, the table provides a description of what was reported to have happened in the study and a subjective judgment regarding protection from bias (low risk of bias, high risk of bias or unclear risk of bias).

Measures of treatment effect

We analyzed dichotomous data by calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed using 95% confidence intervals (CI). We pooled trial results according to the duration of follow up at the time at which outcomes were assessed.

Dealing with missing data

The four general recommendations for dealing with missing data in Cochrane Reviews were followed (Higgins 2009).

Whenever possible we contacted the original investigators to request missing data.
We clearly stated the assumptions of any methods used to cope with missing data.
We performed sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions that are made.
We addressed the potential impact of missing data on the findings of the review in the Discussion section.

Assessment of heterogeneity

We assessed heterogeneity (degree of difference between the results of different trials) in the results of the trials using a Chi² test of heterogeneity and the I² statistic measure of inconsistency.

The Chi² test assesses whether observed differences in results are compatible with chance alone. A low P value (or a large Chi² statistic relative to its degree of freedom) provides evidence of heterogeneity of intervention effects (variation in effect estimates beyond chance). A useful statistic for quantifying inconsistency is the I² (measure of inconsistency). A rough guide to interpretation of the I² statistic is as follows: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity (Higgins 2009).

We also investigated heterogeneity through subgroup and sensitivity analyses as defined below (Higgins 2002; Higgins 2003).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. There are several types of reporting bias: publication bias, time‐lag bias, multiple (duplicate) publication bias, location bias, citation bias, language bias and outcome reporting bias .

To avoid reporting bias we searched comprehensively for studies that met the eligibility criteria for a Cochrane Review. We searched multiple sources but study reports may selectively present results, reference lists may selectively cite sources and duplicate publication of results can be difficult to spot. Furthermore, the availability of study information may be subject to time‐lag bias, particularly in fast‐moving research areas. In order to reduce reporting biases we included unpublished studies and trial registries. Prospective trial registration has the potential to substantially reduce the effects of publication bias.

Small study effects are one of the possible causes of publication bias, i.e. a tendency for estimates of the intervention effect to be more beneficial in smaller studies. Funnel plots allow for a visual assessment of whether small study effects are present in the meta‐analysis. Funnel plots are valid for continuous outcomes but less so for dichotomous outcomes. When there was evidence of small study effects we attempted a funnel plot to understand the source of the small study effects and considered their implications in sensitivity analyses (Higgins 2009).

Data synthesis

We used the Mantel‐Haenszel method (Review Manager (RevMan) RevMan 2011) to estimate risk ratios (RR) and 95% confidence intervals (CI) for dichotomous data. We used a fixed‐effect model and performed a sensitivity analysis by repeating the above analysis using a random‐effects model (DerSimonian and Laird method) (DerSimonian 1986). We analyzed time‐to‐event outcomes as hazard ratios (HR) and estimated their variances as described by Parmar et al (Parmar 1998). We pooled time‐to‐event variables using the inverse of variance. We analyzed continuous data using the mean and standard deviation (SD) of each trial and calculating the effect size (average mean difference) and the 95% CI.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses in order to assess the impact of these possible sources of heterogeneity on mortality at the end of follow up and on complete remission (CR).

Age > 60 versus age < 60 including children (or otherwise defined for elderly AML).
Type of treatment: induction versus consolidation.
Type of CSF: G‐CSF versus GM‐CSF.
Patients undergoing chemotherapy only versus those undergoing allogeneic HSCT.

Sensitivity analysis

We performed sensitivity analyses in order to assess the robustness of the findings to different aspects of the trials' methodology: allocation concealment (adequate or unclear), allocation generation (adequate or unclear), blinding (double‐blinded or unblinded studies) and intention‐to‐treat analysis (ITT).

Results

Description of studies

The computerized search strategy identified 1421 potentially relevant publications, of which we considered 89 publications for further investigation. Of them, we excluded 46 publications, reporting on 40 trials, as described below. We included 43 publications reporting on 19 trials.

Included studies

Nineteen trials (43 publications) performed between the years 1990 and 2003 and including a total of 5256 patients (range 53 to 803 patients per trial) fulfilled the inclusion criteria (Amadori 2005; Beksac 2010; Bernasconi 1998; Bradstock 2001; Dombret 1995; Estey 1999; Godwin 1998; Harousseau 2000; Heil 1997; Lehrnbecher 2007; Lowenberg 1997; Milligan 2006; Nakajima 1995; Rowe 1995; Stone 1995; Usuki 2002; Wheatley 2009; Witz 1998; Zittoun 1996).

Type of patients

Patients with AML were defined according to the WHO 2008 classification. In four studies the age of the patients ranged from 15 to 60 years (Bradstock 2001; Harousseau 2000; Lowenberg 1997; Zittoun 1996), in six studies the age of the patients was above 55 years (Amadori 2005; Dombret 1995; Godwin 1998; Rowe 1995; Stone 1995; Witz 1998), in one study patients' ages were lower than 18 years (Lehrnbecher 2007) and in the remaining studies, patients' ages were higher than 15 years with no upper limit (Beksac 2010; Heil 1997; Usuki 2002).

Chemotherapy regimens

Seventeen trials included patients undergoing induction chemotherapy (Amadori 2005; Beksac 2010; Bernasconi 1998; Bradstock 2001; Dombret 1995; Estey 1999; Godwin 1998; Heil 1997; Lehrnbecher 2007; Lowenberg 1997; Nakajima 1995; Rowe 1995; Stone 1995; Usuki 2002; Wheatley 2009; Witz 1998; Zittoun 1996), one trial included patients undergoing consolidation chemotherapy (Harousseau 2000) and one trial included patients undergoing salvage chemotherapy (Milligan 2006).

The chemotherapy protocols used in the trials were heterogeneous. They consisted of different combinations of anthracyclines (daunorubicin, idarubicin or mitoxantrone) and cytarabine with or without etoposide. In seven trials the chemotherapy regimen included intravenous (IV) daunorubicin 45 to 60 mg/m² for three to four days and intravenous cytarabine 100 to 200 mg/m² for seven days with etoposide (Heil 1997) or without it ( Dombret 1995; Godwin 1998; Lowenberg 1997; Rowe 1995; Stone 1995; Zittoun 1996). In five trials the regimen included intravenous idarubicin 8 to 12 mg/m² and intravenous cytarabine 100 mg/m² with etoposide (Bernasconi 1998; Bradstock 2001; Witz 1998) or without it (Beksac 2010; Lehrnbecher 2007). One trial also combined idarubicin with fludarabine (Estey 1999). Two trials consisted of mitoxantrone‐containing regimens with cytarabine and etoposide (Amadori 2005; Harousseau 2000). Three trials included several chemotherapy regimens depending on physicians' choice and the population's age (Milligan 2006; Usuki 2002; Wheatley 2009). In one trial the chemotherapy regimen was not reported (Nakajima 1995).

Intervention

Type of CSF

The CSF used in five trials was GM‐CSF (Lowenberg 1997; Rowe 1995; Stone 1995; Witz 1998; Zittoun 1996), while in 14 trials G‐CSF was used (Amadori 2005; Beksac 2010; Bernasconi 1998; Bradstock 2001; Dombret 1995; Estey 1999; Godwin 1998; Harousseau 2000; Heil 1997; Lehrnbecher 2007; Milligan 2006; Nakajima 1995; Usuki 2002; Wheatley 2009).

Schedule

CSF administration started concurrent with chemotherapy in three trials (Estey 1999; Milligan 2006; Witz 1998), during the 48‐hour period post‐chemotherapy in 10 trials (Amadori 2005; Bernasconi 1998; Bradstock 2001; Dombret 1995; Harousseau 2000; Heil 1997; Lowenberg 1997; Stone 1995; Usuki 2002; Zittoun 1996) and 48 hours after chemotherapy completion in five trials (Beksac 2010; Godwin 1998; Lehrnbecher 2007; Rowe 1995; Wheatley 2009).

Excluded studies

We excluded 40 trials (46 publications). Reasons for exclusion were the following:

Non‐randomized studies: 15 trials (Bernell 1994; Braess 2006; Buchner 2004; Chen 1998; Estey 1990; Freud 1995; Godwin 1995; Kalaycio 2001; Kern 1998; Maslak 1996; Montillo 1998; Moore 1997; Schriber 1994; Takeshita 1995; Takeshita 2000).
Studies which did not randomize CSF: four trials (Hanel 2001; Ossenkopple 2004; Stone 2001; Thomas 2007b).
Studies which randomized different schedules of CSF: four trials (Ohtake 2006; Sierra 2005; Takeyama 1995; von Lilienfeld Toal 2007).
Randomized studies of CSF with a low number of AML patients included: two trials (Bishop 2000; Ojeda 1999).
Randomized study with use of monocyte colony‐stimulating factor which was not in the included characteristics (Ohno 1997).
Studies evaluating the role of CSFs for the purpose of priming (e.g. before and/or only for the duration of chemotherapy): nine trials (Buchner 1993; Frenette 1995; Hast 2003; Heil 1995; Lowenberg 1997; Lowenberg 2003; Ohno 1994; Rowe 2004; Thomas 2007a).
Studies which evaluated CSFs for the purpose of stem cell collection: two trials (Morton 2001;Schmitz 1998).
Double publication: two trials (Creutzig 2006;Goldstone 2001).

