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1 Febrile Neutropenia revisited : what has been learnt and what remains to be learned ? Prof. Jean Klastersky, MD, PhD Institut Jules Bordet, Université.

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Presentation on theme: "1 Febrile Neutropenia revisited : what has been learnt and what remains to be learned ? Prof. Jean Klastersky, MD, PhD Institut Jules Bordet, Université."— Presentation transcript:

1 1 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

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3 3 G.P. Bodey, Ann Int Med, 1966 The risk of infection increases with the severity and duration of neutropenia

4 4 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

5 5 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 ?

6 6 Disease Citation Relative Risk (95% CI) 0.5410.9860.297 0.9764.6910.203 Doorijian Gisselbrecht Pettengell 0.9516.4260.141 All Lymphoma0.6081.0370.357 1.17456.8610.024 0.96847.9920.020 1.0955.2930.226 0.3361.2130.093 0.3283.0730.035 0.4611.7820.119 Bui Chevallier Crawford Fossa Trillet-Lenoir Timmer-Bonte Vogel 0.2014.1720.010 All Solid Tumors0.4700.9340.237 Combined 0.5490.8360.360 0.10.20.5125 Favours G-CSFFavours No G-CSF Updated meta-analysis of prophylactic G-CSF: Infection-related mortality N.M. Kuderer, JCO, 2007

7 77 Current Guidelines for primary prophylaxis with G-CSFs FN risk level ASCOEORTCNCCN Moderate to high (> 20 %) Use G-CSFs Intermediate (10-20 %) RecommendConsiderConsider Low (< 10 %) Notspecified Not recommended Consider other risk factors than intensity of chemotherapy ++++++

8 8 CRAWFORD (1991) (n=59 SCLC) LALAMI (2001) (n=48 breast ca) Incidence of FN after the first cycle of chemotherapy (without CSF) 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

9 9 Resolution without complication : 363/416 (87%, 95% CI : 84%-90%) Outcome of FN and univariate analysis 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% 167188 Risk of FN 10%-20% 106139 Risk of FN > 20% 48100 Use of growth factors Risk of FN < 10% 1311 Risk of FN 10%-20% 1720 Risk of FN > 20% 1210

10 10 Optimal schedule for G-CSF  Schedules for G-CSF in breast cancer with a 7% risk of Febrile Neutropenia  480 µg/daydays 8 -14  480 µg/day,days 8, 10,12,14  300 µg/daydays 8 -14  300 µg/daydays 8,10,12,14  *300 µg/daydays 8 and 12 * equivalent to the other schedules with respect to grade 3 and 4 neutropenia P. Papaldo et al., J Clin Oncol, 2005

11 11 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 27 (3.5) 62 (7.9) 0.44 (0.28 – 0.68) < 0.001 Probable infection 109 (14.0) 152 (19.4) 0.72 (0.57-0.90) 0.005 Hospitalization for infection 52 (6.7) 81 (10.3) 0.64 (0.46 – 0.90) 0.01 M. Cullen et al., NEJM, 2005 * No effect on mortality

12 12 Prophylactic levofloxacin to prevent bacterial infection in patients with hematological cancer and neutropenia PlaceboLevofloxacin Febrile Neutropenia*308/363 (85 %)243/375 (65 %) (Mortatility and tolerability : similar) GIMEMA, NEJM, 205 *p = 0.001

13 13 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 ?

14 14 Ps. aeruginosa Empirical therapy with carbenicillin plus gentamicin reduced dramatically (21 %) the mortality associated with Pseudomonas sepsis

15 15 Score derived from the logistic equation of the MASCC predictive model (1386 patients with FN) J. Klastersky et al., J. Clin. Oncol. 2001 CharacteristicPoints 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

16 16 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

17 17 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

18 18 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) Death10 Serious complications 01 Intolerance to AB 03 Persistance of fever 56 Mean cost per episode (£) 840470 Mean nursing hours per episode 2111 Innes et al., Brit. J. Cancer, 2003

19 19 J. Klastersky et al., JCO, 2006

20 20 J. Klastersky et al., JCO, 2006

21 21 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. patients with persisting fever 4/19 (21 %). patients with medical reason. patients with medical reason 4/42 (9 %). patients without medical reason. patients without medical reason 2/38 (2%) J. Klastersky et al., 2005

22 22 J. Klastersky et al., JCO, 2006

23 23 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.

