1. 3ème Atelier Thématique en Hématologie (ATHEM) 22 novembre 2013 Dr S. Alfandari Médecin Référent en antibiothérapie et Hygiéniste, CH Tourcoing Infectiologue Consultant, Service des Maladies du sang, CHRU Lille www.infectio-lille.com Dr S. Alfandari Médecin Référent en antibiothérapie et Hygiéniste, CH Tourcoing Infectiologue Consultant, Service des Maladies du sang, CHRU Lille www.infectio-lille.com Antifungal therapy in haematology patients: Empirical or preemptive ?

2.  Lectures: Gilead, MSD, Novartis, Pfizer  Meetings: Gilead, MSD, Pfizer, Sanofi  French ID society administrator: Astellas - Astra Zeneca - Gilead - Viiv Healthcare - Janssen Cilag - MSD - Sanofi Pasteur MSD - Pfizer - Bayer Pharma - BMS - Abbott - Roche - Novartis – Vitalaire - Biofilm control - GSK - Celestis Potential conflicts of interest

3.  All haematology patients ◦ No, that’s prophylaxis  Haematology patients with mycological evidence of IFI ◦ No, that’s targeted treatment  Febrile neutropenia patients ◦ Yes, but which patients ? What treatment are we talking about ?

4.  Standard of care since the 2002 IDSA guidelines  Supporting studies ◦ Pizzo et al. AMJ 1982  50 patients with fever & 7 days broad spectrum AB randomized to  AB stop/continuing AB/ AB + amphotericin B  Infections: 9/6/2 ◦ EORTC. AMJ 1989  132 patients with fever & 4 days AB randomized w - w/o AmB  1,5% (n=1) vs 9% IFI (n=6)  No significant difference in overall mortality Empirical antifungal therapy in febrile neutropenia patients

5. Three large trials: similar results - few events

6.  Pro ◦ Early IFI Rx ◦ Another step in antimicrobial therapy  Might delay escalation therapy to carbapenems  Psychological support: « we DO something » to treat the fever  Con ◦ Most patients receive unnecessary Rx: no infection/no IFI ◦ Adverse events ◦ Costs ◦ New diagnostic tools allow for early diagnosis Pro/con empirical AF therapy

7.  Decreasing IFI risk in haematology patients ◦ 90’s  17-25% in AML/allograft (Bodey, EJCMID 1992, Guiot CID 1994) ◦ 00’s  ~10% in AML (Nosary, AJH 2001, Cornely, NEJM 2007) and allograft (Ullmann, NEJM 2007)  Including arms without mould-active prophylaxis from randomized trials ◦ 10’s  Unfrequent event with generalized mould-active prophylaxis  <5%  High antifungal costs ◦ ~830000€/year (1M $) in Lille Haematology department ◦ ~90% of antiinfectives costs Why is this a hot issue ?

8.  Empirical ◦ Fever driven  Pre-emptive ◦ Diagnostic driven  Biomarkers  Imaging ◦ Non standardized definition: confusion risk in literature A new strategy: preemptive therapy

9.  Clinical: ◦ Pneumonia  Imaging: ◦ Typical or not?  Biomarkers: ◦ Galactomannan antigenemia ◦ -D glucan ◦ PCR ◦ Mannan, antimannan  Combinations of several criteria ? No consensus on the criteria for a pre-emptive strategy Slide courtesy C Cordonnier

10. Galactomannan and CT-Based Preemptive Antifungal Therapy Maertens et al CID 2005; 41:1242–50

11.  117 febrile episodes  30 persistent fever / 28 relapsing fever while ATB ◦ 41 (30%) with empirical criteria ◦ 9 have GM Ag + and receive AF  32 Rx NOT given  10 non febrile episodes with GM Ag + treated  Outcome: ◦ Overall survival: 81,9% ◦ 22 IFD with 3 breakthrough infections  2 non fatal candidemias  One autopsy diagnosed zygomycosis (non febrile) Galactomannan and CT-Based Preemptive Antifungal Therapy Maertens et al CID 2005; 41:1242–50

12.  403 allo-HSCT, Day-100 fu, randomized to  AmB-L 3 mg/kg/d  A- PCR monitoring (n=196) ◦ 1x PCR+ or persistent fever >5 d or pulm infiltrate:  B- Empirical antifungal therapy (n=207) ◦ Persistent fever >5 d (w ou w/o PCR+) or pulm infiltrate PCR-Based Preemptive Antifungal Therapy Hebart et al BMT 2009;43: 553-61 PCREmpiricalp N treated112 (57.1%)76 (36.7%)0.003 N proven/probable IFI1617NS N death D304 (1.5%)13 (6.3%)0.015 N total death D1003234NS

