Prophylaxis and treatment of IFI in Hematological patients

Livio Pagano

Istituto di Ematologia

Università Cattolica del Sacro Cuore

Roma

Robenshtok et al. J Clin Oncol 2007

Antifungal Activity Vori + Posa > 75% sensible, 50%, < 5%; mixed colours

AmB Fluco Itra Vori Caspo Posa

C. albicans

C. parapsilosis

C. tropicalis

C. glabrata

C. krusei

A. fumigatus

A. flavus

A. terreus

Zygomycetes

Fusarium spp.

Cortesy of B. de Pauw

Voriconazole Prophylaxis in allo-HSCTs

N patients IFD P-value

Wingard et al,

Blood 2010

(allo-HSCTs)

Voriconazole 305 16 aspergillosis*

3 candidemia

3 zygomycosis

0.11

*(0.05) Fluconazole 295 7 aspergillosis*

3 candidemia

2 zygomicosis

Marks et al,

Br J Haemat 2011

(allo-HSCTs)

Voriconazole 234 5 aspergillosis

0 candidemia

0 zygomycosis

Composite

endpoint:

Vori > Itra Itraconazole 255 1 aspergillosis

2 candidemia

0 zygomicosis

Standard azoles (n = 298)

Posaconazole (n = 304)

0

5

10

15

20

25

Nu

mb

er

of

IFIs

30

35

2

25

7

20

p < .001

Aspergillosis All IFIs

p < .001

Treatment phase*

4

33

14

26

p = .003

All IFIs Aspergillosis

p < .001

100-day period after randomization†

2%

1%

5%

1%

8%

7%

11%

9%

Cornely et al. N Engl J Med. 2007;356:348-359

*On-treatment period. †Fixed-time period.

Posaconazole prophylaxis in AML

IFDs incidence

Posaconazole Prophylaxis in Allo- HSCT Transplant Recipients with GVHD

Results – Proven/Probable Invasive Fungal Infections

Fixed Treatment Period* Posaconazole

n = 291 Fluconazole n = 288

Posaconazole n = 301

Fluconazole n = 299

0

2

4

6

8

10

12

14

16

Nu

mb

er o

f IF

Is

P = .004

P = .001

Exposure Period†

7 3

22

17

All IFIs Aspergillosis

P = .07

P = .006

16

7

27

21

All IFIs Aspergillosis

5%

2% 2% 1%

9%

7% 8%

6%

*Fixed-time period. †On-treatment period. Ullman et al. NEJM 2007

FLUCO

VORICO

ITRA

POSA

CASPO

L-AmB

CT

ECIL-3

allo HSCT

C-I

A-I

-

A-I

C-I

B-I

A-I

A-I

-

-

C-I

C-I

neutropeni

German

allo HSCT

C-I

A-I

C-II

C-II

C-I

C-I

A-I

A-I

C-I

-

C-II

-

IDSA - - B-I A-I - -

British - - A-I A-I - -

AML-MDS

NCCN

allo HSCT

-

-

2B

2B

-

-

1

1

-

2B

2B

2B

International Guidelines on antifungal prophylaxis in AML and allo-HSCT

Years Type N° pts IFDs incidence%

RCT

Cornelly et al, NEJM 2007 2002-05 RCT 304 7 2%

Real life series

Michallet et al, Med Mycol 2011 2007-08 Pros 55 2 3.6%

Candoni et al, EHA 2011 2009-10 Retro 55 2 4%

Lerolle et al, ICAAC 2011 2007-10 Retro 209 8 3.8%

Hahn et al, Mycoses 2011 2007-08 Retro 21 1 5%

Egerer et al, Mycoses 2011 2007-09 Retro 76 1 1.3%

Vehreschild et al, JAC 2010 2006-08 Retro 77 3 3.9%

Busca et al, 5th TIMM 2011 2009-10 Retro 61 0 0

Ananda-Rajah,Haematol ‘11 2006-10 Retro 68 0 0

ALL STUDIES 622 17 2.7%

Posaconazole in AML

Proven/probable IFDs: 2.7% (0-5%)

Pagano et al. Haematologica 2012

703 patients recorded in SEIFEM 2010 study

No systemic prophylaxis or less than 7 days of prophylaxis 68 patients

260 patients with Posaconazole prophylaxis

93 patients with Itraconazole prophylaxis

508 patients with Systemic Prophylaxis

Not conventional AML therapy (Support or contenitive) 127 patients

353 patients with Posaconazole or Itraconazole Prophylaxis

7 patients others Prophylaxis (5 Voriconazole, 1 Caspofungin and 1 Ambisone)

148 patients with Fluconazole prophylaxis

Itraconazole

N°93 Posaconazole

N°260 p-value

Age (median[IQR]) 60 [49-67] 56 [44-65] 0.08

% of men 52.2% 45% 0.23

Duration of prophylaxis 21 [15-26] 21 [16-28] 0.70

Deep Neutropenia (>7days)

87 (93.5%) 240 (92.3%) 0.69

Median duration of neutropenia ( days [IQR])

22 [16-27.5] 23 [18-29] 0.25

CVC 75 (80.6%) 200 (76.9%) 0.45

Performance Status 0-1 2-4

72 (77.4%) 21 (22.6%)

204 (78.5%) 56 (21.5%)

0.83

Antracycline based chemotherapy (Y/N)

81/93 (87.1%) 242/260 (93.1%) 0.08

Comparison between the two groups

Main clinical characteristics and risk factors

POSACONAZOLE 260 patients

ITRACONAZOLE 93 patients

36

(38.7%)

49

(18.9%)

ALL IFDs

Possible/

probable/

proven

p <0.001

3 (3.2%) 3 (1.1%)

YEAST IFDs

probable/

proven p n.s.

10

(10.7%)

7

(2.7%)

MOLD IFDs

probable/

proven p 0.02

Prophylaxis efficacy analysis

IFDs incidence

Courtesy of P. Donnelly

GM

Defining posaconazole efficacy: Secondary endpoints 1

Does POSA reduce incidence of possible IFDs?

0% 20% 40% 60% 80% 100%

POSA

ITRA

NO IFDs

possible

prov/prob

24%

15%

p 0.03

Defining posaconazole efficacy: Secondary endpoints

ITRA

N°93 POSA N°260

p-value

Frontline antifungal approach 41 (45.1%) 69 (26.6%) 0.001

Empirical 21 (22.6%) 53 (20.3%) 0.49

Pre-emptive 13 (14%) 12 (4.6%) 0.003

Target 7 (7%) 4 (1.5%) 0.004

Mean duration of frontline AF approach 15 [10-22] 12 [8-15] 0.05

Empirical 12 [8.5-19] 11 [7-14] 0.27

Pre-emptive 15 [9.5-24] 14 [10-26] 0.62

Target 18 [5-20] 12.5 [10-18] 0.46

2 Does POSA reduce subsequent antifungal therapies?

Defining posaconazole efficacy: Secondary endpoints 3

Does POSA reduce IFD-attributable mortality?

Itraconazole Posaconazole p-value

AM - Attributable mortality (%) 4/36 (11.1%) 2/49 (4.1%) 0.21

Molds AM 4/33 (12.1%) 0/46 (0%) 0.03

Yeasts AM 0/3 (0%) 2/3 (66.7%) 0.2

0%

20%

40%

60%

80%

100%

ITRA POSA

deaths

all cases

11% 4%

4 0.0

00.2

00.4

0

Pro

bab

ility

of d

ea

th

0 20 40 60 80 100analysis time

Itraconazole Posaconazole

Kaplan-Meier failure estimates

Pr>chi2 = 0.0023

Does POSA reduce overall mortality?

Defining posaconazole efficacy: Secondary endpoints

0 20 40 60 80 100

0.30

0.20

0.10

0.00

Posaconazole Fluconazole or Itraconazole

0.25

0.15

0.05

p = .04*

Cornelly et al NEJM 2006

In RCT posaconazole emerged as a valid antifungal prophylaxis in high risk patients

Our “real life” experience confirmed posaconazole to be an efficacious prophylaxis producing -reduction of proven/probable IFD -reduction of antifungal therapies -reduction of overall mortality

The role of diagnostic tools (i.e. galactomannan, PCR) after posaconazole remains to be defined, as well as the optimal management of febrile neutropenia:

EMPIRICAL or PRE-EMPTIVE ?

Febril Events %

Bacterial 301 34.6

Fungal 95 10.9

Viral 7 0,8

DTRF 48 5,5

FUO 386 44,4

Mixed infections 32 3,6

Fungi/Bacteria 23

Bacteria/Virus 6

Fungi/Virus 2

Bacteria/Fungi/Virus 1

TOTAL 868

Experience in 19 Hematological Divison in Italy between 2007-2009

Ann Hematol (2012) 91:767–774

Antifungal agent Daily dose Level of

Recommendation

Evidence for

Efficacy Safety

Liposomal AmB** 3 mg/kg A I I

Caspofungin** 50 mg A I I

ABLC 5 mg/kg B I I

ABCD 4 mg/kg B I I

Voriconazole 2x 3 mg/kg iv B I I

Itraconazole* 200 mg iv B I I

Micafungin 100 mg B II II

AmB deoxycholate** 0.5-1 mg/kg B/D I I

Fluconazole 400 mg iv C I I

ECIL 3: Antifungal drugs for Empirical Therapy

* FDA and **EMA-approved drugs for empirical therapy

Response rates (%) in studies on empirical antifungal therapy

d-AmB L-AMB Fluco Itra Vori Caspo ABCL

Viscoli et al 66 - 75 - - - -

Prentice et al 46 64 - - - - -

Malik et al 46 - 56 - - - -

White et al 43 - - - - - 50

Walsh et al 49 50 - - - - -

Winston et al 67 - 68 - - - -

Wingard et al - 42 - - - - 33

Boogaerts et al 38 - - 47 - - -

Walsh et al - 30 - - 24 - -

Walsh et al - 33 - - - 34 -

?

Period

o a r

isch

io

SURVEY

SYMPTOMATIC APPROACH

GM GM GM GM GM GM GM GM GM GM GM

TC TC TC

GMpos

GM GM GM

TC GMpos

Febbre

4gg

Courtesy of C. Girmenia

Maertens et al. Clin Infect Dis 2005

Girmenia et al. JCO 2009

PRE-EMPTIVE

DIAGNOSIC-DRIVEN

As a consequence it has been suggested to substitute the empirical approach with pre-emptive antifungal approach

3 12

62% 38%

13 (9%) 4 (3%)

95% 97%

150 143

Breaktrough IFI

survivors

PRE-EMPTIVE Imaging, clinics

laboratory

EMPIRICAL 3 days

persisting fever

293 neutropenic patients

p<0.02

Antifungals TX

IFI in Induction (p<0.01)

Cordonnier et al. CID 2009

Descriptive, not randomized, not interventional study

Haematologica. 2011 Sep; 96(9):1366-70

EMPIRICAL THERAPY

• Administration of an antifungal agent to a neutropenic patients with persistent fever without a known source of infection and unresponsive to appropriate antibacterial agents

• 190 patients

PRE-EMPTIVE THERAPY

• Administration of an antifungal agent to patients with laboratory tests or radiographic signs indicative of invasive fungal disease, without definitive proof from histopathology or cultures in an appropriate clinical subset.*

• 207 patients

* According to Maertens et al, Clin Infect Dis 2005;

Empirical

n°190

Pre-emptive

n°207

Proven/probable

IFDs

14 (7.4%)

49 (23.7%)

p-value 0.001

Empirical vs Pre-Emptive IFDs incidence

Type of IFDs

Moulds 8

(57%)

Yeasts 6

(43%)

Moulds 40

(82%)

Yeasts 9

(18%)

57%

43%

82%

18%

Empirical

n°190

Pre-emptive

n°207

IFD-attributable mortality rate

p-value 0.002

Empirical vs Pre-Emptive IFDs OUTCOME

0

5

10

15

20

25

30

35

40

45

50

empirical pre-emptive

all

deaths

7%

22%

VARIABLES Dead (n°45) Survivors (n°352) P-value

UNIVARIATE ANALYSIS

Male sex 29 (64.4) 200 (56.8) 0.32

Age (year [mean SD]) 62 ±10 54 ±16 <0.001

Underlying HMs - AML - NHL - ALL - Other

34 (75.5) 6 (13.3) 4 (8.9) 1 (2.2)

287 (81.5)

24 (6.8) 21 (5.9) 20 (5.7)

0.33 0.13 0.5

Clinical factors - Central venous catheter - Neutropenia - Antifungal prophylaxis - Steroid use

21 (46.7) 40 (88.9) 20 (44.4) 6 (13.3)

180 (51.1) 326 (92.6) 194 (55.1)

27 (7.6)

0.57 0.38 0.17 0.19

Etiology - Yeasts - Molds

4 (8.9)

8 (17.8)

15 (4.3)

36 (10.2)

0.17 0.13

Empirical treatment 12 (26.7) 178 (50.6) 0.002

MULTIVARIATE ANALYSIS

Age (year [mean SD]) 0.006

Empirical antifungal treatment 0.01

Indication for empirical/preemptive antifungal therapy from International

Guidelines

BSH 2008 ECIL 2009 IDSA 2010

Empirical A Ib B II A I (for high risk)

Pre-emptive Not Reported

No Grading B II

What is better ???

Fever-driven ? Diagnostic-driven?

Taking in account: 1.Patients to treat 2.Toxicity 3.Efficacy of the approach 4.Outcome 5.Costs 6.Prophylaxis

AutoHSCT Kidney Tx Solid tumor Immune Disorder

ALL Heart transplantation CLL COPD AIDS NHL

AlloHSCT (GVHD) MDS (induction) AML (induction) Lung transplantation AlloHSCT (no GVHD) AML (consolidation) Liver transplantation

LOW RISK

INTERMEDIATE RISK

HIGH RISK

Underlying condition

Pagano et al, J Antimicrob Chemother, 2011

Toxicity of antifungal agents used in empirical and pre-emptive approach

D-AmB L-AmB Itra Caspo Vorico

Liver 20% 6-17% 3% 8% 8%

Renal 14% 5-11% 5% 2% 11%

Infusion-related 70% 30-50% 20% 35% 30%

Discontinuation 20% 7-15% 20% 5% 10%

OVERALL

TOXICITY

High Medium Low Very

Low

Low

Bogaert et al, Ann Int Med 2001; Walsh et al, N Eng J Med 1999, 2002, 2004

CT-scan Dose Efficacy (mSv)

Equal to standard thorax X-ray

Skull Cervical spine Dorsal spine Thorax Abdomen Lumbar spine

1.7 1.7 7.7 7.8 5.1 8.8

85 85

385 390 255 440

Warning: toxicity of exams ??!!??

AmB 0.5mg AmB 0.8mg AmB AmB 0.3mg

Day 1 4 7 10

2cms/day in vitro

Aspergilosis progression with not therapeutic doses

0%

5%

10%

15%

20%

25%

30%

35%

< 12 hrs 12-24 hrs 24-48 hrs > 48 hrs

Mortality

Delay in start of antifungal treatment

Morrell M et al. Antimicrob Agents Chemother. 2005

Delay in the empirical treatment: a potential risk factor for mortality

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25 30 35 40 45

Days from symptoms to initiation of appropriate therapy

Mo

rta

lity

at

12

we

ek

s

CART identified breakpoint

Chamilos et al. Clin Infect Dis 2008

Zygomycosis

Candida

Incidence: 5.8% vs 12.6% (p 0.002)

AMR: 24% vs 13% (p: ns)

Caspofungin

Voriconazole

L-AmB

SEIFEM-C Report: Outcome in AML

CID 2007, 44: 1521-2

Only EMPIRIC

Costs

Courtesy of B de Pauw

n Death

(%)

IFI

(% )

AMR

Posaconazole prophylaxis 573

Antifungal therapy 131 (23%)

Empirical 104 (79%)

Voriconazole 3 1 (33%) 2(66) 0

Caspofungin 30 13 (43%) 17(56) 2

L-AmB 64 21 (33%) 37(58) 4

Pre-emptive 20 (15%)

Voriconazole 6 1 (17%) 0 0

Caspofungin 2 1 (50%) 0 0

L-AmB 10 2 (20%) 0 0

Target 12 (6%)

SEIFEM-2010 study Pre-hospital risk factors for IFD in newly diagnosed

Acute Myeloid Leukemia

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer:2010 update by the IDSA

Freifeld CID 2011

In my opinion Empirical antifungal therapy now-a-days plays an

important role in HM patients

It is mainly indicated in particular subset of patients at very high risk

Equally indicated Caspo and L-AmB

On the contrary, only a pre-emptive antifungal diagnostic strategy was advised for those at standard risk

Start an empirical treatment do not justify not performing a timely diagnostic work-up

As suggested by various Opinion Leaders, empirical therapy is a very useful tool to BUY TIME