Risk of bias in included studies

See Characteristics of included studies, 'Risk of bias' tables.

We assessed generation of randomization sequence as adequate in four studies (classified as low risk of bias). In the other 15 studies the method of randomization was not specified (classified as high risk of bias).

Allocation

Allocation concealment was adequate in 12 studies (classified as low risk of bias). In the remaining seven studies the method of allocation concealment was not clear (classified as high risk of bias).

Blinding

Four studies were conducted in a double‐blinded manner (placebo‐controlled), however it was not mentioned which persons were blinded. All the remaining trials were open or blinding was not reported.

Incomplete outcome data

In all trials the numbers and reasons for dropout were reported in the original articles.

Selective reporting

All the included trials were published in full text.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9

Primary outcomes

1. All‐cause mortality at the end of study follow up

Fourteen trials including 4119 patients reported all‐cause mortality. The end of study follow up ranged between three and seven years. The addition of colony‐stimulating factors (CSFs) to chemotherapy yielded no difference in all‐cause mortality between patients treated with chemotherapy and CSFs and those treated with chemotherapy alone, with a risk ratio (RR) of 1.01 (95% confidence interval (CI) 0.98 to 1.05) (Figure 1). The results did not change when we performed a sensitivity analysis using a random‐effects model (Figure 2).

Forest plot of comparison: All‐cause mortality at the end of follow up

When tested, the quality of allocation concealment (adequate or unclear) had no statistically significant impact on the results. Pooled RR of trials with adequate allocation concealment was 1.03 (95% CI 0.99 to 1.07, 10 trials) at the end of follow up.

Subgroup analysis of the primary outcome

Results were not influenced by age of patients or type of CSFs.

In subgroup of patients older than 60 years versus younger than 60 years, CSFs did not reduce all‐cause mortality, with a RR of 1.01 (95% CI 0.97 to 1.05, eight trials) and 1.08 (95% CI 0.97 to 1.20, five trials) respectively (Figure 3; Figure 4).

Type of CSF had no effect on outcomes. Mortality of patients treated with G‐CSF (RR 1.00; 95% CI 0.97 to 1.05, nine trials) and GM‐CSF (RR 1.05; 95% CI 0.96 to 1.14, four trials) was similar.

We did not conduct a subgroup analysis by type of chemotherapy since only one trial included patients who received consolidation chemotherapy while most trials included patients who received induction chemotherapy.

Also, we did not conduct a subgroup analysis by conventional chemotherapy versus allogeneic transplantation since no trial included patients undergoing allogeneic transplantation.

2. Overall survival

Eleven trials including 3335 patients reported on overall survival. The addition of CSFs to chemotherapy yielded no difference in overall survival between patients treated with chemotherapy and CSFs and those treated with chemotherapy alone, with a hazard ratio (HR) of 1.00 (95% CI 0.93 to 1.08, 11 trials) (Figure 2).

Secondary outcomes

All‐cause mortality at 30 days

Eleven trials including 3319 patients reported all‐cause mortality at 30 days. The addition of CSFs to chemotherapy yielded no difference in all‐cause mortality between patients treated with chemotherapy and CSFs and those treated with chemotherapy alone, with a RR of 0.97 (95% CI.0.80 to 1.18) (Figure 3).

Complete remission (CR)

Seventeen trials including 4774 patients reported CR rate.

The addition of CSF to chemotherapy compared to placebo or no intervention did not alter the rate of CR, with a RRof 1.03 (95% CI 0.99 to 1.07) (Figure 4).

Forest plot of comparison: 3 Complete remission, outcome: 3.1 Complete response.

Disease‐free survival (DFS)

Seven trials including 1639 patients reported on DFS. There was no difference in DFS between patients receiving or not receiving CSFs(HR 1.00; 95% CI 0.90 to 1.13) (Figure 5).

Forest plot of comparison: 4 Disease‐free survival, outcome: 4.1 Disease‐free survival.

Relapse rate

Ten trials including 2189 patients reported on relapse rate. The addition of CSFs to chemotherapy yielded no difference in relapse rate between the two groups(RR 0.97; 95% CI 0.89 to 1.05) (Figure 6).

Episodes of febrile neutropenia per patient

Ten trials including 2140 patients reported on episodes of febrile neutropenia. The use of CSFs did not decrease the occurrence of these events(RR 0.98; 95% CI 0.94 to 1.03) (Figure 10).

Bacteremias

Seven trials including 1638 patients reported on bacteremias. The administration of CSFs did not decrease the occurrence of bacteremias(RR 0.96; 95% CI 0.82 to 1.12) (Figure 11).

Invasive fungal infections

Four trials including 929 patients reported invasive fungal infections. The addition of CSFs did not decrease the occurrence of invasive fungal infections(RR 1.40; 95% CI 0.90 to 2.19) (Figure 12).

Duration of neutropenia

Seventeen studies reported on neutropenia duration. In studies where neutropenia was defined as less than 0.5 x 10⁹ /L neutrophils (nine trials) the median duration of neutropenia ranged between 12 and 24 days in the CSFs arm and between 17 and 29 days in the control arm (Amadori 2005; Bradstock 2001; Godwin 1995; Harousseau 2000 ; Heil 1997; Lehrnbecher 2007; Stone 1995; Witz 1998; Zittoun 1996). In studies where neutropenia was defined as less than 1.0 x 10⁹/L neutrophils (four trials) the median duration of neutropenia ranged between 7 and 26 days in the CSF arm and between 16 and 30 days in the control arm (Bernasconi 1998; Dombret 1995; Estey 1999; Milligan 2006). CSFs significantly shortened the duration of neutropenia in all studies except for one (Zittoun 1996). We could not conduct a meta‐analysis on this outcome since it is a non‐normally dispersed variable and outcomes were reported as medians in most trials with different dispersion measures, and were non‐normally dispersed.

Hospital stay duration

Twelve trials reported on the duration of hospitalization. The median duration of hospitalization ranged between 23 and 36 days in the CSF arm and between 27 and 38 days in the control arm. Several studies reported on a significant shortening of hospitalization duration with CSF administration (Amadori 2005; Harousseau 2000; Heil 1997; Milligan 2006 ; Wheatley 2009), while others showed no significant difference (Beksac 2010; Bradstock 2001; Godwin 1995; Lowenberg 1997; Stone 1995; Witz 1998). Due to the variability in data reporting we could not conduct a meta‐analysis on this outcome.

Any adverse events

Only two studies reported on the total number of adverse events, therefore we could not conduct a meta‐analysis. One study reported on 11 cases with adverse events in the CSF arm while no adverse events were reported in the control arm (Usuki 2002). Another study reported on 25 cases in the CSF arm compared to nine cases in the control arm (Zittoun 1996).

Adverse events requiring discontinuation of CSFs

Four studies, including 770 patients, reported on adverse events requiring discontinuation of CSFs (Rowe 1995; Stone 1995; Witz 1998; Zittoun 1996). There were marginally statistically more adverse events requiring discontinuation of CSFs in the CSF arm compared to the control arm(RR 1.33; 95% CI 1.00 to 1.76) (Figure 13).

In addition, three studies reported on adverse events of grade three to four and in all of them there was no statistical difference between the CSF arm and the control (Amadori 2005; Bradstock 2001; Godwin 1995).

Secondary leukemia

There was no report of secondary leukemia in any of the included studies, except for Lehrnbecher 2007 who described three events of secondary malignancies in the control arm compared to one event in the CSF arm.

Discussion

Summary of main results

Our aim was to assess the influence of colony‐stimulating factors (CSFs) on the prevention and treatment of infectious complications in acute myelogenous leukemia (AML) patients. The addition of CSFs did not alter all‐cause mortality in the short and long term. The administration of CSFs did not affect the occurrence of episodes of neutropenic fever, bacteremias or invasive fungal infections. There was also no effect on hematological outcomes, including complete remission, relapse rate or disease‐free survival.

Potential biases in the review process

We carried out a subgroup analysis according to age (above 60 years) which did not show any advantage for the addition of CSFs to chemotherapy in elderly patients. Nevertheless, this analysis included only eight trials. Furthermore, we could not perform a subgroup analysis by type of treatment (induction versus consolidation) or by leukemia prognostic factors such as cytogenetic analysis, due to lack of data.

A meta‐analysis of secondary outcomes such as neutropenia and hospitalization duration could not be carried out since these variables were not given as mean numbers but mostly as medians which are parameters that are not distributed normally and thus cannot be pooled in a meta‐analysis. We therefore conducted a descriptive analysis of these outcomes.

Agreements and disagreements with other studies or reviews

The American Society of Clinical Oncology (ASCO) recommendations state that it is reasonable to use CSFs after induction chemotherapy in AML patients despite lack of evidence to prove this (Smith 2006), whereas the British Society of Haematology guidelines are more straightforward in not recommending the routine use of CSFs for the post‐induction period (Milligan 2006). Both the ASCO and the British Society of Haematology guidelines state that CSFs can be recommended after the completion of the consolidation phase on the basis of two randomized controlled trials showing a significant decrease in duration of neutropenia (Harousseau 2000; Heil 1997; Milligan 2006; Smith 2006).