24 24 Mortality in 3190 patients with febrile neutropenia 30 days after entry (IATCG trials Vb, VIII, IX and XI Bacteremia (%) No Bacteremia (%) No evaluable patients 8052385 Causes of Death Infections Infections + other* Infections Infections + other* 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

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26 26 Outcome and distribution : complicated versus uncomplicated bacteremias Single gram positive Single gram negative Polymicrobial TotalComplicationsDeathsTotalComplicationsDeathsTotalComplicationsDeaths Clinical site of infection 128 21 % 5 % 82 21 % 23 % 25 16 % No clinical site of infection 155 19 % 5 % 86 24 % 13 % 23 30 % 9 % J. Klastersky et al., J. Antimicrob. Chemother., 2007

27 27 Mortality rate in bacteremic patients stratified by classes of the MASCC score and type of bacteremia MASCC score Gram+Gram- Total (Nr.) Deaths (%) Total (Nr.) Deaths (%) < 15 18282343 15-208966423 ≥ 21 1762816 Klastersky et al., J. Antimicrob. Chemother., 2007

28 28 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

29 29 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

30 30 We can predict the high risk patients What can we do for improving the outcome of FN in that subset of patients ?

31 31 Response to empiric combination antimicrobial therapy vs monotherapy in patients with leukemia Combination(cephalosporin + amikacin) Monotherapy (cephalosporin) Klastersky et al. (1988) 6/121/16 Tamura et al. (2004) 33/4524/45 39/57 (68 %)25/61 (40 %)

32 32 Therapeutic CSF: Infection-Related Mortality CitationEffectLU Anaissie0.3200.0323.184 Aviles0.2740.0930.810 Biesma 3.7830.141101.826 Garcia-Carb1.4410.2368.809 Lopez-Hern0.4250.0355.106 Mayordomo1.6800.16916.664 Ravaud0.3240.0138.229 Combined0.5260.2691.031 0.010.1110100 Favours CSF Favours No CSF

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34 34 Description of patients with death within 2 weeks of Emergency Department presentation among a total of 48 admitted for neutropenic fever AgeGenderMalignancy Positive ED blood cultures ICUMASCCscore Description of death 55FAMLNo From ED 8 Improving 2 days prior to death suddenly with cardiac arrest 35FAML Group g strep From floor 12 Aspergillosis on lung biopsy, respiratory failure, DNR decided 58MWaldenstrom’sNo From floor 21 Bacteremia, intracranial bleed, respiratory failure, DNR decided 57MAMLNo From floor 21 Was discharged recently but readmitted to palliative care, DNR decided 80FAMLEnterobacterNo19 Bacteremia, pneumonia, respiratory failure, DNR decided 93FMyelodysplasiaNoNo19 DNR decided DM Courtney et al; The Oncologist, 2009

35 35 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 ?

36 363636 Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during Neutropenia YEARSTUDY ANTIFUNGAL AGENTS COMPARED 1982198919961998199819992000200020012002 2004 Pizzo et al EORTC Viscoli et al. Malik et al. White et al.. Walsh et al. Winston et al. Wingard et al. Boogaerts et al. Walsh et al. Conventional ampho B vs no antifungal therapy Conventional ampho B vs fluconazole Conventional ampho B vs ampho B colloidal dispersion Conventional ampho B vs liposomal ampho B Conventional ampho B vs fluconazole Liposomal ampho B vs ampho B lipid complex Conventional ampho B vs itraconazole Liposomal ampho B vs voriconazole Liposomal ampho B vs caspofungin

37 37 FAILURES of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) Liposomal ampho B VoriconazoleCaspofungin (961)(415)(556) Breakthrough FI 45 (4.6) 8 (1.9) 29 (5.2) No cure of base line FI 22 (2.2) 7 (1.6) 13 (2.3) Total failures* 67 (6.9 %) 15 (3.6 %) 42 (7.7 %) *p = 0.03 J. Klastersky, NEJM, 2004

38 38 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

39 39 Empirical versus preemptive therapy in febrile neutropenic patients not responding patients to empirical broad spectrum antibiotic therapy EPE 150 patients 143 patients Diagnosed IFI 4 (2.6 %) 13 (9.0 %) P < 0.02 Overall survival 147 (98 %) 136 (95 %) NS IFI related mortality 0 (0 %) 3 (2.1 %) P = 0.12 Mean cost (euros) 3.5953.745NS C. Cordonnier et al., Blood, 2006 Empirical vs pre-emptive approach (PE) Results

40 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

41 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 pathophysiologically- oriented 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

42 42 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

43 43 Thank you for your kind attention and « Au revoir »


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