13.  Drug: AmB or AmB-L daily / CrCl  Empirical arm ◦ Fever driven  Pre-emptive arm ◦ Pneumonia, shock, skin lesions evocative of IFI, sinusitis, orbititis, hepatosplenic abscesses, grade 4 mucositis, ◦ Aspergillus colonization, or one GM Ag + Multiple criteria based Preemptive Antifungal Therapy Cordonnier et al CID 2009 48:1042–51

14. Multiple criteria based Preemptive Antifungal Therapy Empirical (N=150)Preemptive (N=143)P Fever before ATF (d)713<.01 Duration of fever (d)18.3 NS Patients with ATF %62.739.2<10 -4 Days of ATF7.44.5<.01 Survival97%95%NS Proven/probable IFI2,7%9%<0.02 Cordonnier et al CID 2009 48:1042–51

15. Empirical Pre-emptive IFI in Pre-emptive IFI in Empirical Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051 15 Days Neutropenia Induction AML Consolidation AML or Auto-HSCT Multiple criteria based Preemptive Antifungal Therapy Cordonnier et al CID 2009 48:1042–51

16.  Observational study, 146 AL/auto-HSCT pts ◦ 220 neutropenic episodes (NE) ◦ Intensive diagnosis work-up if fever > 4d or recurrent fever  3 consecutive daily GM, chest CT, etc… ◦ AF if: proven-probable-possible IFI or persistent fever + « clinical deterioration »  AF given: 48 / 159 (30.2%) ◦ 84 / 159 (52.8%) if following usual guidelines  IFI Proven/probable: 14% (25% high risk patients) Clinically driven Preemptive Antifungal Therapy Girmenia et al., J Clin Oncol, 2010;28:667-74

17.  Data collection 397 HM patients ◦ 190 empirical (fever driven) ◦ 207”pre-emptive” (imaging or mycology or non specific lab tests)  More probable/proven IFI in pre-emptive arm ◦ 23.7 vs 7.4% - p<0.001  Increased IFI mortality in pre-emptive arm ◦ 22.5% vs 7.1%  Limits ◦ Non interventional, diagnostic work up not standardized, candida colonization included in preemptive Observational: Empiric versus “pre- emptive” Pagano et al Haematologica 2011; 96:1363-70

18.  240 AML/allo-HSCT, open label, randomized study  Standard strategy:  Fever => CT scan+/-BAL  Empirical AF till results then back to prophylaxis or up to targeted  Biomarker strategy:  PCR/GM Ag + (or persistent fever if negative) => CT scan+/-BA  Preemptive AF if typical images  No AF if atypical or no CT abnormalities PCR/CTscan-Based Preemptive Antifungal Therapy Morrissey, et al. Lancet ID 2013;13:519

19. PCR/CTscan-Based Preemptive Antifungal Therapy Morrissey, et al. Lancet ID 2013;13:519 Standard group (n=122) Biomarker group (n=118) p AF use39 (32%)18 (15%)0·002 Mortality All-cause18 (15%)12 (10%)0·31 IA-related6 (5%)3 (3%)0·5 Other IFI-related02 (2%)0·24 IA incidence Proven1 (1%) 1·0 Probable016 (14%)<0·0001 Possible06 (5%)0·013 Other IFI incidence Proven4 (3%)5 (4%)0·75 Probable01 (1%)0·49

20.  Allo HCST/ AML/ALL induction chemo ◦ Fluconazole prophylaxis for all patients ◦ One (sponsored) drug: caspofungin ◦ Assesment of PCR/GM/BDG  Empirical arm ◦ 4-d fever (or recurring fever after 2-d apyrexia)  Pre-emptive arm ◦ GM Ag >0.5 or ◦ Aspergillus sputum culture or ◦ New infiltrate on chest X-ray or ◦ Dense limited lesion on CT scan Enrolling: EORTC 65091 trial

21.  Widespread posaconazole prophylaxis  Switched to: ◦ Empirical therapy: Fever based &/or ◦ Preemptive therapy: Biomarkers/imaging based  Switched back to posaconazole prophylaxis ◦ For fever/biomarkers based Rx and no nodules on CT scan What we use in Lille: best of both worlds !

22. Maertens et al. Haematologica 2012;97:325-327. Patterns of IFI in practice

23. Conclusion:  Preemptive therapy promising ◦ AF sparing ◦ IFI mortality seems lower then in empirical Rx ◦ More proven/probable IFI diagnosed  We need ◦ A standardized definition of preemptive therapy ◦ Better diagnostic tools  Standardized PCR  GM assays with = sensitivity in patients w or w/o posa proph ◦ Shorter delays for CT scan access (< 48h ?)