3ème Atelier Thématique en Hématologie (ATHEM)22 novembre 2013

Dr S. AlfandariMédecin Référent en antibiothérapie et Hygiéniste, CH TourcoingInfectiologue Consultant, Service des Maladies du sang, CHRU Lillewww.infectio-lille.com

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 criteriafor 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: 553-61

PCR Empirical p

N treated 112 (57.1%) 76 (36.7%) 0.003

N proven/probable IFI 16 17 NS

N death D30 4 (1.5%) 13 (6.3%) 0.015

N total death D100 32 34 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 2009 48:1042–51

Multiple criteria based Preemptive Antifungal Therapy

Empirical (N=150) Preemptive (N=143) P

Fever before ATF (d) 7 13 <.01Duration of fever (d) 18.3 18.3 NSPatients with ATF % 62.7 39.2 <10-4

Days of ATF 7.4 4.5 <.01Survival 97% 95% NSProven/probable IFI 2,7% 9% <0.02

Cordonnier et al CID 2009 48:1042–51

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 AMLor

Auto-HSCT

Multiple criteria based Preemptive Antifungal Therapy

Cordonnier et al CID 2009 48:1042–51

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; 96:1363-70

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 use 39 (32%) 18 (15%) 0·002

MortalityAll-cause 18 (15%) 12 (10%) 0·31IA-related 6 (5%) 3 (3%) 0·5Other IFI-related 0 2 (2%) 0·24

IA incidenceProven 1 (1%) 1 (1%) 1·0Probable 0 16 (14%) <0·0001Possible 0 6 (5%) 0·013

Other IFI incidenceProven 4 (3%) 5 (4%) 0·75Probable 0 1 (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 65091 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;97:325-327.

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 ?)