Cochrane Database of Systematic Reviews (Reviews) || Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

Colony-stimulating factors for prevention and treatment of

infectious complications in patients with acute myelogenous

leukemia (Review)

Gurion R, Belnik-Plitman Y, Gafter-Gvili A, Paul M, Vidal L, Ben-Bassat I, Shpilberg O,

Raanani P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2012, Issue 6

http://www.thecochranelibrary.com

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

(Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

17ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

26DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 All-cause mortality, Outcome 1 All-cause mortality at 30 days. . . . . . . . . . 60

Analysis 1.2. Comparison 1 All-cause mortality, Outcome 2 All-cause mortality at the end of follow up. . . . . . 61

Analysis 1.3. Comparison 1 All-cause mortality, Outcome 3 All-cause mortality subgroup analysis age > 60. . . . 62

Analysis 1.4. Comparison 1 All-cause mortality, Outcome 4 All-cause mortality subgroup analysis age < 60. . . . 63

Analysis 1.5. Comparison 1 All-cause mortality, Outcome 5 All-cause mortality sensitivity analysis for allocation

concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 1.6. Comparison 1 All-cause mortality, Outcome 6 All-cause mortality sensitivity analysis using random effects

model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 2.1. Comparison 2 Overall survival, Outcome 1 Overall survival. . . . . . . . . . . . . . . . 66

Analysis 3.1. Comparison 3 Complete remission, Outcome 1 Complete response. . . . . . . . . . . . . 67

Analysis 4.1. Comparison 4 Disease-free survival, Outcome 1 Disease-free survival. . . . . . . . . . . . . 68

Analysis 5.1. Comparison 5 Relapse rate, Outcome 1 Relapse rate. . . . . . . . . . . . . . . . . . . 69

Analysis 6.1. Comparison 6 Bacteremias, Outcome 1 Bacteremias. . . . . . . . . . . . . . . . . . . 70

Analysis 7.1. Comparison 7 Invasive fungal infections, Outcome 1 Invasive fungal infections. . . . . . . . . 71

Analysis 8.1. Comparison 8 Episodes of febrile neutropenia, Outcome 1 Episodes of febrile neutropenia. . . . . 72

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

discontinuation of CSFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

73APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iColony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

(Review)


[Intervention Review]

Colony-stimulating factors for prevention and treatment ofinfectious complications in patients with acute myelogenousleukemia

Ronit Gurion1, Yulia Belnik-Plitman1, Anat Gafter-Gvili2, Mical Paul3, Liat Vidal2, Isaac Ben-Bassat4 , Ofer Shpilberg1, Pia Raanani1

1Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. 2Department of Medicine

E, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. 3Infectious Diseases Unit, Sackler Faculty of Medicine, Tel Aviv,

Israel. 4Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Contact address: Pia Raanani, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski

Street, Petah Tikva, 49100, Israel. [email protected].

Editorial group: Cochrane Haematological Malignancies Group.

Publication status and date: Edited (conclusions changed), comment added to review, published in Issue 6, 2012.

Review content assessed as up-to-date: 24 January 2011.

Citation: Gurion R, Belnik-Plitman Y, Gafter-Gvili A, Paul M, Vidal L, Ben-Bassat I, Shpilberg O, Raanani P. Colony-stimulating

factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database of

Systematic Reviews 2012, Issue 6. Art. No.: CD008238. DOI: 10.1002/14651858.CD008238.pub3.


A B S T R A C T

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).

1Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia

(Review)


mailto:[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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.


(Review)


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

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)

⊕⊕©©

low1,2

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


(0.98 to 1.05)

4029

(14 studies)

⊕⊕©©

low1,3

729 per 1000 736 per 1000

(715 to 766)

Moderate

758 per 1000 766 per 1000

(743 to 796)

All cause mortality sub-

group analysis age>60



(0.97 to 1.06)

2035

(7 studies)

⊕⊕©©

low1,2

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775 per 1000 782 per 1000

(751 to 821)

Moderate

852 per 1000 861 per 1000

(826 to 903)

All-cause mortality sub-

group analysis age<60



(0.97 to 1.2)

1079

(5 studies)

⊕⊕©©

low1,2

533 per 1000 576 per 1000

(517 to 640)

Moderate

493 per 1000 532 per 1000

(478 to 592)

All-cause mortality -

sensitivity analysis



(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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B A C K G R O U N D

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 ma-

lignant cells gradually replace and inhibit the growth and matu-

ration of normal erythroid, myeloid and megakaryocytic precur-

sors (Hoffman 2008). Acute myelogenous leukemia results from

sporadic acquired somatic mutations in hematopoietic progeni-

tors 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 diagno-

sis 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, re-

spectively (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 in-

formation, 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 di-

vided 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 defin-

ing 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 treat-

ment of AML is highly suppressive and thus worsens myelosup-

pression. Moreover, it is more frequently associated with infec-

tious complications than regimens used to treat solid tumors. Al-

most all AML patients suffer from prolonged grade 4 neutrope-

nia 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 hematopoi-

etic 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 transfu-

sions, 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 re-

views 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-re-

lated outcomes. Patients with AML were included in these reviews,

although not always separately. For example, Dekker 2006 con-

ducted a meta-analysis including 34 trials to estimate the efficacy

of CSFs in stem cell transplantation. The results of this meta-anal-

ysis 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 induc-

tion or consolidation treatment. Furthermore, the study popula-

tion 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 in-

cluded only children and the patients included in this meta-anal-

ysis 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 as-

sessed the use of growth factors during and after chemotherapy,

regardless of the indication. Thus, our review offers the opportu-

nity 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 pro-

liferation, differentiation and functions of hematopoietic cells.

More than 20 different molecules of CSFs have been identi-

fied. 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 circulat-


(Review)


ing 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 neu-

trophils, eosinophils, macrophages and sometimes lymphocytes.

Different types of G-CSF and GM-CSF have been tested in clin-

ical trials (De Vita 2001).

CSFs may be administered in the context of AML in three

scenarios:

1. 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.

2. After chemotherapy and/or allogeneic HSCT in order to

accelerate myeloid regeneration and decrease the incidence and

severity of neutropenia-associated infectious complications.

3. 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 ther-

apy, salvage treatment or conditioning for HSCT) and continued

for more than 24 hours, in order to accelerate myeloid regenera-

tion and decrease the incidence and severity of neutropenia-asso-

ciated 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 ac-

companied 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 re-

view 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 neu-

trophil 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 contro-

versial. In vitro laboratory investigations have provided ample ev-

idence 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 neu-

tropenia 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 de-

crease 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.

O B J E C T I V E S

• 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).

M E T H O D S

Criteria for considering studies for this review

Types of studies


(Review)


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 neo-

plasms, AML not otherwise specified, myeloid sarcoma, myeloid

proliferations related to Down syndrome) (Vardiman 2009)) at all

stages of treatment after the administration of chemotherapy (in-

duction, 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 intra-

venously 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 neutrope-

nia (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 col-

lection 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/).


(Review)


http://www.ebmt.org/






http://www.exphem.org/



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 au-

thors, we obtained the full article and the two review authors in-

spected 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 inclu-

sion criteria for methodological quality. We extracted information

about randomization and allocation concealment, blinding, sam-

ple 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, blind-

ing, 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


(Review)


using 95% confidence intervals (CI). We pooled trial results ac-

cording 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 het-

erogeneity of intervention effects (variation in effect estimates be-

yond 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 impor-

tant; 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 sensi-

tivity analyses as defined below (Higgins 2002; Higgins 2003).

Assessment of reporting biases

Reporting biases arise when the dissemination of research find-

ings 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 robust-

ness of the findings to different aspects of the trials’ methodology:

allocation concealment (adequate or unclear), allocation genera-

tion (adequate or unclear), blinding (double-blinded or unblinded

studies) and intention-to-treat analysis (ITT).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.


(Review)


The computerized search strategy identified 1421 potentially rele-

vant publications, of which we considered 89 publications for fur-

ther investigation. Of them, we excluded 46 publications, report-

ing 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 che-

motherapy (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 consolida-

tion chemotherapy (Harousseau 2000) and one trial included pa-

tients undergoing salvage chemotherapy (Milligan 2006).

The chemotherapy protocols used in the trials were heteroge-

neous. They consisted of different combinations of anthracyclines

(daunorubicin, idarubicin or mitoxantrone) and cytarabine with

or without etoposide. In seven trials the chemotherapy regimen in-

cluded 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 etopo-

side (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).


(Review)


• 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 per-

sons 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: 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

Primary outcomes

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

Fourteen trials including 4119 patients reported all-cause mortal-

ity. The end of study follow up ranged between three and seven

years. The addition of colony-stimulating factors (CSFs) to che-

motherapy 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 ran-

dom-effects model (Figure 2).


(Review)


Figure 1. 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 in-

cluded 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).


(Review)


Figure 2. Forest plot of comparison: 2 Overall survival, outcome: 2.1 Overall survival.

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 dif-

ference in all-cause mortality between patients treated with che-

motherapy and CSFs and those treated with chemotherapy alone,

with a RR of 0.97 (95% CI.0.80 to 1.18) (Figure 3).

Figure 3. Forest plot of comparison: 1 All-cause mortality, outcome: 1.1 All-cause mortality at 30 days.


(Review)


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).

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).

Figure 5. Forest plot of comparison: 4 Disease-free survival, outcome: 4.1 Disease-free survival.


(Review)


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).

Figure 6. Forest plot of comparison: 5 Relapse rate, outcome: 5.1 Relapse rate.

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 bac-

teremias(RR 0.96; 95% CI 0.82 to 1.12) (Figure 11).

Invasive fungal infections

Four trials including 929 patients reported invasive fungal infec-

tions. 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


(Review)


Twelve trials reported on the duration of hospitalization. The me-

dian duration of hospitalization ranged between 23 and 36 days in

the CSF arm and between 27 and 38 days in the control arm. Sev-

eral 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 re-

ported 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.


