febrile neutropenia revisited : what has been learnt and what remains to be learned ?
DESCRIPTION
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. The risk of infection increases with the severity and duration of neutropenia. - PowerPoint PPT PresentationTRANSCRIPT
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Febrile Neutropenia revisited : Febrile Neutropenia revisited : what has been learnt and what what has been learnt and what
remains to be learned ?remains to be learned ?
Prof. Jean Klastersky, MD, PhDProf. Jean Klastersky, MD, PhD
Institut Jules Bordet,Institut Jules Bordet,
Université Libre de BruxellesUniversité Libre de Bruxelles
Brussels, BelgiumBrussels, Belgium
33
G.P. Bodey, Ann Int Med, 1966
The risk of infection increases with the The risk of infection increases with the
severity and duration of neutropeniaseverity and duration of neutropenia
44
Febrile NeutropeniaHistorical 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
55
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 pre-emptive treatment and/or earlier diagnosis ?
1)Prevention is essential; should the present indications for G-CSF use be extended ?
66
Disease Citation Relative Risk (95% CI)
0.541 0.986 0.2970.976 4.691 0.203
DoorijianGisselbrechtPettengell 0.951 6.426 0.141
All Lymphoma 0.608 1.037 0.357
1.174 56.861 0.0240.968 47.992 0.0201.095 5.293 0.2260.336 1.213 0.0930.328 3.073 0.0350.461 1.782 0.119
BuiChevallierCrawfordFossaTrillet-LenoirTimmer-BonteVogel 0.201 4.172 0.010
All Solid Tumors 0.470 0.934 0.237
Combined 0.549 0.836 0.360
0.1 0.2 0.5 1 2 5
Favours G-CSF Favours No G-CSF
Updated meta-analysis of prophylacticG-CSF: Infection-related mortality
N.M. Kuderer, JCO, 2007
7777
Current Current GGuidelines for uidelines for pprimary rimary pprophylaxis rophylaxis withwith G-CSFsG-CSFs
FN risk levelFN risk level ASCOASCO EORTCEORTC NCCNNCCN
Moderate to high Moderate to high
(> 20 %)(> 20 %)
Use G-CSFsUse G-CSFs Use G-CSFsUse G-CSFs Use G-CSFsUse G-CSFs
Intermediate Intermediate
(10-20 %)(10-20 %)
RecommendRecommend ConsiderConsider ConsiderConsider
Low (< 10 %)Low (< 10 %) Not Not
specifiedspecified
Not Not recommendedrecommended
Not Not recommendedrecommended
Consider other risk Consider other risk factors than factors than intensity of intensity of chemotherapychemotherapy
++++ ++++++ ++
88
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%
Secondary prevention of subsequent FN in patients who had a first episode
99
Resolution without complication : 363/416 (87%, 95% CI : 84%-90%)Resolution without complication : 363/416 (87%, 95% CI : 84%-90%)
Outcome of FN and univariate analysisOutcome of FN and univariate analysis
Resol.Resol. Compl.Compl. DeathDeath
Risk of FN < 10%Risk of FN < 10% 180180 19 (9%)19 (9%) 9 (4%)9 (4%)
Risk of FN 10%-20%Risk of FN 10%-20% 123123 15 (10%)15 (10%) 9 (6%)9 (6%)
Risk of FN > 20%Risk of FN > 20% 6060 11 (16%)11 (16%) 0 (0%)0 (0%)
No use of prophylactic growth factorsNo use of prophylactic growth factors
Risk of FN < 10%Risk of FN < 10% 167167 1818 88
Risk of FN 10%-20%Risk of FN 10%-20% 106106 1313 99
Risk of FN > 20%Risk of FN > 20% 4848 1010 00
Use of growth factorsUse of growth factors
Risk of FN < 10%Risk of FN < 10% 1313 11 11
Risk of FN 10%-20%Risk of FN 10%-20% 1717 22 00
Risk of FN > 20%Risk of FN > 20% 1212 11 00
1010
Optimal schedule for G-CSFOptimal schedule for G-CSF
Schedules for G-CSF in breast cancer with a 7% risk Schedules for G-CSF in breast cancer with a 7% risk of Febrile Neutropeniaof Febrile Neutropenia
480 480 µµg/dayg/day days 8 -14days 8 -14
480 480 µµg/day,g/day, days 8, 10,12,14days 8, 10,12,14
300 300 µµg/dayg/day days 8 -14days 8 -14
300 300 µµg/dayg/day days 8,10,12,14days 8,10,12,14
*300 *300 µµg/dayg/day days 8 and 12days 8 and 12