A recent meta‐analysis which focused on AML patients was published by Wang et al. The authors compared the use of granulocyte colony‐stimulating factor (G‐CSF) in AML patients receiving chemotherapy to placebo or no treatment. It concentrated on overall survival and remission rate and showed that the addition of G‐CSF did not alter overall survival (Wang 2009a), yet it showed an improved complete remission in the G‐CSF arm compared to the control arm (Wang 2009b). These conclusions regarding overall survival were based only on seven randomized controlled trials (RCTs). Conversely, the present systematic review summarizes all the evidence currently available, including 19 RCTs which used G‐CSF as well as GM‐CSF, and thus is more powerful in its capacity to support or challenge these results. Regarding the outcome of complete remission Wang's meta‐analysis included five RCTs; one of them was published with partial results (Goldstone 2001). In our meta‐analysis, however, the conclusions are based on 17 RCTs; 12 of them used G‐CSF.

Another systematic review and meta‐analysis has recently been published by Heuser et al. The authors evaluated the use of CSFs in adult AML patients receiving chemotherapy in two separate meta‐analyses: primary prophylaxis and priming. The first meta‐analysis, focusing on primary prophylaxis, included 14 RCTs with 4069 participants. It showed that CSFs decreased time to neutrophil recovery and hospitalization stay, yet it did not influence other important outcomes(i.e. complete remission rate, event/disease‐free survival or overall survival. The second meta‐analysis, focusing on the use of CSFs for priming, also consisted of 14 studies with 4518 participants. There was no difference in complete remission rate, event/disease‐free survival or overall survival (Heuser 2010). Our meta‐analysis focused on primary prophylaxis only, yet it included RCTs irrespective of age. Therefore, it included more RCTs on this subject (19 RCTs versus 14 RCTs in Heuser et al). The results of both meta‐analyses were similar.

Authors' conclusions

Implications for practice.

In summary, colony‐stimulating factors should not be given routinely to acute myelogenous leukemia patients post‐chemotherapy since they do not improve overall survival, or infectious parameters including the rate of bacteremias and invasive fungal infections. Yet, our results show that, on the other hand, they do not adversely affect hematological outcomes such as complete remission, relapse rate and disease‐free survival.

Implications for research.

Further randomized controlled trials should be encouraged in order to examine the role of colony‐stimulating factors in specific acute myelogenous leukemia patient subgroups, such as elderly patients, those at different treatment stages and those with various genetic abnormalities.

Feedback

Inappropriate conclusions, 4 October 2011

Summary

The review has the title: “Colony‐stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.” This makes it clear what the review is about, namely the possibility of preventing or treating infections by using colony‐stimulating factors (CSFs). This could be life‐saving. Acute myelogenous leukaemia has a high mortality rate and the patients may die from infections acquired during chemotherapy‐induced neutropenia. Accordingly, the primary outcomes in the review are mortality outcomes. The review did not find an effect on any major outcome. The abstract tells us that the relative risk or hazard ratio was 1 for all‐cause mortality, overall survival, complete remission rates, relapse rates, disease‐free survival and bacteremias. For invasive fungal infections, there was a non‐significant tendency towards more infections when CSF was used (RR 1.40; 95% CI 0.90 to 2.19).     1. “Authors’ conclusions” in the abstract do not reflect these unequivocally negative findings: “The addition of CSFs to chemotherapy does not adversely influence all‐cause mortality, complete remission or relapse rates in patients with AML. Although the benefit of CSFs is limited to reduction of neutropenic and febrile days, they can be administered safely when necessary.”   This conclusion is inappropriate. When the relative risk and hazard ratio for all the most important outcomes are 1, with narrow confidence intervals, as the total sample size was very large (19 trials including 5256 patients), it is inappropriate to say that CSFs “does not adversely influence all‐cause mortality, complete remission or relapse rates.” The hope was that CSF would work, i.e. reduce these outcomes, which it did not, and the authors should say so, rather than concluding that CSFs reduce neutropenic and febrile days and can be administered safely when necessary.

2. Furthermore, it is not appropriate to give a result in the conclusions that was not given under Results in the abstract.

3. These drugs are highly expensive. When exactly do the authors imagine they should be used when they have no effect on the outcomes that matter? One should not use expensive drugs that were supposed to reduce infections and deaths for reducing days with fever. That can be obtained with very cheap drugs.

4. The conclusions are not in accordance with the findings and the title of the review and should be changed; neutropenic and febrile days should not appear in the abstract at all.

5. I find it likely that the “Authors’ conclusions” either reflect the biases of the authors, or the editors, or the peer reviewers.

Did the editors ask the authors to change their conclusions into something more positive than they had intended?
Did the editors (or peer reviewers) have conflicts of interest related to companies marketing colony‐stimulating factors?

Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback..

Reply

Reply to point 1:

The goal of this review as stated in the objectives paragraph was:

“‐ To evaluate the safety and efficacy of CSFs administered after induction, consolidation or salvage treatment and after HSCT in patients with AML.

‐ To evaluate the safety of CSFs in young versus elderly patients as defined per study (usually older than 55 to 60 years).”

We agree that we could not show a beneficial effect in terms of efficacy. Nevertheless, as the main concern with the administration of growth factors in AML patients is their safety, the “raison d'être” of our review was to establish their safe use in AML. This indeed was shown in our results for all AML patients as well as for the subgroup of elderly patients, as manifested by the fact that, as stated by the critic himself, the relative risks and hazard ratios for all the most important outcomes were 1, with narrow confidence intervals.

Nevertheless, in view of the feedback we revised:

1. Authors' conclusions in the abstract:

"In summary, colony‐stimulating factors should not be given routinely to acute myelogenous leukemia patients post‐chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections."

2. The authors' conclusions in the main text / Implications for practice:

"In summary, colony‐stimulating factors should not be given routinely to acute myelogenous leukemia patients post‐chemotherapy since they do not improve overall survival, or infectious parameters including the rate of bacteremias and invasive fungal infections. Yet, our results show that, on the other hand, they do not adversely affect hematological outcomes such as complete remission, relapse rate and disease‐free survival."

Reply to point 2:

We agree that it is not appropriate to give a result in the conclusions that was not given under results. We therefore changed our conclusions in the abstract and the conclusions in the main text / Implications for practice as stated in "Reply to point 1".

Reply to point 3:

We accepted the feedback and changed our conclusions in the abstract and the conclusions in the main text/implications for practice as stated in "Reply to point 1".

Reply to point 4:

We accepted the feedback and changed our conclusions in the abstract and conclusions / Implications for practice as stated in "Reply to point 1". We deleted neutropenic and febrile days from the authors' conclusions in the abstract.

Reply to point 5 (from the Editorial Base):

All the authors of the review filled out the conflict of interest statement and declared that they had no conflict of interest. During the time the editors have commented on the present review, the Editorial Base had not yet asked the editors for the disclosure of potential conflicts of interest. After reviewing the e‐mail exchange on this review the Editorial Base and the Feedback Editor were not able to identify any indications for conflicts of interest on the side of the editors. The editorial discussion was mainly about methodological/statistical issues. None of the editors questioned the initial conclusions of the authors.

In the meantime the CHMG adapted the group’s policy: Since November 2011 the Editorial Base asks all editors to disclose their potential conflicts of interest with respect to each review they comment on. The conflict of interest statement can be requested at the Editorial Base.

Contributors

Gurion R, Belnik‐Plitman Y, Gafter‐Gvili A, Paul M, Vidal L, Ben‐Bassat I, Shpilberg O, Raanani P: author and co‐authors of the review

Trelle S, Kluge S, Skoetz N: Feedback Editor, Managing Editor, Co‐ordinating Editor of the Cochrane Haematological Malignancies Group

What's new

Date	Event	Description
11 May 2012	New citation required and conclusions have changed	Changes made in full text and abstract
11 May 2012	Feedback has been incorporated	Amended review according to valid feedback

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Acknowledgements

We thank Prof. Lowenberg and Prof. Beksac for providing complementary data from their trials.