(Review)


A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

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


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


Control Overall survival

Overall survival


722 per 1000 722 per 1000

(696 to 749)

HR 1

(0.93 to 1.08)

3335

(11 studies)

⊕⊕©©

low1,2



CI: Confidence interval; HR: Hazard ratio;






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.

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http://www.thecochranelibrary.com/view/0/SummaryFindings.html

Complete remission for prevention and treatment of infectious complications in patients with acute myelogenous leukemia


Settings:inpatients

Intervention: Complete remission


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


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)









1 Some of the studies lack allocation concealement

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


Settings:inpatients

Intervention: Disease free survival


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


Control Disease free survival

Disease free survival Study population OR 1

(0.9 to 1.13)

1639

(7 studies)

⊕⊕©©

low1,2

728 per 1000 728 per 1000

(706 to 751)

Moderate

722 per 1000 722 per 1000

(700 to 746)



CI: Confidence interval; OR: Odds ratio;






1 Part of the studies were not blinded and allocation was not concealed2 The CI was wide

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Relapse rate for prevention and treatment of infectious complications in patients with acute myelogenous leukemia


Settings:

Intervention: Relapse rate


(95% CI)

No of Participants

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(GRADE)

Comments


Control Relapse rate

Relapse rate Study population RR 0.97

(0.89 to 1.05)

2189

(10 studies)

⊕⊕©©

low1,2

513 per 1000 498 per 1000

(456 to 539)

Moderate

547 per 1000 531 per 1000

(487 to 574)









1 Not in all studies was allocation concealed2 CI interval is not narrow

21

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Bacteremias for prevention and treatment of infectious complications in patients with acute myelogenous leukemia


Settings:inpatients

Intervention: Bacteremias


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


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)









1 Very wide CI

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


Settings:

Intervention: Invasive fungal infections


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


Control Invasive fungal infec-

tions

Invasive fungal infection Study population RR 1.4

(0.9 to 2.19)

929

(4 studies)

⊕⊕©©

low1,2

62 per 1000 87 per 1000

(56 to 136)

Moderate

53 per 1000 74 per 1000

(48 to 116)









1 Most studies were not allocation concealed or blinded2 Very wide CI

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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


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


Control Episodes of febrile neu-

tropenia

Episodes of febrile neu-

tropenia


(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)









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

24

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


Settings:inpatients

Intervention: Adverse events requiring discontinuation of CSFs


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


Control Adverse events requir-

ing discontinuation of

CSFs

Adverse events requir-

ing discontinuation of

CSFs


(1 to 1.76)

770

(4 studies)

⊕©©©

very low1,2

156 per 1000 207 per 1000

(156 to 274)

Moderate

21 per 1000 28 per 1000

(21 to 37)









1 Very wide CI2 Allocation of most studies was not concealed and generally studies were not blinded2

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D I S C U S S I O N

Summary of main results

Our aim was to assess the influence of colony-stimulating factors

(CSFs) on the prevention and treatment of infectious complica-

tions in acute myelogenous leukemia (AML) patients. The addi-

tion 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 consoli-

dation) or by leukemia prognostic factors such as cytogenetic anal-

ysis, due to lack of data.

A meta-analysis of secondary outcomes such as neutropenia and

hospitalization duration could not be carried out since these vari-

ables 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 otherstudies or reviews

The American Society of Clinical Oncology (ASCO) recommen-

dations state that it is reasonable to use CSFs after induction che-

motherapy in AML patients despite lack of evidence to prove this

(Smith 2006), whereas the British Society of Haematology guide-

lines 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 pub-

lished by Wang et al. The authors compared the use of granulo-

cyte colony-stimulating factor (G-CSF) in AML patients receiv-

ing 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 over-

all 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 capac-

ity 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 neu-

trophil recovery and hospitalization stay, yet it did not influence

other important outcomes(i.e. complete remission rate, event/dis-

ease-free survival or overall survival. The second meta-analysis, fo-

cusing on the use of CSFs for priming, also consisted of 14 studies

with 4518 participants. There was no difference in complete re-

mission 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.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

In summary, colony-stimulating factors should not be given rou-

tinely 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 or-

der 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.

A C K N O W L E D G E M E N T S

We thank Prof. Lowenberg and Prof. Beksac for providing com-

plementary data from their trials.


(Review)


R E F E R E N C E S

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.∗ Amadori S, Suciu S, Jehn U, Stasi R, Thomas X, Marie

JP, et al.EORTC/GIMEMA Leukemia Group. Use of

glycosylated recombinant human G-CSF (lenograstim)

during and/or after induction chemotherapy in patients 61

years of age and older with acute myeloid leukemia: final

results of AML-13, a randomized phase-3 study. Blood

2005;106(1):27–34.

Amadori SA, Suciu S, Jehn U, Thomas X, Marie JP, Muus P,

et al.Lenograstim combined with induction chemotherapy

in elderly patients with AML: results of a randomized phase

III trial (AML-13) of the EORTC Leukemia Group and

the GIMEMA Cooperative Group. European Hematology

Association Website (http://www.ehaweb.org) 2003.

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.

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.

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.

Bradstock KF, Matthews JP, Young GAR, Lowentahl RM.

Effects of lenograstim (glycosylated huG-CSF) after high

dose cytarabine based induction chemotherapy for adult

acute myeloid leukemia (AML) [abstract]. Blood 1999;94

(10 Suppl 1):299a.

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.

Dombret H, Yver A, Chastang C, Degos L. Increased

frequency of complete remission by lenograstim

recombinant human granulocyte colony-stimulating

factor (rhG-CSF) administration after intensive induction

chemotherapy in elderly patients with de novo acute

myeloid leukemia (AML): final results of a randomized

multi-centre double-blind controlled study. Blood 1994;84

(10 Suppl 1):231a.

Dombret H, Yver A, Chastang C, Fenaux P, Bordessoule

D, Reiffers J. European multicentre phase III randomized

placebo-controlled study of lenograstim recombinant

glycosylated human granulocyte colony stimulating factor

(rhG-CSF) in elderly patients with de novo acute myeloid

leukemia (AML). British Journal of Haematology 1994;87

(Suppl 1):154.

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.

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.∗ Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith

CP, Hynes HE, et al.A double-blind placebo-controlled

trial of granulocyte colony-stimulating factor in elderly

patients with previously untreated acute myeloid leukemia:

a Southwest oncology group study (9031). Blood 1998;91

(10):3607–15.

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.

Harousseau JL, Witz F, Desablens B, Leprise PY, Francois

S, Delain M, et al.G-CSF after intensive consolidation

chemotherapy in acute myeloid leukemia. Blood 1997;90

(10 Suppl 1):504a.

Harousseau JL, Witz F, Desablens B, Leprise PY, Francois

S, Delain M, et al.G-CSF after intensive consolidation

chemotherapy in acute myeloid leukemia (AML). Blood

1997;90(10 Suppl 1 (Pt 1)):504–5a.

Heil 1997 {published data only}∗ 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.

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


(Review)


de-novo acute myeloid leukemia. Blood 1995;86(10 Suppl

1):267a.

Heil G, Hoelzer D, Sanz MA, Lechner K, Noens L, Szer

J, et al.Long-term survival data from a phase 3 study of

Filgrastim as an adjunct to chemotherapy in adults with de

novo acute myeloid leukemia. Leukemia 2006;20(3):404–9.

Heil G, Hoelzer D, Sanz MA, Lechner K, Yin JA, Noens L,

et al.Long-term survival from a phase 3 study of filgrastim

in remission induction and consolidation therapy for adults

with de novo acute myeloid leukemia. Blood 2002;100(11

Pt 2).

Heil G, Sanz M, Lechner K, Yin J, Noens L, Papa G, et

al.Results of a randomized double-blind placebo controlled


early consolidation therapy for adults with de-novo acute

myeloid leukemia. Annals of Hematology 1997;74 Suppl 1:

A4.

Heil G, Sanz MA, Lechner K, Lju YJ, Noens L, Papa G, et

al.Results of a randomized, double-blind placebo controlled


early consolidation therapy for adults with de-novo acute

myeloid leukemia. Annals of Hematology 1996;73(Suppl 2):

A90.

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.∗ 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.

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.

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.∗ 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.

Nakajima 1995 {published data only}

Nakajima H, Ikeda Y, Hirashima K, Toyama K, Okuma M,

Saito H, et al.A randomized controlled study of r.GCSF in

patients with neutropenia after induction therapy for acute

myelogenous leukemia (G.CSF Clinical Study Group).

Rinsho Ketsueki 1995;36(6):597–605.

Rowe 1995 {published data only}

Rowe JM, Andersen JW, Mazza JJ, Bennett JM, Paietta E,

Hayes FA, et al.A randomized placebo-controlled phase

III study of granulocyte-macrophage colony-stimulating

factor in adult patients (> 55 to 70 years of age) with acute

myelogenous leukemia: a study of the Eastern Cooperative

Oncology Group (E1490). Blood 1995;86(2):457–62.

Stone 1995 {published data only}

Stone R, George S, Berg D, Paciucci P, Schiffer C. GM-CSF

’v’ placebo during remission induction for patients greater

than or equal to 60 years old with de novo acute myeloid

leukemia: CALGB study 8923. Proceedings of the American

Society of Clinical Oncology 1994;130:304.∗ Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA,

Schulman P, et al.GM-CSF after initial chemotherapy for

elderly patients with primary AML. New England Journal of

Medicine 1995;332(25):1671–7.

Usuki 2002 {published data only}

Usuki K, Urabe A, Masaoka T, Ohno R, Mizoguchi H,

Hamajima N, et al.Gran AML Study Group. Efficacy of

granulocyte colony-stimulating factor in the treatment of

acute myelogenous leukaemia: a multicentre randomized

study. British Journal of Haematology 2002;116(1):103–12.