**equivalent to the equivalent to the other other schedules with respect to grade 3 and 4 neutropeniaschedules with respect to grade 3 and 4 neutropenia
P. Papaldo et al., J Clin Oncol, 2005 P. Papaldo et al., J Clin Oncol, 2005
1111
Incidence of febrile episodes, probable infections, and hospitalization for infection*
LevofloxacinLevofloxacin
(N=781)(N=781)
PlaceboPlacebo
(N=784)(N=784)
Relative RiskRelative Risk
(95 % CI)(95 % CI)P ValueP Value
Nb of patients (%)Nb of patients (%)
Febrile episodeFebrile episode27 (3.5)27 (3.5) 62 (7.9)62 (7.9) 0.44 (0.28 – 0.68)0.44 (0.28 – 0.68) < 0.001< 0.001
Probable Probable infectioninfection 109 (14.0)109 (14.0) 152 (19.4)152 (19.4) 0.72 (0.57-0.90)0.72 (0.57-0.90) 0.0050.005
Hospitalization Hospitalization for infectionfor infection 52 (6.7)52 (6.7) 81 (10.3)81 (10.3) 0.64 (0.46 – 0.90)0.64 (0.46 – 0.90) 0.010.01
M. Cullen et al., NEJM, 2005* No effect on mortality
1212
Prophylactic levofloxacin to prevent bacterial infection in patients with hematological cancer
and neutropenia
Placebo Levofloxacin
Febrile Neutropenia* 308/363 (85 %) 243/375 (65 %)
(Mortatility and tolerability : similar)
GIMEMA, NEJM, 205
*p = 0.001
1313
2) Empirical therapy with broad spectrum antibiotics remains a basic rule; to be adapted to the risk of complications !
1)Prevention (antibiotics or G-CSF’s) is essential; should the present indications be extended ?
3) Occult fungal infection should be suspected early in patients with prolonged neutropenia; do we need empirical or pre-emptive treatment ?
1414
Ps. aeruginosa
Empirical therapy with carbenicillin plus gentamicin reduced dramatically (21 %) the mortality associated with Pseudomonas sepsis
1515
Score derived from the logistic equation of the MASCC predictive model
(1386 patients with FN)
J. Klastersky et al., J. Clin. Oncol. 2001
CharacteristicCharacteristic PointsPoints
Burden of illnessBurden of illness
No or mild symptomsNo or mild symptoms 55
Moderate symptomsModerate symptoms 33
No hypotensionNo hypotension 55
No chronic obstructive pulmonary diseaseNo chronic obstructive pulmonary disease 44
Solid tumor or no previous fungal infection in Solid tumor or no previous fungal infection in hematological cahematological ca
44
Outpatient statusOutpatient status 33
No dehydrationNo dehydration 33
Age < 60 yearsAge < 60 years 22
Threshold: score ≥ 21(maximum 26) predicting less than 5% of severe complications
1616
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
1717
Response rates and final outcome of low- and not low-risk 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 %)
Death before resolution
0 (0%) 8 (36 %)
A. Uys et al., Supp. Care Cancer, 2004
p < 0.001
1818
Oral Antibiotics with early hospital discharge compared with In-patient intravenous antibiotics for low-risk FN in cancer patients: a prospective
randomized study
Intravenous ABIntravenous AB
In patientIn patient
(60)(60)
Oral ABOral AB
Out patientOut patient
(66)(66)
DeathDeath 11 00
Serious complications Serious complications 00 11
Intolerance to ABIntolerance to AB 00 33
Persistance of feverPersistance of fever 55 66
Mean cost per episode (£)Mean cost per episode (£) 840840 470470
Mean nursing hours per Mean nursing hours per episodeepisode
2121 1111
Innes et al., Brit. J. Cancer, 2003
2121
Occurrence of serious medical complications
Overall (all orally treated patients)Overall (all orally treated patients) 9/178 (5 %)9/178 (5 %)
Patients discharged earlyPatients discharged early 0/79 (0 %)0/79 (0 %)
Patients not discharged earlyPatients not discharged early 9/99 (9 %)9/99 (9 %)
. patients with persisting fever. patients with persisting fever 4/19 (21 %)4/19 (21 %)
. patients with medical reason. patients with medical reason 4/42 (9 %)4/42 (9 %)
. patients without medical reason. patients without medical reason 2/38 (2%)2/38 (2%)
J. Klastersky et al., 2005
2323
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.
