Febrile Neutropenia revisited :
what has been learnt and what
remains to be learned ?
Prof. Jean Klastersky, MD, PhD
Institut Jules Bordet,
Université Libre de Bruxelles
Brussels, Belgium
1
2
The risk of infection increases with the
severity and duration of neutropenia
G.P. Bodey, Ann Int Med, 1966
3
Febrile Neutropenia
Historical Background
 First description around 1900
 Rare until development of chemotherapy
 In the 1960s: mainly in acute leukemia with profound
neutropenia Gram negative sepsis common with 90 % mortality
 Empirical therapy with synergistic combinations of antibiotics
reduced mortality to + 10 %
 In the1980s: development of chemotherapy for solid tumors
leading to less severe and less protracted neutropenias
 For multiple reasons, replacement of Gram negative infections
by Gram positive severity of infections decreases
 FN becomes a heterogeneous syndrome
 Risk-stratification models allow for identification of low risk
patients with additional treatment options
 Increase of fungal sepsis in specific groups of neutropenic
patients leads to widespread use of empirical antifungal agents
4
1)Prevention is essential; should the
present indications for G-CSF use be
extended ?
2) Empirical antimicrobial therapy remains
a basic rule; can it be adapted to the risk
of complications ?
3) Occult fungal infections are common in
patients with prolonged neutropenia;
what do we need : empirical or preemptive treatment and/or earlier
diagnosis ?
5
Updated meta-analysis of prophylactic
G-CSF: Infection-related mortality
Disease
0.1 0.2 0.5 1
Citation
Doorijian
Gisselbrecht
Pettengell
All Lymphoma
Bui
Chevallier
Crawford
Fossa
Trillet-Lenoir
Timmer-Bonte
Vogel
All Solid Tumors
Combined
2
5
Relative Risk (95% CI)
0.541
0.976
0.951
0.986 0.297
4.691 0.203
6.426 0.141
0.608
1.037 0.357
1.174 56.861 0.024
0.968 47.992 0.020
1.095 5.293 0.226
0.336 1.213 0.093
0.328 3.073 0.035
0.461 1.782 0.119
0.201 4.172 0.010
0.470
0.934 0.237
0.549
0.836 0.360
Favours G-CSF Favours No G-CSF
N.M. Kuderer, JCO, 2007
6
Current Guidelines for primary prophylaxis
with G-CSFs
FN risk level
ASCO
EORTC
NCCN
Moderate to high
(> 20 %)
Use G-CSFs
Use G-CSFs
Use G-CSFs
Intermediate
(10-20 %)
Recommend
Consider
Consider
Low (< 10 %)
Not
specified
Not
recommended
Not
recommended
++
+++
+
Consider other risk
factors than
intensity of
chemotherapy
7
Secondary prevention of subsequent FN
in patients who had a first episode
CRAWFORD (1991)
(n=59 SCLC)
LALAMI (2001)
(n=48 breast ca)
Incidence of FN after the first
cycle of chemotherapy
(without CSF)
100%
100%
Incidence of FN after the
second cycle of chemotherapy
(with CSF)
23%
6%
8
Outcome of FN and univariate analysis
Resolution without complication : 363/416 (87%, 95% CI : 84%-90%)
Resol.
Compl.