Wheatley 2009 {published data only}

Goldstone AH, Burnett AK, Milligan DW, Prentice AG,

Wheatley K. Lack of benefit of G-CSF on complete

remission and possible increased relapse risk in AML: an

MRC study of 800 patients. Blood 1997;90(10 Suppl 1 (Pt

1)):583a.∗ Wheatley K, Goldstone AH, Littlewood T, Hunter

A, Burnett AK. Randomized placebo-controlled trial of

granulocyte colony stimulating factor (G-CSF) as supportive

care after induction chemotherapy in adults patients with

acute myeloid leukemia: a study of the United Kingdom

Medical Research Council Adult Leukaemia Working Party.

British Journal Haematology 2009;146(1):54–63.

Witz 1998 {published data only}

Witz F, Harousseau JL, Cahn JY, Abgrail JF, Briere J,

Sadoun A. GM-CSF during and after remission induction

treatment for elderly patients with acute myeloid leukemia

(AML). Blood 1994;84:231a.

Witz F, Harousseau JL, Cahn JY, Abgrall JF, Briere J, Sadoun

A, et al.GM-CSF during and after remission induction


(AML). Annals of Hematology 1995;70 Suppl 1:A135.

Witz F, Harousseau JL, Sadoun A, Guyotat D, Berthou C,

Cah JY. GM-CSF during and after remission induction


(AML). British Journal of Haematology 1996;93(Suppl 2):

134.

Witz F, Harousseau JL, Sadoun A, Guyotat D, Berthou

C, Cahn JY, et al.GM-CSF during and after remission


(Review)


induction treatment for elderly patients with acute myeloid

leukemia (AML). Blood 1995;86(10 Suppl 1):512a.∗ Witz F, Sadoun A, Perrin MC, Berthou C, Brière J, Cahn

JY. A Placebo controlled study of recombinant human GM-

CSF administered during and after induction treatment for

de novo AML in elderly patients. Blood 1998;8:2722–30.

Zittoun 1996 {published data only}

Zittoun R, Mandelli F, de WT, Willemze R, Thaler J, Hayat

M. Recombinant human granulocyte-macrophage colony-

stimulating factor (GM-CSF) during induction treatment

of acute myelogenous leukemia (AML). A randomized trial

from EORTC-GIMEMA leukemia cooperative groups.

Blood 1994;84:231a.∗ Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler

J, Stryckmans P, et al.Granulocyte-macrophage colony-

stimulating factor associated with induction treatment of

acute myelogenous leukemia: a randomized trial by the

European Organization for Research and Treatment of

Cancer Leukemia Cooperative Group. Journal of Clinical

Oncology 1996;14(7):2150–9.

References to studies excluded from this review

Bernell 1994 {published data only}

Bernell P, Kimby E, Hast R. Recombinant human

granulocyte-macrophage colony-stimulating factor in

combination with standard induction chemotherapy in

acute myeloid leukemia evolving from myelodysplastic

syndromes: a pilot study. Leukemia 1994;8(10):1631.

Bishop 2000 {published data only}

Bishop MR, Tarantolo SR, Geller RB, Lynch JC, Bierman

PJ, Pavletic ZS, et al.A randomized double blind trial of

filgrastim (granulocyte colony stimulating factor) vs placebo

following allogeneic blood stem cell transplantation. Blood

2000;96(1):80.

Braess 2006 {published data only}

Braess J, Fiegl M, Reichle A, Wormann B, Oruzio D, Staib

P, et al.A randomized phase II trial for primary induction

therapy in AML using sequential high dose cytarabine

arabinoside and mitoxantrone and pegylated G-CSF

for shortening therapy induced neutropenia. Annals of

Hematology 2006;85(Suppl 1):28.

Buchner 1993 {published data only}

Buchner T, Hiddemann W, Rottmann R, Zuhlsdorf M,

Wortmann B, Maschmeyer G, et al.Granulocyte colony-

stimulating factor in acute myeloid leukemia. Annals of

Hematology 1994;Suppl 1:9a.∗ Buchner T, Hiddemann W, Wormann B, Maschmeyer G,

Ludwig W, Sauerland MC. Granulocyte colony-stimulating

factor in acute myeloid leukemia. Annals of Hematology

1993;66(6):116a.

Buchner 2004 {published data only}

Buchner T, Berdel WE, Hiddemann W. Priming with

granulocyte colony-stimulating factor - relation to high dose

cytarabine in acute myeloid leukemia. New England Journal

of Medicine 2004;350(21):2215.

Chen 1998 {published data only}

Chen SH, Liang DC, Liu HC. High-dose cytarabine

containing chemotherapy with or without granulocyte

colony-stimulating factor for children with acute leukemia.

American Journal of Hematology 1998;58(1):20.

Creutzig 2006 {published data only}

Creutzig U, Reinhardt D, Lehrnbecher T, Ziimmermann

M. G-CSF during induction, increased dose intensity

during consolidation and intensified therapy for standard

risk patients in the pediatric trial AML-BFM 98. Annals of

Hematology 2006;85(Suppl 1):63.

Creutzig U, Zimmermann M, Lehrnbecher T, Graf N,

Hermann J, Niemeyer CM, et al.Less toxicity by optimizing

chemotherapy, but not by addition of granulocyte colony-

stimulating factor in children and adolescents with acute

myeloid leukemia: results of AML-BFM 98. Journal of

Clinical Oncology 2006;24(27):4499.

Estey 1990 {published data only}

Estey EH, Dixon D, Kantarjian HM, Keating MJ,

McCredie K, Bodey GP, et al.Treatment of poor-prognosis,

newly diagnosed acute myeloid leukemia with ara-c and

recombinant human granulocyte-macrophage colony-

stimulating factor. Blood 1990;75(9):1766.

Frenette 1995 {published data only}

Frenette PS, Desforges JF, Schenkein DP, Rabson A,

Slapack CA, Miller KB. Granulocyte-macrophage colony

stimulating factor (GM-CSF) priming in the treatment of

elderly patient with acute myelogenous leukemia. American

Journal of Hematology 1995;49(1):48.

Freud 1995 {published data only}

Freud DA, Dittus RS. Double-blind, placebo-controlled

trial of daunorubicin and cytarabine with and without

recombinant human granulocyte colony-stimulating factor

in elderly patients with acute myeloid leukemia: economic

evaluation with attention to inpatient and outpatient

resource utilization. Journal of National Cancer Institute

Monograph 1995;19:37.

Godwin 1995 {published data only}

Godwin J. Design and conduct of double-blind, placebo-

controlled trial of daunorubicin and cytarabine with or

without granulocyte colony stimulating factor in elderly

patients with acuta myeloid leukemia: a Southwest

Oncology Group study. Journal National Cancer Institute

Monograph 1995;19:31–5.

Goldstone 2001 {published data only}

Goldstone AH, Burnett AK, Wheatley K, Smith AG,

Hutchinson RM, Clarck RE. Attempts to improve outcomes

in AML in older patients: results of UK MRC AML11.

Blood 2001;98:1302.

Hanel 2001 {published data only}

Hanel M, Friedrichsen K, Hanel A, Herbst R, Morgner A,

Neser S, et al.Mito-flag as salvage therapy for relapsed and

refractory AML. Onkologie 2001;24(4):356.

Hast 2003 {published data only}

Hast R, Hellstrom-Lindberg E, Ohm L, Bjorkholm L,

Celsing F, Dahl IM, et al.No benefit from adding GM-CSF


(Review)


to induction chemotherapy in transforming myelodysplastic

syndromes: better outcome in patients with less proliferative

disease. Leukemia 2003;17:1827.

Heil 1995 {published data only}

Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber

C, et al.GM-CSF in a double-blind randomized placebo

controlled trial in therapy of adult patients with de-novo

acute myeloid leukemia (AML). Annals of Hematology 1993;

66(6):A117.∗ Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber

C, et al.GM-CSF in a double-blind randomized, placebo

controlled trial in therapy of adult patients with de novo

acute myeloid leukemia. Leukemia 1995;9(1):3.

Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber

C, et al.GM-CSF in the therapy of de-novo AML patients:

an update of a double-blind randomized, placebo controlled

trial. Annals of Hematology 1994;68 Suppl 1:A34.

Heil G, Chadid L, Seipelt G, Mitrou P, Hoelzer D, Kolbe

K, et al.GM-CSF in a double-blind randomized, placebo

controlled trial in therapy of adult patients with de-novo

acute myeloid leukemia (AML). Annals of Hematology 1992;

65(Suppl):A67.

Kalaycio 2001 {published data only}

Kalaycio M, Pohlman B, Elson P, Lichtin A, Hussein

A, Tripp B, et al.Chemotherapy for acute myelogenous

leukemia in the elderly with cytarabine, mitoxantrone,

and granulocyte-macrophage colony stimulating factor.

American Journal of Clinical Oncology 2001;24(1):58.

Kern 1998 {published data only}

Kern W, Aul C, Maschmeyer G, Schonrock-Nabulsi R,

Ludwig WD, Bartholomaus A, et al.Granulocyte colony-

stimulating factor shortens duration of critical neutropenia

and prolongs disease-free survival after sequential high dose

cytosine arabinoside and mitoxantrone (S-HAM ) salvage

therapy for refractory and relapsed acute myeloid leukemia.

Annals of Hematology 1998;77:115.

Lofgren 2004 {published data only}

Lofgren C, Paul C, Astrom M, Hast R, Hedenius M,

Lerner R, et al.Granulocyte-macrophage colony-stimulating

factor to increase efficacy of mitoxantrone, etoposide and

cytarabine in previously untreated elderly patients with acute

myeloid leukaemia: a Swedish multicentre randomized trial.

British Journal of Haematology 2004;124(4):474.

Lowenberg 1997b {published data only}∗ Lowenberg B, Suciu C, Archimbaud E, Ossenkoppele G,

Verhoef GE, Vellenga E, et al.Use of recombinant GMCSF

during and after remission induction chemotherapy in

patients aged 61 years and older with AML: final report

of AML-11, a phase III randomized study of leukemia

cooperative group of EORTC-LCG and HOVON. Blood

1997;90(8):2952.

