Febrile Neutropenia revisited : what has been learnt and what remains to be learned ?

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

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

4. 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

5. 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 pre-emptive treatment and/or earlier diagnosis ?

6. Doorijian Gisselbrecht Pettengell Bui Chevallier Crawford Fossa Trillet-Lenoir Timmer-Bonte Vogel Updated meta-analysis of prophylacticG-CSF: Infection-related mortality Disease Citation 0.1 0.2 0.5 1 2 5 Relative Risk (95% CI) 0.541 0.986 0.297 0.976 4.691 0.203 0.951 6.426 0.141 All Lymphoma 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 All Solid Tumors 0.470 0.934 0.237 Combined 0.549 0.836 0.360 Favours G-CSF Favours No G-CSF N.M. Kuderer, JCO, 2007

7. Current Guidelines for primary prophylaxis withG-CSFs 7

8. Secondary prevention of subsequent FN in patients who had a first episode

9. Outcome of FN and univariate analysis Resolution without complication : 363/416 (87%, 95% CI : 84%-90%)

10. 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

11. Incidence of febrile episodes, probable infections, and hospitalization for infection* * No effect on mortality M. Cullen et al., NEJM, 2005

12. Prophylactic levofloxacin to prevent bacterial infection in patients with hematological cancer and neutropenia *p = 0.001 (Mortatility and tolerability : similar) GIMEMA, NEJM, 205

13. 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 ?

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

15. Score derived from the logistic equation of the MASCC predictive model (1386 patients with FN) J. Klastersky et al., J. Clin. Oncol. 2001 Threshold: score ≥ 21(maximum 26) predicting less than 5% of severe complications

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. Response rates and final outcome of low- and not low-risk patients with febrile neutropenia as predicted y the MASCC risk-index score A. Uys et al., Supp. Care Cancer, 2004 p < 0.001

18. Oral Antibiotics with early hospital discharge compared with In-patient intravenous antibiotics for low-risk FN in cancer patients: a prospective randomized study Innes et al., Brit. J. Cancer, 2003

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

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

21. Occurrence of serious medical complications J. Klastersky et al., 2005

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

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. Mortality in 3190 patients with febrile neutropenia 30 days after entry (IATCG trials Vb, VIII, IX and XI (*) mainly hemorrhage and extensive cancer

26. Outcome and distribution : complicated versus uncomplicated bacteremias J. Klastersky et al., J. Antimicrob. Chemother., 2007

27. Klastersky et al., J. Antimicrob. Chemother., 2007

28. Factors predicting bacteremia*(multivariate analysis) * «  when tested in the validation set, the model was poorly predictive » Adapted from Viscoli et al., Europ. J. Cancer, 1994

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

31. Response to empiric combination antimicrobial therapy vs monotherapy in patients with leukemia

32. 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 1.031 0.01 0.1 1 10 100 Favours CSF Favours No CSF

34. Description of patients with death within 2 weeks of Emergency Department presentation among a total of 48 admitted for neutropenic fever DM Courtney et al; The Oncologist, 2009

35. 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 ?

36. Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during Neutropenia 36 36

37. FAILURESof Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) *p = 0.03 J. Klastersky, NEJM, 2004

38. Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy * Autopsy-based data

39. Empirical versus preemptive therapy in febrile neutropenic patients not responding patients to empirical broad spectrum antibiotic therapy Empirical vs pre-emptive approach (PE) Results C. Cordonnier et al., Blood, 2006

40. What do we need beyond empiric ofpre-emptive therapy of suspected fungal infections in febrile neutropeniccancer patients ? Predictive models of patients at risk of developing fungal infections Early and specific tools for diagnosing fungal infection and monitoring therapy More reliable antifungal therapies

41. Conclusions Prevention is essential : the indications forG-CSF should be extended to « low risk » patients with solid tumors Empirical antimicrobial therapy : should be supplemented with more pathophysiologically-oriented approaches and early intensive care in high risk patients Occult fungal infections : require definition of high riskgroups and earlier specific diagnosis, in addition to empirical therapy

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. Thankyou for yourkind attention and « Au revoir »