Appendices

Appendix 1. CENTRAL search strategy

Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3)

ID	Search
#1	MeSH descriptor Hematopoietic Cell Growth Factors explode all trees
#2	(pegylated granulocyte colony‐stimulating factor, human)
#3	"granulocyte colony‐stimulating factor, Tyr(1)‐Tyr(3)‐"
#4	MeSH descriptor Colony‐Stimulating Factors explode all trees
#5	MeSH descriptor Colony‐Stimulating Factors, Recombinant explode all trees
#6	MeSH descriptor Granulocyte Colony Stimulating Factor, Recombinant explode all trees
#7	MeSH descriptor Granulocyte Colony‐Stimulating Factor explode all trees
#8	MeSH descriptor Granulocyte‐Macrophage Colony‐Stimulating Factor explode all trees
#9	MeSH descriptor Macrophage Colony‐Stimulating Factor explode all trees
#10	(RHGCSF or RH‐GCSF or RHGMCSF or RH‐GMCSF)
#11	(RMETHUG* or RHMETHUG* or R‐METHUG* or RH‐METHUG*)
#12	(RHUG* or RHUGM*)
#13	(GCSF* or G‐CSF*)
#14	(GM‐CSF* or GMCSF*)
#15	(GRANULOYT NEAR/3 FATOR)
#16	(MAROPHAG NEAR/5 FATOR)
#17	(FILGRASTIM*)
#18	(neupogen*)
#19	(religrast*)
#20	(nugraf*)
#21	(LENOGRASTIM*)
#22	(Granocyte*)
#23	(Euprotin*)
#24	(PEGFILGRASTIM)
#25	(Neulasta*)
#26	(LEUKINE*)
#27	(sagramostim*)
#28	(MOLGRAMOSTIN*)
#29	(macrogen*)
#30	(Mielogen*)
#31	(Leucomax*)
#32	(nartograstim*)
#33	(pegnartograstim*)
#34	(ecogramostim*)
#35	(regramostim*)
#36	(leridistim*)
#37	(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36)
#38	MeSH descriptor Leukemia, Myeloid, Acute explode all trees
#39	MeSH descriptor Leukemia, Myeloid explode all trees
#40	MeSH descriptor Acute Disease explode all trees
#41	(#39 AND #40)
#42	(acut* or akut* or agud* or aigu) and (myelo or nonlympho* or granulocytic* or monocyt* or megakaryoblast* or promyelocyt* or erythroblast) and (leukem* or leuc*)
#43	(myelo* and naegel* ) and (leukem or leuc*)
#44	(erythroleukem)
#45	(di guglielmo*)
#46	(erythremic* NEAR myelos*)
#47	MeSH descriptor Leukemia, Monocytic, Acute explode all trees
#48	MeSH descriptor Leukemia, Megakaryoblastic, Acute explode all trees
#49	MeSH descriptor Leukemia, Myelomonocytic, Acute explode all trees
#50	MeSH descriptor Leukemia, Promyelocytic, Acute explode all trees
#51	MeSH descriptor Leukemia, Erythroblastic, Acute explode all trees
#52	(aml)
#53	(#38 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52)
#54	(#37 AND #53)

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Appendix 2. MEDLINE search strategy

1	Hematopoietic Cell Growth Factors/
2	pegylated granulocyte colony‐stimulating factor, human.nm.
3	"granulocyte colony‐stimulating factor, Tyr(1)‐Tyr(3)‐".nm.
4	COLONY‐STIMULATING FACTORS/
5	exp COLONY‐STIMULATING FACTORS, RECOMBINANT/
6	exp GRANULOCYTE COLONY STIMULATING FACTOR, RECOMBINANT/
7	exp GRANULOCYTE COLONY‐STIMULATING FACTOR/
8	exp GRANULOCYTE‐MACROPHAGE COLONY‐STIMULATING FACTOR/
9	MACROPHAGE COLONY‐STIMULATING FACTOR/
10	(RHG?CSF$ or RH‐G?CSF$ or RHGM?CSF$ or RH‐GM?CSF$).tw.
11	(RMETHUG$ or RHMETHUG$ or R‐METHUG$ or RH‐METHUG$).tw.
12	(RHUG$ or RHUGM$).tw.
13	(GCSF$ or G‐CSF$).tw.
14	(GM‐CSF$ or GMCSF$).tw.
15	(GRANULO?YT$ adj3 FA#TOR$).tw.
16	(MA#ROPHAG$ adj5 FA#TOR$).tw.
17	FILGRASTIM$.tw,hw,nm,kf.
18	neupogen$.tw,hw,nm,kf.
19	religrast$.tw,kf,nm,kf.
20	nugraf$.tw,kf,nm,kf.
21	LENOGRASTIM$.tw,hw,nm,kf.
22	Granocyte.tw,hw,nm,kf.
23	Euprotin.tw,hw,nm,kf.
24	PEG?FILGRASTIM$.tw,hw,nm,kf.
25	Neulasta.tw,hw,nm,kf.
26	LEUKINE.tw,hw,nm,kf.
27	sagramostim$.tw,kf,nm,ot.
28	MOLGRAMOSTIN$.tw,hw,nm,kf.
29	macrogen$.tw,kf,nm,ot.
30	Mielogen$.tw,kf,nm,ot.
31	Leucomax$.tw,hw,nm,kf.
32	nartograstim$.tw,kf,nm,ot.
33	pegnartograstim$.tw,kf,nm,ot.
34	ecogramostim$.tw,kf,nm,ot.
35	regramostim$.tw,kf,nm,ot.
36	leridistim$.tw,kf,ot.
37	or/1‐36
38	exp LEUKEMIA, MYELOID, ACUTE/
39	LEUKEMIA, MYELOID/
40	ACUTE DISEASE/
41	39 and 40
42	(acut$ or akut$ or agud$ or aigu$).tw,kf,ot.
43	((myelo$ or nonlympho$ or granulocytic$ or monocyt$ or megakaryoblast$ or promyelocyt$ or erythroblast$) and (leuk?em$ or leuc$)).tw,kf,ot.
44	42 and 43
45	(myelo$ and naegel$ and (leuk?em$ or leuc$)).tw,kf,ot.
46	erythroleuk?em$.tw,kf,ot.
47	di guglielmo$.tw,kf,ot.
48	(erythremic$ adj myelos$).tw,kf,ot.
49	LEUKEMIA, MONOCYTIC, ACUTE/
50	LEUKEMIA, MEGAKARYOBLASTIC, ACUTE/
51	LEUKEMIA, MYELOMONOCYTIC, ACUTE/
52	LEUKEMIA, PROMYELOCYTIC, ACUTE/
53	LEUKEMIA, ERYTHROBLASTIC, ACUTE/
54	aml.tw,kf,ot.
55	or/44‐54
56	38 or 41 or 55
57	randomized controlled trial.pt.
58	controlled clinical trial.pt.
59	randomized.ab.
60	placebo.ab.
61	drug therapy.fs.
62	randomly.ab.
63	trial.ab.
64	groups.ab.
65	or/57‐64
66	humans.sh.
67	65 and 66
68	37 and 56
69	67 and 68
	Lines 1 to 37: Search part for CSF. The search consists of subject heading and text word search. In, for example, search line 5 the MeSH‐term was exploded (exp). This search command lets you retrieve results that contain the subject heading in combination with all of its narrower terms. It is necessary to use a text word search. The search term ran in the fields tw (text word), kf (keyword), ot (original title), nm (name of substance) and hw (subject heading word). Lines 40 to 56: Search part for the disease AML. Line 57 to 68: Cochrane RCT search filter for MEDLINE/OVID. Line 69: Result of the search.

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Data and analyses

Comparison 1. All‐cause mortality.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality at 30 days	11	3319	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.80, 1.18]
1.1 30 days	11	3319	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.80, 1.18]
2 All‐cause mortality at the end of follow up	14	4119	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.98, 1.05]
2.1 End of follow up	14	4119	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.98, 1.05]
3 All‐cause mortality subgroup analysis age > 60	8	2125	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.97, 1.05]
4 All‐cause mortality subgroup analysis age < 60	5	1079	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.97, 1.20]
5 All‐cause mortality sensitivity analysis for allocation concealment	10	3405	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.99, 1.07]
6 All‐cause mortality sensitivity analysis using random effects model	14	4119	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.96, 1.04]
6.1 End of follow up	14	4119	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.96, 1.04]

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1.1 — Comparison 1 All‐cause mortality, Outcome 1 All‐cause mortality at 30 days.

1.2 — Comparison 1 All‐cause mortality, Outcome 2 All‐cause mortality at the end of follow up.

1.3 — Comparison 1 All‐cause mortality, Outcome 3 All‐cause mortality subgroup analysis age > 60.

1.4 — Comparison 1 All‐cause mortality, Outcome 4 All‐cause mortality subgroup analysis age < 60.

1.5 — Comparison 1 All‐cause mortality, Outcome 5 All‐cause mortality sensitivity analysis for allocation concealment.

1.6 — Comparison 1 All‐cause mortality, Outcome 6 All‐cause mortality sensitivity analysis using random effects model.

Comparison 2. Overall survival.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	11	3335	Hazard Ratio (95% CI)	1.00 [0.93, 1.08]

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2.1 — Comparison 2 Overall survival, Outcome 1 Overall survival.

Comparison 3. Complete remission.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete response	17	4774	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.99, 1.07]

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3.1 — Comparison 3 Complete remission, Outcome 1 Complete response.

Comparison 4. Disease‐free survival.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival	7	1639	Hazard Ratio (95% CI)	1.00 [0.90, 1.13]

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4.1 — Comparison 4 Disease‐free survival, Outcome 1 Disease‐free survival.

Comparison 5. Relapse rate.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse rate	10	2189	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.89, 1.05]

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5.1 — Comparison 5 Relapse rate, Outcome 1 Relapse rate.

Comparison 6. Bacteremias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Bacteremias	7	1638	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.82, 1.12]

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6.1 — Comparison 6 Bacteremias, Outcome 1 Bacteremias.