Lowenberg B, Suciu S, Zittoun R, Ossenkoppele G,

Boogaerts MA, Wijermans P, et al.GM-CSF during as well

as after induction chemotherapy (CT) in elderly patients

with acute myeloid leukemia (AML). The EORTC-

HOVON Phase III trial (AML 11). Blood 1995;86(10

Suppl 1):433a.

Lowenberg 2003 {published data only}

Lowenberg B, Van Putten W, Theobald M, Gmur J,

Verdonck L, Sonneveld P, et al.Effect of priming with

granulocyte colony-stimulating factor on the outcome of

chemotherapy for AML. New England Journal of Medicine

2003;349:743.

Maslak 1996 {published data only}

Maslak PG, Weiss MA, Berman E, Yao TJ, Tyson D, Golde

DW, et al.Granulocyte colony-stimulating factor following

chemotherapy in elderly patients with newly diagnosed

acute myelogenous leukemia. Leukemia 1996;10(1):32.

Montillo 1998 {published data only}

Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S,

Pinto A, et al.Fludarabine, cytarabine, and G-CSF (FLAG)

for the treatment of poor risk acute myeloid leukemia.

American Journal of Hematology 1998;58(2):105.

Moore 1997 {published data only}

Moore JO, Dodge RK, Amrein PC, Kolitz J, Lee EJ,

Powell B, et al.Granulocyte-colony stimulating factor (

filgrastim) accelerates granulocyte recovery after intensive

postremission chemotherapy for acute myeloid leukemia

with aziridinyl benzoquinone and mitoxantrone: Cancer

and Leukemia Group B study 9022. Blood 1997;89(3):780.

Morton 2001 {published data only}

Morton J, Hutchins C, Durrrant S. Granulocyte-colony

stimulating factor (G-CSF)-primed allogeneic bone marrow:

significantly less graft-versus-host disease and comparable

engraftment to G-CSF-mobilized peripheral blood stem

cells. Blood 2001;98:3186.

Ohno 1994 {published data only}

Ohno R, Naoe T, Kanamaru A, Yoshida M, Hiraoka A,

Kobayashi T, et al.A double blind controlled study of G-

CSF started two days before induction therapy in refractory

AML. Blood 1994;83(8):2086.

Ohno 1997 {published data only}

Ohno R, Miyawaki S, Hatake K, Kuriyama K, Saito K,

Kanamaru A, et al.Human urinary macrophage colony-

stimulating factor reduces the incidence and duration of

febrile neutropenia and shortens the period required to

finish three courses of intensive consolidation therapy in

acute myeloid leukemia: a double-blind controlled study.

Journal of Clinical Oncology 1997;15(8):2954.

Ohtake 2006 {published data only}

Ohtake S, Yagasaki F, Miyawaki S, Matsuda M, Taguchi H,

Matsushima T, Toba K, Yoshida M, Naoe T, Ueda R, Ohno

R. A multicenter prospective randomized study of G-CSF

in consolidation chemotherapy for elderly patients with

AML. Haematologica abstract book 2006;91(Suppl 1).

Ojeda 1999 {published data only}

Ojeda E, Garcia-Bustos J, Aguado M, Arrieta R, Quevedo

E, Yuste VJ, et al.A prospective randomized trial of G-CSF

after autologous blood stem cells transplantation. Bone

Marrow Transplant. 1999;24(6):601.


(Review)


Ossenkopple 2004 {published data only}

Ossenkopple GJ, Graveland WJ, Sonneveld P, Daenen SM,

Biesma DH, Verdonck LF, et al.The value of fludarabine in

addition to ARA-C and G-CSF in the treatment of patients

with high-risk myelodysplastic syndromes and AML in

elderly patients. Blood 2004;103:2908.

Rowe 2004 {published data only}

Rowe JM, Neuberg D, Freidenberg W, Bennet JM, Paietta

E, Makary AZ, et al.A phase III study of 3 induction

regimens and of priming with GM-CSF in older adults with

AML: a trial by ECOG. Blood 2004;103(2):479.

Schmitz 1998 {published data only}

Schmitz N, Bacigalupo A, Hasenclever D, Nagler A,

Gluckman E, Clark P, et al.Allogeneic bone marrow

transplantation vs filgrastim - mobilised peripheral blood

progenitor cell transplantation in patients with early

leukemia: first results of a randomised multicentre

trial of the European Group for Blood and Marrow

Transplantation. Bone Marrow Transplantation 1998;21

(10):995.

Schriber 1994 {published data only}

Schriber JR, Chao NJ, Long GD, Negrin RS, Tierney DK,

Kusnierz-Glaz C, et al.Granulocyte colony-stimulating

factor after allogeneic bone marrow transplantation. Blood

1994;84(5):1680.

Sierra 2005 {published data only}

Sierra J, Bosi A, Szer J, Kassis J, Yang BB, Kido A, et

al.A single dose of pegfilgrastim successfully supports

recovery from prolonged neutropenia following induction

chemotherapy for AML. Haematologica abstract book 2005;

90(Suppl 2):176.

Stone 2001 {published data only}

Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA,

Schulman PP, et al.Postremission therapy in older patients

with de novo acute myeloid leukemia: a randomized trial

comparing mitoxantrona and intermediate dose cytarabine

and standard dose cytarabine. Blood 2001;98(3):548.

Takeshita 1995 {published data only}

Takeshita A, Ohno R, Hirashima K, Toyama K, Okuma M,

Saito H, et al.A randomized double-blind controlled study

of recombinant human granulocyte colony-stimulating

factor in patient with neutropenia induced by consolidation

chemotherapy for acute myeloid leukemia (G-CSF clinical

study group). Rinsho Ketsueki 1995;36(6):606–14.

Takeshita 2000 {published data only}

Takenshita A, Saito H, Toyama K, Horiuchi A, Kuriya

S, Furusawa S, et al.Efficacy of a new formulation of

lenograstim (recombinant glycosylated human granulocyte

colony stimulating factor) containing gelatin for the

treatment of neutropenia after consolidation chemotherapy

in patients with AML. Internal Journal of Hematology 2000;

71(2):136–43.

Takeyama 1995 {published data only}

Takeyama H, Yamada H, Eml N, Saito H, Takeshita

A, Ohno R, et al.Efficacy of early administration of G-

CSF after intensive chemotherapy in acute leukemia: a

randomized controlled trial. Tokai Infection Study Group

on Hematological Disorders. Rinsho Ketsueki 1995;36(11):

1257.

Thomas 1999 {published data only}

Thomas X, Fenaux P, Dombret H, Delair S, Dreyfus F,

Tilly H, et al.Granulocyte-macrophage colony-stimulating

factor (GM-CSF) to increase efficacy of intensive sequential

chemotherapy with etoposide, mitoxantrone and cytarabine

(EMA) in previously treated acute myeloid leukemia: a

multicenter randomized placebo-controlled trial (EMA91

Trial). Leukemia 1999;13(8):1214–20.

Thomas 2007a {published data only}

Thomas X, Raffoux E, Botton S, Pautas C, Arnaud P,

de Revel T, et al.Effect of priming with granulocyte-

macrophage colony-stimulating factor in younger adults

with newly diagnosed acute myeloid leukemia: a trial by

the Acute Leukemia French Association (ALFA) Group.

Leukemia 2007;21(3):453.

Thomas 2007b {published data only}

Thomas X, Suciu S, Rio B, Leone G, Broccia G, Fillet G,

et al.Autologous stem cell transplantation after complete

remission and first consolidation in acute myeloid leukemia

patients aged 61-70 years: results of prospective EORTC

GIMEMA AML-13 trial. Haematologica 2007;92(3):389.

von Lilienfeld Toal 2007 {published data only}

von Lilienfeld Toal, Hahn Ast C, Kirchner H, Flieger

D, Dolken G, Glasmacher A. A randomized comparison

of immediate versus delayed application of G-CSF in

induction therapy for patients with acute myeloid leukemia

unfit for intensive chemotherapy. Haematologica 2007;92

(12):1719.

Additional references

Ascioglu 2002

Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J,

Crokaert F, et al.Defining opportunistic invasive fungal

infections in immunocompromised patients with cancer

and hematopoietic stem cell transplants: an international

consensus. Clinical Infectious Disease 2002;34:7–14.

Bennet 1976

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton

DA, Gralnick HR, Sultan C. Proposals for the classification

of the acute leukaemias.. British Journal of Haematology

1976;33(4):451–8.

Bennett 2001

Bennett CL, Hynes D, Godwin J, Stinson TJ, Golub RM,

Appelbaum FR. Economic analysis of granulocyte colony

stimulating factor as adjunct therapy for older patients

with acute myelogenous leukemia (AML): estimated

from a Southwest Oncology Group clinical trial. Cancer

Investigation 2001;19(6):603–10.

Bernstein 1998

Bernstein SH, Nademanee AP, Vose JM. A multicenter

study of platelet recovery and utilization in patients

after myeloablative therapy and hematopoietic stem cell

transplantation. Blood 1998;91:3509.


(Review)


Channa 2002

Channa J, Hashmi KZ. Role of recombinant granulocyte-

macrophage colony-stimulating factors in reducing the

duration of neutropenia. Journal of the College of Physicians

and Surgeons - Pakistan 2002;12:53841.

Cheson 1990

Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett

JM, Bloomfield CD, et al.Report of the National Cancer

Institute-sponsored workshop on definitions of diagnosis

and response in acute myeloid leukemia. Journal of Clinical

Oncology 1990;8:813–9.

Clark 2000

Clark OA, Lyman G, Castro AA, Clark LG, Djulbegovic

B. Colony stimulating factors for chemotherapy induced

febrile neutropenia. Cochrane Database of Systematic Reviews

2000, Issue 4. [DOI: 10.1002/14651858.CD003039]

De Vita 2001

Griffin JD. Hematopoietic growth factors. In: DeVita VT

Jr, Hellman S, Rosenberg SA editor(s). Cancer: Principles

and Practice of Oncology. 6th Edition. Lippincott Williams

& Wilkins, 2001.