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Mortality in 3190 patients with febrile neutropenia 30 days after entry (IATCG trials
Vb, VIII, IX and XI
Bacteremia (%)Bacteremia (%) No Bacteremia (%)No Bacteremia (%)
No evaluable patientsNo evaluable patients 805805 23852385
Causes of DeathCauses of Death
InfectionsInfections Infections + other* Infections + other*
other*other*
48 (5.9)48 (5.9)
20 (205)20 (205)
29 (3.6)29 (3.6)
71 (2.9)71 (2.9)
35 (105)35 (105)
83 (3.5)83 (3.5)
P=0.001P=0.001
Total n° of deathsTotal n° of deaths 97 (12.0)97 (12.0) 189 (7.9)189 (7.9) P=0.003P=0.003
(*) mainly hemorrhage and extensive cancer
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Outcome and distribution : complicated Outcome and distribution : complicated versus uncomplicated bacteremiasversus uncomplicated bacteremias
Single gram positiveSingle gram positive Single gram negativeSingle gram negative PolymicrobialPolymicrobial
TotalTotal ComplicationsComplications DeathsDeaths TotalTotal ComplicationsComplications DeathsDeaths TotalTotal ComplicationsComplications DeathsDeaths
Clinical site of Clinical site of infectioninfection
128128 21 %21 % 5 %5 % 8282 21 %21 % 23 %23 % 2525 16 %16 % 16 %16 %
No clinical site No clinical site of infectionof infection
155155 19 %19 % 5 %5 % 8686 24 %24 % 13 %13 % 2323 30 %30 % 9 %9 %
J. Klastersky et al., J. Antimicrob. Chemother., 2007
2727
Mortality rate in bacteremic patients Mortality rate in bacteremic patients stratified by classes of the MASCC score stratified by classes of the MASCC score
and type of bacteremiaand type of bacteremia
MASCC MASCC scorescore
Gram+Gram+ Gram-Gram-
Total Total (Nr.)(Nr.)
Deaths Deaths (%)(%)
Total Total (Nr.)(Nr.)
Deaths Deaths (%)(%)
< 15< 15 1818 2828 2323 4343
15-2015-20 8989 66 6464 2323
≥ ≥ 2121 176176 22 8181 66
Klastersky et al., J. Antimicrob. Chemother., 2007
2828
Factors predicting bacteremia*Factors predicting bacteremia*(multivariate analysis)(multivariate analysis)
High fever (> 39°C)High fever (> 39°C) P < 0.001P < 0.001
Presence of shockPresence of shock P < 0.001P < 0.001
Clinical site of infectionClinical site of infection P = 0.04P = 0.04
Antifungal prophylaxisAntifungal prophylaxis P < 0.001P < 0.001
Platelets > 50.000/ulPlatelets > 50.000/ul P < 0.001P < 0.001
Duration of granylocytopenia > 6 daysDuration of granylocytopenia > 6 days P < 0.001P < 0.001
* « when tested in the validation set, the model was poorly predictive »
Adapted from Viscoli et al., Europ. J. Cancer, 1994
2929
ROC curves for predicting ROC curves for predicting mortality mortality in the test population in the test population (N = 1003)(N = 1003)
AUC :MASCC : 0.778, 95% CI : 0.715-0.840MASCC + B : 0.790, 95% CI : 0.729-0.851MASCC + GNB : 0.791, 95% CI : 0.729-0.0.854
3030
We can predict the high risk patientsWe can predict the high risk patients
What can we do for improving the What can we do for improving the
outcome of FN in that subset of patients ?outcome of FN in that subset of patients ?
3131
Response to empiric combination antimicrobial therapy vs monotherapy in
patients with leukemia
Combination(cephalosporin + amikacin)
Monotherapy
(cephalosporin)
Klastersky et al. (1988)
6/12 1/16
Tamura et al. (2004)
33/45 24/45
39/57 (68 %) 25/61 (40 %)
3232
Therapeutic CSF:Infection-Related Mortality
Citation Effect L U
Anaissie 0.320 0.032 3.184
Aviles 0.274 0.093 0.810
Biesma 3.783 0.141 101.826
Garcia-Carb 1.441 0.236 8.809
Lopez-Hern 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 1.0310.01 0.1 1 10 100
Favours CSF Favours No CSF
3434
Description of patients with death within 2 weeks of Description of patients with death within 2 weeks of Emergency Department presentation among a total of Emergency Department presentation among a total of
48 admitted for neutropenic fever48 admitted for neutropenic fever
AgeAge GenderGender MalignancyMalignancy Positive EDPositive ED
blood culturesblood cultures
ICUICU MASCCMASCC
scorescore
Description of deathDescription of death
5555 FF AMLAML NoNo From EDFrom ED 88 Improving 2 days prior to Improving 2 days prior to death suddenly with death suddenly with cardiac arrestcardiac arrest
3535 FF AMLAML Group g strepGroup g strep From floorFrom floor 1212 Aspergillosis on lung Aspergillosis on lung biopsy, respiratory failure, biopsy, respiratory failure, DNR decidedDNR decided
5858 MM Waldenstrom’sWaldenstrom’s NoNo From floorFrom floor 2121 Bacteremia, intracranial Bacteremia, intracranial bleed, respiratory failure, bleed, respiratory failure, DNR decidedDNR decided
5757 MM AMLAML NoNo From floorFrom floor 2121 Was discharged recently Was discharged recently but readmitted to palliative but readmitted to palliative care, DNR decidedcare, DNR decided
8080 FF AMLAML EnterobacterEnterobacter NoNo 1919 Bacteremia, pneumonia, Bacteremia, pneumonia, respiratory failure, DNR respiratory failure, DNR decideddecided
9393 FF MyelodysplasiaMyelodysplasia NoNo NoNo 1919 DNR decidedDNR decided
DM Courtney et al; The Oncologist, 2009
3535
2) Empirical therapy with broad spectrum antibiotics remains a basic rule; be adapted to the risk of complications !
1)Prevention (antibiotics or G-CSF’s) is essential; should the present indications be extended ?
3) Occult fungal infection should be suspected early in patients with prolonged neutropenia; do we need empirical or pre-emptive treatment ?
363636363636
Randomized Studies Comparing Empirical Treatment Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during with Antifungal Agents for Persisting Fever during
NeutropeniaNeutropenia
YEARYEAR STUDYSTUDY ANTIFUNGAL AGENTS COMPAREDANTIFUNGAL AGENTS COMPARED
19821982
19891989
19961996
19981998
19981998
19991999
20002000
20002000
20012001
20022002
20020044
Pizzo et alPizzo et al
EORTCEORTC
Viscoli et al.Viscoli et al.
Malik et al.Malik et al.
White et al..White et al..
Walsh et al.Walsh et al.
Winston et al.Winston et al.
Wingard et al.Wingard et al.
Boogaerts et al.Boogaerts et al.
Walsh et al.Walsh et al.
Walsh et al.Walsh et al.
