Antifungal management in the haematology patient

Antifungal management in the haematology patient David W. Denning University Hospital of South Manchester The University of Manchester

Treatment

Invasive aspergillosis

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Invasive aspergillosis

Why most and not all?

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Arguments for not using voriconazole 1.

Amphotericin B is a broader spectrum agent

Frequency of mucormycosis in leukaemia 391 pts with leukaemia (225 with AML) and a filamentous fungal infection 80% neutropenia for >14 days, and 71% neutropenic at time of diagnosis 85% pulmonary infection Antemortem diagnosis in 79% Aspergillus 296 (76%) Mucorales 45 (11.5%) Fusarium 6 Other 4 Unidentified in 40 Overall mortality in 3 months 74%, 51% attributable Pagano et al, Hemtaologia 2001;86:862

Intrinsic and acquired resistance among the Aspergilli Amphotericin B resistance

A. terreus

A. nidulans

A. flavus

Azole resistance

A. fumigatus

A. niger

Species of Aspergillus causing IA Species

A. fumigatus

Voriconazole RCT (MITT)

TransNet (surveillance)

MSG multicentre study

85 (77%)

136 (74%)

171 (67%)

A. flavus

7

16

41

A. niger

9

13

14

A. terreus

6

10

8

Other

3

8

4

167

16

18

Not speciated Multiple

28

Filamentous fungi and antifungal drug activity Highly active Very active Active Inactive Amphotericin B Caspofungin Voriconazole

% frequency Posaconazole

75

5

5 2

1

10

1

1

Arguments for not using voriconazole 1. Amphotericin B is a broader spectrum agent – No 2. AmBisome is equivalent to voriconazole in IA

Randomised study of invasive aspergillosis with voriconazole versus amphotericin B 391 pts received either 1) Voriconazole 4 mg/d BID (after loading) for 12wks (or OLAT) or 2) AmB 1.0 mg/kg/d for 12wks (or OLAT) mITT analysis Success (%) Severe AEs (%) Renal tox (%) Died (all) (%) Vori 53 13 1 29 AmB

32

} 21%

24

10

42

} 13%

Herbrecht, Denning et al, NEJM 2002;347:408

Survival after primary Rx with amphotericin B or voriconazole

Survival (percent)

100 80 60 40

Voriconazole Amphotericin B

20

0

0

2

4

6

8

Number of patients at risk 144 131 125 117 111 133 117 99 87 84 Overall logrank test p=0.015

10 12 Weeks 107 80

102 Voriconazole 77 Amphotericin B

Herbrecht, Denning et al, NEJM 2002;347:408

Impact of second line treatment after voriconazole versus amphotericin B Initial randomised Rx only

Success (CR+PR)/Total (%) Voriconazole Ampho B 51/99 (51) 1/26 (4)

Patients who switched Rx Lipid Ampho B Itraconazole Combination

25/52 (48) 5/14 (36) 11/17 (65) 0/1

Reason for switch Intolerance 8/16 (50) Insufficient clinical response 5/19 (26) Chronic suppression 11/14 (79) Overall success

76/144 (53)

41/107 (38) 14/47 (38) 18/38 (50) 0/9

27/72 (38) 4/21 (19) 6/10 (60) 42/133 (32)

Patterson et al, Clin Infect Dis 2005;41:1448

Randomised study of invasive aspergillosis with Amphocil versus amphotericin B 174 pts received either 1) Amphocil 6 mg/d for >2wks after symptoms gone or 2) AmB 1.0 – 1.5 mg/kg/d >2wks after symptoms gone 70/174 (40%) in high risk (HSCT, liver Tx, AIDS, brain) ITT analysis Amphocil AmB

Success (%) Tox (%) 13 83 15

83

Renal tox (%) Died (due to IA)(%) 23 59 (22) 41

67 (20)

Bowden et al Clin Infect Dis 2002;35:359

Randomised study of invasive aspergillosis with 2 doses of AmBisome 339 pts randomised to receive either 1) L-AmB 3 mg/d for 2+wks (169 randomised; 107 in MITT) or 2) L-AmB 10 mg/d for 2+wks (162 randomised; 94 in MITT) 44/201 (22%) high risk (HSCT, AIDS)

MITT analysis L-AmB 3

CR + PR 50%

Stop Rx 20%

Renal tox 14%

Died 28%

L-AmB 10

46%

32%

31%

41%

Cornely et al, Clin Infect Dis 2007;44:1289

AmBiload trial results Response LAmB 3 mg/kg (n = 107)

LAmB 10 mg/kg (n = 94)

Survival L-AmB 3 mg/kg L-AmB 10 mg/kg

Overall Response

P = NS 50 40 30 50 %

20

46%

p = 0.089

10 0

End of Treatment

Weeks Cornely et al, Clin Infect Dis 2007;44:1289

Denning, CID 2007:45:1106

AmbiLoad study favours Ambisome compared to voriconazole because of better responding patient population, earlier diagnosis and possibly softer response criteria Denning, CID 2007:45:1106

Herbrecht et al, NEJM 2002:347:408

Open study of invasive aspergillosis with caspofungin as primary therapy 61 pts with chemotherapy or auto HSCT received Caspofungin 70 then 50mg IV daily

 33% response rate

Survival by day 84 = 33/61 (54%) Viscoli et al, JAC 2009;64:1274

Herbrecht at al, New Engl J Med 2002:347:408-15

Open study of invasive aspergillosis with caspofungin as primary therapy 42 pts with allo HSCT , 24 eligible, Rx Caspofungin 70 then 50mg IV /d Unrelated donors in 16 patients; acute or chronic GVHD was present in 15, 12 patients were neutropenic (125 countries Supported by the Fungal Research Trust – 20 year anniversary in 2011