Dekker 2006

Dekker A, Bulley S, Beyene J, Dupuis LL, Doyle JJ,

Sung L. Meta-analysis of randomized controlled trials of

prophylactic granulocyte colony-stimulating factor and

granulocyte-macrophage colony-stimulating factor after

autologous and allogeneic stem cell transplantation. Journal

of Clinical Oncology 2006;24(33):5207–15.

DerSimonian 1986

DerSimonian R, Laird N. Meta-analysis in clinical trials.

Controlled Clinical Trials 1986;7:177–88.

Goker 2001

Goker H, Haznedaroglu IC, Chao NJ. Acute graft vs host

disease: pathobiology and management. Experimental

Hematology 2001;29(3):259–77.

Griffin 1986

Griffin JD, Lowenberg B. Clonogenic cells in acute

myeloblastic leukemia. Blood 1986;68:1185.

Heuser 2010

Heuser M, Zapf A, Morgan M, Krauter J, Ganser A.

Myeloid growth factors in acute myeloid leukemia:

systematic review of randomized controlled trials. Annals of

Hematology 2011;90(3):273–81.

Higgins 2002

Higgins JPT, Thompson SG. Quantifying heterogeneity in

a meta-analysis. Statistics in Medicine 2002;21:1539–58.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG.

Measuring inconsistency in meta-analyses. BMJ 2003;327:

557–60.

Higgins 2009

Higgins JPT, Green S, editors. Cochrane Handbook

for Systematic Reviews of Interventions 5.0.2 [updated

September 2009]. The Cochrane Collaboration, 2009.

Available from www.cochrane-handbook.org.

Hoffman 2008

Miller KB, Pihan G. Clinical manifestations of acute

myeloid leukemia. In: Hoffman R, Furie B, Benz Jr. EJ,

McGlave P, Silberstein LE, Shattil SJ editor(s). Hematology:

Basic Principles and Practice. 5th Edition. Churchill

Livingstone, 2008.

Inoue 1990

Inoue C, Murate T, Hotta T, Satio H. Response of leukemic

cells to the sequential combination of GM-CSF and G-CSF.

International Journal of Cell Cloning 1990;8(1):54–62.

Lee 2003

Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-

host disease. Biology of Blood and Marrow Transplantation

2003;9(4):215–33.

Lemoli 1991

Lemoli RM, Gulati SC, Strife A, Lambek C, Perez A,

Clarkson BD. Proliferative response of human acute myeloid

leukemia cells and normal marrow enriched progenitor cells

to human recombinant growth factors IL-3, GM-CSF and

G-CSF alone and in combination. Leukemia 1991;5(5):

386–91.

Lowenberg 1988

Lowenberg B, Salem M, Delwel R. Effect of recombinant

multi-CSF, GM-CSF,G-CSF and M-CSF on the

proliferation and maturation of human AML in vitro. Blood

Cells 1988;14(2-3):539–49.

Nichols 2003

Nichols WG. Management of infectious complications in

the hematopoietic stem cell transplant recipient. Journal of

Intensive Care Medicine 2003;18:295.

Ohno 1990

Ohno R, Tomonaga M, Kobayashi T, Kanamaru A,

Shirakawa S, Masaoka T, et al.Effect of granulocyte colony

stimulating factor after intensive induction therapy in

relapsed or refractory acute leukemia. New England Journal

of Medicine 1990;323(13):871–7.

Ohno 1993

Ohno R, Hiraoka A, Tanimoto M, Asou N, Kuriyama K,

Kobayashi T, et al.No increase of leukemia who received

granulocyte colony stimulating factor for life threatening

infection during remission induction and consolidation

therapy. Blood 1993:197.

Ottmann 2007

Ottmann OG, Bug G, Krauter J. Current status of growth

factors in the treatment of acute myeloid and lymphoblastic

leukemia. Seminars in Hematology 2007;44:183–92.

Park 1989

Park LS, Waldron PE, Friend D, Sassenfeld HM, Price V,

Anderson D, et al.Interleukin-3, GM-CSF, and G-CSF

receptor expression on cell lines and primary leukemia cells:

receptor heterogeneity and relationship to growth factor

responsiveness. Blood 1989;74(1):56–65.

Parmar 1998

Parmar MK, Torri V, Stewart L. Extracting summary

statistics to perform meta-analyses of the published


(Review)


literature for survival endpoints. Statistics in Medicine 1998;

17:2815–34.

RevMan 2011

The Nordic Cochrane Centre, The Cochrane Collaboration.

Review Manager (RevMan). 5.1. Copenhagen: The Nordic

Cochrane Centre, The Cochrane Collaboration, 2011.

Smith 2006

Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage

JO, Balducci L, et al.2006 update of recommendations for

the use of white blood cell growth factors: an evidence-

based clinical practice guideline. Journal of Clinical Oncology

2006;24(19):3187–205.

Souza 1986

Souza LM, Boone TC, Gabrilove JL, Lai PH, Zsebo KM,

Murdock DC, et al.Recombinant human granulocyte

colony-stimulating factor: effects on normal and leukemic

myeloid cells.. Science 1986;232(4746):61–5.

Sung 2004

Sung L, Nathan PC, Lange B, Beyene J, Buchanan GR.

Prophylactic granulocyte colony-stimulating factor and

granulocyte-macrophage colony-stimulating factor decrease

febrile neutropenia after chemotherapy in children with

cancer: a meta-analysis of randomized controlled trials.

Journal of Clinical Oncology 2004;22(16):3350–6.

Vardiman 2009

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz

MJ, Porwit A, et al.The 2008 revision of the World Health

Organization (WHO) classification of myeloid neoplasms

and acute leukemia: rationale and important changes. Blood

2009;114(5):937–51.

Vellenga 1987

Vellenga E, Young DC, Wagner K, Wiper D, Ostapovicz

D, Griffin JD. The effect of GM-CSF and G-CSF in

promoting growth of clonogenic cells in acute myeloblastic

leukemia. Blood 1987;69:1771.

Wang 2009a

Wang J, An L, Chen S, Ouyang J, Zhou R, Chen B, et

al.Prophylactic use of granulocyte colony-stimulating factor

after chemotherapy does not affect survival rate in acute

myeloid leukemia: a meta-analysis. Acta Haematologica

2009;121(4):223–6.

Wang 2009b

Wang J, Zhan P, Ouyang J, Chen B, Zhou R. Prophylactic

use of granulocyte colony-stimulating factor after induction

chemotherapy in patients with newly diagnosed acute

myeloid leukemia may increase the complete remission

rate: a meta-analysis of five randomised controlled trials.

Leukemia Lymphoma 2009;50(3):457–9.∗ Indicates the major publication for the study


(Review)


C H A R A C T E R I S T I C S O F S T U D I E S

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 cytara-

bine 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 consid-

ered ineligible: 5 in group A, 10 in group

B, 10 in group C, and 10 in group D. Rea-

sons for ineligibility included insufficient


(Review)


Amadori 2005 (Continued)

data in 13, concomitant malignant diseases

in 11, prior chemotherapy in 4, inadequate

performance status in 3, leukemia super-

vening after a myeloproliferative disorder

in 2, and other causes in 2. Ineligible pa-

tients 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

Beksac 2010

Methods Randomized, controlled, open trial

Median follow up: 3 years


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



Notes

Risk of bias



bias)

Low risk Adequate, shuffling

Allocation concealment (selection bias) Low risk Adequate, sealed and opaque envelopes


(Review)


Beksac 2010 (Continued)


bias)

All outcomes

High risk No blinding


All outcomes


Selective reporting (reporting bias) High risk Although one of the outcomes in the Meth-

ods 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)

Bernasconi 1998

Methods Randomized controlled trial

Maximal range follow up: 25 months


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 re-

ceived 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 bacteremias

Notes

Risk of bias



bias)



(Review)


Bernasconi 1998 (Continued)

Allocation concealment (selection bias) Unclear risk Not reported


bias)

All outcomes



All outcomes

Unclear risk No withdrawals and protocol violations af-

ter 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 Re-

sults section

Other bias Unclear risk Day of randomization was not reported

Bradstock 2001




Median age: 43 years (range 15 to 60)

Male: 67% in the control arm, 48% in the G-CSF arm


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


Outcomes All-cause mortality at 1 year and at the end of follow up

Overall survival

Infection-related mortality


Notes

Risk of bias



(Review)


Bradstock 2001 (Continued)


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 tele-

phoning the ALSG trial centre.”


bias)

All outcomes



All outcomes

Low risk Quote: “A total of 114 eligible patients had

been enrolled at that time; 54 had been ran-

domised 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 with-

drawn 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.”


the Methods section, were reported in the

Results section

Other bias Low risk The randomization was performed before

initiation of chemotherapy

Dombret 1995


Follow up: 3.5 years


Median age: 70 years (range: 64 to 83)



Europe, multicenter

Interventions Induction chemotherapy: IV daunorubicin 45 mg/m2 for 4 days + IV continuous cy-

tarabine 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



(Review)


Dombret 1995 (Continued)

Outcomes All-cause mortality at 30 days, 1 year and at the end of follow up

Overall survival



Number of invasive fungal infections

Notes

Risk of bias



bias)




bias)

All outcomes



All outcomes

Low risk Quote: “one patient was lost to follow-up

in each treatment group.”


the Methods section, were reported in the

Results section

Other bias High risk Randomization was done on day 8 of the

induction chemotherapy. Therefore, pa-

tients who were unsuitable for chemother-

apy or declined during chemotherapy were

not randomized

Estey 1999


Median follow up: 35 weeks


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


(Review)


Estey 1999 (Continued)

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


Overall survival




Notes

Risk of bias



bias)




bias)

All outcomes



All outcomes

Unclear risk Quote: “All but four of the 215 were eligi-

ble, 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


Godwin 1998

Methods Double-blind, placebo-controlled study

Median follow up: 33 months



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


(Review)


Godwin 1998 (Continued)

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



Disease-free survival

Notes Funding: academic

Risk of bias



bias)




bias)

All outcomes

Low risk Double-blinding (not specified who was

blinded)


All outcomes

Low risk Quote: “The analyses are based on intent to

treat and include the 211 patients with cen-

trally confirmed diagnoses of AML. Nine

of these 211 cases failed to meet other eli-

gibility 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.