Comparison 7. Invasive fungal infections.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Invasive fungal infections	4	929	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.90, 2.19]

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7.1 — Comparison 7 Invasive fungal infections, Outcome 1 Invasive fungal infections.

Comparison 8. Episodes of febrile neutropenia.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Episodes of febrile neutropenia	9	2140	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.94, 1.03]

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8.1 — Comparison 8 Episodes of febrile neutropenia, Outcome 1 Episodes of febrile neutropenia.

Comparison 9. Adverse events requiring discontinuation of CSFs.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events requiring discontinuation of CSFs	4	770	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.00, 1.76]

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9.1 — Comparison 9 Adverse events requiring discontinuation of CSFs, Outcome 1 Adverse events requiring discontinuation of CSFs.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Amadori 2005.

Methods	Randomized, open‐label, controlled trial   Median follow up: 4.7 years
Participants	722 patients Median age: 54 years Male: 53% Newly diagnosed AML patients receiving induction chemotherapy Europe, multi‐center
Interventions	Induction chemotherapy: MICE (IV mitoxantrone 7 mg/m² on days 1, 3, 5; IV cytarabine 100 mg/m² on days 1 to 7; IV etoposide 100 mg/m² on days 1 to 3) IV G‐CSF 150 µg/m²/d starting with or after chemotherapy (depending on trial's arm) and discontinued if blast cells increased > 2‐fold during chemotherapy course or blast cells persisted at significant levels (> 1 x 10⁹/L) for 3 days after chemotherapy completion, or if blasts at significant level (> 1 x 10⁹/L) reappeared after chemotherapy completion, or until WBC > 10 x 10⁹/L, or when serious toxicity attributed to G‐CSF occurred   The trial included 4 arms: G‐CSF during and after chemotherapy (A) versus G‐CSF after chemotherapy (B) versus G‐CSF during chemotherapy (C‐arm excluded) versus control (D)
Outcomes	All‐cause mortality at 30 days and at the end of follow up Number of patients achieving complete remission (CR) Number of patients with relapse
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "randomization was performed centrally"
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: "open‐label"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "A total of 35 patients were considered ineligible: 5 in group A, 10 in group B, 10 in group C, and 10 in group D. Reasons for ineligibility included insufficient data in 13, concomitant malignant diseases in 11, prior chemotherapy in 4, inadequate performance status in 3, leukemia supervening after a myeloproliferative disorder in 2, and other causes in 2. Ineligible patients were also included in the intention‐to‐treat analysis."
Selective reporting (reporting bias)	Low risk	All the outcomes which were described in the Methods section were reported in the Results section
Other bias	Low risk	The day of randomization is the first day of chemotherapy

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Beksac 2010.

Methods	Randomized, controlled, open trial   Median follow up: 3 years
Participants	260 patients Median age: 38.5 years, range 16 to 60 years Male: 56.9% Newly diagnosed AML patients who had received induction chemotherapy Turkey, multicenter
Interventions	Induction chemotherapy: IV cytarabine 100 mg/m²/d for 10 days + IV idarubicin 12 mg/m²/d for 3 days IV G‐CSF 5 µg/d starting on day 8 until neutrophil count > 0.5 x 10⁹/L for 2 days The trial included 2 arms: G‐CSF after chemotherapy versus control
Outcomes	All‐cause mortality at the end of follow up Number of patients achieving complete remission (CR) Number of patients with relapse
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate, shuffling
Allocation concealment (selection bias)	Low risk	Adequate, sealed and opaque envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not reported
Selective reporting (reporting bias)	High risk	Although one of the outcomes in the Methods section was disease‐free survival, it was not described in the Results section
Other bias	High risk	Randomization was done on day 8 after chemotherapy and only if marrow blasts were less than 20%, so some of the patients were excluded (died or medically declined)

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Bernasconi 1998.

Methods	Randomized controlled trial   Maximal range follow up: 25 months
Participants	105 patients Median age: 58 years in the G‐CSF arm and 57 years in the control arm Male: 28% in the G‐CSF arm and 29% in the control arm De novo myelodysplastic syndrome (RAEB, RAEB‐T) and AML patients who had received induction chemotherapy Italy, multicenter
Interventions	Induction chemotherapy: idarubicin 12 mg/m² on days 1, 2 + etoposide 60 mg/m²/12hr for 5 days + cytarabine 120 mg/m²/12 hr for 5 days SC G‐CSF 5 µg/kg/d starting 48 hrs after the end of chemotherapy until neutrophil count > 10 x 10⁹/L or until day 21 The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 30 days Number of patients achieving complete remission (CR) Number of patients with relapse Number of bacteremias
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No withdrawals and protocol violations after randomization reported. Not reported if the analysis was performed on an ITT basis.
Selective reporting (reporting bias)	Unclear risk	Not all the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	Day of randomization was not reported

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Bradstock 2001.

Methods	Randomized controlled trial   Median follow up: 3.6 years
Participants	114 patients Median age: 43 years (range 15 to 60) Male: 67% in the control arm, 48% in the G‐CSF arm Newly diagnosed AML patients who had received induction chemotherapy Australia, multicenter
Interventions	Induction chemotherapy: ICE (cytarabine 3 gr/m² every 12 hrs on days 1, 3, 5, 7 + etoposide 75 mg/m² on days 1 to 7 + idarubicin 12 mg/m² on days 1 to 3 , later dose was reduced to 9 mg/m² d/t toxicity) SC G‐CSF 5 µg/kg/d starting on day 8 after chemotherapy until recovery of neutrophils > 2 x 10⁹/L for 3d or > 5 x 10⁹/L for 1 day or evidence of residual leukemia in day 28 bone marrow biopsy The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 1 year and at the end of follow up Overall survival Infection‐related mortality Number of patients achieving complete remission (CR)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The method of randomisation was based on a biased coin design."
Allocation concealment (selection bias)	Low risk	Quote: "Patients were randomised by telephoning the ALSG trial centre."
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "A total of 114 eligible patients had been enrolled at that time; 54 had been randomised to receive lenograstim and 60 to no cytokine. Two patients, both on the no cytokine arm, were inevaluable with respect to the primary endpoint: one was withdrawn from the trial before commencing induction therapy due to pneumonia and one died from non‐protocol‐related causes 2 days after commencing induction. These patients are included in the response and survival comparisons. The remaining 112 randomised patients provided the basis of the toxicity comparisons."
Selective reporting (reporting bias)	Low risk	All the outcomes which were described in the Methods section, were reported in the Results section
Other bias	Low risk	The randomization was performed before initiation of chemotherapy

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Dombret 1995.

Methods	Randomized controlled trial   Follow up: 3.5 years
Participants	173 patients Median age: 70 years (range: 64 to 83) Male: 54% in the G‐CSF arm and 56% in the control arm Newly diagnosed AML patients who had received induction chemotherapy Europe, multicenter
Interventions	Induction chemotherapy: IV daunorubicin 45 mg/m² for 4 days + IV continuous cytarabine 200 mg/m² for 7 days SC G‐CSF 5 µg/kg/d starting on day 9 after chemotherapy until neutrophil recovery > 1 x 10⁹/L for 3 days or maximum 28 days The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 30 days, 1 year and at the end of follow up Overall survival Number of patients achieving complete remission (CR) Number of bacteremias Number of invasive fungal infections
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "one patient was lost to follow‐up in each treatment group."
Selective reporting (reporting bias)	Low risk	All the outcomes which were described in the Methods section, were reported in the Results section
Other bias	High risk	Randomization was done on day 8 of the induction chemotherapy. Therefore, patients who were unsuitable for chemotherapy or declined during chemotherapy were not randomized.

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Estey 1999.

Methods	Randomized controlled trial   Median follow up: 35 weeks
Participants	216 patients Median age: 65 With AML or RAEB/RAEB‐T who received induction chemotherapy USA
Interventions	Induction chemotherapy: FAI (fludarabine 30 mg/m²/d on days 1 to 4 + cytarabine 2 gr/m²/d on days 1 to 4 + idarubicin 12 mg/m²/d on days 2 to 4); ATRA 45 mg/m²/d in divided doses G‐CSF 200 µg/m²/d: in patients with WBC count<10 x 10⁹/L start on day 1; in patients with WBC count 10 x 10⁹‐50 x 10⁹/L start on day 1 (simultaneously with chemotherapy); in patients with WBC count > 50 x 10⁹/L start on day 2 until neutrophil recovery > 1 x 10⁹/L The trial included 4 arms: G‐CSF versus ATRA and G‐CSF versus ATRA versus control
Outcomes	All‐cause mortality at 30 days, 1 year and at the end of follow up Overall survival Number of patients achieving complete remission (CR) Number of bacteremias Number of invasive fungal infections
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "All but four of the 215 were eligible, and we include all 215 in this report."
Selective reporting (reporting bias)	Unclear risk	All the outcomes which were described in the Methods section were reported in the Results section
Other bias	Unclear risk	Day of randomization was not reported

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Godwin 1998.