Death
Risk of FN < 10%
180
19 (9%)
9 (4%)
Risk of FN 10%-20%
123
15 (10%)
9 (6%)
Risk of FN > 20%
60
11 (16%)
0 (0%)
No use of prophylactic growth factors
Risk of FN < 10%
167
18
8
Risk of FN 10%-20%
106
13
9
Risk of FN > 20%
48
10
0
Use of growth factors
Risk of FN < 10%
13
1
1
Risk of FN 10%-20%
17
2
0
Risk of FN > 20%
12
1
0
9
Optimal schedule for G-CSF
 Schedules for G-CSF in breast cancer with a 7% risk
of Febrile Neutropenia
 480 µg/day
days 8 -14
 480 µg/day,
days 8, 10,12,14
 300 µg/day
days 8 -14
 300 µg/day
days 8,10,12,14
 *300 µg/day
days 8 and 12
*equivalent to the other schedules with respect to grade 3 and 4 neutropenia
P. Papaldo et al., J Clin Oncol, 2005
10
Incidence of febrile episodes, probable infections,
and hospitalization for infection*
Levofloxacin
(N=781)
Placebo
(N=784)
Relative Risk
(95 % CI)
P Value
Nb of patients (%)
Febrile episode
Probable
infection
Hospitalization
for infection
27 (3.5)
62 (7.9)
0.44 (0.28 – 0.68)
< 0.001
109 (14.0)
152 (19.4)
0.72 (0.57-0.90)
0.005
52 (6.7)
81 (10.3)
0.64 (0.46 – 0.90)
0.01
* No effect on mortality
M. Cullen et al., NEJM, 2005
11
Prophylactic levofloxacin to prevent bacterial
infection in patients with hematological cancer
and neutropenia
Febrile Neutropenia*
Placebo
Levofloxacin
308/363 (85 %)
243/375 (65 %)
*p = 0.001
(Mortatility and tolerability : similar)
GIMEMA, NEJM, 205
12
1)Prevention (antibiotics or G-CSF’s) is
essential; should the present indications
be extended ?
2) Empirical therapy with broad spectrum
antibiotics remains a basic rule; to be
adapted to the risk of complications !
3) Occult fungal infection should be
suspected early in patients with
prolonged neutropenia; do we need
empirical or pre-emptive treatment ?
13
Empirical therapy with carbenicillin
plus gentamicin reduced
dramatically (21 %) the mortality
associated with Pseudomonas
sepsis
Ps. aeruginosa
14
Score derived from the logistic equation of the
MASCC predictive model
(1386 patients with FN)
Characteristic
Points
Burden of illness
 No or mild symptoms
5
 Moderate symptoms
3
No hypotension
5
No chronic obstructive pulmonary disease
4
Solid tumor or no previous fungal infection in
hematological ca
4
Outpatient status
3
No dehydration
3
Age < 60 years
2
Threshold: score ≥ 21(maximum 26) predicting less
than 5% of severe complications
J. Klastersky et al., J. Clin. Oncol. 2001
15
Medical complications considered serious
 Hypotension : systolic blood pressure less than 90
mmHg
 Respiratory failure : arterial oxygen pressure less than
60 mmHg
 Disseminated intravascular coagulation
 Confusion or altered mental state
 Congestive cardiac failure seen on chest x-ray and
requiring treatment
 Bleeding severe enough to require transfusion
 Arrhythmia or ECG changes requiring treatment
 Renal failure requiring investigation and/or treatment
with IV fluids, dialysis, or any other intervention
J. Klastersky et al., JCO, 2000
16
Response rates and final outcome of low- and not lowrisk patients with febrile neutropenia as predicted y the
MASCC risk-index score
Low risk (n=58)
Not low risk (n=22)
Response to
empiric antibiotic
therapy
47 (81 %)
2 (9%)
Resolution without
complications
57 (98 %)
3 (14 %)
0 (0%)
8 (36 %)
Death before
resolution
A. Uys et al., Supp. Care Cancer, 2004
p < 0.001
17
Oral Antibiotics with early hospital discharge
compared with In-patient intravenous antibiotics
for low-risk FN in cancer patients: a prospective
randomized study
Intravenous AB
In patient
(60)
Oral AB
Out patient
(66)
Death
1
0
Serious complications
0
1
Intolerance to AB
0
3
Persistance of fever
5
6
Mean cost per episode (£)
840
470
Mean nursing hours per
episode
21
11
Innes et al., Brit. J. Cancer, 2003
18
J. Klastersky et al., JCO, 2006
19
J. Klastersky et al., JCO, 2006
20
Occurrence of serious medical complications
Overall (all orally treated patients)
9/178 (5 %)
Patients discharged early
0/79 (0 %)
Patients not discharged early
9/99 (9 %)
. patients with persisting fever
4/19 (21 %)
. patients with medical reason
4/42 (9 %)
. patients without medical reason
2/38 (2%)
J. Klastersky et al., 2005
21
J. Klastersky et al., JCO, 2006
22
Conclusions
 Simplified management of FN (oral and ambulatory) has
great potential for quality of life and cost reduction
 Our study suggests that it is feasible and safe in a
significant proportion (44 %) of patients predicted to be
at low risk of complications using the MASCC score
 Observation for 24-48 hours seems critical even if
criteria for early discharge are fullfilled; 9 % of patients
maintained hospitalized for
« good » or « bad » reasons developed severe
complications
 Low risk prediction and suitability for oral outpatient
treatment are to some extent different issues; safe
prediction of the feasibility of early discharge remains to
be established.