Harousseau 2000

Methods Randomized, open, controlled trial



Median age: 47.5 years in the G-CSF arm and 45 years in the control arm


Patients with de novo AML who received consolidation chemotherapy

France, multicenter


(Review)


Harousseau 2000 (Continued)

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



Overall survival

Relapse rate


Notes Funding: industry

Risk of bias



bias)


Allocation concealment (selection bias) Low risk Quote: “Central randomization”


bias)

All outcomes



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)



Other bias Low risk Randomization was done before the initia-

tion of chemotherapy

Heil 1997

Methods Randomized, double-blind, controlled trial




Male: 54%

Patients with AML who had received induction chemotherapy

Europe, multicenter


(Review)


Heil 1997 (Continued)


tarabine 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



Overall survival





Risk of bias



bias)


Allocation concealment (selection bias) Low risk Quote: “Patients were centrally random-

ized after 6 days of chemotherapy”


bias)

All outcomes

Low risk Double-blinding: blinded study drug


All outcomes

Low risk Quote: “All analyses, with the exception of

disease-free survival and analysis of courses

subsequent to induction course 1, were per-

formed in an intent-to-treat manner, i.e.

, including all randomized patients in the

treatment groups assigned at randomiza-

tion. The analysis of disease-free survival

only included patients who achieved a CR.

”



Other bias High risk Randomization was done on the sixth day

of chemotherapy


(Review)


Lehrnbecher 2007




Age: < 16 years

Male: 59.6% in the G-CSF arm and 46.2% in the control arm


Europe, multicenter

Interventions Induction chemotherapy: AIE 1st induction (cytarabine at dose of 100 mg/m2/d con-

tinuous 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



Overall survival





Risk of bias



bias)


Allocation concealment (selection bias) Low risk Quote: “Randomization was centrally per-

formed using the permuted block method.

”


bias)

All outcomes



All outcomes

Low risk Quote: “All efficacy analyses were per-

formed according to the intent-to-treat

principle.”



Other bias High risk Quote: “randomization regarding G-CSF

performed on day 15.”


(Review)


Lowenberg 1997




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) ver-

sus GM-CSF after chemotherapy versus GM-CSF during chemotherapy (arm excluded)

versus control



Relapse rate



Risk of bias



bias)


Allocation concealment (selection bias) Low risk Central randomization


bias)

All outcomes



All outcomes

Low risk Quote: “A total of 274 patients were ran-

domized. Twenty-one patients were not as-

sessable 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


(Review)


Lowenberg 1997 (Continued)

= 6).”

Selective reporting (reporting bias) Unclear risk All the outcomes described in the Methods



Milligan 2006




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



Overall survival



Relapse rate

Notes

Risk of bias



bias)

Low risk Quote: “allocation was computer gener-

ated”

Allocation concealment (selection bias) Low risk Quote: “randomization was performed by

telephone call to the central trial office”


bias)

All outcomes



(Review)


Milligan 2006 (Continued)


All outcomes

Unclear risk Quote: “all analyses are performed on the

“intention to treat” principle with all pa-

tients analyzed in their allocated arms, ir-

respective of whether they actually received

their allocated treatment ”




Nakajima 1995



Age: < 16 years


Japan, multicenter

Interventions Induction chemotherapy - unknown

IV G-CSF 5 µg/kg/d




Notes

Risk of bias



bias)




bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Unclear risk Not reported


(Review)


Rowe 1995

Methods Double-blind, randomized study

Median follow up: 13.1 months



Male: not reported


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


Notes Funding: academic

Risk of bias



bias)




bias)

All outcomes

Low risk Double-blinding


All outcomes

Low risk Quotes: “Of these patients, 117 were eligi-

ble and evaluable: 60 on the GM-CSF arm

and 57 on the placebo arm. Reasons for

exclusion were prior chemotherapy (1 pa-

tient), no follow-up (2 patients), and wrong

pathology (4 patients).”

“All eligible and evaluable patients to be

included in an intent-to-treat analysis.”




(Review)


Rowe 1995 (Continued)

Other bias Unclear risk The day of randomization was not reported

Stone 1995

Methods Randomized, double-blind trial

Median follow up: not mentioned



Male: 56%

Patients with primary AML as defined by FAB who had received induction chemotherapy

USA, multicenter


tarabine 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


Overall survival

Number of patients achieving complete remission (CR),



Risk of bias



bias)

Low risk Quote: “The computer program control-

ling the randomization was a general pro-

gram 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 tele-

phone call to the CALGB Statistical Cen-

ter.”


bias)

All outcomes

Low risk Double-blinding. Not reported who was

blinded.


All outcomes

Low risk Quotes: “Since all enrolled patients were

randomized, no patients were excluded

from the primary analyses.”


(Review)


Stone 1995 (Continued)

“The primary analyses in this study fol-

lowed the intention-to-treat principle”

Selective reporting (reporting bias) Unclear risk Disease-free survival was one of the out-

comes 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

Usuki 2002




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




Overall survival


Disease free survival

Notes

Risk of bias



bias)


Allocation concealment (selection bias) Low risk Central


bias)

All outcomes



(Review)


Usuki 2002 (Continued)


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 ran-

domized from October 1993 to Septem-

ber 1996. Sixteen patients had their di-

agnosis 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 with-

drawn from the study and the remaining

245 patients were included in the analyses.

”


section were reported in the results section

Other bias High risk The randomization day was the first day

after completion of chemotherapy

Wheatley 2009

Methods Randomized, placebo-controlled trial



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


Outcomes All-cause mortality at 30 days, at 1 year and at the end of follow up

Overall survival




(Review)


Wheatley 2009 (Continued)

Relapse rate


Risk of bias



bias)


Allocation concealment (selection bias) Low risk Quote: “Randomizations were performed

by telephone call to a central randomiza-

tion office”


bias)

All outcomes



All outcomes

Unclear risk Quotes: “The principal analyses were ‘in-

tention-to-treat’ on all randomized pa-

tients, with a subsidiary analysis of the ma-

jor clinical endpoints performed excluding

patients who did not commence G-CSF or

placebo.”

“599 (75%) were known to have com-

menced 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 mis-

take and other



Other bias Unclear risk The day of randomization is unclear

Witz 1998





Male: 56.5%

Patients with previously untreated de novo AML as defined by FAB who received induc-

tion chemotherapy

France, multicenter


(Review)


Witz 1998 (Continued)

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


Overall survival



Relapse rate




Risk of bias



bias)




bias)

All outcomes



All outcomes

Low risk Quotes: “All eligible patients who received

the randomly assigned treatment were in-

cluded in the analysis for comparison be-

tween 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 in-

duction 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 medica-

tion, one received the medication only dur-

ing induction treatment, one received the

medication only after induction treatment,

and one received chemotherapy with high-


(Review)


Witz 1998 (Continued)

dose Ara-C).”



Other bias Unclear risk The day of randomization was not reported

Zittoun 1996




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) ver-

sus GM-CSF after chemotherapy versus GM-CSF during chemotherapy (arm excluded)

versus control



Relapse rate


Risk of bias



bias)


Allocation concealment (selection bias) Low risk Quote: “Randomization was centrally per-

formed at the EORTC Data Center in

Brussels using the minimization tech-

nique”


bias)

All outcomes



(Review)


Zittoun 1996 (Continued)


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.”


the methods section were reported in the

results section


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


(Review)


(Continued)

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 pe-

ripheral 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


(Review)


(Continued)

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

AML: acute myelogenous leukemia; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte macrophage colony-stim-

ulating factor; RCT: randomized controlled trial


(Review)


D A T A A N D A N A L Y S E S

Comparison 1. All-cause mortality

Outcome or subgroup titleNo. 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


4 All-cause mortality subgroup

analysis age < 60


5 All-cause mortality sensitivity

analysis for allocation

concealment


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]

Comparison 2. Overall survival


studies

No. of


1 Overall survival 11 3335 Hazard Ratio (95% CI) 1.00 [0.93, 1.08]

Comparison 3. Complete remission


studies

No. of


1 Complete response 17 4774 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.99, 1.07]


(Review)


Comparison 4. Disease-free survival


studies

No. of


1 Disease-free survival 7 1639 Hazard Ratio (95% CI) 1.00 [0.90, 1.13]

Comparison 5. Relapse rate


studies

No. of


1 Relapse rate 10 2189 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.89, 1.05]

Comparison 6. Bacteremias


studies

No. of


1 Bacteremias 7 1638 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.82, 1.12]

Comparison 7. Invasive fungal infections


studies

No. of


1 Invasive fungal infections 4 929 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.90, 2.19]

Comparison 8. Episodes of febrile neutropenia


studies

No. of


1 Episodes of febrile neutropenia 9 2140 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.94, 1.03]


(Review)


Comparison 9. Adverse events requiring discontinuation of CSFs


studies

No. of


1 Adverse events requiring

discontinuation of CSFs


Analysis 1.1. Comparison 1 All-cause mortality, Outcome 1 All-cause mortality at 30 days.