Methods	Double‐blind, placebo‐controlled study   Median follow up: 33 months
Participants	234 patients Median age: 68 years (range: 56 to 88) Male: 58% Patients with AML FAB M0 to M7 who had received induction chemotherapy USA, multicenter
Interventions	Induction chemotherapy: IV cytarabine 200 mg/m²/d 1‐7d + IV daunorubicin 45 mg/m²/d 1‐3d and 2 consolidations ‐ IV daunorubicin 30 mg/m² 1‐2d + cytarabine 200 mg/m²/d 1‐7d IV G‐CSF 400 µg/m²/d starting on day 11 of induction or on day 8 of consolidation until neutrophil recovery > 1 x 10⁹/L The trial included 2 arms: G‐CSF versus placebo
Outcomes	All‐cause mortality at 1 year and at the end of follow up Overall survival Infection‐related mortality Number of patients achieving complete remission (CR) Disease‐free survival
Notes	Funding: academic
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blinding (not specified who was blinded)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "The analyses are based on intent to treat and include the 211 patients with centrally confirmed diagnoses of AML. Nine of these 211 cases failed to meet other eligibility criteria."
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	High risk	The randomization was performed on day 11 of induction.

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Harousseau 2000.

Methods	Randomized, open, controlled trial   Median follow up: 26 months
Participants	194 patients Median age: 47.5 years in the G‐CSF arm and 45 years in the control arm Male: 49% in the G‐CSF arm and 50% in the control arm Patients with de novo AML who received consolidation chemotherapy France, multicenter
Interventions	Consolidation chemotherapy: ICC1 (cytarabine 3 g/m² every 12 hrs for days 1 to 4 + mitoxantrone 12 mg/m² on days 5 to 6) + ICC2 (amsacrine 150 mg/m² for 5 days + etoposide 100 mg/m² for 5 days) SC G‐CSF 5 µg/kg/d starting on day 8 of consolidation until recovery of neutrophil count > 1 x 10⁹/L or > 0.5 x 10⁹/L for 3 days The trial included 2 arms: G‐CSF versus placebo
Outcomes	All‐cause mortality at 30 days Overall survival Relapse rate Number of bacteremias
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Central randomization"
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Of the 194 patients, 29 (15%) could not proceed to ICC2 (16 in the G‐CSF arm and 13 in the control arm)
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Low risk	Randomization was done before the initiation of chemotherapy

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Heil 1997.

Methods	Randomized, double‐blind, controlled trial   Median follow up: 24 months
Participants	521 patients Median age: 54 years (range: 16 to 89) Male: 54% Patients with AML who had received induction chemotherapy Europe, multicenter
Interventions	Induction chemotherapy: IV daunorubicin 45 mg/m² for 3 days + IV continuous cytarabine 200 mg/m² for 7 days + IV etoposide 100 mg/m² for 5 days SC G‐CSF 5 µg/kg/d starting 24 hours after the last dose of chemotherapy until recovery of neutrophil count > 1 x 10⁹/L or > 0.5 x 10⁹/L for 3 days The trial included 2 arms: G‐CSF versus placebo
Outcomes	All‐cause mortality at 30 days and at the end of follow up Overall survival Infection‐related mortality Number of patients achieving complete remission (CR) Disease‐free survival
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Patients were centrally randomized after 6 days of chemotherapy"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blinding: blinded study drug
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "All analyses, with the exception of disease‐free survival and analysis of courses subsequent to induction course 1, were performed in an intent‐to‐treat manner, i.e., including all randomized patients in the treatment groups assigned at randomization. The analysis of disease‐free survival only included patients who achieved a CR."
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	High risk	Randomization was done on the sixth day of chemotherapy

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Lehrnbecher 2007.

Methods	Randomized controlled trial   Median follow up: 4.1 years
Participants	429 patients Age: < 16 years Male: 59.6% in the G‐CSF arm and 46.2% in the control arm Patients with AML who had received induction chemotherapy Europe, multicenter
Interventions	Induction chemotherapy: AIE 1st induction (cytarabine at dose of 100 mg/m²/d continuous on days 1 to 2 and infusion every 12 hours on 3‐8d; idarubicin 12 mg/m² on 3‐5d; etoposide 150 mg/m² on 6‐8d; IT cytarabine on days 0, 8) + HAM 2nd induction IV/SC G‐CSF 5 µg/kg/d starting on day 15 after the start of chemotherapy until the neutrophil count was > 0.5 x 10⁹/L for 3 consecutive days The trial included 2 arms: G‐CSF versus placebo
Outcomes	All‐cause mortality at 30 days and at the end of follow up Overall survival Infection‐related mortality Number of patients achieving complete remission (CR) Disease‐free survival
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was centrally performed using the permuted block method."
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "All efficacy analyses were performed according to the intent‐to‐treat principle."
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	High risk	Quote: "randomization regarding G‐CSF performed on day 15."

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Lowenberg 1997.

Methods	Randomized controlled trial   Median follow up: 5 years
Participants	274 patients Mean age: 42 years (+/‐ 12) Male: 56% Patients with previously untreated newly diagnosed AML according to FAB who had received induction chemotherapy Europe, multicenter
Interventions	Induction chemotherapy: first course: IV daunorubicin 45 mg/m² on days 1, 2, 3 & cytarabine 200 mg/m² on days 1 to 7. 2nd course: IV amsacrine 120 mg/m² on days 4, 5, 6 and cytarabine 1 gr/m² every 12 hr on days 1 to 6 IV/SC GM‐CSF 5 µg/kg/d starting at the end of chemotherapy (course 1‐ day 8, course 2 ‐ day 7) until the neutrophil count was > 0.5 x 10⁹/L for 3 consecutive days or until 28 days The trial included 4 arms: GM‐CSF during and after chemotherapy (arm excluded) versus GM‐CSF after chemotherapy versus GM‐CSF during chemotherapy (arm excluded) versus control
Outcomes	All‐cause mortality at the end of follow up Number of patients achieving complete remission (CR) Relapse rate Number of bacteremias
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Central randomization
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "A total of 274 patients were randomized. Twenty‐one patients were not assessable and excluded from the analysis for the following reasons: treatment had been started before randomization (n = 3), no diagnosis of AML (n = 6), age greater than 60 years (n = 1), no treatment (n = 3), no data available (n = 1), and the possibility of placebo treatment instead of GM‐CSF (n = 6)."
Selective reporting (reporting bias)	Unclear risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	Day of randomization was not reported

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Milligan 2006.

Methods	Randomized controlled trial   Median follow up: 4 years
Participants	356 patients Age: 15 years and older (no median/mean reported) Male ‐ 96% in the G‐CSF arm and 87% in the control arm Patients with relapsed/refractory AML or AML with adverse cytogenetics in CR after chemotherapy who had received re‐induction chemotherapy Britain, Ireland and New Zealand
Interventions	Reinduction chemotherapy: ADE (ara‐c, daunorubicin, etoposide)/FLA (fludarabine, ara‐c) IV/SC G‐CSF 5 µg/kg/d starting on day 1 of chemotherapy until the neutrophil count was > 0.5 x 10⁹/L for 2 consecutive days or until 28 days The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 30 days, 1 year and at the end of follow up Overall survival Number of patients achieving complete remission (CR) Disease‐free survival Relapse rate
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "allocation was computer generated"
Allocation concealment (selection bias)	Low risk	Quote: "randomization was performed by telephone call to the central trial office"
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "all analyses are performed on the “intention to treat” principle with all patients analyzed in their allocated arms, irrespective of whether they actually received their allocated treatment "
Selective reporting (reporting bias)	Unclear risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	Day of randomization was not reported

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Nakajima 1995.

Methods	Randomized controlled trial
Participants	95 patients Age: < 16 years Patients with AML who had received induction chemotherapy Japan, multicenter
Interventions	Induction chemotherapy ‐ unknown IV G‐CSF 5 µg/kg/d The trial included 2 arms: G‐CSF versus placebo
Outcomes	All‐cause mortality at 30 days Infection‐related mortality
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not reported
Selective reporting (reporting bias)	Unclear risk	Not reported

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Rowe 1995.

Methods	Double‐blind, randomized study   Median follow up: 13.1 months
Participants	124 patients Median age: 64 years Male: not reported Patients with AML who had received induction chemotherapy USA, multicenter
Interventions	Induction chemotherapy: induction ‐ daunorubicin 60 mg/m²/d on days 1 to 3 and cytarabine 25 mg/m² IV push on day 1 followed by 100 mg/m²/d by continuous infusion on days 1 to 7; consolidation ‐ for patients that entered CR, 1 course of cytarabine 1.5 g/m² every 12 hr over 1 hr for 12 doses IV GM‐CSF 250 µg/m²/d starting on day 11 after the start of chemotherapy until the neutrophil count was > 1.5 x 10⁹or until a maximum of 42 days The trial included 2 arms: GM‐CSF versus placebo
Outcomes	All‐cause mortality at 1 year Overall survival Number of patients achieving complete remission (CR)
Notes	Funding: academic
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quotes: "Of these patients, 117 were eligible and evaluable: 60 on the GM‐CSF arm and 57 on the placebo arm. Reasons for exclusion were prior chemotherapy (1 patient), no follow‐up (2 patients), and wrong pathology (4 patients)." "All eligible and evaluable patients to be included in an intent‐to‐treat analysis."
Selective reporting (reporting bias)	Unclear risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	The day of randomization was not reported

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Stone 1995.

