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 Dr S. Alfandari Médecin Référent en antibiothérapie et Hygiéniste, CH Tourcoing Infectiologue Consultant, Service des Maladies du sang, CHRU Lille Antifungal therapy in haematology patients: Empirical or preemptive ?

 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

 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 ?

 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

Three large trials: similar results - few events

 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

 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 ?

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

 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

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

 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

 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: 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 D NS

 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 :1042–51

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 % <10 -4 Days of ATF7.44.5<.01 Survival97%95%NS Proven/probable IFI2,7%9%<0.02 Cordonnier et al CID :1042–51

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

 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

 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:

 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

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

 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 trial

 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 !

Maertens et al. Haematologica 2012;97: Patterns of IFI in practice

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 ?)