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

Comparison: 1 All-cause mortality

Outcome: 1 All-cause mortality at 30 days

Study or subgroup CSFplacebo/notreatment Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 30 days

Amadori 2005 53/360 25/182 18.6 % 1.07 [ 0.69, 1.67 ]

Bernasconi 1998 3/53 8/52 4.5 % 0.37 [ 0.10, 1.31 ]

Dombret 1995 13/88 17/85 9.7 % 0.74 [ 0.38, 1.43 ]

Harousseau 2000 2/100 2/94 1.2 % 0.94 [ 0.14, 6.54 ]

Heil 1997 21/259 25/262 13.9 % 0.85 [ 0.49, 1.48 ]

Milligan 2006 14/178 16/178 9.0 % 0.88 [ 0.44, 1.74 ]

Nakajima 1995 7/47 4/48 2.2 % 1.79 [ 0.56, 5.71 ]

Usuki 2002 7/120 5/125 2.7 % 1.46 [ 0.48, 4.47 ]

Wheatley 2009 48/401 48/402 26.9 % 1.00 [ 0.69, 1.46 ]

Witz 1998 20/110 19/122 10.1 % 1.17 [ 0.66, 2.07 ]

Zittoun 1996 1/27 2/26 1.1 % 0.48 [ 0.05, 4.99 ]

Total (95% CI) 1743 1576 100.0 % 0.97 [ 0.80, 1.18 ]

Total events: 189 (CSF), 171 (placebo/no treatment)

Heterogeneity: Chi2 = 5.75, df = 10 (P = 0.84); I2 =0.0%

Test for overall effect: Z = 0.32 (P = 0.75)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours CSFs Favours control


(Review)


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



Outcome: 2 All-cause mortality at the end of follow up



1 End of follow up

Amadori 2005 307/360 155/182 13.7 % 1.00 [ 0.93, 1.08 ]

Beksac 2010 59/123 59/137 3.7 % 1.11 [ 0.85, 1.45 ]

Bradstock 2001 29/54 35/60 2.2 % 0.92 [ 0.66, 1.28 ]

Dombret 1995 75/88 73/85 5.0 % 0.99 [ 0.88, 1.12 ]

Godwin 1998 90/106 90/105 6.0 % 0.99 [ 0.89, 1.11 ]

Heil 1997 205/259 212/262 14.1 % 0.98 [ 0.90, 1.07 ]

Lowenberg 1997 36/60 34/63 2.2 % 1.11 [ 0.82, 1.51 ]

Milligan 2006 135/178 135/178 9.0 % 1.00 [ 0.89, 1.12 ]

Rowe 1995 39/44 44/46 2.9 % 0.93 [ 0.82, 1.05 ]

Stone 1995 162/193 150/195 9.9 % 1.09 [ 0.99, 1.20 ]

Usuki 2002 69/120 81/125 5.3 % 0.89 [ 0.73, 1.08 ]

Wheatley 2009 302/401 286/402 19.0 % 1.06 [ 0.97, 1.15 ]

Witz 1998 78/114 99/126 6.3 % 0.87 [ 0.75, 1.02 ]

Zittoun 1996 19/27 10/26 0.7 % 1.83 [ 1.06, 3.15 ]

Total (95% CI) 2127 1992 100.0 % 1.01 [ 0.98, 1.05 ]


Heterogeneity: Chi2 = 17.23, df = 13 (P = 0.19); I2 =25%



0.02 0.1 1 10 50

Favours CSF Favours placebo/no tx


(Review)


Analysis 1.3. Comparison 1 All-cause mortality, Outcome 3 All-cause mortality subgroup analysis age > 60.



Outcome: 3 All-cause mortality subgroup analysis age > 60



Amadori 2005 307/360 155/182 25.3 % 1.00 [ 0.93, 1.08 ]

Beksac 2010 59/123 59/137 6.8 % 1.11 [ 0.85, 1.45 ]

Dombret 1995 75/88 73/85 9.1 % 0.99 [ 0.88, 1.12 ]

Godwin 1998 90/106 90/105 11.1 % 0.99 [ 0.89, 1.11 ]

Rowe 1995 39/44 44/46 5.3 % 0.93 [ 0.82, 1.05 ]

Stone 1995 162/193 150/195 18.3 % 1.09 [ 0.99, 1.20 ]

Wheatley 2009 104/110 103/111 12.6 % 1.02 [ 0.95, 1.09 ]

Witz 1998 78/114 99/126 11.5 % 0.87 [ 0.75, 1.02 ]

Total (95% CI) 1138 987 100.0 % 1.01 [ 0.97, 1.05 ]





0.2 0.5 1 2 5

Favours CSF Favours pkacebo/no tx


(Review)


Analysis 1.4. Comparison 1 All-cause mortality, Outcome 4 All-cause mortality subgroup analysis age < 60.



Outcome: 4 All-cause mortality subgroup analysis age < 60



Bradstock 2001 29/54 30/60 9.9 % 1.07 [ 0.75, 1.53 ]

Harousseau 2000 27/100 31/94 11.1 % 0.82 [ 0.53, 1.26 ]

Lowenberg 1997 36/67 34/69 11.7 % 1.09 [ 0.79, 1.51 ]

Wheatley 2009 198/291 183/291 63.7 % 1.08 [ 0.96, 1.22 ]

Zittoun 1996 19/27 10/26 3.5 % 1.83 [ 1.06, 3.15 ]

Total (95% CI) 539 540 100.0 % 1.08 [ 0.97, 1.20 ]





0.01 0.1 1 10 100

Favours experimental Favours control


(Review)


Analysis 1.5. Comparison 1 All-cause mortality, Outcome 5 All-cause mortality sensitivity analysis for

allocation concealment.



Outcome: 5 All-cause mortality sensitivity analysis for allocation concealment



Amadori 2005 307/360 155/182 17.2 % 1.00 [ 0.93, 1.08 ]

Beksac 2010 59/123 59/137 4.7 % 1.11 [ 0.85, 1.45 ]

Bradstock 2001 29/54 35/60 2.8 % 0.92 [ 0.66, 1.28 ]

Heil 1997 205/259 212/262 17.6 % 0.98 [ 0.90, 1.07 ]

Lowenberg 1997 36/60 34/63 2.8 % 1.11 [ 0.82, 1.51 ]

Milligan 2006 135/178 135/178 11.3 % 1.00 [ 0.89, 1.12 ]

Stone 1995 162/193 150/195 12.5 % 1.09 [ 0.99, 1.20 ]

Usuki 2002 69/120 81/125 6.6 % 0.89 [ 0.73, 1.08 ]

Wheatley 2009 302/401 286/402 23.8 % 1.06 [ 0.97, 1.15 ]

Zittoun 1996 19/27 10/26 0.9 % 1.83 [ 1.06, 3.15 ]

Total (95% CI) 1775 1630 100.0 % 1.03 [ 0.99, 1.07 ]





0.01 0.1 1 10 100



(Review)


Analysis 1.6. Comparison 1 All-cause mortality, Outcome 6 All-cause mortality sensitivity analysis using

random effects model.



Outcome: 6 All-cause mortality sensitivity analysis using random effects model


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 End of follow up

Amadori 2005 307/360 155/182 15.1 % 1.00 [ 0.93, 1.08 ]

Beksac 2010 59/123 59/137 2.1 % 1.11 [ 0.85, 1.45 ]

Bradstock 2001 29/54 35/60 1.4 % 0.92 [ 0.66, 1.28 ]

Dombret 1995 75/88 73/85 7.9 % 0.99 [ 0.88, 1.12 ]

Godwin 1998 90/106 90/105 9.1 % 0.99 [ 0.89, 1.11 ]

Heil 1997 205/259 212/262 12.8 % 0.98 [ 0.90, 1.07 ]

Lowenberg 1997 36/60 34/63 1.6 % 1.11 [ 0.82, 1.51 ]

Milligan 2006 135/178 135/178 8.5 % 1.00 [ 0.89, 1.12 ]

Rowe 1995 39/44 44/46 7.9 % 0.93 [ 0.82, 1.05 ]

Stone 1995 162/193 150/195 10.8 % 1.09 [ 0.99, 1.20 ]

Usuki 2002 69/120 81/125 3.5 % 0.89 [ 0.73, 1.08 ]

Wheatley 2009 302/401 286/402 13.2 % 1.06 [ 0.97, 1.15 ]

Witz 1998 78/114 99/126 5.5 % 0.87 [ 0.75, 1.02 ]

Zittoun 1996 19/27 10/26 0.5 % 1.83 [ 1.06, 3.15 ]

Total (95% CI) 2127 1992 100.0 % 1.00 [ 0.96, 1.04 ]


Heterogeneity: Tau2 = 0.00; Chi2 = 17.23, df = 13 (P = 0.19); I2 =25%



0.02 0.1 1 10 50



(Review)


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


Comparison: 2 Overall survival

Outcome: 1 Overall survival

Study or subgroup CSFplacebo/notreatment Hazard Ratio Weight Hazard Ratio

n/N n/N

Exp[(O-E)/V],Fixed,95%

CI


CI

Bradstock 2001 29/54 35/60 2.6 % 0.84 [ 0.51, 1.37 ]

Dombret 1995 75/88 73/85 6.1 % 0.95 [ 0.69, 1.31 ]

Godwin 1998 90/106 90/105 7.3 % 0.95 [ 0.71, 1.27 ]

Harousseau 2000 27/100 31/94 2.3 % 0.73 [ 0.44, 1.23 ]

Heil 1997 205/259 212/262 17.5 % 1.00 [ 0.83, 1.21 ]

Milligan 2006 135/178 135/178 10.8 % 1.03 [ 0.81, 1.31 ]

Rowe 1995 39/44 44/46 3.4 % 0.65 [ 0.42, 1.00 ]

Stone 1995 162/193 150/195 12.6 % 1.20 [ 0.96, 1.50 ]

Usuki 2002 69/120 81/125 6.0 % 0.90 [ 0.65, 1.24 ]

Wheatley 2009 302/401 262/402 24.3 % 1.15 [ 0.98, 1.35 ]

Witz 1998 78/114 99/126 7.1 % 0.77 [ 0.57, 1.03 ]

Total (95% CI) 100.0 % 1.00 [ 0.93, 1.08 ]




0.5 0.7 1 1.5 2



(Review)


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


Comparison: 3 Complete remission

Outcome: 1 Complete response



Amadori 2005 203/360 89/182 7.9 % 1.15 [ 0.97, 1.37 ]