Conventional ampho B vs no antifungal therapyConventional ampho B vs no antifungal therapy
Conventional ampho B vs no antifungal therapyConventional ampho B vs no antifungal therapy
Conventional ampho B vs fluconazoleConventional ampho B vs fluconazole
Conventional ampho B vs fluconazoleConventional ampho B vs fluconazole
Conventional ampho B vs ampho B colloidal Conventional ampho B vs ampho B colloidal dispersiondispersion
Conventional ampho B vs liposomal ampho BConventional ampho B vs liposomal ampho B
Conventional ampho B vs fluconazoleConventional ampho B vs fluconazole
Liposomal ampho B vs ampho B lipid complexLiposomal ampho B vs ampho B lipid complex
Conventional ampho B vs itraconazoleConventional ampho B vs itraconazole
Liposomal ampho B vs voriconazoleLiposomal ampho B vs voriconazole
Liposomal ampho B vs caspofunginLiposomal ampho B vs caspofungin
3737
FAILURESFAILURES of Empirical Antifungal Therapy of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal in Microbiologically Demonstrated Fungal
Infections (FI)Infections (FI)
Liposomal Liposomal ampho Bampho B
VoriconazoleVoriconazole CaspofunginCaspofungin
(961)(961) (415)(415) (556)(556)
Breakthrough Breakthrough FIFI
45 (4.6)45 (4.6) 8 (1.9)8 (1.9) 29 (5.2)29 (5.2)
No cure of No cure of base line FIbase line FI
22 (2.2)22 (2.2) 7 (1.6)7 (1.6) 13 (2.3)13 (2.3)
Total failures*Total failures* 67 (6.9 %)67 (6.9 %) 15 (3.6 %)15 (3.6 %) 42 (7.7 %)42 (7.7 %)
*p = 0.03 J. Klastersky, NEJM, 2004
3838
Prevalence of fungal infections in Prevalence of fungal infections in persistently neutropenic patients not persistently neutropenic patients not
receiving empirical therapyreceiving empirical therapy
Pizzo et al. (1982)Pizzo et al. (1982) 1818
EORTC (1989)EORTC (1989) 28*28*
Guiot et al. (1993)Guiot et al. (1993) 26*26*
Corey and Boeckh (2002)Corey and Boeckh (2002) 4545
Maertens et al. (2005)Maertens et al. (2005) 2121
* Autopsy-based data
3939
Empirical versus preemptive therapy in febrile Empirical versus preemptive therapy in febrile neutropenic patients not responding patients to neutropenic patients not responding patients to
empirical broad spectrum antibiotic therapyempirical broad spectrum antibiotic therapy
EE PEPE
150 patients150 patients 143 patients143 patients
Diagnosed IFIDiagnosed IFI 4 (2.6 %)4 (2.6 %) 13 (9.0 %)13 (9.0 %) P < 0.02P < 0.02
Overall survivalOverall survival 147 (98 %)147 (98 %) 136 (95 %)136 (95 %) NSNS
IFI related mortalityIFI related mortality 0 (0 %)0 (0 %) 3 (2.1 %)3 (2.1 %) P = 0.12P = 0.12
Mean cost (euros)Mean cost (euros) 3.5953.595 3.7453.745 NSNS
C. Cordonnier et al., Blood, 2006
Empirical vs pre-emptive approach (PE)
Results
What do we need beyond empiric ofWhat do we need beyond empiric ofpre-emptive therapy of suspected fungal pre-emptive therapy of suspected fungal
infections in febrile neutropenicinfections in febrile neutropeniccancer patients ?cancer patients ?
1)1) Predictive models of patients at risk of Predictive models of patients at risk of developing fungal infectionsdeveloping fungal infections
2)2) Early and specific tools for diagnosing Early and specific tools for diagnosing fungal infection and monitoring therapyfungal infection and monitoring therapy
3)3) More reliable antifungal therapiesMore reliable antifungal therapies
ConclusionsConclusions
1)1) Prevention is essential : the indications forPrevention is essential : the indications forG-CSF should be extended to « low risk » G-CSF should be extended to « low risk » patients with solid tumorspatients with solid tumors
2)2) Empirical antimicrobial therapy : should be Empirical antimicrobial therapy : should be supplemented with more pathophysiologically-supplemented with more pathophysiologically-oriented approaches and early intensive care in oriented approaches and early intensive care in high risk patientshigh risk patients
3)3) Occult fungal infections : require definition of Occult fungal infections : require definition of high riskgroups and earlier specific diagnosis, high riskgroups and earlier specific diagnosis, in addition to empirical therapyin addition to empirical therapy
4242
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