23
Mortality in 3190 patients with febrile
neutropenia 30 days after entry (IATCG trials
Vb, VIII, IX and XI
Bacteremia (%)
No Bacteremia (%)
No evaluable patients
805
2385
Causes of Death
Infections
Infections + other*
other*
48 (5.9)
20 (205)
29 (3.6)
71 (2.9)
35 (105)
83 (3.5)
P=0.001
Total n° of deaths
97 (12.0)
189 (7.9)
P=0.003
(*) mainly hemorrhage and extensive cancer
24
25
Outcome and distribution : complicated
versus uncomplicated bacteremias
Single gram positive
Single gram negative
Polymicrobial
Total
Complications
Deaths
Total
Complications
Deaths
Total
Complications
Deaths
Clinical site of
infection
128
21 %
5%
82
21 %
23 %
25
16 %
16 %
No clinical site
of infection
155
19 %
5%
86
24 %
13 %
23
30 %
9%
J. Klastersky et al., J. Antimicrob. Chemother., 2007
26
Mortality rate in bacteremic patients
stratified by classes of the MASCC score
and type of bacteremia
MASCC
Gram+
Gramscore
Total Deaths Total Deaths
(Nr.)
(%)
(Nr.)
(%)
< 15
18
28
23
43
15-20
≥ 21
89
176
6
2
64
81
23
6
Klastersky et al., J. Antimicrob. Chemother., 2007
27
Factors predicting bacteremia*
(multivariate analysis)
High fever (> 39°C)
P < 0.001
Presence of shock
P < 0.001
Clinical site of infection
P = 0.04
Antifungal prophylaxis
P < 0.001
Platelets > 50.000/ul
P < 0.001
Duration of granylocytopenia > 6 days
P < 0.001
* « when tested in the validation set, the
model was poorly predictive »
Adapted from Viscoli et al., Europ. J. Cancer, 1994
28
ROC curves for predicting mortality in the test population (N = 1003)
AUC :
MASCC : 0.778, 95% CI : 0.715-0.840
MASCC + B : 0.790, 95% CI : 0.729-0.851
MASCC + GNB : 0.791, 95% CI : 0.729-0.0.854
29
We can predict the high risk patients
What can we do for improving the outcome
of FN in that subset of patients ?
30
Response to empiric combination
antimicrobial therapy vs monotherapy in
patients with leukemia
Combination(cephalosporin + Monotherapy
amikacin)
(cephalosporin)
Klastersky et al.
(1988)
6/12
1/16
Tamura et al.
(2004)
33/45
24/45
39/57 (68 %)
25/61 (40 %)
31
Therapeutic CSF:
Infection-Related Mortality
Citation
Effect
Anaissie
0.320 0.032
3.184
Aviles
0.274 0.093
0.810
Biesma
3.783
Garcia-Carb 1.441
Lopez-Hern
L
U
0.141 101.826
0.236
8.809
0.425 0.035
5.106
Mayordomo 1.680
0.169
16.664
Ravaud
0.324 0.013
8.229
Combined
0.526 0.269
1.031
0.01
0.1
1
10
100
Favours CSF Favours No CSF
32
33
Description of patients with death within 2 weeks of
Emergency Department presentation among a total of
48 admitted for neutropenic fever
Age
Gender
Malignancy
Positive ED
blood cultures
ICU
MASCC
score
Description of death
55
F
AML
No
From ED
8
Improving 2 days prior to
death suddenly with
cardiac arrest
35
F
AML
Group g strep
From floor
12
Aspergillosis on lung
biopsy, respiratory failure,
DNR decided
58
M
Waldenstrom’s
No
From floor
21
Bacteremia, intracranial
bleed, respiratory failure,
DNR decided
57
M
AML
No
From floor
21
Was discharged recently
but readmitted to palliative
care, DNR decided
80
F
AML
Enterobacter
No
19
Bacteremia, pneumonia,
respiratory failure, DNR
decided
93
F
Myelodysplasia
No
No
19
DNR decided
DM Courtney et al; The Oncologist, 2009
34
1)Prevention (antibiotics or G-CSF’s) is
essential; should the present indications
be extended ?
2) Empirical therapy with broad spectrum
antibiotics remains a basic rule; be
adapted to the risk of complications !
3) Occult fungal infection should be
suspected early in patients with
prolonged neutropenia; do we need
empirical or pre-emptive treatment ?
35
Randomized Studies Comparing Empirical Treatment
with Antifungal Agents for Persisting Fever during
Neutropenia
YEAR
STUDY
ANTIFUNGAL AGENTS COMPARED
1982
Pizzo et al
Conventional ampho B vs no antifungal therapy
1989
EORTC
Conventional ampho B vs no antifungal therapy
1996
Viscoli et al.
Conventional ampho B vs fluconazole
1998
Malik et al.
Conventional ampho B vs fluconazole
1998
White et al..
Conventional ampho B vs ampho B colloidal
dispersion
1999
Walsh et al.
Conventional ampho B vs liposomal ampho B
2000
Winston et al.
Conventional ampho B vs fluconazole
2000
Wingard et al.
Liposomal ampho B vs ampho B lipid complex
2001
Boogaerts et al. Conventional ampho B vs itraconazole
2002
Walsh et al.
Liposomal ampho B vs voriconazole
2004
Walsh et al.
Liposomal ampho B vs caspofungin
36
FAILURES of Empirical Antifungal Therapy
in Microbiologically Demonstrated Fungal
Infections (FI)
Liposomal
ampho B
(961)
Breakthrough
FI
No cure of
base line FI
Total failures*
*p = 0.03
Voriconazole Caspofungin
(415)
(556)
45 (4.6)
8 (1.9)
29 (5.2)
22 (2.2)
7 (1.6)
13 (2.3)
67 (6.9 %)
15 (3.6 %)
42 (7.7 %)
J. Klastersky, NEJM, 2004
37
Prevalence of fungal infections in
persistently neutropenic patients not
receiving empirical therapy
Pizzo et al. (1982)
18
EORTC (1989)
28*
Guiot et al. (1993)
26*
Corey and Boeckh (2002)
45
Maertens et al. (2005)
21
* Autopsy-based data
38
Empirical versus preemptive therapy in febrile
neutropenic patients not responding patients to
empirical broad spectrum antibiotic therapy
Empirical vs pre-emptive approach (PE)
Results
Diagnosed IFI
Overall survival
IFI related mortality
Mean cost (euros)
E
PE
150 patients
143 patients
4 (2.6 %)
13 (9.0 %)
P < 0.02
147 (98 %)
136 (95 %)
NS
0 (0 %)
3 (2.1 %)
P = 0.12
3.595
3.745
NS
C. Cordonnier et al., Blood, 2006
39
What do we need beyond empiric of
pre-emptive therapy of suspected fungal
infections in febrile neutropenic
cancer patients ?
1) Predictive models of patients at risk of
developing fungal infections
2) Early and specific tools for diagnosing
fungal infection and monitoring therapy
3) More reliable antifungal therapies
Conclusions
1)
Prevention is essential : the indications for
G-CSF should be extended to « low risk »
patients with solid tumors
2)
Empirical antimicrobial therapy : should be
supplemented with more pathophysiologicallyoriented approaches and early intensive care in
high risk patients
3)
Occult fungal infections : require definition of
high riskgroups and earlier specific diagnosis,
in addition to empirical therapy
The past two decades have witnessed major
progress in the supportive management of
cancer patients who develop fever and
neutropenia. Morbidity and mortality have been
dramatically reduced, and for many patients
therapies are simplier, less toxic and more
appropriately delineated according the patient’s
risk status. Despite these progresses, however,
numerous challenges remain to be addressed
and important problems to be solved
42
Thank you for
your kind attention
and
« Au revoir »
43