Beksac 2010 77/123 89/137 5.6 % 0.96 [ 0.80, 1.16 ]

Bernasconi 1998 23/53 17/52 1.1 % 1.33 [ 0.81, 2.18 ]

Bradstock 2001 44/54 44/59 2.8 % 1.09 [ 0.90, 1.33 ]

Dombret 1995 62/88 40/85 2.7 % 1.50 [ 1.15, 1.95 ]

Estey 1999 61/107 49/108 3.2 % 1.26 [ 0.96, 1.64 ]

Godwin 1998 43/106 52/105 3.5 % 0.82 [ 0.61, 1.11 ]

Heil 1997 178/259 177/262 11.7 % 1.02 [ 0.90, 1.14 ]

Lehrnbecher 2007 154/161 149/156 10.1 % 1.00 [ 0.96, 1.05 ]

Lowenberg 1997 46/60 47/63 3.1 % 1.03 [ 0.84, 1.26 ]

Milligan 2006 103/178 109/178 7.3 % 0.94 [ 0.80, 1.12 ]

Rowe 1995 36/60 25/57 1.7 % 1.37 [ 0.96, 1.96 ]

Stone 1995 99/193 106/195 7.0 % 0.94 [ 0.78, 1.14 ]

Usuki 2002 97/120 96/125 6.3 % 1.05 [ 0.92, 1.20 ]

Wheatley 2009 292/401 302/402 20.1 % 0.97 [ 0.89, 1.05 ]

Witz 1998 69/110 74/122 4.7 % 1.03 [ 0.84, 1.27 ]

Zittoun 1996 13/27 20/26 1.4 % 0.63 [ 0.40, 0.98 ]

Total (95% CI) 2460 2314 100.0 % 1.03 [ 0.99, 1.07 ]





0.5 0.7 1 1.5 2



(Review)


Analysis 4.1. Comparison 4 Disease-free survival, Outcome 1 Disease-free survival.


Comparison: 4 Disease-free survival

Outcome: 1 Disease-free survival

Study or subgroup CSFplacebo/notreatment Hazard Ratio Weight Hazard Ratio

n/N n/N


CI


CI

Godwin 1998 36/43 46/52 6.9 % 0.82 [ 0.53, 1.27 ]

Heil 1997 142/178 140/177 23.9 % 1.00 [ 0.79, 1.26 ]

Milligan 2006 71/103 78/108 13.2 % 0.89 [ 0.65, 1.22 ]

Rowe 1995 18/27 13/21 2.6 % 0.98 [ 0.48, 2.00 ]

Usuki 2002 64/97 64/96 10.9 % 0.99 [ 0.70, 1.40 ]

Wheatley 2009 203/292 206/302 34.6 % 1.11 [ 0.91, 1.35 ]

Witz 1998 40/69 57/74 8.0 % 1.00 [ 0.67, 1.50 ]

Total (95% CI) 100.0 % 1.00 [ 0.90, 1.13 ]




0.5 0.7 1 1.5 2



(Review)


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


Comparison: 5 Relapse rate

Outcome: 1 Relapse rate



Amadori 2005 145/203 64/89 16.0 % 0.99 [ 0.85, 1.16 ]

Beksac 2010 37/123 50/137 8.5 % 0.82 [ 0.58, 1.17 ]

Bernasconi 1998 20/39 15/27 3.2 % 0.92 [ 0.59, 1.46 ]

Harousseau 2000 36/100 43/94 8.0 % 0.79 [ 0.56, 1.11 ]

Lehrnbecher 2007 49/154 43/149 7.9 % 1.10 [ 0.78, 1.55 ]

Lowenberg 1997 25/46 26/47 4.6 % 0.98 [ 0.68, 1.42 ]

Milligan 2006 60/103 71/108 12.5 % 0.89 [ 0.72, 1.10 ]

Wheatley 2009 172/292 163/302 28.8 % 1.09 [ 0.95, 1.26 ]

Witz 1998 40/69 57/74 9.9 % 0.75 [ 0.59, 0.95 ]

Zittoun 1996 7/13 5/20 0.7 % 2.15 [ 0.87, 5.35 ]

Total (95% CI) 1142 1047 100.0 % 0.97 [ 0.89, 1.05 ]





0.5 0.7 1 1.5 2



(Review)


Analysis 6.1. Comparison 6 Bacteremias, Outcome 1 Bacteremias.


Comparison: 6 Bacteremias

Outcome: 1 Bacteremias



Dombret 1995 14/88 13/85 6.0 % 1.04 [ 0.52, 2.08 ]

Godwin 1998 50/106 45/105 20.6 % 1.10 [ 0.82, 1.48 ]

Harousseau 2000 40/100 45/94 21.2 % 0.84 [ 0.61, 1.15 ]

Lehrnbecher 2007 25/161 23/156 10.7 % 1.05 [ 0.63, 1.77 ]

Lowenberg 1997 10/60 6/63 2.7 % 1.75 [ 0.68, 4.52 ]

Stone 1995 47/193 53/195 24.1 % 0.90 [ 0.64, 1.26 ]

Witz 1998 24/110 34/122 14.7 % 0.78 [ 0.50, 1.23 ]

Total (95% CI) 818 820 100.0 % 0.96 [ 0.82, 1.12 ]





0.5 0.7 1 1.5 2



(Review)


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


Comparison: 7 Invasive fungal infections

Outcome: 1 Invasive fungal infections



Dombret 1995 4/88 0/85 1.7 % 8.70 [ 0.48, 159.11 ]

Godwin 1998 21/104 16/103 54.6 % 1.30 [ 0.72, 2.35 ]

Lehrnbecher 2007 4/161 0/156 1.7 % 8.72 [ 0.47, 160.67 ]

Witz 1998 11/110 13/122 41.9 % 0.94 [ 0.44, 2.01 ]

Total (95% CI) 463 466 100.0 % 1.40 [ 0.90, 2.19 ]





0.5 0.7 1 1.5 2



(Review)


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


Comparison: 8 Episodes of febrile neutropenia

Outcome: 1 Episodes of febrile neutropenia



Bradstock 2001 11/54 13/60 1.6 % 0.94 [ 0.46, 1.92 ]

Dombret 1995 42/88 41/85 5.5 % 0.99 [ 0.73, 1.35 ]

Heil 1997 236/259 241/261 31.7 % 0.99 [ 0.94, 1.04 ]

Lehrnbecher 2007 78/161 72/156 9.7 % 1.05 [ 0.83, 1.32 ]

Lowenberg 1997 51/60 48/63 6.2 % 1.12 [ 0.94, 1.33 ]

Stone 1995 112/179 118/184 15.4 % 0.98 [ 0.83, 1.14 ]

Usuki 2002 92/120 95/125 12.3 % 1.01 [ 0.88, 1.16 ]

Witz 1998 93/110 121/122 15.1 % 0.85 [ 0.79, 0.92 ]

Zittoun 1996 22/27 19/26 2.6 % 1.12 [ 0.83, 1.50 ]

Total (95% CI) 1058 1082 100.0 % 0.98 [ 0.94, 1.03 ]





0.01 0.1 1 10 100



(Review)


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

requiring discontinuation of CSFs.


Comparison: 9 Adverse events requiring discontinuation of CSFs

Outcome: 1 Adverse events requiring discontinuation of CSFs

Study or subgroup CSFs Control Risk Ratio Risk Ratio


Rowe 1995 0/62 0/62 0.0 [ 0.0, 0.0 ]

Stone 1995 60/179 56/182 1.09 [ 0.81, 1.47 ]

Witz 1998 15/110 5/122 3.33 [ 1.25, 8.85 ]

Zittoun 1996 4/27 0/26 8.68 [ 0.49, 153.60 ]

Total (95% CI) 378 392 1.33 [ 1.00, 1.76 ]

Total events: 79 (CSFs), 61 (Control)




0.01 0.1 1 10 100

Favours experimental Favours control

A P P E N D I C E S

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


(Review)


http://www3.interscience.wiley.com/cochrane/searchHistory?mode=runquery%26qnum=1






























(Continued)

#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 (RHG*CSF* or RH-G*CSF* or RHGM*CSF* or RH-GM*CSF*)

#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 (GRANULO*YT* NEAR/3 FA*TOR*)

#16 (MA*ROPHAG* NEAR/5 FA*TOR*)

#17 (FILGRASTIM*)

#18 (neupogen*)

#19 (religrast*)

#20 (nugraf*)

#21 (LENOGRASTIM*)

#22 (Granocyte*)

#23 (Euprotin*)

#24 (PEG*FILGRASTIM*)

#25 (Neulasta*)

#26 (LEUKINE*)

#27 (sagramostim*)

#28 (MOLGRAMOSTIN*)


(Review)


































































































(Continued)

#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 (leuk*em* or leuc*)

#43 (myelo* and naegel* ) and (leuk*em* or leuc*)

#44 (erythroleuk*em*)

#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


(Review)

















































































































































































(Continued)

#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)

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.


(Review)







































(Continued)

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


(Review)


(Continued)

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


(Review)


(Continued)

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.

F E E D B A C K

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.


(Review)


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


(Review)


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

W H A T ’ S N E W

Last assessed as up-to-date: 24 January 2011.

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

H I S T O R Y

Protocol first published: Issue 1, 2010

Review first published: Issue 9, 2011

C O N T R I B U T I O N S O F A U T H O R S

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.


(Review)


D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

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

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antineoplastic Combined Chemotherapy Protocols [∗therapeutic use]; Granulocyte Colony-Stimulating Factor [∗therapeutic use];

Granulocyte-Macrophage Colony-Stimulating Factor [∗therapeutic use]; Induction Chemotherapy [methods]; Infection [∗drug ther-

apy; etiology]; Leukemia, Myeloid, Acute [complications; ∗drug therapy; mortality]

MeSH check words

Humans


(Review)


Documents

Cochrane Database of Systematic Reviews (Reviews) || Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia