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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

22

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

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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

1919

J. Klastersky et al., JCO, 2006

2020

J. Klastersky et al., JCO, 2006

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

2222

J. Klastersky et al., JCO, 2006

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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2626

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

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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 %)

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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

3333

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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

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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

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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

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Thank you foryour kind attention

and« Au revoir »