Methods	Randomized, double‐blind trial   Median follow up: not mentioned
Participants	388 patients Median age: 69 years Male: 56% Patients with primary AML as defined by FAB who had received induction chemotherapy USA, multicenter
Interventions	Induction chemotherapy: IV daunorubicin 45 mg/m² for 3 days + IV continuous cytarabine 200 mg/m² for 7 days IV GM‐CSF 5 µg/kg/d starting one day after the cytarabine infusion was completed until life‐threatening toxicity due to study drug or neutrophil recovery > 1 x 10⁹/L or peripheral myeloblast count > 1 x 10⁹/L The trial included 2 arms: GM‐CSF versus placebo
Outcomes	All‐cause mortality at the end of follow up Overall survival Number of patients achieving complete remission (CR), Number of bacteremias
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The computer program controlling the randomization was a general program used for randomized studies of the CALGB."
Allocation concealment (selection bias)	Low risk	Quote: "randomly assigned to one of the two treatment groups by means of a telephone call to the CALGB Statistical Center."
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐blinding. Not reported who was blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quotes: "Since all enrolled patients were randomized, no patients were excluded from the primary analyses." "The primary analyses in this study followed the intention‐to‐treat principle"
Selective reporting (reporting bias)	Unclear risk	Disease‐free survival was one of the outcomes in the Methods section, but it was not described in the Results section
Other bias	Low risk	The first day of chemotherapy was the day of randomization

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Usuki 2002.

Methods	Randomized controlled trial   Median follow up: 20 months
Participants	270 patients Mean age: 49.5 +/‐ 16.5, range: 15 to 87 years Male: 65% Patients with newly diagnosed de novo AML as defined by FAB who had received induction chemotherapy Japan, multicenter
Interventions	Various induction regimens: BHAC‐DM; BHAC‐DMP; BHAC‐EDM, depending on each hospital IV G‐CSF 200 mg/m²/d starting 48 hours after the completion of chemotherapy until neutrophil count > 1.5 x 10⁹/L The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 30 days and at the end of follow up Infection‐related mortality Overall survival Number of patients achieving complete remission (CR) Disease free survival
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Central
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "All analyses were performed in an intent‐to‐treat manner, i.e. including all patients assigned to each group at the time of randomization." Quote: "A total of 270 patients were randomized from October 1993 to September 1996. Sixteen patients had their diagnosis amended to another disease (15 had myelodysplastic syndrome and one had acute lymphoblastic leukaemia), two patients had severe heart or liver failure, five patients concomitantly received G‐CSF during induction chemotherapy, and two patients were treated with all‐trans retinoic acid. These 25 patients were withdrawn from the study and the remaining 245 patients were included in the analyses."
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the results section
Other bias	High risk	The randomization day was the first day after completion of chemotherapy

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Wheatley 2009.

Methods	Randomized, placebo‐controlled trial   Median follow up: 5 years
Participants	803 patients Median age of patients: 49 years (range: 15 to 77) Male: 53% Patients with de novo AML or secondary AML defined by FAB received induction chemotherapy Britain, multicenter
Interventions	Induction chemotherapy: AML12 (ADE 10 + 3 + 5 or MAE 3 + 10 + 5) or AML11 (ADE, DAT or MAC) IV G‐CSF 263 µg/d starting on day 8 from the end of chemotherapy (18 days after the start of ADE, MAE or DAT and 13 days after the start of MAC) until recovery of neutrophil count > 0.5 x 10⁹/L for 2 days or for 10 days maximum The trial included 2 arms: G‐CSF versus control
Outcomes	All‐cause mortality at 30 days, at 1 year and at the end of follow up Overall survival Number of patients achieving complete remission (CR) Disease‐free survival Relapse rate
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Randomizations were performed by telephone call to a central randomization office"
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quotes: "The principal analyses were ‘intention‐to‐treat’ on all randomized patients, with a subsidiary analysis of the major clinical endpoints performed excluding patients who did not commence G‐CSF or placebo." "599 (75%) were known to have commenced either the G‐CSF or placebo" Reasons not to receive G‐CSF or placebo include: patients either died before, or were too ill, or refused, or were not given by mistake and other
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	The day of randomization is unclear

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Witz 1998.

Methods	Randomized controlled trial   Median follow up: 3 years
Participants	244 patients Median age: 65 years Male: 56.5% Patients with previously untreated de novo AML as defined by FAB who received induction chemotherapy France, multicenter
Interventions	Induction chemotherapy: IV idarubicin 8 mg/m²/d for 5 days + cytarabine 100 mg/m²/d for 7 days IV GM‐CSF 5 µg/kg/d starting on day 1 (12 hr after chemotherapy was started) until recovery of neutrophil count > 0.5 x 10⁹/L for 3 days or for 28 days maximum The trial included 2 arms: GM‐CSF versus control
Outcomes	All‐cause mortality at 30 days and at the end of follow up Overall survival Number of patients achieving complete remission (CR) Disease‐free survival Relapse rate Number of bacteremias Number of invasive fungal infections
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quotes: "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." "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)."
Selective reporting (reporting bias)	Low risk	All the outcomes described in the Methods section were reported in the Results section
Other bias	Unclear risk	The day of randomization was not reported

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Zittoun 1996.

Methods	Randomized controlled trial   Median follow up: 34 months
Participants	102 patients Median age: 42 years (range: 17 to 59) in the G‐CSF arm and 45 years (range: 26 to 59) in the control arm Patients with previously untreated AML who received induction chemotherapy Europe, multicenter
Interventions	Induction chemotherapy: IV daunorubicin 45 mg/m²/d in days 1 to 3 + IV cytarabine 200 mg/m²/d in days 1 to 7 IV GM‐CSF 5 µg/kg/d starting on day 8 until recovery of neutrophil count or till 28 days The trial included 4 arms: GM‐CSF during and after chemotherapy (arm excluded) versus GM‐CSF after chemotherapy versus GM‐CSF during chemotherapy (arm excluded) versus control
Outcomes	All‐cause mortality at 30 days and at the end of follow up Number of patients achieving complete remission (CR) Relapse rate
Notes	Funding: industry
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was centrally performed at the EORTC Data Center in Brussels using the minimization technique"
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "In all analyses, the intention‐to‐treat principle was used, i.e., all patients were kept in the treatment arm allocated by randomization."
Selective reporting (reporting bias)	Low risk	All the outcomes which were described in the methods section were reported in the results section
Other bias	Unclear risk	Day of randomization was not reported

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AML: acute myelogenous leukemia; CR: complete remission; d: day; EORTC: European Organization; for Research and Treatment of Cancer; G‐CSF: granulocyte colony‐stimulating factor; GM‐CSF: granulocyte macrophage colony‐stimulating factor; hr: hour; ITT: intention‐to‐treat; IV: intravenous; WBC: white blood cell

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Bernell 1994	G‐CSF was started 48 hours prior to chemotherapy Not a RCT
Bishop 2000	Most patients were not AML (only 6 out of 55 had AML)
Braess 2006	There was no randomization to G‐CSF or control/placebo
Buchner 1993	GM‐CSF was started 48 hours prior to chemotherapy
Buchner 2004	Not a RCT
Chen 1998	Not a RCT
Creutzig 2006	Double publication with Lehrnbecher 2007
Estey 1990	Historical control Not a RCT
Frenette 1995	GM‐CSF was started prior to chemotherapy
Freud 1995	Cost‐effectiveness study of a RCT in elderly patients with AML with or without G‐CSF
Godwin 1995	Not a RCT
Goldstone 2001	Double publication with Wheatley 2009. Goldstone's paper presents the results of AML11 trial, while Wheatley's presents the results of AML11 AND ANL12.
Hanel 2001	There was no randomization to G‐CSF or control/placebo
Hast 2003	GM‐CSF was started 48 hours prior to chemotherapy in patients with WBC < 50000
Heil 1995	GM‐CSF was started 48 hours prior to chemotherapy
Kalaycio 2001	Not a RCT
Kern 1998	Historical control Not a RCT
Lofgren 2004	Aim of the study was priming (1 day before chemotherapy)
Lowenberg 1997b	GM‐CSF started 1 day before chemotherapy
Lowenberg 2003	G‐CSF was given concurrently with chemotherapy only
Maslak 1996	Historical control and not a RCT
Montillo 1998	Not a RCT
Moore 1997	Not a RCT ‐ a study comparing tandem groups
Morton 2001	Patients were randomized to receive growth factor‐induced bone marrow or growth factor‐induced peripheral blood stem cells for allogeneic stem cell transplantation
Ohno 1994	Aim of the study was priming (2 days before chemotherapy)
Ohno 1997	Used monocyte‐colony stimulating factor and not granulocyte‐colony‐stimulating factor or granulocyte‐monocyte‐stimulating factor
Ohtake 2006	Comparison of 2 schedules of G‐CSF (prophylactic versus therapeutic) and not randomized between G‐CSF and control
Ojeda 1999	Included patients with carcinoma of breast and lymphoma. Only a minority were AML patients
Ossenkopple 2004	RCT that randomized to G‐CSF, cytarabine and fludarabine or G‐CSF and cytarabine
Rowe 2004	Aim of the study was priming (2 days before chemotherapy)
Schmitz 1998	RCT that randomized to bone marrow‐derived stem cell transplantation or filgrastim‐mobilized peripheral blood stem cell transplantation
Schriber 1994	Not a RCT
Sierra 2005	Comparison of 2 schedules of G‐CSF (pegfilgrastim versus filgrastim)
Stone 2001	Comparison of postremission therapy ‐ mitoxantrone and intermediate‐dose cytarabine compared to standard‐dose cytarabine
Takeshita 1995	Not a RCT
Takeshita 2000	Retrospective study
Takeyama 1995	Randomization was between routine addition of G‐CSF after chemotherapy and addition of G‐CSF in case of neutropenic fever
Thomas 1999	GM‐CSF was given during chemotherapy only
Thomas 2007a	Aim of the study was priming (G‐CSF during chemotherapy only)
Thomas 2007b	Randomization to autologous stem cell transplantation or not
von Lilienfeld Toal 2007	Randomization between 2 schedules of G‐CSF (immediate versus delayed G‐CSF) in induction therapy for patients with AML

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AML: acute myelogenous leukemia; G‐CSF: granulocyte colony‐stimulating factor; GM‐CSF: granulocyte macrophage colony‐stimulating factor; RCT: randomized controlled trial

Contributions of authors

Ronit Gurion ‐ conception and design, provision of study material, protocol development, search for trials, data extraction, analysis and data interpretation, writing of the review and final approval

Yulia Belnik‐Plitman‐ conception and design, provision of study material, protocol development, search for trials, data extraction, final approval of the review.

Anat Gafter‐Gvili ‐ conception and design, provision of study material, protocol development, data extraction, final approval of the review, methodological advice.

Mical Paul ‐ conception and design, protocol development, provision of study material, data extraction, analysis and data interpretation, writing of the review and final approval, clinical and scientific advice.

Liat Vidal ‐ provision of study material, protocol development, data extraction, analysis and data interpretation, final approval of the review, methodological advice.

Isaac Ben‐Bassat ‐ conception and design, protocol development, final approval of the review, clinical and scientific advice.

Ofer Shpilberg ‐ conception and design, protocol development, final approval of the review, clinical and scientific advice.

Pia Raanani ‐ conception and design, provision of study material, protocol development, analysis and data interpretation, writing of the review and final approval, clinical and scientific advice.

Sources of support

Internal sources

Young Investigator's Grant, Rabin Medical Center, Beilinson Hospital , Israel.

A 30,000 NIS grant donated to young investigator ‐ Dr. Ronit Gurion

External sources

No sources of support supplied

Declarations of interest

None known.

Edited (conclusions changed), comment added to review

References

References to studies included in this review

Amadori 2005 {published data only}

Amadori S, Suciu S, Jehn U, Stasi R, Thomas X, Marie JP, et al. Use of glycosylated recombinant human G‐CSF during and/or after induction chemotherapy in elderly patients with acute myeloid leukemia: final results of AML‐13, a randomized phase III study of the EORTC and GIMEMA Leukemia Groups. Blood 2003;102:177a. [Google Scholar]
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Beksac 2010 {published data only}

Beksac M, Ali R, Ozcelik T, Ozcan M, Ozcebe O, Bayik M, et al. Short and long term effects of granulocyte colony‐stimulating factor during induction therapy in acute myeloid leukemia patients younger than 65: results of a randomized multicenter phase III trial. Leukemia Research 2011;35(3):340‐5. [DOI] [PubMed] [Google Scholar]

Bernasconi 1998 {published data only}

Bernasconi C, Alessandrino EP, Bernasconi P, Bonfichi M, Lazarino M, Canevari A, et al. Randomized clinical study comparing aggressive chemotherapy with or without G‐CSF support for high risk myelodysplastic syndromes or secondary acute myeloid leukemia evolving from MDS. British Journal of Haematology 1998;102:678‐83. [DOI] [PubMed] [Google Scholar]

Bradstock 2001 {published data only}

Bradstock. Effects of glycosylated recombinant human granulocyte colony‐stimulating factor after high‐dose cytarabine based chemotherapy for adult acute myeloid leukemia. Leukemia 2001;15:1331‐8. [DOI] [PubMed] [Google Scholar]
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Dombret 1995 {published data only}

Dombret H, Chastang C, Fenaux P, Reiffers J, Bordessoule D, Bouabdallah R, et al. A controlled study of recombinant human G‐CSF in elderly patients after treatment for AML. New England Journal of Medicine 1995;332(25):1678‐83. [DOI] [PubMed] [Google Scholar]
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Estey 1999 {published data only}

Estey E, Thall P, Pierce S, Cortes J, Beran M, Kantarjian H, et al. Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/‐ all‐trans retinoic acid +/‐ granulocyte colony‐stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood 1999;93(8):2478‐84. [PubMed] [Google Scholar]

Godwin 1998 {published data only}

Godwin JE, Kopecky KJ, Head DR, Hynes HE, Balcerzak SP, Appelbaum FR. A double‐blind placebo controlled trial of G‐CSF in elderly patients with previously untreated acute myeloid leukemia: a South West Oncology Group study. Blood 1995;86(10 Suppl 1):434a. [PubMed] [Google Scholar]
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Harousseau 2000 {published data only}

Harousseau. G‐CSF after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the GOELAM. Journal of Clinical Oncology 2000;18(4):780‐7. [DOI] [PubMed] [Google Scholar]
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Heil 1997 {published data only}

Heil G, Hoelzer D, Sanz MA, Lechner K, Liu YJ, Papa G, et al. Results of a randomized, double‐blind, placebo‐controlled phase III study of filgrastim in remission induction and early consolidation therapy for adults with de‐novo acute myeloid leukemia. Blood 1995;86(10 Suppl 1):267a. [PubMed] [Google Scholar]
Heil G, Hoelzer D, Sanz MA, Lechner K, Liu Yin JA, Papa G, et al. A randomized, double‐blind, placebo‐controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 1997;90(12):4710‐8. [PubMed] [Google Scholar]
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Heil G, Sanz M, Lechner K, Yin J, Noens L, Papa G, et al. Results of a randomized double‐blind placebo controlled phase III study of filgrastim in remission induction and early consolidation therapy for adults with de‐novo acute myeloid leukemia. Annals of Hematology 1997;74 Suppl 1:A4. [PubMed] [Google Scholar]
Heil G, Sanz MA, Lechner K, Lju YJ, Noens L, Papa G, et al. Results of a randomized, double‐blind placebo controlled phase III study of filgrastim in remission induction and early consolidation therapy for adults with de‐novo acute myeloid leukemia. Annals of Hematology 1996;73(Suppl 2):A90. [PubMed] [Google Scholar]

Lehrnbecher 2007 {published data only}

Lehrnbecher T, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Creutzig U. Impact of granulocyte colony‐stimulating factor during induction therapy in children with acute myelogenous leukemia: results from the prospective and randomized trial AML‐BFM 98. Blood 2004;104(11):796a. [Google Scholar]
Lehrnbecher T, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Creutzig U. Prophylactic human granulocyte colony‐stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 2007;109(3):936‐43. [DOI] [PubMed] [Google Scholar]

Lowenberg 1997 {published data only}

Lowenberg B. Value of different modalities of granulocyte‐macrophage colony‐stimulating factor applied during or after induction therapy of AML. Journal of Clinical Oncology 1997;15(12):3496‐506. [DOI] [PubMed] [Google Scholar]

Milligan 2006 {published data only}

Milligan DW, Wheatley K, Craig JI, Littlewood TJ, Burnett AK. Randomised comparison of FLA versus ADE, with or without G‐CSF and with or without ATRA, for high‐risk AML: results of the MRC AML‐HR trial. Hematology Journal 2004;5(Suppl 2):202. [Google Scholar]
Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK, NCRI Haematological Oncology Clinical Studies Group. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high‐risk acute myeloid leukemia, and addition of G‐CSF and ATRA are not beneficial: results of the MRC AML‐HR randomized trial. Blood 2006;107(12):4614‐22. [DOI] [PubMed] [Google Scholar]

Nakajima 1995 {published data only}

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Rowe 1995 {published data only}

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PERMALINK

Colony‐stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

Ronit Gurion

Yulia Belnik‐Plitman

Anat Gafter‐Gvili

Mical Paul

Liat Vidal

Isaac Ben‐Bassat

Ofer Shpilberg

Pia Raanani

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. All cause mortality for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 2. Overall survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 3. Complete remission for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 4. Disease free survival for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 5. Relapse rate for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 6. Bacteremias for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 7. Invasive fungal infections for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 8. Episodes of febrile neutropenia for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Summary of findings 9. Adverse events requiring discontinuation of CSFs for prevention and treatment of infectious complications in patients with acute myelogenous leukemia.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Intervention

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Characteristics of trials

Characteristics of participants

Characteristics of interventions

Characteristics of outcome measures as defined above

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Included studies

Type of patients

Chemotherapy regimens

Intervention

Type of CSF

Schedule

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Effects of interventions

Primary outcomes

1. All‐cause mortality at the end of study follow up

1.